KR20160124829A - Therapeutic methods employing noribogaine and related compounds - Google Patents

Abstract

The present invention provides a method of treating a disease or disorder as described herein in a patient comprising administering to the patient a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a non- .

Description

[0001] THERAPEUTIC METHODS EMPLOYING NORBOGAIN AND RELATED COMPOUNDS [0002]

Cross-reference to related application

This application claims priority from U.S. Provisional Patent Application No. 61 / 941,387, filed February 18, 2014; 61 / 945,746, filed February 27, 2014; 61 / 941,390, filed February 18, 2014; 62 / 035,335, filed August 8, 2014; 61 / 952,731, filed March 13, 2014; 61 / 952,727, filed March 13, 2014; 62 / 005,851, filed May 30, 2014; 61 / 952,733, filed March 13, 2014; 62 / 005,847, filed May 30, 2014; 61 / 952,738, filed March 13, 2014; 62 / 005,855, filed May 30, 2014; 61 / 952,741, filed March 13, 2014; 62 / 005,841, filed May 30, 2014; 61 / 952,744, filed March 13, 2014; 62 / 005,858, filed May 30, 2014; 62 / 007,346, filed June 3, 2014; 62 / 024,388, filed July 14, 2014; And 62 / 033,538, filed August 5, 2014; And U.S. Patent Application No. 14 / 195,822, filed March 3, 2014, 14 / 292,632 filed May 30, 2014, and 14 / 485,514 filed September 12, 2014; And International Patent Application No. PCT / US14 / 19692, filed February 28, 2014, each of which is incorporated herein by reference in its entirety.

The technical field of the present invention

The present invention relates to the use of a Norbitogen, a Norbitogen, or a pharmaceutically acceptable salt and / or solvate thereof in a dosage amount that provides a therapeutic serum concentration for treating a disease or disorder in a patient.

The norbornene is sometimes referred to as 12-hydroxy ibocine. U. S. Patent No. 2,813, 873 claims a Norwegian patent even if it is "12-O-demethylisoborane ", but provides an inaccurate structure for this bovine. Norbigovan can be illustrated by the formula:

.

.

Norbogophanes and their pharmaceutically acceptable salts have recently received considerable attention as non-toxic alkaloids (US Patent No. 6,348,456) and strong analgesics (US Patent No. 7,220,737) useful for treating drug dependence. Such treatment generally requires the administration of a high dose of Norvigor, typically 0.1 mg to 100 mg / kg body weight.

Norbyborgins are metabolites of Ibogain found in humans, dogs, rats and monkeys. Prior art suggests that higher doses of ibuprofen are useful as a treatment for addiction, but the use of ibocaine is associated with adverse side effects. In the United States, Ibogaine is classified as a Schedule I regulatory substance. It has been suggested that Norbyborg has a longer and longer lasting activity in humans than in bovine cats to reduce the craving for addictive substances and to treat chemical dependence. U.S. Patent No. 6,348,456, which is incorporated herein by reference in its entirety, discloses a highly refined Norwegian phosphorus, and although human data indicative of an effective dose for treating drug addiction has not been provided, 100 mg / kg body weight / day.

Therapeutic doses of Norovigrin for long-term treatment in humans have not been previously addressed, particularly since it is valid as well as a safe dosing protocol. In addition, prior to the present invention, it was uncertain as to whether Norwegian bovine could be administered therapeutically and at the same time safe doses to the patient.

Addiction

Nicotine addiction is generally related to smoking, although other forms of nicotine addiction (eg, chewing tobacco) are common. Smoking and other forms of nicotine use poses a serious threat to overall health status. In the United States alone, annual deaths from smoking (including environmental exposure, ie "secondhand smoke") exceeded 440,000. In the United States, the costs associated with smoking-related illnesses totaled $ 96 billion in medical costs, with a loss of productivity of $ 97 billion annually. Furthermore, smoking significantly increases the risk of multiple diseases, including coronary artery disease, stroke, lung cancer and other cancers and chronic obstructive pulmonary disease. Smoking is estimated to be 46 million people in the United States, 20.6% of the US population.

More than 40% of current smokers attempt to quit smoking every year. Various approved therapies (barrenicin, bupropion, nicotine patch / gum, nicotine nasal spray / inhaler, hypnotherapy, biofeedback) have long been a clinical use for treating nicotine dependence. Current therapies for smoking cessation tend to focus on counseling, behavioral therapy, such as hypnosis and / or pharmacologic therapy. It is difficult to quit smoking, and many attempts may be needed, depending on the technique used, the success rate is between 4% and 25%. Because of stress, weight gain and withdrawal symptoms, the user will again smoke. Further, nicotine replacement therapies (eg, nicotine patches, nicotine gum, nicotine nasal sprays or nicotine inhalers) do not directly treat nicotine addiction, since the patient is intoxicated with nicotine throughout the treatment.

Nicotine addicts in remission can present mental symptoms of nicotine addiction shortly after the physical symptoms of nicotine addiction have disappeared. Many smokers experience smoking again due to stress or an environmental signal. For example, approximately 50% of recurrences occur when a smoker experiences alcohol.

Taking into account the enormous harmfulness of smoking and other forms of nicotine use to the human body, the high degree of cost to the health care system, the addictive nature of nicotine use, and the difficulty of quitting even when using conventional therapies, There remains a severe need for an effective strategy. There is also an extreme need for an effective strategy to prevent the recurrence of nicotine addiction in nicotine addicts at the remission.

Alcohol dependence (also referred to as alcohol abuse, alcoholism or alcoholism) also has serious public health problems worldwide. As many as 140 million people around the world have alcohol abuse problems, nevertheless only a small percentage of them have been treated. Alcohol abuse can cause damage to almost all organs in the body, including the brain. Long-term alcohol abuse causes or contributes to a number of diseases including cirrhosis, pancreatitis, epilepsy, dementia, heart disease, gastric ulcer, damage to the central and / or peripheral nervous system, cancer, multiple neuropathy, malnutrition and death It is known.

When alcohol dependence treatment becomes complicated, alcohol-dependent patients generally experience significant, potentially fatal, withdrawal symptoms while attempting to stop using alcohol. Acute withdrawal symptoms last for 1 to 3 weeks after discontinuation of alcohol consumption. Acute withdrawal symptoms include anxiety, seizures, developmental delirium, hallucinations, tremor, and heart failure. Late-acute withdrawal symptoms can last considerably longer and symptoms such as anxiety, depression, sleep disturbances, fatigue and tension are common.

Treatment for alcohol dependence generally involves individual and / or group therapy following detoxification. Detoxification may include treatment with a medicament (e.g., benzodiazepine) that reduces withdrawal symptoms. However, drugs such as benzodiazepines have a number of negative side effects, including harmful psychological effects and physical dependence. Benzodiazepines are known to increase alcohol craving in patients with alcohol dependence and are therefore not suitable for long-term treatment of alcohol dependence / poisoning. Alcohol-dependent patients have a high rate of recurrence.

Alcohol consumption has been shown to stimulate the release of endogenous opioids in both the human and experimental animals. Alcohol effects on opioid systems are believed to be important for drug-induced compensation and for sensitivity to alcohol as well as recurrence for alcohol use.

Due to the severity and duration of withdrawal symptoms, alcohol-dependent patients have a high recurrence rate. There is a significant need for a method for preventing recurrence of alcohol use by detoxifying patients as well as effective and non-additive treatments for acute and follow-up acute withdrawal symptoms.

Alcohol consumption has been shown to stimulate the recurrence of endogenous opioids in both the human and experimental animals. The alcohol effect on opioid systems is believed to be important for drug-induced compensation and recurrence of alcohol use as well as sensitivity to alcohol.

Substance addiction is a serious public health problem worldwide. In the United States, as many as 23.5 million people have drug or alcohol abuse problems, only a small percentage of them being treated.

When treatment of drug addiction becomes complicated, drug addicts generally experience significant withdrawal symptoms while attempting to stop using alcohol. Acute withdrawal symptoms from drug dependence include sweating, heart palpitations, palpitations, muscle tension, chest tightness, dyspnea, progression, nausea, vomiting, diarrhea, seizures, heart attacks, stroke, hallucinations, Which is characterized by dramatic and traumatic symptoms. Withdrawal symptoms may also include severe craving for the drug, fatigue, lack of pleasure, anxiety, inability, drowsiness, suicidal thoughts, and sometimes agitation or extreme suspicion or paranoia. Once the acute withdrawal symptoms settle, the subsequent acute withdrawal syndrome can last for months or years. Subsequent acute withdrawal symptoms include physical, emotional, and psychological symptoms such as fatigue, depression, lack of motivation, and increased pain sensation. Acute and follow-up withdrawal symptoms are a major cause of comeback for drug addicts using drugs after treatment, even when the patient was drug free for a significant amount of time.

Treatment has been developed as an attempt to improve acute and post-acute withdrawal symptoms, but this treatment does not work for all types of drugs. In addition, treatment of withdrawal symptoms may require the use of other addictive substances (for example, morphine, buprenorphine or methadone). Due to the severity and duration of withdrawal symptoms, poisoning patients have a high rate of recurrence. There is a significant need for an effective, non-addictive treatment for acute and follow-up acute withdrawal symptoms.

Prior art suggested that higher doses of ibuprofen are useful as addiction treatments, but the use of ibocaine is associated with hallucinations and other adverse side effects. In the United States, Ibogaine is classified as a Schedule I regulatory substance.

Pain and migraine

Pain is broadly defined as an unpleasant sensory experience associated with, or described for, acute or potential tissue damage. Explanation of sensory pain occurs when the peripheral nerve endings, called infiltrating receptors, are stimulated and subsequently transmit signals through sensory neurons in the spinal cord. The signal is then transmitted to the brain at the time when the subject is aware of the pain.

There are a number of pain categories and categories, for example, can be grouped into four categories according to the source and the related infringer: (1) skin pain; (2) body tongs; (3) visceral pain; And (4) neurogenic pain. Other pain classifications include acute pain and chronic pain. Acute pain is defined as short-term pain or pain with an easily identifiable cause. Acute pain indicates a current impairment of tissue or disease, and can be painful after "quick" and "sharp" pain. Acute pain is concentrated in one area before being more comfortable. Acute pain generally responds well to medicines (eg, morphine).

Chronic pain can be medically defined as pain that lasts for more than six months. This persistent or intermittent pain often lasts longer than his purpose because it does not help the body prevent damage. This is often more difficult to treat than acute pain. Management of specialists is generally necessary to treat any pain that has become full. In addition, stronger medicines are typically used for a long period of time in an attempt to control pain. This can lead to drug dependence. For example, opioids are used for a long period of time to control chronic pain in some instances. Drug tolerance, chemical dependence, and even psychological addiction can occur.

Degenerative chronic pain affects tens of millions of people each year, and costs hundreds of millions of dollars in medicines, physiotherapy, and loss of productivity. Numerous therapies have been developed in an attempt to improve pain in his various categories of pain. Current methods for treating chronic pain have limited success rates and can, in some cases, cause chemical dependence.

Migraine (also referred to as "headache") is a neurological disorder in which the symptoms include moderate to severe severity of headache, including sensation of zone, vomiting, sensory input (light, sound and / or odor) Gender and / or aura. Migraine headache can last for a long period of time, usually 4 to 72 hours. Migraine affects approximately 15% of the human population and up to 2.2% of the population experiences chronic migraine. In the United States, the costs associated with migraine (for example, patient care, loss of productivity, etc.) are estimated at up to $ 17 billion annually.

Migraine is generally managed by prevention of triggering, symptom control and prevention using pharmaceutical preparations. Acupuncture, acupressure, massage and rest can also be used. Biofeedback, neurostimulator or migraine surgery can be used in cases of more severe, especially when not responding to other treatments. Considering the prevalence of migraine and the difficulty of treatment and / or prevention, there remains an urgent need for an effective strategy for treating and preventing migraine and its symptoms.

Depression, anxiety, mental disorders and related disorders

The CDC estimates that about one in ten adults in the United States suffer from depression. High levels of depression are correlated with a high percentage of other diseases, including obesity, heart disease, and stroke.

Similarly, anxiety-related disorders are widespread in the United States. Anxiety-related disorders include obsessive-compulsive disorder, panic disorder, social anxiety disorder, and generalized anxiety disorder.

PTSD affects at some point in their lives from about 8% of Americans. More significantly, up to 30% of people, including veterans spending time in the engagement area, experience PTSD. PTSD is increasingly recognized as a major problem for US troops returning from Iraq and Afghanistan, as well as for troops participating in previous wars, and a potential contributor to a high rate of suicide among veterans.

Impulse control disorders are a class of psychiatric disorders involving impairment that resists temptation, desire or impulse (impulsivity), which is potentially harmful to the patient and / or others. DSM-5 (May 2013) of the American Psychiatric Association includes "impulse control disorders" characterized by a problem of emotional and behavioral self-regulation. These include, but are not limited to, borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), asthma, mood disorder, morbidity, morbidity, intermittent explosive disorder, pathological wall, sexual impulse, , Morbid skin tearing and obsessive shopping. Impulse control disorders can be associated with anxiety disorders and / or OCD.

Violence and anger are associated with multiple mental disorders, particularly when they are not balanced with the outcome of stimulation and / or morbid anger. These include, but are not limited to: rebellious disorder, attention deficit / hyperactivity disorder and behavioral disorders (in children and adolescents), psychotic disorders, bipolar disorder, antisocial, borderline, paranoia and narcissistic personality disorders, . Pathological anger and violence account for a large proportion of violent crimes, including many eye-catching crimes involving multiple victims. A very moody object is much described in the American prison system.

Food intake

More than two-thirds of adults in the United States are overweight, and nearly half of them are obese. The US weight loss market is estimated to be worth over 60 billion; Weight loss alone accounts for more than $ 1 billion. However, many weight loss products have a suspicious efficacy to do well and contain dangerous ingredients in the worst case. Obesity greatly increases the individual's risk for various diseases including coronary heart disease, hypertension, stroke, type 2 diabetes, abnormal levels of blood fat, metabolic syndrome, cancer, osteoarthritis, sleep apnea, clonal problems and gallstone disease.

Opioid analgesic tolerance

Addictive opioid analgesics, such as morphine, are well known and exceptionally powerful analgesics. These opioids act as mu receptor agonists. Upon administration, opioids initiate a cascade of biological events involving increased serotonin and dopamine expression. As is well known, continued use of a number of these opioids (especially at high doses) translates into a significant risk of dependence / addiction. In addition, the potential addiction to such opioids is a serious problem that limits the therapeutic use of addictive opioids as analgesics. For example, the use of morphine as an analgesic is common in terminally ill patients suffering from severe pain, where poisoning is no longer a problem.

Drug tolerance to opioid analgesics is conventional, and may be psychological and / or physiological. Patients with tolerance to opioid analgesics should not be addicted to analgesics or abuse analgesics. When the patient's response to the drug is reduced, drug tolerance occurs, requiring an increase in dose to achieve the same purposeful effect. There are several possible ways to develop tolerance, including receptor desensitization, receptor phosphorylation, receptor internalisation, or down-regulation and up-regulation of the inhibition pathway.

Drug tolerance requires increased dosages of anesthetic to provide sustained anesthetic effects. However, high doses of opioids can cause serious complications and side effects, including physical dependence, addiction, respiratory depression, nausea, sedation, luck or discomfort, reduced gastrointestinal motility and itching.

Norbyborgins are metabolites of Ibogain found in humans, dogs, rats and monkeys. Therapeutic doses of Norbitogens for the treatment of drug addiction and other diseases in humans have not been previously addressed, particularly if it is effective, but also relates to a safe dosing protocol. In addition, prior to the present invention, it was uncertain as to whether noriboglobin can be administered safely and therapeutically to the patient.

depression

Norovigrin is a well known member of the family of bivalves of alkaloids, sometimes referred to as 12-hydroxyribogens. U.S. Pat. No. 2,813,873 claims "12-O-demethylisoborgine", but provides a Norwegian patent for the Norwegian patent, while providing an inaccurate structural formula for Ibogain. The structure of the norbornene is now fully appreciated and is found to combine the characteristics of tryptamine, tetrahydrohavine and indole azepine. Norbogophanes can be represented by the following formula:

.

.

Depressive disorders include major depressive and emotional disorders (American Psychiatric Association, 1994a; American Psychiatric Association, 1994b). Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or incontinence episodes. Major depressive episodes are usually defined as significant and relatively persistent depressive or discomfort that interfere with daily function (almost daily for at least two weeks); It may include at least four of the following eight symptoms: appetite changes, changes in sleep, psychomotor fluctuations or retardation, loss of interest in daily activities or decreased sexual impulses, increased fatigue, guilt or nonsense, Or concentration impairment, and suicidal attempts or suicidal thoughts. Emotionally impaired disorder is not severe enough to be called a major depressive episode, but involves a type of depression that lasts much longer than the major depressive disorder without a higher stage.

Post-Traumatic Stress Disorder (PTSD) as defined by DSM-III-R / IV (American Psychiatric Association, 1987; American Psychiatric Association, 1994a) is a de facto or threatening death or serious injury, Exposure to traumatic events with threats to physical integrity, and reactions involving intense fear, helplessness or fear. Although PTSD is classified as an anxiety disorder, PTSD distinguishes it from other anxiety disorders due to the need for exposure to traumatic events.

Symptoms resulting from exposure to traumatic events include re-experiencing events in the form of invasive thinking, recall or delusions, and re-experiencing events in the form of physiological responses to extreme psychological distress and exposure to signals for events; A sense of insensitivity to the general reaction that has become evident as a reduced interest in considerable activity, a disagreement with another, a limited scope of influence, or a reduced sense of future ; And autonomic nervous system arousals, including hyperactivity, exaggerated awakening reactions, sleep disturbances, concentration impairment, and explosion of innocence or anger. PTSD diagnosis requires that the symptoms are present for at least one month and cause clinically significant pain or disability in the social, occupational or other important functional areas.

Considering the prevalence and impact of depression and PTSD, there is a need for treatment to address these problems. Prior to the embodiments described herein, therapeutic doses of Norvigans and derivatives thereof for the treatment of depression and / or PTSD in humans with an acceptable QT interval prolongation, particularly if it is not only effective but also about a safe dosing protocol, It has never been processed before.

Although Noriboglobin has been described for the treatment of substance abuse, its use in humans is complicated by the fact that the range in prior art is exceptionally broad (0.01 to 1000 mg / kg body weight). Further, human clinical trials demonstrate that lower doses of Norvigans have minimal effects on withdrawal symptoms in patients who are poisoned. Thus, the previously disclosed broad range has been found to be insufficient for some human therapies in the lower part of this range.

In addition, the use of Norvigor phosphorus provides a dose-dependent prolongation of the QT interval of the treated patient to unacceptably provide higher doses of Norvigor. The extended QT interval is a marker of potential polymorphic ventricular tachycardia, which is a serious arrhythmia that can cause death.

The present invention provides a method of treating withdrawal symptoms, wherein the treatment with a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, in a narrow range of Norviga, from about 1 mg / kg body weight to about 4 mg / kg body weight, And / or an increase in time for re-consumption of opioid use in patients with opioid-addiction. Preferably, the dose range that provides both therapeutic results and acceptable QT interval prolongations of less than about 50 milliseconds in opioid and opioid-like drug addicted humans is from about 1.3 mg / kg body weight to about 4 mg / kg body weight, More preferably from about 1.3 mg / kg body weight to about 3 mg / kg body weight, or any sub-range or sub-value within the aforementioned range. Opioid-like drugs, including cocaine, ketamine and methamphetamine, are not opioids, but act through opioid receptors and thus addiction to these drugs can be treated by Norbiggan.

In some embodiments, unit doses that provide both treatment results and acceptable QT interval prolongations of less than about 50 milliseconds in opioid and oiopoid-like drug addicted humans are from about 60 mg to about 150 mg. In some embodiments, the unit dose that provides both treatment results and acceptable QT interval prolongation of less than about 50 milliseconds in opioid and ohypeide-like drug addicted humans is about 120 mg. In some embodiments, the unit dose that provides both treatment results and acceptable QT interval prolongations of less than about 50 milliseconds in opioid and oiopoid-like drug addicted humans is about 2 mg / kg body weight.

In some embodiments, the patient is administered an initial dose of at least one additional dose followed by a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof. In one embodiment, the initial dose is about 50 mg to about 120 mg. In one embodiment, the at least one additional capacity is lower than the initial capacity. In one embodiment, the at least one additional dose is from about 5 mg to about 50 mg. In one embodiment, such a dosing regimen provides a mean serum concentration of Norvigovin from about 50 ng / ml to about 180 ng / ml. In one embodiment, the one or more additional doses maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml over a period of time. In one embodiment, one or more additional doses are administered periodically.

In a preferred embodiment, the narrow therapeutic dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, as described above, unexpectedly prolongs the QT interval in human addiction patients to an unacceptable level Do not. An opioid or opioid-like drug addict is expected to receive a therapeutic dose of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, in a clinical setting using cardiac monitoring. In some embodiments, the patient may be asked to evaluate the tolerability for prolongation of the QT interval, for example, to determine whether the patient has any pre-existing cardiac condition depriving him of treatment , Will be pre-screened.

Some aspects of the present invention are directed to the use of opioids of a patient having a much lower dose of Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, for example, a therapeutic dose of about 80% (Or an opioid-like drug) in opioid-addicted patients treated to improve the efficacy of the opioid (or opioid-like drug). That is, lower doses of Norvigor can prevent recurrence of opioid use in patients who are not physically addicted to the opioid. Without being bound by theory, it is believed that the desensitization of one or more receptors in the brain by opioids or opioid-like drugs, and / or the desensitization of one or more receptors, by the opioid or opioid- Patients who are no longer physically intoxicated with opioids or opioid-like drugs are believed to need less phosphorus to prevent relapse because they are reversed when they stop taking. This lower retention capacity of the Norwegian bogin causes QT interval prolongation that does not require clinical cardiac monitoring.

In some embodiments, the retention capacity of the norbornene phosphorus is from about 5 mg to about 100 mg. In some embodiments, the retention capacity of the norbornene phosphorus is about 1.5 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 1 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.9 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.8 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.7 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.6 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.5 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.4 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.3 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.2 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.1 mg / kg body weight.

In some embodiments, a therapeutic dose of Norviga, a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, administered to a patient, provides a serum concentration of about 1000 to about 6000 ng * h / ml Suffice. In some embodiments, a therapeutic dose of Norviga, a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof administered to a patient provides a maximum serum concentration (Cmax) of less than about 250 ng / ml Suffice. In a preferred embodiment, the therapeutic dose provides a Cmax of from about 100 ng / ml to about 200 ng / ml.

In some embodiments, a therapeutic dose of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, administered to a patient is administered at an average serum concentration of about 50 ng / ml to about 180 ng / ml, Is sufficient to provide any subranges or subvalues between. In a preferred embodiment, the dose of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt or solvate thereof administered to a patient provides an average serum concentration of about 80 ng / ml to about 100 ng / ml.

In some embodiments, a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein a high (therapeutic) dose of Norviga is administered for a period of time to improve the most significant withdrawal to the patient, is then administered (Retentive) dose is administered to prevent recurrence of opioid or opioid-like drug use. In some embodiments, a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein a therapeutic dose of Norviga is administered for a period of time to improve the most significant withdrawal symptoms in a patient is administered, , Or a pharmaceutically acceptable salt or solvate thereof, is administered to a subject in need thereof, wherein the amount of Norvigor is reduced (diminishes) over time until it is reached. In some embodiments, a high initial therapeutic dose is administered followed by a lower therapeutic dose. In some embodiments, the dose of Norvigor phosphorus decreases over time from a higher therapeutic dose to a lower therapeutic dose.

In some embodiments, the dose of a Norbitogen, derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the Norbitogen, which provides an average serum concentration of from about 50 ng / ml to about 180 ng / ml, is administered in a single dose. In some embodiments, the dose of a Norbitogen, a Norbitogen, or a pharmaceutically acceptable salt or solvate thereof, which provides an average serum concentration of about 50 ng / ml to about 180 ng / ml, is administered as a multiple dose. In an embodiment, the average dose of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof is from about 1 mg / kg to about 3 mg / kg. In another preferred embodiment, the total dose of a Norbigand, Norbogor derivative, or a pharmaceutically acceptable salt or solvate thereof is from about 1 mg / kg to about 2.5 mg / kg.

In some embodiments, the serum concentration is sufficient to inhibit or improve said abuse while maintaining a QT interval of about 500 milliseconds (ms) during said treatment. In a preferred embodiment, the serum concentration is sufficient to inhibit or improve said abuse while maintaining a QT interval of less than about 450 ms during said treatment.

In some embodiments, a therapeutic dose of a Norbitogen, a Norbitogor derivative, or a pharmaceutically acceptable salt or solvate thereof provides an extension of the QT interval of less than about 80 ms. In an embodiment, the retention capacity, the noribogain derivative, or a pharmaceutically acceptable salt or solvate thereof of the norbornene phosphorus provides an extension of the QT interval of less than about 50 ms. In some embodiments, the Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the sustained or therapeutic dose is Norvig, provides an extension of the QT interval of less than about 30 ms. In a preferred embodiment, the retention capacity, the noribogan derivative, or a pharmaceutically acceptable salt or solvate thereof of the norbornene phosphorus provides an extension of the QT interval of less than about 20 ms. In one embodiment, the QT prolongation is equal to or less than that observed in a patient receiving methadone treatment. In a preferred embodiment, the patient is tested to determine the QT interval prior to treatment with Norwegian phosphorus, and if the clinician determines that the QT prolongation is at an unacceptable risk, the treatment with Norwegian bone will be prohibited.

In another embodiment, a norbobene or a pharmaceutically acceptable salt thereof is administered.

Opioid or opioid-like substance abuse

In one aspect, herein, a therapeutically effective amount of a compound of the present invention is administered to a patient in such a way as to provide a mean serum concentration of about 50 ng / ml to about 180 ng / ml, a therapeutic dose of Norbogov, a Norbogophore derivative, or a pharmaceutically acceptable salt thereof There is provided a method of treating opioid or opioid-like drug abuse in a human patient afflicted with an opioid or an opioid-like drug, said method comprising administering to said opioid or opioid- It is sufficient to maintain a QT interval of less than about 500 ms during treatment.

In one embodiment, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, is administered as a single dose or multiple doses. In another embodiment, the method comprises

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein said initial dose provides an average serum concentration of about 50 ng / ml to about 180 ng / ml ; And

b) Wherein the at least one additional dose is at least once an additional dose of norbober to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof, And administering the solvate.

In another embodiment, the initial dose is about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg. In another embodiment, at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further, additional doses are administered from about 6 hours to about 24 hours after the previous dose. In another embodiment, the method further comprises selecting a preselected addict patient to assess tolerability for prolongation of the QT interval. In another embodiment, the maximum serum concentration is from about 40 ng / ml to about 250 ng / ml. In another embodiment, the serum concentration of the Noribogloin is from about 1000 ng * hr / ml to about 5800 ng * hr / ml.

In another aspect, there is provided herein a method of administering a dosage of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the Norbitogen is provided to the patient in an average serum concentration of from about 50 ng / ml to about 180 ng / There is provided a method of treating opioid or opioid-like drug abuse in a human patient afflicted with an opioid or an opioid-like drug comprising the steps of: Sufficient to maintain QT interval extension.

In one embodiment, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, is administered as a single dose or multiple doses.

In another embodiment, the method comprises:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of from about 50 ng / ml to about 180 ng / ml; And

b) Wherein the at least one additional dose is at least one additional dose of Norviga so as to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof And administering the cargo.

In another embodiment, the initial dose is about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg. In another embodiment, at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further additional doses are administered from about 6 hours to about 24 hours after the previous dose.

In another aspect, there is provided herein a method of administering a dosage of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the Norbitogen is provided to the patient in an average serum concentration of from about 50 ng / ml to about 180 ng / There is provided a method of attenuating withdrawal symptoms in a human patient having such symptoms due to an opioid or opioid-like drug addiction comprising the steps of: Lt; RTI ID = 0.0 > QT < / RTI >

In one embodiment, withdrawal symptoms are due to acute withdrawal symptoms. In another embodiment, the Norvigor, Norbigor derivative, or a pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple dose. In another embodiment, the method comprises:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng / ml to about 180 ng / ml; And

b) At least one additional dose of a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the at least one additional dose is a Norviga so as to maintain an average serum concentration of from about 50 ng / ml to about 180 ng / ml for a period of time And administering an additional dose.

In another embodiment, the initial dose is about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg. In another embodiment, at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further, additional doses are administered from about 6 hours to about 24 hours after the previous dose.

In another aspect, provided herein is a method of preventing the recurrence of an abuse in a previously treated patient to improve opioid or opioid-like drug abuse abuse, the method comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of Norviga, Derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the patient no longer abuses the opioid or opioid-like drug, the dosage being about 70% of the therapeutic dose, And further, the extension of the QT interval does not exceed about 30 ms.

In one embodiment, the total dosage amount of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof is from about 5 mg to about 100 mg / day.

nicotine

The present invention is based, in part, on the discovery that the direct blood flow of Norvigans at very low doses reduces the desire for smoking. These dosages were well described earlier. The direct blood flow of the Norwegian phosphorus improves the amount of Norwegian phosphorus delivered to the brain because the Norwegian phosphorus does not initially cross the liver before it reaches the brain as it is ingested. The direct bloodstream delivery of Norbyboline involves sublingual, pulmonary and intranasal delivery, where the Norbybogans are absorbed directly into the bloodstream and then into the brain. Rapid delivery of Norwegian borne to the brain typically results in a significant reduction in craving for smoking on a fast basis of less than 5 minutes after administration.

It is believed that Norviga phosphorus binds to some receptors in the brain, including nicotine acetylcholine receptors (nAChR) and opioid receptors (e.g., mu-opioid receptors). Without being bound by theory, it is believed that nAChR has a greater binding affinity for phosphoryl donors than other receptors in the brain. This allows the treatment of nicotine addiction and / or nicotine craving using a much lower dose of Norbogophane than that currently used for the treatment of other conditions, such as opioid withdrawal symptoms. Furthermore, in remission, a nicotine addict may not exhibit somatic symptoms of addiction, but rather may have a psychological aspiration for cigarettes or other forms of nicotine, or may be able to anticipate such a desire in certain circumstances. It is anticipated that a lower dose of Norbogolin would be needed to treat or prevent nicotine craving in this situation than is necessary in patients currently poisoned with nicotine, without being bound by it and the theory.

In one aspect, the invention is directed to a method of treating nicotine addiction, including the administration of a therapeutic amount of Norbogophane, or preventing recurrence of nicotine use. As used herein, unless otherwise specified, the Norbitogans include Norbitogans, Norbitogens derivatives or their respective pharmaceutically acceptable salts.

In one aspect, the invention is directed to treating nicotine addiction in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a norbobene phosphorus by direct bloodstream transfer. In one aspect, a therapeutically effective amount of a norbobene or derivative is less than about 50 ng to less than 10 μg / kg body weight. In some embodiments, a therapeutically effective amount of a norbobene or a norbobagene derivative is administered once a day, twice a day, or two or more times a day.

In another aspect, the invention is directed to treating nicotine addiction in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a norbobene or a derivative thereof, or a pharmaceutically acceptable salt thereof, , A norbornene or derivative or a pharmaceutically acceptable salt thereof, is administered by sublingual, intranasal, or intrapulmonary delivery.

In one aspect, the present invention is directed to a method of preventing the recurrence of nicotine use, including the administration of a prophylactic dose of Norbogophane to inhibit behavioral craving for nicotine. As used herein, unless otherwise specified, the Noribogaine comprises a Noribogain, a Noribogain derivative, or a respective pharmaceutically acceptable salt thereof.

In one aspect, the present invention is directed to preventing the recurrence of nicotine use in a patient in need of prevention, comprising administering a prophylactically effective amount of a norfubgerine to the patient by direct bloodstream transfer. In one aspect, a prophylactically effective amount of Noribucogloin is about 50 ng to less than 10 μg / kg body weight. In some embodiments, a prophylactically effective amount of a norbobene or a norbobagene derivative is administered once a day, twice a day, or two or more times a day. In some embodiments, a prophylactically effective amount is administered when the patient feels craving for nicotine or expects a feeling of cravings.

In another aspect, the invention provides a method of preventing the recurrence of nicotine use in a patient in need thereof, comprising administering to the patient a prophylactically effective amount of a noribogan derivative, or a pharmaceutically acceptable salt thereof, , Wherein the noribogan, derivative or salt thereof is administered by sublingual, intranasal, or intrapulmonary delivery.

In one aspect, there is provided a method of treating nicotine addiction in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a norbobene derivative, or a pharmaceutically acceptable salt thereof, Wherein said therapeutically effective amount is from about 50 ng to less than 10 μg / kg body weight per day.

In one embodiment, the therapeutically effective amount is from about 50 ng to about 1 [mu] g / kg body weight per day. In another embodiment, the Norvigor, Norvigor's derivative, or a pharmaceutically acceptable salt thereof, is administered by sublingual, intranasal, or intrapulmonary delivery. In another embodiment, the therapeutically effective amount is administered once daily. In another embodiment, the therapeutically effective amount is administered more than once per day.

In one aspect, a method of preventing nicotine craving in a patient in need thereof, comprising administering to the patient a prophylactically effective amount of a norbobagene, a derivative thereof, or a pharmaceutically acceptable salt thereof, Wherein said prophylactically effective amount is from about 50 ng to less than 10 μg / kg body weight per day.

In one embodiment, the patient is no longer physically addicted to nicotine. In another embodiment, the prophylactically effective amount is from about 50 ng to about 1 μg / kg body weight per day. In another embodiment, the Norvigor, Norvigor's derivative, or a pharmaceutically acceptable salt thereof, is administered by sublingual, intranasal, or intrapulmonary delivery. In another embodiment, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt thereof, is administered according to the criteria as required, as determined by the subject. In another embodiment, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt thereof is administered prior to the occurrence of the nicotine craving. In another embodiment, a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt thereof is administered after nicotine craving has occurred.

Alcohol dependence

Although Noriboglobin has been disclosed for the treatment of alcohol dependency, its use in humans is complicated by the fact that the range in prior art is exceptionally broad (0.01 to 1000 mg / kg body weight). Further, human clinical studies demonstrate that lower doses of Norvigor have minimal effects on withdrawal symptoms in addicted patients. Thus, the broad range disclosed above has now been found to be insufficient for human therapy at the lower end of this range.

The present invention is based on the surprising discovery that treatment with a narrow dosage range of Norvigor derivatives, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the Norviga is from about 1 mg / kg body weight to about 8 mg / kg body weight, Partly on the surprising discovery that it provides a curative reduction of withdrawal symptoms in patients with depression. Preferably, the dose range that provides both treatment outcomes and QT interval prolongation of less than 50 milliseconds in poisoned humans is from about 1.3 mg / kg body weight to about 4 mg / kg body weight and more preferably from about 1.3 mg / Kg body weight to about 3 mg / kg body weight, or any sub-range or sub-value within the aforementioned range.

In a preferred embodiment, the narrow therapeutic doses of the Noriboglobin, Norbogophane derivatives, or pharmaceutically acceptable salts and / or solvates thereof, as described above, prolong the QT interval to an unacceptable level in human patients Do not. It is anticipated that therapeutic doses of Norvigor, Norvigor, or a pharmaceutically acceptable salt and / or solvate thereof will be administered in a clinical setting using heart monitoring for an alcohol dependent patient. In some embodiments, the patient may be asked to evaluate the tolerability for prolongation of the QT interval, for example, to determine whether the patient has any pre-existing cardiac condition or other indicator that deprives the patient of the < RTI ID = Will be pre-selected to determine whether or not In one embodiment, a patient exhibiting a QT interval prolongation of less than about 20 ms after treatment with one or more therapeutic doses of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, No further clinical monitoring will be required.

Some aspects of the present invention are directed to a pharmaceutical composition comprising a far lower dose of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, for example, a therapeutic dose of about 80% or less to improve alcohol dependence It is additionally based on the discovery that alcohol use may be effective in preventing recurrence in treated addicts. That is, lower doses of Norvigor phyton can prevent the recurrence of alcohol use by patients who are no longer physically dependent on alcohol. Without being bound by theory, a patient who is no longer physically dependent on alcohol is at least partially prevented from recurring because changes made to the brain by alcohol dependence are at least partially reversed when the patient is detoxified from the alcohol It is believed that fewer Norwegians need a phosphorus. This lower, retention capacity of the Norwegian bogin causes QT interval prolongation that does not require clinical cardiac monitoring.

In some embodiments, a therapeutic dose of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof administered to a patient is administered at an average serum concentration of about 50 ng / ml to about 850 ng / It is sufficient to provide any subranges or subvalues therebetween. In a preferred embodiment, the dose of a Norviga, a Norviga, or a pharmaceutically acceptable salt and / or solvate thereof administered to a patient provides an average serum concentration of about 50 ng / ml to about 400 ng / ml .

In some embodiments, the patient is administered a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the Norvigor is a high (therapeutic) dose for a period of time to improve the most significant withdrawal symptoms , Followed by a lower (sustained) dose administered to prevent recurrence of the use of alcohol. In some embodiments, the patient is administered a therapeutically effective amount of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof for a period of time to improve the most significant withdrawal symptoms, A norovogen derivative, or a pharmaceutically acceptable salt and / or solvate thereof, is administered wherein the amount of the Norvigor is reduced (decreasing) with time until the maintenance dose is reached. In some embodiments, a high initial therapeutic dose is administered, followed by a lower therapeutic dose. In some embodiments, the dose of Norvigulin decreases over time from a high therapeutic dose to a low therapeutic dose.

In some embodiments, the dose of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, which provides a mean serum concentration of from about 50 ng / ml to about 850 ng / ml, do. In some embodiments, the dose of a norbyborg derivative, or a pharmaceutically acceptable salt and / or solvate thereof, that provides a mean serum concentration of from about 50 ng / ml to about 850 ng / ml is administered in multi- do. In some embodiments, the total dose of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 1 mg / kg to about 8 mg / kg. In a preferred embodiment, the total dose of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 1 mg / kg to about 4 mg / kg. In another preferred embodiment, the total dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 1 mg / kg to 3 mg / kg.

In some embodiments, the serum concentration of the Norbitogloin is sufficient to inhibit or ameliorate said dependency while maintaining a QT interval of less than 500 milliseconds (ms) during said treatment. In some embodiments, therapeutic doses of a Norbitogen, a Norbitogor derivative, or a pharmaceutically acceptable salt and / or solvate thereof provide an extension of the QT interval of less than 80 ms. In one embodiment, the retention capacity, the noribogain derivative, or a pharmaceutically acceptable salt and / or solvate thereof of the norbornene phosphorus provides an extension of the QT interval of less than 50 ms. In some embodiments, the Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the sustained or therapeutic dose is Norvig, provides an extension of the QT interval of less than 30 ms. In a preferred embodiment, the retention capacity, noribogan derivative, or pharmaceutically acceptable salt and / or solvate thereof of the Noribogloin provides an extension of the QT interval of less than 20 ms. In a preferred embodiment, the patient is tested to determine the QT interval prior to treatment with Norwegian phosphorus, and the Norwegian pharmacy regimen will be prohibited if the clinician determines that the QT prolongation is at an unacceptable risk.

In one aspect, dosage amounts of a norbyborg derivative, or a pharmaceutically acceptable salt and / or solvate thereof, which provides a patient with an average serum concentration of about 50 ng / ml to about 500 ng / A method of treating alcohol dependence in a human patient suffering from alcohol dependence comprising administering a therapeutically effective amount of a compound of formula I wherein the concentration is sufficient to improve said dependency while maintaining a QT interval of less than about 500 ms during said treatment.

In one embodiment, the compound is administered as a single dose or multi-dose dose of a Norwegian, Norwegian-derived derivative, or a pharmaceutically acceptable salt and / or solvate thereof. In another embodiment, the total dosage of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 1.3 mg / kg to about 4 mg / kg per day. In another embodiment, the total dosage of a Norvigor, Norbigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 1.5 mg / kg to about 3 mg / kg per day. In another embodiment, the total dosage of a Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 2 mg / kg to about 4 mg / kg per day. In another embodiment, the total dosage of a Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 2 mg / kg to about 3 mg / kg per day. In another embodiment, the total dosage amount of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is about 2 mg / kg per day. In another embodiment, the dosage of a Norvigor, Norbogor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, provides an average serum concentration of about 50 ng / ml to about 200 ng / ml. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms. In another embodiment, the method further comprises selecting a pre-selected addict patient to assess tolerability for prolongation of the QT interval. In another embodiment, the pre-screening step comprises verifying that the treatment in which the Norwegian bone does not result in a QT interval of greater than about 500 ms. In another embodiment, the pre-sorting step comprises verifying that the treatment in which the Norwegian bone does not result in a QT interval of greater than about 470 ms. In another embodiment, the pre-sorting step comprises verifying that the treatment in which the Norwegian borrower does not result in a QT interval of greater than about 450 ms.

In another aspect, the dosage amount of a norbyborne, nordoborgain, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the patient is provided with an average serum concentration of from about 50 ng / ml to about 400 ng / A method for attenuating withdrawal symptoms in a human patient susceptible to withdrawal symptoms due to alcohol dependence, the method comprising administering an effective amount of at least about 500 milliseconds Gt; QT < / RTI >

In one embodiment, withdrawal symptoms are due to acute withdrawal symptoms. In another embodiment, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the total dosage of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 1.3 mg / kg to about 4 mg / kg per day. In another embodiment, the total dosage of a Norvigor, Norbigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 1.5 mg / kg to about 3 mg / kg per day. In another embodiment, the total dosage of a Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 2 mg / kg to about 4 mg / kg per day. In another embodiment, the total dosage of a Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 2 mg / kg to about 3 mg / kg per day. In another embodiment, the total dosage amount of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is about 2 mg / kg per day. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.

In one aspect, provided herein is a method of preventing recurrence of alcohol abuse in a patient being treated to ameliorate alcohol abuse, the method comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of Norbigov, Or a pharmaceutically acceptable salt and / or solvate, wherein the patient is no longer physically dependent on the alcohol.

In one embodiment, the maintenance dose is less than about 70% of the therapeutic dose and further the extension of the QT interval does not exceed about 30 ms. In another embodiment, the dosage is less than about 70% of the therapeutic dose and further the extension of the QT interval does not exceed about 20 ms. In another embodiment, a norbobene or a pharmaceutically acceptable salt and / or solvate thereof is administered.

Drug addiction

Although Noriboglobin has been described for the treatment of substance abuse, its use in humans is complicated by the fact that the range in prior art is exceptionally broad (0.01 to 1000 mg / kg body weight). Furthermore, human clinical trials demonstrate that lower doses of Norvigor have minimal effects on withdrawal symptoms in patients who are poisoned. Thus, the broad range disclosed above has now been found to be insufficient for human therapy at the lower end of this range.

The present invention provides a method of treating withdrawal symptoms in a patient who has been treated with a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, in a narrow range of Norviga, from 1 mg / kg body weight to 4 mg / kg body weight And / or an increase in time for re-consumption of drug use. ≪ Desc / Clms Page number 2 > Preferably, the dose range that provides both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds is 1.3 mg / kg body weight to 4 mg / kg body weight and more preferably 1.3 mg / Kg body weight to 3 mg / kg body weight or lower, or any lower range or lower value within the above-mentioned range.

In some embodiments, the dose providing treatment outcome and an acceptable QT interval extension of less than 50 milliseconds in drug-challenged humans is about 120 mg. In some embodiments, the dose providing a therapeutic outcome and an acceptable QT interval prolongation of less than 50 milliseconds in a drug addicted human is about 2 mg / kg body weight.

In some embodiments, the patient is administered an initial dose of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses. In one embodiment, the initial dose is 75 mg to 120 mg. In one embodiment, the at least one additional capacity is lower than the initial capacity. In one embodiment, the at least one additional dose is from 5 mg to 50 mg. In one embodiment, this dosage regimen provides an average serum concentration of Norvibogloins from 50 ng / ml to 180 ng / ml. In one embodiment, one or more additional doses maintain an average serum concentration of between 50 ng / ml and 180 ng / ml over a period of time. In one embodiment, one or more additional doses are administered periodically.

In some embodiments, the narrow therapeutic doses of the Norovagene, Norbogophane derivatives, or pharmaceutically acceptable salts and / or solvates thereof described above, predict the QT interval to an unacceptable level in human poisoning patients Do not prolong it. A drug-poisoned patient is expected to receive a therapeutic dose of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof in a clinical setting using cardiac monitoring. In some embodiments, the patient determines whether or not the patient has any pre-existing cardiac condition that deprives the patient of treatment using a Norbogophane, for example, to assess tolerability for prolongation of the QT interval Will be pre-selected.

Some aspects of the present invention are directed to a method for improving the abuse of a substance, wherein less than about 80% of the therapeutic dose of a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, To the discovery that drug use may be effective in preventing recurrence of drug use in the treated addicted patient. That is, low doses of Norbitogens can prevent recurrence of the use of addictive substances in patients who are no longer physically addicted to it. Without being bound by theory, since the drug does not compete with the phosphorus binding to the receptor binding, and / or the desensitization of one or more receptors in the brain by the drug is reversed when the patient stops taking the drug Patients who are no longer addicted to drugs are believed to need fewer Norwegian boys to prevent relapse. This lower, retention capacity of the Norwegian bogin causes QT interval prolongation that does not require clinical cardiac monitoring.

In some embodiments, the retention capacity of the norbornene phosphorus is from 5 mg to 100 mg. In some embodiments, the retention capacity of the norbornene phosphorus is about 1.5 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 1 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.9 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.8 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.7 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.6 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.5 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.4 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.3 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.2 mg / kg body weight. In some embodiments, the retention capacity of the norbornene phosphorus is about 0.1 mg / kg body weight.

In some embodiments, a therapeutic dose of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, administered to a patient is administered at an average serum concentration of 50 ng / ml to 400 ng / ml, Is sufficient to provide any subranges or subvalues between. In a preferred embodiment, the dose of a Norviga, a Norviga, or a pharmaceutically acceptable salt and / or solvate thereof administered to a patient provides an average serum concentration of 50 ng / ml to 180 ng / ml.

In some embodiments, the patient is administered a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, which has a high (therapeutic) dose of Norviga for a period of time to improve the most significant withdrawal symptoms , Followed by a lower (sustained) dose administered to prevent recurrence of drug use. In some embodiments, the patient is administered a therapeutically effective amount of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, to improve the most significant withdrawal symptoms, Or a pharmaceutically acceptable salt and / or solvate thereof, is administered to a subject in need thereof, wherein the amount of Norvigor is reduced (diminishes) with time until it is reached. In some embodiments, a high initial therapeutic dose is administered and a lower therapeutic dose is administered. In some embodiments, the dose of Norvigovin decreases over time from a higher therapeutic dose to a lower therapeutic dose.

In some embodiments, the dose of a Norbitogen, a Norbitogen, or a pharmaceutically acceptable salt and / or solvate thereof, which provides an average serum concentration of 50 ng / ml to 180 ng / ml, is administered as a single dose. In some embodiments, the dose of a Norbigand, a Noribogain derivative, or a pharmaceutically acceptable salt and / or solvate thereof, which provides an average serum concentration of 50 ng / ml to 180 ng / ml, is administered as a multiple dose. In an embodiment, the total dose of a norbyborne, norbyborne derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from 1 mg / kg to 3 mg / kg. In another embodiment, the total dose of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from 1 mg / kg to 2.5 mg / kg.

In some embodiments, the serum concentration is sufficient to inhibit or improve said abuse while maintaining a QT interval of less than 500 milliseconds (ms) during said treatment. In some embodiments, therapeutic doses of a Norbitogen, a Norbitogor derivative, or a pharmaceutically acceptable salt and / or solvate thereof provide an extension of the QT interval of less than 80 ms. In one embodiment, the retention capacity, the noribogain derivative, or a pharmaceutically acceptable salt and / or solvate thereof of the norbornene phosphorus provides an extension of the QT interval of less than 50 ms. In some embodiments, the Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the sustained or therapeutic dose is Norvig, provides an extension of the QT interval of less than 30 ms. In an embodiment, the retention capacity, the noribogan derivative, or a pharmaceutically acceptable salt and / or solvate thereof of the norbornene phosphorus provides an extension of the QT interval of less than 20 ms. In one embodiment, QT prolongation is equal to or less than that observed in a patient who has received methadone treatment. In a preferred embodiment, the patient is tested to determine the pre-treatment QT interval using the Norbogogine, and if the clinician determines that the QT prolongation is at an unacceptable risk, the treatment with Norbogog will be prohibited.

In another aspect, there is provided the use of a dosage form of a Norbitogen, a Norbitogen, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the patient is provided with a mean serum concentration of 50 ng / ml to 180 ng / There is provided a method of treating substance abuse in a human patient that has been substance-depleted, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment .

In one embodiment, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, is administered as a single dose or multiple doses. In another embodiment, the method comprises the following steps:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / ml to 180 ng / ml; And

b) Wherein the at least one additional dose is at least once an additional dose of norbober to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof, Administering the solvate.

In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered and additional doses are administered between 6 hours and 24 hours after the previous dose. In another embodiment, the method further comprises selecting a preselected, poisoned patient to assess tolerance to prolongation of the QT interval.

In another aspect, there is provided a method of treating a patient in need of such treatment comprising administering to a patient a Norbitogen, a Norbitogen, or a pharmaceutically acceptable salt and / or solvate thereof, which provides a mean serum concentration of 50 ng / ml to 180 ng / There is provided a method for treating substance abuse in a substance-deprived human patient, the concentration being such as to inhibit or ameliorate said abuse while maintaining a QT interval extension of less than about 20 ms during said treatment during said treatment Suffice.

In one embodiment, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, is administered as a single dose or multiple doses. In another embodiment, the method comprises the following steps:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / ml to 180 ng / ml; And

b) Wherein the at least one additional dose is at least once an additional dose of norbober to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof, Administering the solvate.

In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further doses are administered between 6 hours and 24 hours after the additional pre-dose dose.

In another aspect, there is provided the use of a dosage form of a Norbitogen, a Norbitogen, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the patient is provided with a mean serum concentration of 50 ng / ml to 180 ng / There is provided a method of attenuating withdrawal symptoms in a human patient susceptible to withdrawal symptoms due to drug addiction comprising the step of administering a therapeutically effective amount of a compound of formula Is sufficient.

In another embodiment, withdrawal symptoms are due to acute withdrawal symptoms. In another embodiment, the compound is administered as a single dose or multi-dose dose of a Norvigrin, Norbogor derivative, or a pharmaceutically acceptable salt and / or solvate thereof. In another embodiment, the method comprises the following steps:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / ml to 180 ng / ml; And

b) Wherein the at least one additional dose is at least once an additional dose of norbober to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof, Administering the solvate.

In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further doses are administered between 6 hours and 24 hours after the additional pre-dose dose.

In another aspect, provided herein is a method of preventing the recurrence of drug abuse in a patient being treated to ameliorate said abuse, said method comprising administering to said patient a therapeutically effective amount of a compound selected from the group consisting of Norviga, Wherein the patient is no longer abusing the drug, the dosage is less than about 70% of the therapeutic dose, and, further, the prolongation of the QT interval Is about 30 ms or less.

In another embodiment, the total dosage amount of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof is from 50 mg to 100 mg per day.

ache

In some embodiments, the present invention contemplates the surprising discovery that treatment using a narrow dosage range of overbodies of from about 0.1 mg / kg body weight to about 8 mg / kg body weight provides therapeutic relief of pain. Preferably, the dosage range providing both treatment outcomes and acceptable QT interval prolongation of less than 50 milliseconds in humans is from about 0.1 mg / kg body weight to about 3 mg / kg body weight and more preferably from about 0.7 mg / Kg body weight to about 2 mg / kg body weight or lower, or any sub-range or sub-value within the above-mentioned range.

In some embodiments, the narrow therapeutic dose of the above described hypogonadism does not prolong the QT interval to unacceptable levels in human patients. In some embodiments, the patient is administered a therapeutic dose of ibocaine in a clinical setting using cardiac monitoring. In some embodiments, the patient determines whether the patient has any pre-existing cardiac condition that is deprived of their treatment from the treatment using ibocaine, for example, to assess tolerance to prolongation of the QT interval Will be pre-selected. In one embodiment, a patient exhibiting a QT interval prolongation of less than about 20 ms after treatment with one or more therapeutic doses of ibocaine will not require additional clinical monitoring. In one embodiment, the patient is not monitored after administration of the bogogan.

In some embodiments, the therapeutic dose of the therapeutic dose administered to the patient is sufficient to provide an average serum concentration of about 50 ng / ml to about 850 ng / ml, or any subranges or subvalues therebetween. In a preferred embodiment, the dose of hypogonadism administered to a patient provides an average serum concentration of about 50 ng / ml to about 400 ng / ml.

In some embodiments, a dose of ibocaine that provides an average serum concentration of about 50 ng / ml to about 850 ng / ml is administered as a single dose. In some embodiments, a dose of ibocaine that provides an average serum concentration of about 50 ng / ml to about 850 ng / ml is administered as a multiple dose. In some embodiments, the total dose of ibocaine is from about 0.1 mg / kg to about 8 mg / kg. In one embodiment, the total dose of ibocaine is from about 0.1 mg / kg to about 3 mg / kg. In another embodiment, the total dose of ibocaine is about 0.7 mg / kg to 1.5 mg / kg.

In one aspect, the step of administering a dosage of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the Norbitogen provides a mean serum concentration of 50 ng / ml to 180 ng / Wherein the concentration is sufficient to alleviate and / or inhibit the pain while maintaining a QT interval of less than about 500 ms during the treatment.

In one embodiment, the compound is administered as a single dose or multi-dose dose of a Norwegian, Norwegian-derived derivative, or a pharmaceutically acceptable salt and / or solvate thereof. In one embodiment, the method comprises the steps of:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / ml to 180 ng / ml; And

b) Wherein the at least one additional dose is at least once an additional dose of norbober to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof, Administering the solvate.

In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further doses are administered between 6 hours and 24 hours after the additional pre-dose dose. In another embodiment, the method further comprises selecting a preselected, poisoned patient to assess tolerance to prolongation of the QT interval. In another embodiment, the total dosage amount of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof is from 70 mg to 150 mg per day.

In another aspect, there is provided the use of a dosage amount of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the Norbitogen provides a mean serum concentration of 50 ng / ml to 180 ng / Wherein the concentration is sufficient to alleviate and / or inhibit the pain while maintaining a QT interval extension of less than about 20 ms during the treatment.

In one embodiment, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, is administered as a single dose or multiple doses. In another embodiment, the method comprises the following steps:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / ml to 180 ng / ml; And

b) Wherein the at least one additional dose is at least once an additional dose of norbober to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof, Administering the solvate.

In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further doses are administered between 6 hours and 24 hours after the additional pre-dose dose.

In another aspect, there is provided the use of a dosage amount of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the Norbitogen provides a mean serum concentration of 50 ng / ml to 180 ng / There is provided a method of alleviating pain symptoms in a human subject susceptible to pain symptoms wherein the concentration is sufficient to maintain the QT interval of less than about 500 ms during the treatment while attenuating the symptoms.

In another embodiment, the pain symptoms are due to chronic pain. In another embodiment, the compound is administered as a single dose or multi-dose dose of a Norvigrin, Norbogor derivative, or a pharmaceutically acceptable salt and / or solvate thereof. In another embodiment, the method comprises the following steps:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / ml to 180 ng / ml; And

b) Wherein the at least one additional dose is at least once an additional dose of norbober to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof, Administering the solvate.

In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further doses are administered between 6 hours and 24 hours after the additional pre-dose dose.

migraine

The invention provides a method of treating a migraine headache comprising administering to a subject a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of & It is partly based on the incredible discovery that it provides an immediate mitigation. Preferably, the dose provides both treatment outcomes and acceptable QT interval prolongations of less than about 50 milliseconds (ms) in humans.

The present invention is based in part on the discovery that Norvigans reduce the frequency, severity and / or length of headache and especially migraine. The present invention is further based on the discovery that direct bloodstream delivery of Norvigans at very low doses can treat and / or prevent migraine headaches. The direct blood flow of the Norwegian bogin improves the amount of Norwegian phosphorus delivered to the brain because the Norwegian bovine is not passed through the liver at first before it reaches the brain as it is ingested. The direct bloodstream delivery of Norbyborain involves sublingual, buccal, pulmonary and intranasal delivery, where the Norvasc phosphorus is absorbed directly into the bloodstream for delivery into the brain. Rapid delivery of Norwegian boron to the brain typically can result in a significant reduction in migraine symptoms in less than 15 minutes after administration.

Although not all stages are experienced in all cases, migraine headaches can include four stages. The first stage is a progenitor, and the patient experiences sensitivity to inorganism, emotional changes, depression or mood swings, fatigue, malnutrition, constipation, constipation or diarrhea, and smell and / or noise. The second stage is the aura stage characterized by visual, sensory or motor effects. Only a subset of migraine headaches include the aura. The third stage is pain; Pain is accompanied by nausea, vomiting, sensitivity to sensory infiltration, fatigue, inertness, dizziness, mild headache, confusion, dimness, nasal discharge, diarrhea, frequent urination, pale or sweating. The final stage may be post-hoc, and migraine headache may include a sick feeling, impairment of accidental function, fatigue, headache, mood swings, gastrointestinal symptoms, and weakness.

Causes of migraine are unclear, but migraine headaches can be caused by spasms, including hormonal changes, stress, hunger, fatigue, specific smells, food, bad air quality, Migraine can also be affected by genetic factors.

In one aspect, the invention is directed to a method of treating or preventing migraine and / or symptoms thereof, comprising the administration of a therapeutically effective amount of a Norboggan. As used herein, unless otherwise specified, the Norbiggan phosphorus is a Norbiggan, a Norbogophane derivative, or a respective pharmaceutically acceptable salt thereof. In one embodiment, the patient is co-administered with a therapeutically effective amount of a formulation known to treat migraine in addition to Norwegian. In a preferred embodiment, the co-treatment does not result in a QT interval extension of greater than 50 ms. In one embodiment, the compounds are both administered simultaneously. In one embodiment, the compounds are administered at different times (e.g., sequentially).

In one aspect, the invention is directed to treating a migraine and / or a symptom thereof in a patient in need of treatment, comprising administering a therapeutically effective amount of a norbobene or derivative by direct blood flow to the patient. In one aspect, the therapeutically effective amount of the norbobene or derivative is from about 50 ng to about 10 μg / kg body weight. In some embodiments, a therapeutically effective amount of a norbobene or norbobar derivative is administered once a day, twice a day, or two or more times a day. In one embodiment, a formulation known to treat and / or prevent migraine is also administered.

In another aspect, the invention provides a method of treating a migraine and / or a symptom thereof in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a Norvigene or a derivative thereof, or a pharmaceutically acceptable salt thereof, Wherein the norbornene or derivative or a pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, buccal, or intrapulmonary delivery.

The present invention is directed to a method of preventing migraine and / or symptoms thereof, including the administration of a prophylactic amount of a noribogan to prevent or ameliorate migraine headache and / or its symptoms. As used herein, unless otherwise specified, the Norbiggan phosphorus is a Norbiggan, a Norbogophane derivative, or a respective pharmaceutically acceptable salt thereof. In one embodiment, a formulation known to treat and / or prevent migraine is also administered.

In one aspect, the present invention is directed to preventing migraine and / or symptoms thereof in a patient in need of such prevention, comprising administering a prophylactically effective amount of a norbobigain to the patient by direct bloodstream transfer. In one aspect, a prophylactically effective amount of a Norbitcogen is from about 1 mg to about 2 mg / kg body weight. In one aspect, a prophylactically effective amount of a Norbitcogen is from about 50 ng to about 10 μg / kg body weight. In some embodiments, a prophylactically effective amount of a norbobene or a norbobagene derivative is administered once a day, twice a day, or two or more times a day. In some embodiments, a prophylactically effective amount is administered periodically (e. G., Daily). In some embodiments, a prophylactically effective amount is administered prior to, concurrently with, or immediately after a potential trigger for migraine headache. In some embodiments, a prophylactically effective amount is administered when the subject feels the onset of at least one symptom of migraine. In one embodiment, a formulation known to treat and / or prevent migraine is also administered.

In another aspect, the invention provides a method of treating a migraine headache in a patient in need of prevention, comprising administering to the patient a prophylactically effective amount of a noribogan derivative, or a pharmaceutically acceptable salt or solvate thereof, The present invention provides a method of preventing the symptoms thereof, wherein the norbornene derivative, or a salt thereof, is administered by sublingual, intranasal, buccal, or intrapulmonary delivery.

As will be apparent to those skilled in the art upon reading this disclosure, the present invention, in one aspect, provides a method of treating or preventing a disorder or condition in a patient in need of such treatment or prophylaxis, comprising administering to said patient a therapeutically effective amount of a norbogen, a norbobagene derivative, a norbigene prodrug, A method of treating or preventing migraine and / or symptoms thereof in a subject, comprising administering each pharmaceutically acceptable salt. In one embodiment, the method further comprises administering at least one agent known to treat or prevent migraine and / or its symptoms.

In another aspect, the present invention provides a pharmaceutical composition comprising at least one formulation known to treat and / or prevent migraine, a therapeutically or prophylactically effective amount of a noribogan derivative, or a pharmaceutically acceptable salt or solvate thereof, , And, optionally, a pharmaceutically acceptable excipient, for the treatment and / or prevention of migraine.

In another aspect, the invention provides a method of treating migraine and / or symptoms thereof in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a norbobene derivative, or a pharmaceutically acceptable salt thereof, A method of treatment is provided.

In one embodiment, the therapeutically effective amount is from about 50 ng to about 10 μg / kg body weight per day. In another embodiment, the therapeutically effective amount is from about 1 mg to about 4 mg / kg body weight per day. In another embodiment, the Norvigor, Norvigor's derivative, or a pharmaceutically acceptable salt thereof, is administered by sublingual, buccal, intranasal, or intrapulmonary delivery. In another embodiment, the therapeutically effective amount is administered once daily. In another embodiment, the therapeutically effective amount is administered more than once per day.

In another aspect, there is provided herein a method of treating migraine and / or symptoms thereof in a patient in need of such prevention, comprising administering to the patient a prophylactically effective amount of a noribogan derivative, or a pharmaceutically acceptable salt thereof, A preventive method is provided.

In one embodiment, the prophylactically effective amount is from about 50 ng to about 10 μg / kg body weight per day. In another embodiment, the prophylactically effective amount is less than about 90% of the therapeutically effective amount. In another embodiment, the Norvigor, Norvigor's derivative, or a pharmaceutically acceptable salt thereof, is administered by sublingual, intranasal, buccal, or intrapulmonary delivery. In another embodiment, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt thereof, is administered according to the required criteria as determined by the subject. In another embodiment, the QT interval of the patient is not extended by more than about 30 ms. In another embodiment, the method further comprises administering at least one agent known to treat and / or prevent migraine and / or its symptoms. In another embodiment, the at least one agent is selected from the group consisting of analgesics, tryptam, ergotamine, and dexamethasone.

Reduced tolerance to opioid analgesics

The present invention relates, in part, to the use of a Norbogogine for the control of tolerance to addictive opioid analgesics in patients who have developed or are at risk of developing tolerance to analgesic agents. In this way, while effective analgesia can be achieved in the patient, the patient can be sensitized to the addictive opioid analgesic. The term " re-sensitizing a patient "is used herein to refer to reducing and / or eliminating, abrogating, and / or reversing tolerance to analgesic agents. In one aspect, patients who have been sensitized get a therapeutic benefit from lower doses of opioid analgesics than before. In one aspect, a compromised patient obtains an improved therapeutic effect from the same dose of opioid analgesics compared to prior to sensitization.

In one embodiment, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered concurrently with the opioid analgesic. In one embodiment, the Norvigor, Norbigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof may be administered after the administration of the analgesic agent, for example, 1, 2, 3, 4, 8, 10, 12, 24 hours or more. In one embodiment, one dose of Noribucogloin is administered. In one embodiment, two doses of Noribucogloin are administered. In one embodiment, the opioid analgesic is stopped for a period of time, while the Norvigorine is administered. In one embodiment, the non-opioid analgesic is administered, while the opioid analgesic is discontinued. In one embodiment, the Norvigrin acts as an analgesic. In one embodiment, the opioid analgesic is not discontinued during treatment with Norviga.

In some embodiments, a unit dose that provides an acceptable QT interval prolongation of less than 50 milliseconds and treatment results in an opioid-tolerable human is about 120 mg. In some embodiments, a unit dose that provides an acceptable QT interval extension of less than 50 milliseconds and a treatment result in an opioid-tolerable human is 2 mg / kg body weight.

In one aspect, there is provided herein a method of modulating tolerability to an opioid analgesic in a patient suffering from opioid analgesic therapy, the method comprising administering to the patient a therapeutically effective amount of a therapeutically effective amount of an opioid analgesic selected from the group consisting of Norviga, Norvig, < RTI ID = 0.0 > Or an amount of a pharmaceutically acceptable salt and / or solvate thereof, at the same time as or simultaneously with the opioid analgesic therapy, wherein the concentration re-sensitizes the patient to an opioid as an analgesic agent, Is sufficient to maintain a QT interval of less than about 500 ms during the treatment.

In one embodiment, the compound is administered as a single dose or multi-dose dose of a Norwegian, Norwegian-derived derivative, or a pharmaceutically acceptable salt and / or solvate thereof. In another embodiment, the method further comprises interrupting the dosage of the analgesic agent. In another embodiment, the method further comprises the step of administering a nebulizer, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the agent is at the same time as the analgesic agent. In another embodiment, during co-administration, the dose of opioid analgesic is reduced. In another embodiment, the method comprises the following steps:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / ml to 180 ng / ml; And

b) Wherein the at least one additional dose is at least once an additional dose of norbober to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof, Administering the solvate.

In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further doses are administered between 6 hours and 24 hours after the additional pre-dose dose. In another embodiment, the method further comprises selecting a preselected, poisoned patient to assess tolerance to prolongation of the QT interval.

In one aspect, there is provided herein a method of modulating tolerability to an opioid analgesic in a patient suffering from opioid analgesic therapy, the method comprising administering to the patient a therapeutically effective amount of a therapeutically effective amount of an opioid analgesic selected from the group consisting of Norviga, Norvig, < RTI ID = 0.0 > Or an amount of a pharmaceutically acceptable salt and / or solvate thereof, at the same time as or simultaneously with the opioid analgesic therapy, wherein the concentration is sufficient to re-sensitize the patient to the opioid as an analgesic agent, It is sufficient to maintain a QT interval extension of less than about 20 ms during treatment.

In one embodiment, the compound is administered as a single dose or multi-dose dose of a Norwegian, Norwegian-derived derivative, or a pharmaceutically acceptable salt and / or solvate thereof. In another embodiment, the method further comprises interrupting the dosage of the analgesic agent. In another embodiment, the method further comprises the step of administering a nebulizer, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the agent is at the same time as the analgesic agent. In another embodiment, during co-administration, the dose of opioid analgesic is reduced. In another embodiment, the method further comprises the steps of:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / ml to 180 ng / ml; And

b) Wherein the at least one additional dose is at least once an additional dose of norbober to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof, Administering the solvate.

In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further doses are administered between 6 hours and 24 hours after the additional pre-dose dose. In another embodiment, the method further comprises selecting a preselected, poisoned patient to assess tolerance to prolongation of the QT interval.

In another embodiment, the opioid analgesic is selected from the group consisting of pentanil, hydrocodone, hydro morpholine, morphine, oxycodone, buprenorphine, codeine, tebine, buprenorphine, methadone, meperidine, tramadol, ≪ / RTI > pentamericin, sufentanil, pentazocine, and oxymorphone. In another embodiment, the opioid analgesic is a morphine.

depression

There is a particular characteristic of the Norwegian borne that exists as a very attractive candidate for the treatment of depression and / or post-traumatic stress disorder (PTSD). These include the interaction of the various receptors with the norbornene in the brain, including nicotine acetylcholine receptors (nAChRs) and opioid receptors (e.g., mu-opioid receptors). In addition, Norvigorins increase brain serotonin by blocking synaptic reabsorption through the SERT transporter. As such, the invention provides a method of treating depression and / or PTSD, or a symptom thereof, comprising administering to a patient a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt and / or solvate thereof ≪ / RTI >

At very low doses, the direct bloodstream delivery of Norvigovin can reduce the symptoms of depression and / or PTSD. Such dosing is well described below. The direct blood flow of the Norwegian Bogin improves the amount of Norvigovin that is delivered to the brain, because the Norwegian Bogin does not pass the liver as it is ingested. The direct bloodstream delivery of Norbycognosin involves sublingual, pulmonary and intranasal intranasal delivery wherein the Noribogloins are absorbed directly into the bloodstream and then delivered to the brain. Rapid delivery of Norwegian phosphorus into the brain, for example, less than 15 minutes, can result in significant reductions in depression and / or PTSD symptoms.

In one aspect, the invention provides a method of treating a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a norbye, a derivative, solvate, or a pharmaceutically acceptable salt and / or solvate thereof, / RTI > and / or PTSD in a mammal. In one embodiment, the invention treats depression. In another embodiment, the invention treats PTSD. In a preferred embodiment, the patient is not addicted to cocaine or opiate. Unlike PTSD, a common anxiety disorder is not a category of the present invention.

In some embodiments, a therapeutically effective amount of a Norvigovir or a pharmaceutically acceptable salt and / or solvate thereof administered to a patient has an average serum concentration of between 50 ng / ml and 180 ng / ml, or any subranges therebetween Or it is sufficient to provide a lower value. In one embodiment, the dose of noribogan or a pharmaceutically acceptable salt and / or solvate thereof administered to a patient provides an average serum concentration of between 50 ng / ml and 150 ng / ml. In one embodiment, the dose of noribogan or its pharmaceutically acceptable salt and / or solvate administered to a patient provides an average serum concentration of 80 ng / ml to 100 ng / ml.

In some embodiments, the serum concentration is sufficient to inhibit or ameliorate the symptoms of depression and / or PTSD, while maintaining a QT interval of less than 500 milliseconds (ms) during the treatment. In some embodiments, the dose of noriboganin or a pharmaceutically acceptable salt and / or solvate thereof provides an extension of the QT interval of less than 50 ms. In some embodiments, the dose of noriboganin or a pharmaceutically acceptable salt and / or solvate thereof provides an extension of the QT interval of less than 30 ms. In a preferred embodiment, the dose of noribogan or a pharmaceutically acceptable salt and / or solvate thereof provides an extension of the QT interval of less than 20 ms. In a preferred embodiment, the patient is tested to determine the pre-treatment QT interval using the Norbogogine, and if the clinician determines that the QT prolongation is at an unacceptable risk, the treatment with Norbogog will be prohibited.

In another aspect, the present invention provides a method of treating or preventing a disorder or condition in which the concentration of a Norvigor derivative, a pharmaceutically acceptable salt and / or solvate thereof, is at least about 6 hours, at least about 12 hours, at about 18 hours, at about 24 hours, at about 36 hours, Administering to the patient a derivative of Norbogophane or Norbogophage in a sustained release manner so as to remain in a therapeutically effective amount for a period of between about 48 hours, about 72 hours, about 96 hours, or any two of these durations Or methods of treating depression and / or PTSD in a patient in need of such treatment.

In another aspect, there is provided a method of treating depression and / or trauma in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a norbyeene derivative, or a pharmaceutically acceptable salt and / or solvate thereof, A method of treating a stress disorder is provided wherein the patient is not intoxicated with cocaine or opiate and the further therapeutically effective amount provides a serum level of about 50 ng / ml to about 180 ng / ml of efficacious mean norbornene , Maintaining a QT interval of less than about 500 ms during the treatment.

In another aspect, there is provided herein a method of treating depression and / or depression in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a norbyeene, a derivative thereof, or a pharmaceutically acceptable salt and / / Or a post traumatic stress disorder, wherein the patient is not intoxicated with cocaine or opiate, and a further therapeutically effective amount is selected from the group consisting of serum levels of about 50 ng / ml to about 180 ng / While maintaining a QT interval extension of less than about 20 ms during the treatment.

In one embodiment, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, is administered as a single dose or multiple doses.

In another embodiment, the method comprises the following steps:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / ml to 180 ng / ml; And

b) Wherein the at least one additional dose is at least once an additional dose of norbober to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof, Administering the solvate.

In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further doses are administered between 6 hours and 24 hours after the additional pre-dose dose. In another embodiment, the method further comprises selecting a preselected patient to assess tolerance to prolongation of the QT interval. In another embodiment, depression is treated. In another embodiment, post-traumatic stress disorder is treated.

unrest

There are certain characteristics of Norwich borne that exist as a very attractive candidate for treatment of anxiety disorders, impulsive control disorders, anger / violence-related disorders or the control of food intake. These include the interaction of the various receptors in the brain with nicotine acetylcholine receptors (nAChRs) and opioid receptors (for example, mu-opioid receptors). In addition, Norbogophage increases brain serotonin levels by blocking synaptic reabsorption through the SERT transporter. As such, the present invention provides a method of treating anxiety disorders, impulse control disorders, anxiety / violence-related disorders, and / or anxiety disorders, comprising administering to a patient a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt and / Or a method of treating the symptoms thereof.

At very low doses, the direct bloodstream delivery of Norwegian phosphorus can reduce the symptoms of anxiety disorders, impulse control disorders, anger / violence-related disorders, or provide control of food intake. Such dosing is well described below. The direct blood flow of the Norwegian bogin improves the amount of Norbogophane delivered to the brain because Norbogophagus does not pass the liver as it is ingested. The direct bloodstream transmission of Norbybola involves sublingual, pulmonary and intranasal delivery, and the Norwegian phosphorus is then directly absorbed into the bloodstream and subsequently transmitted to the brain. Rapid delivery of Norwegian boys into the brain, for example, less than about 15 minutes, can result in significant reductions in anxiety disorders, impulse control disorders, anger / violence-related disorders, or dietary symptoms.

In one aspect, the invention provides a method of treating a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a norbye, a derivative, solvate, or a pharmaceutically acceptable salt and / or solvate thereof, In treating anxiety disorders, impulse control disorders, anger / violence-related disorders, or in regulating food intake. In one embodiment, the invention treats anxiety disorders. In one embodiment, the invention treats OCD. In one embodiment, the invention treats generalized anxiety disorders. In one embodiment, the invention treats social anxiety disorder. In one embodiment, the invention treats panic disorders. In another embodiment, the invention treats impulse control disorders. In another embodiment, the invention treats pathological anger and / or violence. In another embodiment, the invention treats anger / violence-related disorders. In another embodiment, the invention reduces pathological anger in a patient. In another embodiment, the invention reduces violent eruption in a patient. In another embodiment, the invention reduces food intake. In one embodiment, food consumption is reduced. In one embodiment, the cut is reduced. In a preferred embodiment, the patient is not addicted to cocaine or opiate.

In some embodiments, a therapeutic dose of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, administered to a patient is administered at a mean serum concentration of 50 ng / ml to about 180 ng / ml, Is sufficient to provide any subranges or subvalues of < RTI ID = 0.0 > In a preferred embodiment, the dose of noribogan or its pharmaceutically acceptable salt and / or solvate administered to the patient provides an average serum concentration of about 50 ng / ml to about 110 ng / ml. In one embodiment, the dose of Norvigovin or a pharmaceutically acceptable salt and / or solvate thereof administered to a patient provides an average serum concentration of about 50 ng / ml to about 100 ng / ml. In one embodiment, the dose of Norvigovin or a pharmaceutically acceptable salt and / or solvate thereof administered to a patient provides an average serum concentration of less than about 50 ng / ml.

In some embodiments, the serum concentration is less than about 500 milliseconds (ms) during the treatment, while inhibiting or ameliorating symptoms of anxiety disorders, impulse control disorders, anger / violence-related disorders or controlling food intake, Lt; / RTI > In some embodiments, the dose of noribogan phosphorus or a pharmaceutically acceptable salt and / or solvate thereof maintains a QT interval of less than about 450 ms. In some embodiments, the dose of noribogan phosphorus or a pharmaceutically acceptable salt and / or solvate thereof maintains a QT interval of less than about 420 ms.

In some embodiments, the dose of noriboganin or a pharmaceutically acceptable salt and / or solvate thereof provides an extension of the QT interval of less than about 50 ms. In some embodiments, the dose of noriboganin or a pharmaceutically acceptable salt and / or solvate thereof provides an extension of the QT interval of less than about 30 ms. In a preferred embodiment, the dose of noriboganin or a pharmaceutically acceptable salt and / or solvate thereof provides an extension of the QT interval of less than about 20 ms. In a preferred embodiment, the patient is tested to determine the pre-treatment QT interval using Norbogophane, and if the clinician determines that the QT prolongation is at an unacceptable risk, Norbogog's therapy will be prohibited.

In another aspect, the present invention provides a method of treating a condition selected from the group consisting of Norbigae, Norbogogen derivatives, pharmaceutically acceptable salts and / or solvates thereof at a concentration of about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours , About 48 hours, about 72 hours, about 96 hours, or a sustained-release manner to maintain a therapeutically effective amount for a period of time between any two of these durations, the method comprising administering to the patient a derivative of Norbogophane or Norbogophage An impulse control disorder, an anger / violence-related disorder, or a method of controlling food intake in a subject in need of such treatment.

In one aspect, a method of treating anxiety-related disorders, the method comprising administering to the patient a therapeutically effective amount of a norbogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, , Wherein the patient is not intoxicated with cocaine or opiate and a further therapeutically effective amount provides a serum level of efficacious mean Norvir of from about 50 ng / ml to about 180 ng / ml, while about 500 < RTI ID = 0.0 > QT interval less than ㎳.

In one embodiment, the anxiety-related disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and social anxiety disorder.

In one aspect, there is provided herein a method of treating an impulse control disorder in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a norbobene derivative, or a pharmaceutically acceptable salt and / or solvate thereof, A method of treating a disorder is provided wherein the patient is not intoxicated with cocaine or opiate and the further therapeutically effective amount provides a serum level of efficacious mean Norvir of from about 50 ng / ml to about 180 ng / ml, During the treatment, a QT interval of less than about 500 ms is maintained.

In one embodiment, the impulse control disorder is selected from the group consisting of borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder, attention deficit disorder, amnestic disorder, mood disorder, morbidity, morbidity, intermittent explosive disorder, Impulsivity, anxiety, internet addiction, hair growth, pathological skin torture, and compulsive shopping.

In one aspect, there is provided herein a method of treating a disorder or condition in a patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a norbobene derivative, or a pharmaceutically acceptable salt and / or solvate thereof, A method is provided for the modulation and / or attenuation of the appetite, wherein the patient is not addicted to cocaine or opiate, and a further therapeutically effective amount is a serum level of efficacious mean Norvir of from about 50 ng / ml to about 180 ng / While maintaining a QT interval of less than about 500 ms during the treatment.

In one aspect, the present invention provides a method of treating anxiety-related disorders in a patient in need of treatment, comprising administering to the patient a therapeutically effective amount of a norbobene derivative, or a pharmaceutically acceptable salt and / or solvate thereof, A therapeutically effective amount provides a serum level of efficacious mean normobarbital of about 50 ng / ml to about 180 ng / ml, while a QT interval of less than about 500 ms during the treatment is provided Lt; / RTI >

In one embodiment, the method comprises the following steps:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng / ml to about 180 ng / ml; And

b) Wherein the at least one additional dose is at least once an additional dose of norbober to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof, Administering the solvate.

In another embodiment, the initial dose is about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg. In another embodiment, at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further additional doses are administered from about 6 hours to about 24 hours after the previous dose. In another embodiment, the QT interval is less than about 450 ms. In another embodiment, the method further comprises selecting a preselected patient to assess tolerance to prolongation of the QT interval. In another embodiment, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered by sublingual, buccal, intranasal, or intrapulmonary delivery.

Norbogogens induce side effects in some patients. This method is necessary to preselect patients with opioid-addiction to determine the patient ' s tolerability to a therapeutic dose of Norvigans.

Norbygovine is administered to improve acute and post-acute withdrawal symptoms. In particular, the initial testing of Norovigrin therapy by methadone-poisoned patients showed that a single 120 mg dose of Norvigorin provided a generally meaningful therapeutic response whereas a single 60 mg dose of Norviga phosphorus had a generally significant But does not provide a therapeutic response. A single 90 mg dose of Norwegian boson indicates some therapy, but it is an adjuvant treatment for commercial purposes.

Unexpectedly, we found that Norwegian boys behave in a linear pattern on QT interval extension. For example, a double dose of Norwegian boron will cause approximately two times the QT interval extension in patients. As such, QT interval and QT interval extension data obtained from sub-therapeutic doses of less than 120 mg of a Norwegian boron, e.g., from about 90 mg, of the patient ' s tolerance for treatment with therapeutic norborabogue at 120 mg of therapeutic dose Lt; / RTI > This allows the patient to accurately predict the QT interval and QT interval prolongation from the sub-therapeutic dose of less than 120 mg of Norwegian boron without a potentially life-threatening adverse effect on therapeutic dosage of 120 mg Norwegian Bovine It is possible because it can be.

As initially noted above, opioid-poisoned patients treated with 120 mg of Norvigovin represent significantly longer times for re-consumption of opioid alternative therapies than those treated with 60 mg. Patients who received 120 mg of Norvigrin also exhibited a variable QT interval extension with an average extension of approximately 38 milliseconds (ms). Some patients show a QT interval extension of more than 50 ms or a QT interval of more than 500 ms. Patients with QT intervals greater than 500 ms or extended beyond 50 ms are at high risk for ventricular tachycardia and possibly death.

A pre-screening method is provided that predicts whether a patient is eligible for a treatment with Norwegian based on showing an unacceptable QT interval extension or QT interval of 500 milliseconds or more when treated with Norwegian Bone. This method can be used to predict one of either an unacceptable QT interval extension of more than 50 milliseconds or a QT interval of more than 500 milliseconds before the therapeutic dose (120 mg) (Less than 120 mg) for screening for < RTI ID = 0.0 > a < / RTI >

Patient Pre-Screening As will be apparent to those skilled in the art upon reading this disclosure, the present invention provides a method for the treatment or prevention of an opioid-addicted patient, or a treatment or prophylactic treatment as provided herein, in order to determine the patient ' Provides a method of pre-screening other patients who need prevention.

In one aspect, there is provided a pharmaceutical composition comprising an opioid-addicted patient or a subject with a need for treatment or prevention as provided herein, to determine the patient ' s tolerability to a therapeutic dose of Noriboglofen or a pharmaceutically acceptable salt and / There is provided a method of screening a patient, the method comprising the steps of:

Measuring the patient's pre-dose QT interval;

Administering to the patient a sub-therapeutic dose of a norbobene or a pharmaceutically acceptable salt thereof; And

Measuring the QT interval after administration of the patient.

In some embodiments, the method further comprises the following steps:

Determining a difference in QT interval to QT interval after administration to determine a first extension;

Estimating a second prolongation based on a first prolongation, the second prolongation being an estimated QT interval prolongation expected to be observed in the patient at the time of administration of the therapeutic dose of noriboglobin;

Determining the patient ' s tolerability to a therapeutic dose of Norbigovan; And

Administering a therapeutic dose of Norvigovin to the patient or stopping treatment with Norvibol, wherein the therapeutic dose is administered if the second extension is estimated to be less than about 50 msec.

In one embodiment, there is provided a method of screening for an opioid-poisoned patient to determine a patient's tolerability to a therapeutic dose of a norbobene or a pharmaceutically acceptable salt and / or solvate thereof, said method comprising Comprising the steps of:

Measuring a pre-dose QT interval of the patient;

Administering to the patient a sub-therapeutic dose of a norbobene or a pharmaceutically acceptable salt thereof;

Measuring a QT interval after administration of the patient;

Determining a first extension by determining a difference between a pre-administration QT interval and a post-administration QT interval;

Estimating a second prolongation based on a first prolongation, the second prolongation being an estimated QT interval prolongation expected to be observed in the patient at the time of administration of a therapeutic dose of Norbitcine;

Determining the patient ' s tolerability to a therapeutic dose of Norbigovan; And

Administering a therapeutic dose of Norvigovin to the patient or stopping treatment with Norvibol, wherein the therapeutic dose is administered if the second extension is estimated to be less than about 50 msec.

In one embodiment, a therapeutic dose is administered if the second extension is estimated to be less than about 40 ms. In one embodiment, a therapeutic dose is administered if the second extension is estimated to be less than about 30 ms. In one embodiment, a therapeutic dose is administered if the second extension is estimated to be less than about 20 ms. In one embodiment, a therapeutic dose is administered if the second extension is estimated to be less than about 10 ms.

In one embodiment, the therapeutic dose provides an average serum concentration of 50 ng / ml to 180 ng / ml, which inhibits or ameliorates opioid poisoning, while prolonging the QT interval of the patient below the threshold, It is enough to cause 50 ms.

In a preferred embodiment, the therapeutic dose is about 120 mg Norviga. In another embodiment, the therapeutic dose is 70 to 120 mg Norviga. In another embodiment, the therapeutic dose is 100-150 mg Norviga. In another embodiment, the therapeutic dose is greater than 150 mg of Norvigor. In one embodiment, the therapeutic dose is from 1 mg / kg body weight to 4 mg / kg body weight.

In one embodiment, the therapeutic dose is administered in one or more doses, such as one, two, three, four, five or more doses over one or more days.

In one embodiment, the sub-therapeutic dose is administered over one or more doses, such as 1, 2, 3, 4, 5 or more doses.

In one embodiment, the sub-therapeutic doses of Norbogophane may be administered at a dosage of, for example, 80%, 70%, 60%, 50%, 40%, 30% , 20%, or less than 10%, or any lower value or subrange therebetween.

In one embodiment, the sub-therapeutic dose of Noribucogloin is administered in combination with a therapeutically effective amount of a compound selected from the group consisting of, for example, 110 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 10 mg, 5 mg, 2 mg, 1 mg of norbornene, or any lower value or subrange therebetween.

In one embodiment, if the second extension is presumed to be greater than the threshold QT interval extension, the patient is administered a sub-therapeutic dose of Norwegian Bovine.

In one embodiment, if the second extension is presumed to be greater than the threshold QT interval extension, the patient is administered a therapeutic dose of Norbybogan in multiple doses. For example, if the therapeutic dose is 120 mg per day, 60 mg is given every 12 hours. Without being bound by theory, it is believed that multiple administrations reduce QT interval prolongation by lowering the serum concentration of the highest Norwich boron experienced by the patient.

In one embodiment, if the second extension is estimated to be greater than the threshold QT interval extension, the patient is administered an initial dose of Norwegian, followed by one or more additional doses. In one embodiment, the initial dose is 75 mg to 120 mg. In one embodiment, the at least one additional capacity is lower than the initial capacity. In one embodiment, the at least one additional dose is from 5 mg to 50 mg. In one embodiment, such dosing regimens provide an average serum concentration of 50 ng / ml to 180 ng / ml of Norviga. In one embodiment, such dosing regimens provide an average serum concentration of norbobene of between 80 ng / ml and 100 ng / ml. In one embodiment, one or more additional doses maintain an average serum concentration of between 50 ng / ml and 180 ng / ml over a period of time. In one embodiment, one or more additional doses maintain an average serum concentration of 80 ng / ml to 100 ng / ml over a period of time. In one embodiment, one or more additional doses are administered periodically, such as every 4 hours, every 6 hours, every 8 hours, every 12 hours, or every 24 hours.

In one embodiment, the threshold QT interval extension is 50 ms. In one embodiment, the threshold QT interval extension is 40 ms. In one embodiment, the threshold QT interval extension is 30 ms. In one embodiment, the threshold QT interval extension is 20 ms. In one embodiment, the threshold QT interval extension is 10 ms.

In one embodiment, a therapeutically effective amount of Norvigrin is sufficient to provide an average serum concentration of Norviborgins of 50 ng / ml to 180 ng / ml, or 60 ng / ml to 180 ng / ml. In one embodiment, a therapeutically effective amount of Norvigrin is sufficient to provide a mean serum concentration of Norviborgans of 50 ng / ml to 150 ng / ml, or 60 ng / ml to 150 ng / ml. In one embodiment, the therapeutically effective amount of Norbogolin is sufficient to provide a mean serum concentration of Norgiborgone from 50 ng / ml to 100 ng / ml, or 60 ng / ml to 100 ng / ml. In one embodiment, a therapeutically effective amount of Noribucogloin is sufficient to provide an average serum concentration of norbobene of between 80 ng / ml and 100 ng / ml. The range includes both ends, as well as any subranges therebetween.

In one aspect, provided herein is a method for screening opioid-addicted patients to determine a patient's tolerability to a therapeutic dose of a norbobene or pharmaceutically acceptable salt and / or solvate thereof, wherein the method Comprises the steps of:

Measuring a pre-dose QT interval of the patient;

Administering to the patient a sub-therapeutic dose of a norbobene or a pharmaceutically acceptable salt thereof; And

Measuring the QT interval after administration of the patient.

In one embodiment, the method further comprises one or more of the following steps:

Determining a first extension by determining a difference between a pre-administration QT interval and a post-administration QT interval;

Estimating a second prolongation based on a first prolongation, wherein the second prolongation is an estimated QT interval prolongation expected to be observed in the patient at the time of administration of a therapeutic dose of Norbitcine;

Determining the patient ' s tolerability to a therapeutic dose of Norbigovan; And

Administering a therapeutic dose of Norvigovin to the patient, or stopping treatment with Norvibol, wherein the therapeutic dose is administered if the second extension is estimated to be less than about 50 msec.

In another embodiment, the therapeutic dose provides an average serum concentration of 50 ng / ml to 180 ng / ml, which inhibits or ameliorates opioid poisoning while causing an extension of the QT interval in a patient of less than about 50 ms Suffice.

In another embodiment, the method further comprises the following steps:

a) Administering an initial dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / ml to 180 ng / ml; And

b) Wherein the at least one additional dose is at least once an additional dose of norbober to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt or solvate thereof, Administering the solvate.

In another embodiment, the therapeutic dose is administered in one or more dosages. In another embodiment, the sub-therapeutic dose is administered in one or more dosages. In another embodiment, the sub-therapeutic dose is 80% or less of the therapeutic dose. In another embodiment, the sub-therapeutic dose is less than 70% of the therapeutic dose. In another embodiment, the sub-therapeutic dose is from 60 mg to 100 mg. In another embodiment, the sub-therapeutic dose is about 90 mg.

Continuous therapy

In one aspect, the present invention is based on the surprising discovery that treatment with a narrow dosage range of a Norbitogen, a Norbitogor derivative, or a pharmaceutically acceptable salt or solvate thereof provides a therapeutic blood serum concentration in a treated patient do.

In some aspects, the invention provides a method of treating a condition in a patient treatable by a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, while maintaining an acceptable QT interval prolongation in the patient The method comprising the steps of:

comprising the steps of: a) administering to a patient an initial unit dose of a Norbitcogen, a derivative thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the unit dose comprises a therapeutically effective amount of a serum concentration that provides a minimum QT interval prolongation Providing an average serum concentration of 50 ng / ml to 180 ng / ml; And

b) Wherein the at least one additional dose is at least one additional dose of Norviga so as to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml during treatment, or a pharmaceutically acceptable salt or solvate thereof Maintaining said serum concentration, wherein said additional dose or doses continue to be necessary to treat said condition.

In one embodiment, the therapeutic blood serum concentration is from 50 ng / ml to 180 ng / ml. In a preferred embodiment, the therapeutic serum concentration is from 80 ng / ml to 100 ng / ml. In one embodiment, the dose range provides both a treatment outcome in the patient and an acceptable QT interval prolongation of less than 50 milliseconds. In one embodiment, an initial unit dose of a Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof is administered. In one embodiment, the initial unit dose provides a therapeutic blood serum concentration with a minimum QT interval prolongation. In one embodiment, the QT interval is not extended by more than 20 milliseconds.

In some embodiments, the patient is administered one or more additional doses following the initial unit dose of the Norvigor, the Norvigor, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the initial unit dose is from 50 mg to 120 mg. In one embodiment, the at least one additional capacity is lower than the initial capacity. In one embodiment, the at least one additional dose is from 5 mg to 50 mg. In one embodiment, such dosing regimen provides a mean serum concentration of therapeutic norbobene of between 50 ng / ml and 180 ng / ml. In one embodiment, one or more additional doses maintain a therapeutically an average serum concentration of from about 50 ng / ml to about 180 ng / ml over a period of time. In one embodiment, one or more additional doses are administered periodically. In one embodiment, the at least one additional dose is administered from about 6 hours to about 24 hours after administration of the initial unit dose. In one embodiment, the at least one additional dose is administered from about 6 hours to about 24 hours after administration of the previous dose. In one embodiment, one or more doses are administered as a controlled release dosage form.

In one embodiment, the narrow therapeutic doses of the Norovagene, Norbigovan derivatives, or pharmaceutically acceptable salts or solvates thereof described above, unexpectedly extend the QT interval to unacceptable levels in human patients Do not. In some embodiments, the patient may determine, for example, whether the patient has any pre-existing cardiac condition from their treatment from a treatment with a Norwegian patient, in order to assess tolerance to prolongation of the QT interval Will be pre-selected. In some embodiments, the patient undergoes cardiac monitoring during a portion of the treatment. In a preferred embodiment, cardiac monitoring is not required. In one embodiment, the patient is tested to determine the pre-treatment QT interval using Norbogophane, and if the clinician determines that the QT prolongation is at an unacceptable risk, the treatment with Norbogog will be prohibited.

In one aspect, there is provided a method of treating a condition in a patient that can be treated using a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein an acceptable QT interval A method of maintaining an extension is provided, the method comprising the steps of:

a) administering to the patient an initial unit dose of a Norbitogen, a Norbitogor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the unit dose is such that the serum concentration in the patient is at least < RTI ID = 0.0 > ng / ml < / RTI > And

b) Wherein the at least one additional dose is at least one additional dose of Norviga so as to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml during treatment, or a pharmaceutically acceptable salt or solvate thereof ≪ / RTI > periodically,

The additional dose or doses continue if necessary to treat the condition, and the allowable QT interval is not longer than 500 ms.

In one embodiment, the QT interval is extended by less than 50 ms. In another embodiment, the QT interval is extended by less than 20 ms. In another embodiment, the initial unit dose is greater than any at least one additional dose. In another embodiment, the initial unit dose and at least one additional dose are incorporated into a single controlled release formulation. In another embodiment, the initial unit dose is administered as a subunit dose continuously administered until a unit dose level is achieved, wherein the total subunit dose provides an initial unit dose and further provides a therapeutic mean serum concentration do. In another embodiment, the initial unit dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further doses are administered between 6 hours and 24 hours after the additional pre-dose dose. In another embodiment, the method further comprises selecting a preselected, poisoned patient to assess tolerance to prolongation of the QT interval.

In another aspect, there is provided a method of treating a condition in a patient treatable with a Norbitogen, a Norbitogen, or a pharmaceutically acceptable salt or solvate thereof, while maintaining an acceptable QT interval prolongation in the patient , The method comprising the steps of:

a) The method comprising administering to the patient an initial unit dose of a Norbiter, a Norbitogor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the unit dose is selected from the group consisting of a treatment wherein the serum concentration provides a minimum QT interval prolongation Providing an average serum concentration of from about 50 ng / ml to about 180 ng / ml; And

b) Wherein the at least one additional dose is at least one additional dose of Norviga so as to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml during treatment, or a pharmaceutically acceptable salt or solvate thereof ≪ / RTI > wherein said serum concentration is maintained;

The additional dose or doses continue if necessary to treat the condition, and further the allowable QT interval extension is not longer than 50 ms.

In one embodiment, the QT interval extension is less than 20 ms. In another embodiment, the initial unit dose is higher than any at least one additional dose. In another embodiment, the initial unit dose and at least one additional dose are incorporated into a single controlled release dosage form. In another embodiment, the initial unit dose is administered as a subunit dose continuously administered until a unit dose level is achieved, wherein the total subunit dose provides an initial unit dose and further provides a therapeutic average serum concentration . In another embodiment, the initial unit dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further doses are administered between 6 hours and 24 hours after the additional pre-dose dose. In another embodiment, the method further comprises selecting a preselected, poisoned patient to assess tolerance to prolongation of the QT interval.

 In another embodiment, a norbobene or a pharmaceutically acceptable salt and / or solvate thereof is administered.

Formulation

In another aspect, there is provided a pharmaceutically acceptable formulation comprising a unit dose of a Norbitogen, a Norbitogor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the amount of Norbitogorin is administered to the patient Is sufficient to provide a serum concentration of from about 50 ng / ml to about 180 ng / ml when administered. In one embodiment, a unit dose of a Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof is administered in one or more dosages. In another embodiment, the unit dose of a Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof is from about 20 mg to about 120 mg.

Brief Description of the Drawings Figure 1 shows a concentration-time profile with an average Norwich score in healthy subjects after a single oral dose with a 3, 10, 30 or 60 mg dose. Illustration: Individual concentration-time profiles from 0 to 12 hours after 10 mg dose.
Figure 2 shows the glucuronide concentration-time profile with a mean plasma Norwich score in healthy patients after a single oral 30 or 60 mg dose.
Figure 3 shows a concentration-time profile with an average Norwich score in patients with opioid-poisoned after a single oral 60 mg (diamond), 120 mg (square) or 180 mg (triangle) dose of Norvich.
Figure 4 shows the effect of treatment with opioid replacement therapy (OST) on each patient given placebo (circle), or single oral dose of Norvigorn (60 mg, square; 120 mg, triangle; 180 mg, inverted triangle) Fig. The middle horizontal line represents the average. The error bars represent the standard deviation.
Figure 5 shows the treatment results with Norwegian to the final COWS score before re-consumption of the OST; The box contains values representing 25% to 75% quartiles. Diamonds represent the median, and crossbars represent the mean. Whisker represents a value within one standard deviation of the middle-quartile. Abnormal points are not displayed.
6A shows an average change in the total COWS score over the first 6 hours after administration of Norvigor (60 mg, square; 120 mg, triangle; 180 mg, diamond) or placebo (circles). The data is given for the reference COWS score.
FIG. 6B shows the mean curve backprojection (AUC) over the first 6 hour period after administration of Norwich or placebo based on the COWS score data given in FIG. 6A. FIG. Negative changes in scores indicate that withdrawal symptoms have subsided over time.
Figure 7A shows the mean change in total OOWS over the first 6 hours after dosing with Norwegian (60 mg, square; 120 mg, triangle; 180 mg, diamond) or placebo (circle). The data is given for a reference OOWS score.
FIG. 7B shows the mean curve backprojection (AUC) over the first 6 hour period after administration of Norwich or placebo based on the score data given in FIG. 7A. FIG. Negative changes in scores indicate that withdrawal symptoms have subsided over time.
8A is a noreuyi beams (60㎎, square; 120㎎, triangles; 180㎎, diamonds) or after administration of placebo (circle) shows the mean change in total SOWS score over the first 6 hours. The data is given for the reference SOWS score.
Figure 8B shows the mean curve backprojection (AUC) over the first 6 hours after administration of Norwich or placebo based on the SOWS score data given in Figure 8A. Negative changes in scores indicate that withdrawal symptoms have subsided over time.
9A shows an average change in QT interval (QTcl) for each cohort (60 mg, square; 120 mg, triangle; 180 mg, diamond) or placebo (circle) over the first 24 hours after administration.
9B is a graph showing the correlation between the concentration of serum noribody for each patient and ΔQTcl over time. FIG. A straight line expression is given.
Figure 10A illustrates the effects of Noribogyne and Barrenicline in nicotine dependent rats. Data represent mean + standard deviation of mean (SEM). # P &lt;0.10; *** P < 0.001 was compared to vehicle or saline treated groups.
FIG. 10B illustrates the effect of noriboglobin and barrenicin against the percentage of inactive lever press during nicotine self-administration. FIG. Data represent mean + SEM.
Figure 11 shows the effect of Norvigrin on general motor activity of zebrafish during nicotine withdrawal symptoms. The behavioral endpoints tested were: the time to the top half of the tank (panel A), the transition to the top half of the tank (panel B), the transition to the top half of the tank per minute (panel C) (Panel D), time in the upper half of the tank per minute (panel E), average duration of inflow (panel F) and average duration of inflow per minute (panel G).
Figure 12 shows the effect of Norvigrin on general motor activity of zebrafish during nicotine withdrawal. The end point of the test was the moving distance (panel A), velocity (panel B), rotation angle (panel C), number of rotation events (panel D), body / head direction change (panel E) (Panels F and G).
Figure 13 shows the effect of Norwich borne on the frequency of frozen seizure (panel A) and the duration of frozen seizure (panel B and C).
Figure 14 illustrates the effect of treatment with Norviga on migration motility. We used the floating (dark square) to express the frequency of episodes (duration of immobility) by spatial displacement and independent movement. The movement (middle gray square) reflects the overall locomotor activity. High-shift (light gray squares) reflect accelerated swim seizures (individual mean of more than 60%).
Figure 15 shows treatment (top to bottom) with representative trace amounts of chronic nicotine, repeated nicotine withdrawal symptoms (WD), and WD + 1 mg / l of Norbogol, followed by treatment with 5 by Ethovision XT8.5 software Min New Tank Test (NTT).
Figure 16 shows the effect of treatment (in 1-, 5- and 10-mg / l dose) with Norbogh for the general locomotor activity of zebrafish. The behavioral endpoints tested were: the time to the top half of the tank (panel A), the transition to the top half of the tank (panel B), the transition to the top half of the tank per minute (panel C) (Panel D), time in the upper half of the tank per minute (panel E), average inflow duration (panel F) and average inflow duration per minute (panel G).
Figure 17 illustrates the therapeutic effect of Norviga (at 1-, 5- and 10- mg / l dose) on general motility activity of zebrafish. The end point of the test was the moving distance (panel A), velocity (panel B), rotation angle (panel C), number of rotation events (panel D), body / head direction change (panel E) (Panels F and G).
Figure 18 shows the effect of Norvigrin (at 1-, 5- and 10- mg / l dose) on the frequency of freezing seizures (panel A) and the duration of freezing seizures (panel B).
Figure 19 illustrates the therapeutic effect of Norviga on the motility of movement, including the percentage of events per animal (panel A) and duration (panel B). The frequency of episodes (duration of immobility) was expressed by spatial displacement and independent displacement using "floating" (high frequency "HF" or low frequency "LF"). Movement (HF or LF) reflects the frequency of intermediate migraine active episodes. High-shift (HF and LF) reflects accelerated seizures (individual mean of more than 60%).
Figure 20 shows a representative trace amount of control (top row) and Norbybog Phosphate-treated fish (1, 5 and 10 mg / l, from top to bottom) and a 5 minute new tank test with NTT ).

It is to be understood that the invention is not to be limited to the specific embodiments described, but, of course, can vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the invention will be limited only by the accompanying claims.

The detailed description of the invention is divided into various sections only for the sake of the reader's convenience, and the disclosures found in any section may be combined in different sections. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It should be noted that the singular forms used herein and in the appended claims include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "compound" includes a plurality of compounds.

I. Justice

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The following terms as used herein have the following meanings.

The term "about ", when used in the foregoing, includes numerical representations such as, for example, temperature, time, amount, concentration and range, such as 20%, 10%, 5%, 1% And an approximation that may differ by any subrange or subvalue between them. Preferably, the term " about "means that the capacity may differ by +/- 20% when used for capacity. For example, "about 2 mg / kg noribogan" indicates that a dose of 1.6 mg / kg to 2.4 mg / kg of Noribucogloin can be administered to the patient. In another example, about 120 mg per unit dose of Norbovor may indicate that the unit dose may range from 96 mg to 144 mg.

"Administration" refers to the introduction of an agent, such as a Norbigovin, into a patient. Typically, an effective amount is administered, the amount of which can be determined by the treating physician or the like. Any route of administration can be used, such as oral, topical, subcutaneous, peritoneal, intraarterial, inhalation, vaginal, rectal, nasal, intratracheal instillation or drips into the body compartment. Agents, such as Norvigovin, may be administered by direct bloodstream delivery, for example, by sublingual, buccal, intranasal, or intrapulmonary administration.

When used in conjunction with a compound or pharmaceutical composition (and grammatical equivalents), the related terms and phrases "administering" and "administering" refer to the administration of a compound, Refers to an indirect administration which may be administration and / or prescribing the drug. For example, a physician who instructs the patient to self-administer the drug and / or provides the patient with a prescription for the drug is administering the drug to the patient.

"Cyclic administration" or "periodically administered " refers to multiple administration on a daily, weekly or monthly basis. Cyclic administration may also refer to the administration of an agent such as a norbobene phosphate one, two or three times per day. Administration may be through transdermal patches, gums, lozenges, sublingual tablets, intranasal, intrapulmonary, oral or other administration.

"Comprising" or "comprising" is intended to mean that the composition and method include the recited element, but not the exclusion of any other element. &Quot; consisting essentially of " when used to define the compositions and methods, will mean excluding any essential otherwise significant components to the combination for the stated purpose. Accordingly, a composition consisting essentially of an element as defined herein does not substantially affect the basic and novel feature (s) of the claimed invention and does not exclude other materials or steps. "Made" shall mean excluding more components than the minor components of the other components and process steps. The embodiments represented by each of these transition terms are within the scope of the present invention.

As used herein, the term &lt; RTI ID = 0.0 &gt; "Alkyl" refers to monovalent saturated aliphatic hydrocarbon groups having 1 to 12 carbon atoms, 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. The term is intended linear and branched carbon lake as, for example, such as methyl (CH ₃ -), ethyl _{(CH 3 CH 2 -),} n - propyl _{(CH 3 CH 2 CH 2 -} ), isopropyl ((CH ₃ ) ₂ CH-), n - butyl _{(CH 3 CH 2 CH 2 CH} 2 -), isobutyl _{((CH 3) 2 CHCH 2} -), sec - butyl _{((CH 3) (CH 3} CH 2) CH- ), t-comprises a)-butyl ((CH _{3) 3} C-), n-pentyl _{(CH 3 CH 2 CH 2 CH} 2 CH 2 -) , and neopentyl _{((CH 3) 3 CCH 2} . The term "C _x alkyl" refers to an alkyl group having x carbon atoms, where x is an integer, for example, C ₃ refers to an alkyl group having three carbon atoms.

"Alkenyl" means a straight or branched (straight or branched) chain having from 2 to 6 carbon atoms and preferably from 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of vinyl (> C = Lt; / RTI &gt; Such groups are exemplified by, for example, vinyl, allyl and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers.

"Alkynyl" refers to a straight or branched (branched) alkyl group having from 2 to 6 carbon atoms and preferably from 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylene (-C = C-) Monovalent hydrocarbon group. Examples of such alkynyl groups include acetylenic (-C? = CH), and propargyl (-CH ₂ C = CH).

"Substituted alkyl" means an alkyl group substituted with at least one substituent selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, Substituted aryloxy, arylthio, substituted arylthio, carboxyl, ester, (carboxylester) amino, aminosulfonyloxy, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, Substituted cycloalkyl, cycloalkyloxy, cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyl, substituted cycloalkenyl, Substituted alkanoyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, Heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocycleoxy, heterocyclyloxy, heterocyclyloxy, heterocyclyloxy, Reel alkylthio, a substituted heterocyclic thio, nitro, SO ₃ H, substituted sulfonyl, sulfone yloxy, thio-acyl, thiol, alkylthio, and is from 1 to 5, preferably selected from the group consisting of substituted alkylthio Refers to an alkyl group having one to three or more preferably one to two substituents, wherein the substituents are defined herein.

"Substituted alkenyl" means alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy Substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxylester, (carboxylester), aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, Substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkyloxy, cycloalkyloxy, Alkanoyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, Heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocycle, heterocyclyloxy, heterocyclyloxy, heterocyclyloxy, heterocyclyloxy, Reel alkylthio, a substituted heterocyclic thio, nitro, SO ₃ H, substituted sulfonyl, sulfone yloxy, thio-acyl, thiol, alkylthio, and 1-3 substituents selected from the group consisting of substituted alkylthio, and Refers to an alkenyl group preferably having 1 to 2 substituents, wherein the substituents are defined herein, with the proviso that no hydroxy or thiol substitution is attached to the vinyl (unsaturated) carbon atom.

"Substituted alkynyl" means an alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, Substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxylester, (carboxylester), aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, Substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkyloxy, cycloalkyloxy, Alkanoyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, Heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocycle, heterocyclyloxy, heterocyclyloxy, heterocyclyloxy, heterocyclyloxy, Reel alkylthio, a substituted heterocyclic thio, nitro, SO ₃ H, substituted sulfonyl, sulfone yloxy, thio-acyl, thiol, alkylthio, and 1-3 substituents selected from the group consisting of substituted alkylthio, and Refers to an alkynyl group having preferably 1 to 2 substituents, wherein the substituents are defined herein, with the proviso that no hydroxy or thiol substitution is attached to the acetylene carbon atom.

"Alkoxy" refers to an-O-alkyl group, wherein alkyl is defined herein. Alkoxy includes, for example, methoxy, ethoxy, n - propoxy, isopropoxy, n - butoxy, t - butoxy, sec - butoxy and n - pentoxy.

"Substituted alkoxy" refers to an -O- (substituted alkyl) group, wherein substituted alkyl is defined herein.

"Acyl" refers to the groups HC (O) -, alkyl-C (O) -, substituted alkyl-C (O) -, alkenyl- (O) -, substituted alkynyl-C (O) -, cycloalkyl-C (O) -, substituted cycloalkyl- Substituted aryl-C (O) -, heteroaryl-C (O) -, substituted heteroaryl-C (O) -, heterocyclyl Refers to a group -C (O) - and a substituted heterocyclic-C (O) - group, where the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl , Cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are defined herein. Acyl is "acetyl" group CH ₃ C (O) - and a.

"Acylamino" is -NR ³⁸ C (O) alkyl, -NR ³⁸ C (O) substituted alkyl, -NR ³⁸ C (O) cycloalkyl, -NR ³⁸ C (O) cycloalkyl, -NR ³⁸ substituted C (O) cycloalkyl-alkenyl, -NR ³⁸ C (O) alkenyl substituted cycloalkyl-alkenyl, -NR ³⁸ C (O) alkenyl, -NR ³⁸ C (O) substituted Al, -NR ³⁸ C (O) alkynyl, -NR ³⁸ C (O) substituted alkynyl, -NR ³⁸ C (O) aryl, -NR ³⁸ C (O) aryl, -NR ³⁸ C (O) substituted heteroaryl, -NR ³⁸ C ( O) substituted heteroaryl, -NR ³⁸ C (O) heterocyclic and -NR ³⁸ C (O) substituted heterocyclic groups, where R ³⁸ is hydrogen or alkyl and is selected from alkyl, substituted alkyl, alkenyl, Substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclyl, substituted heterocyclyl, The heterocyclic ring is as defined herein.

"Acyloxy" means alkyl-C (O) O-, substituted alkyl-C (O) O-, alkenyl-C (O) O-, substituted alkenyl- Substituted aryl-C (O) O-, cycloalkyl-C (O) O-, substituted alkynyl-C (O) O-, aryl-C (O) O-, cycloalkenyl-C (O) O-, substituted cycloalkenyl-C (O) O-, heteroaryl-C (O) O-, substituted heteroaryl- C (O) O-, heterocyclyl-C (O) O- and substituted heterocyclic-C (O) O- groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein same.

"Amino" refers to the group -NH ₂ .

"Substituted amino" refers to the group -NR ³⁹ R ⁴⁰ wherein R ³⁹ and R ⁴⁰ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO ₂ -alkyl, -SO ₂ -substituted alkyl , -SO ₂ -alkenyl, -SO ₂ -substituted alkenyl, -SO ₂ -cycloalkyl, -SO ₂ -substituted cycloalkyl, -SO ₂ -cycloalkenyl, -SO ₂ -substituted cycloalkenyl , -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl, -SO ₂ -heterocyclic and -SO ₂ -substituted heterocyclic R ³⁹ and R ⁴⁰ are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group with the proviso that R ³⁹ and R ⁴⁰ Are both not hydrogen and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. When R ³⁹ is hydrogen and R ⁴⁰ is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R ³⁹ and R ⁴⁰ are alkyl, the substituted amino group is sometimes referred to herein as a dialkylamino. When referring to mono-substituted amino, it is meant that one of R ³⁹ or R ⁴⁰ is hydrogen, but not both. When referring to disubstituted amino, it means that neither R ³⁹ nor R ⁴⁰ is hydrogen.

Refers to the group -C (O) NR ⁴¹ R ⁴² wherein R ⁴¹ and R ⁴² are ^{independently selected} from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, And R ⁴¹ is independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, And R &lt; ⁴² &gt; are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Alkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

Refers to the group -C (S) NR ⁴¹ R ⁴² wherein R ⁴¹ and R ⁴² are ^{independently selected} from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl , Aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, R ⁴¹ and R ⁴² are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group wherein the alkyl, substituted alkyl, Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Aminocarbonylamino" refers to the group -NR ³⁸ C (O) NR ⁴¹ R ⁴² where R ³⁸ is hydrogen or alkyl and R ⁴¹ and R ⁴² are ^{independently selected} from hydrogen, alkyl, substituted alkyl, alkenyl, Substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclyl, substituted heteroaryl, And R ⁴¹ and R ⁴² are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group wherein the alkyl, substituted alkyl, alkenyl, substituted al Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclyl may be optionally substituted with one or more substituents selected from the group consisting of As defined herein It is as described.

Refers to the group -NR ³⁸ C (S) NR ⁴¹ R ⁴² wherein R ³⁸ is hydrogen or alkyl and R ⁴¹ and R ⁴² are ^{independently selected} from hydrogen, alkyl, substituted alkyl, alkenyl, substituted Substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclyl, substituted heteroaryl, And R ⁴¹ and R ⁴² are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group wherein the alkyl, substituted alkyl, alkenyl, substituted al Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclyl, heterocyclyl, substituted heterocyclyl, heterocyclyl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, substituted heterocyclyl, In the specification, As it described.

"Aminocarbonyloxy" refers to the group -OC (O) NR ⁴¹ R ⁴² wherein R ⁴¹ and R ⁴² are ^{independently selected} from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, , Aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, R ⁴¹ and R ⁴² are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group wherein the alkyl, substituted alkyl, Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Aminosulfonyl" is -SO ₂ NR ⁴¹ R ^42, and refers to the group wherein R ⁴¹ and R ⁴² is hydrogen, alkyl, substituted alkyl, alkenyl, alkenyl substituted alkenyl, alkynyl, substituted alkynyl, aryl, Substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, R ⁴¹ and R ⁴² are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group wherein the alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, Substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Aminosulfonyloxy" refers to the group -O-SO ₂ NR ⁴¹ R ⁴² wherein R ⁴¹ and R ⁴² are ^{independently selected} from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, , Aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, R ⁴¹ and R ⁴² are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group wherein the alkyl, substituted alkyl, Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

Refers to the group -NR ³⁸ -SO ₂ NR ⁴¹ R ⁴² wherein R ³⁸ is hydrogen or alkyl and R ⁴¹ and R ⁴² are ^{independently selected} from hydrogen, alkyl, substituted alkyl, alkenyl, substituted al Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclyl, heterocyclyl, substituted heteroaryl, And R ⁴¹ and R ⁴² are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, In the specification, As it described.

Refers to the group -C (= NR ⁴³ ) NR ⁴¹ R ⁴² wherein R ⁴¹ , R ⁴² and R ⁴³ are ^{independently selected} from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, Substituted heteroaryl, heterocyclic and substituted heterocyclic, wherein the heteroatom is selected from the group consisting of alkyl, alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, And R ⁴¹ and R ⁴² are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic group, wherein the alkyl, substituted alkyl, alkenyl, Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein .

Refers to a monovalent aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) , The condensed ring may or may not be in a direction (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H) The attachment point is an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

"Substituted aryl" means an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, Substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, (Carboxylate) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, substituted cycloalkyloxy, arylthio, substituted arylthio, carboxyl, carboxylester, Substituted cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenyl, substituted cycloalkenyl, substituted cycloalkenyl, substituted cycloalkenyl, Substituted heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heteroaryl, substituted heteroaryl, heteroarylthio, substituted heteroarylthio, substituted heteroarylthio, substituted heteroarylthio, substituted heteroarylthio, substituted heteroarylthio, substituted heteroarylthio, Substituted heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkyl Refers to an aryl group substituted with from 1 to 5, preferably from 1 to 3, or more preferably from 1 to 2 substituents selected from the group consisting of thio, and substituted alkylthio, wherein the substituents are defined herein.

"Aryloxy" refers to an-O-aryl group, wherein aryl is as defined herein and includes, by way of example, phenoxy and naphthoxy.

"Substituted aryloxy" refers to the group -O- (substituted aryl), wherein the substituted aryl is as defined herein.

"Arylthio" refers to an-S-aryl group, wherein aryl is as defined herein.

"Substituted arylthio" refers to the group -S- (substituted aryl), wherein the substituted aryl is as defined herein.

"Carbonyl" refers to divalent -C (O) -, which is equivalent to -C (= O) -.

"Carboxy" or "carboxyl" refers to -COOH or a salt thereof.

"Carboxyl ester" or "carboxy ester" refers to -C (O) O-alkyl, -C (O) O- -C (O) O-alkenyl, -C (O) O-substituted alkynyl, -C (O) O- -C (O) O-substituted cycloalkyl, -C (O) O-cycloalkenyl, -C (O) O-substituted cycloalkenyl, Refers to a group -C (O) O-substituted heteroaryl, -C (O) O-heterocyclyl, and -C (O) O-substituted heterocyclic groups wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, As defined in the specification.

"(Carboxyl ester) amino" is -NR ³⁸ -C (O) O- alkyl, -NR ³⁸ -C (O) O- substituted alkyl, -NR ³⁸ -C (O) O- alkenyl, -NR ³⁸ -C (O) O- substituted alkenyl, -NR ³⁸ -C (O) O- alkynyl, -NR ³⁸ -C (O) O- substituted alkynyl, -NR ³⁸ -C (O) O- aryl, -NR ³⁸ -C (O) O- substituted aryl, -NR ³⁸ -C (O) O- cycloalkyl, -NR ³⁸ -C (O) O- substituted cycloalkyl, -NR ³⁸ -C ( O) O- cycloalkyl-alkenyl, -NR ³⁸ -C (O) O- substituted alkenyl, cycloalkyl, -NR ³⁸ -C (O) O- heteroaryl, -NR ³⁸ -C (O) O- substituted heteroaryl aryl, -NR ³⁸ -C (O) O-, but heterocyclic, and -NR ³⁸ -C (O) O- refers to the group-substituted heterocyclic, R ³⁸ is an alkyl or hydrogen, alkyl, substituted alkyl, alkenyl, Substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclyl, substituted heterocyclyl, The heterocyclic ring is as defined herein.

(O) O-alkyl, -OC (O) O-alkenyl, -OC (O) O-substituted alkenyl, -OC (O) O-alkynyl, -OC (O) O-substituted alkynyl, -OC (O) O- -OC (O) O-substituted cycloalkyl, -OC (O) O-cycloalkenyl, -OC (O) O-substituted cycloalkenyl, (O) O-substituted heteroaryl, -OC (O) O-heterocyclic and -OC (O) O-substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein, As defined.

"Cyano" refers to a -CN group.

"Cycloalkyl" refers to a cyclic alkyl group of 3 to 10 carbon atoms having a single or multicyclic ring, including condensation, bridges, and spirocyclic rings. At least one of the rings may be aryl, heteroaryl or heterocyclic, provided that the point of attachment is through a non-aromatic, non-heterocyclic ring carbon ring ring. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Other examples of cycloalkyl groups include bicyclo [2,2,2,] octane, norbornyl, and spirobicyclo groups such as spiro [4.5] dec-8-yl.

"Cycloalkenyl" refers to a monocyclic or polycyclic ring having 3 to 10 carbon atoms with 1 to 2 sites of a monocyclic or polycyclic ring and having at least one > C = C <cyclic unsaturation and preferably> Refers to non-aromatic cyclic alkyl groups.

"Substituted cycloalkyl" and "substituted cycloalkenyl" are independently selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, Amino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, Substituted arylthio, carboxyl, carboxylate, (carboxylester) amino, (carboxylester) oxy, cyano, cycloalkyl, substituted alkylthio, arylthio, substituted arylthio, Substituted cycloalkyl, cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyl, Substituted heteroaryloxy, heteroaryloxy, heteroaryloxy, heteroaryloxy, heteroaryloxy, substituted heteroaryloxy, heteroaryloxy, cycloalkenyloxy, cycloalkenyloxy, cycloalkenyloxy, cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, Thio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, Refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, haloalkoxy, alkylthio, alkylthio, alkylthio, alkylthio, Are defined herein.

"Cycloalkyloxy" refers to-O-cycloalkyl.

"Substituted cycloalkyloxy" refers to-O- (substituted cycloalkyl).

"Cycloalkylthio" refers to-S-cycloalkyl.

"Substituted cycloalkylthio" refers to -S- (substituted cycloalkyl).

"Cycloalkenyloxy" refers to-O-cycloalkenyl.

"Substituted cycloalkenyloxy" refers to-O- (substituted cycloalkenyl).

"Cycloalkenylthio" refers to-S-cycloalkenyl.

"Substituted cycloalkenylthio" refers to -S- (substituted cycloalkenyl).

"Guanidino" refers to the group -NHC (= NH) NH ₂ .

"Substituted guanidino" refers to -NR ⁴⁴ C (= NR ⁴⁴ ) N (R ⁴⁴ ) ₂ wherein each R ⁴⁴ is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, Two R ⁴⁴ groups attached to a common guanidino nitrogen atom are optionally joined together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic ring optionally substituted with one or more heteroatoms selected from the group consisting of substituted heteroaryl, heterocyclic and substituted heterocyclic, , With the proviso that at least one R ⁴⁴ is not hydrogen and the substituents are as defined herein.

"Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.

"Haloalkyl" refers to an alkyl group substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are as defined herein.

"Haloalkoxy" refers to an alkoxy group substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, with alkoxy and halo as defined herein.

"Haloalkylthio" refers to an alkylthio group substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkylthio and halo are as defined herein.

"Hydroxy" or "hydroxyl" refers to an -OH group.

"Heteroaryl" refers to an aromatic group of 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring, with 1 to 10 carbon atoms. Such a heteroaryl group may have a single ring (e.g., pyridyl, pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl), wherein the condensed rings may or may not be aromatic And / or contain heteroatoms, provided that the point of attachment is through the atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atom (s) of the heteroaryl group is optionally oxidized to provide an N-oxide (N? O), sulfinyl and / or sulfonyl moiety. Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl and furanyl.

"Substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents as defined for the substituted aryl do.

"Heteroaryloxy" refers to-O-heteroaryl.

"Substituted heteroaryloxy" refers to the group -O- (substituted heteroaryl).

"Heteroarylthio" refers to the-S-heteroaryl group.

"Substituted heteroarylthio" refers to the group -S- (substituted heteroaryl).

"Heterocycle" or "heterocyclyl" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, but not aromatic, group of 1 to 10 ring carbon atoms and nitrogen, &Lt; / RTI &gt; wherein R &lt; 1 &gt; Heterocycles include single rings or polycondensation rings including condensed bridges and spirocyclic rings. In the condensed ring system, at least one of the rings may be cycloalkyl, aryl or heteroaryl, provided that the point of attachment is through a non-aromatic heterocyclic ring. In one embodiment, the nitrogen and / or sulfur atom (s) of the heterocyclic group is optionally oxidized to provide an N-oxide, sulfinyl, and / or sulfonyl moiety.

"Substituted heterocyclyl" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to heterocyclyl substituted with one to five or preferably one to three of the same substituents as defined for substituted cycloalkyl Lt; / RTI &gt;

"Heterocyclyloxy" refers to the-O-heterocyclyl group.

"Substituted heterocyclyloxy" refers to the group -O- (substituted heterocyclyl).

"Heterocyclylthio" refers to the-S-heterocyclyl group.

"Substituted heterocyclylthio" refers to the group -S- (substituted heterocyclyl).

Examples of heterocycles and heteroaryls include azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine , Isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, cobolin, phenanthridine, acridine, phenanthroline, isothiazole, phenanthrene Imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4, , 5,6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholine ), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine and tetrahydrofuranyl.

"Nitro" refers to the -NO ₂ group.

"Oxo" is atom (= O) or (--O ^-) refers to.

"Spirocyclic" refers to bicyclic ring systems having a single ring carbon atom common to both rings.

"Sulfonyl" refers to the divalent group -S (O) ₂ -.

A "substituted sulfonyl" is -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO-substituted ₂ -alkenyl, -SO ₂ - alkenyl, -SO _{2-substituted-cycloalkyl,} -SO _{2-substituted} Cycloalkyl, -SO ₂ -cycloalkenyl, -SO ₂ -substituted cycloalkenyl, -SO ₂ -aryl, -SO ₂ -substituted aryl, -SO ₂ -heteroaryl, -SO ₂ -substituted heteroaryl , -SO ₂ - heterocyclic, -SO ₂ -, but refers to the group-substituted heterocyclic, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, Cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. Substituted sulfonic work methyl -SO ₂ - includes group such as -, phenyl -SO ₂ - and -SO ₂ 4-methylphenyl. The term "alkylsulfonyl" is -SO ₂ - refers to an alkyl group. The term "haloalkylsulfonyl" refers to -SO ₂ -haloalkyl, wherein haloalkyl is defined herein. Refers to -NH (substituted sulfonyl), and the term "(substituted sulfonyl) aminocarbonyl" refers to -C (O) NH (substituted sulfonyl) With the proviso that the substituted sulfonyl is as defined herein.

"Sulfonyloxy" refers to -OSO ₂ -alkyl, -OSO ₂ -substituted alkyl, -OSO ₂ -alkenyl, -OSO ₂ -substituted alkenyl, -OSO ₂ -cycloalkyl, -OSO ₂ -substituted cyclo alkyl, -OSO ₂ - cyclo-alkenyl, -OSO ₂ - substituted cycloalkyl-alkenyl, -OSO ₂ - aryl, -OSO ₂ - substituted aryl, -OSO ₂ - heteroaryl, -OSO ₂ - substituted heteroaryl, -OSO ₂ - heterocyclic, -OSO ₂ - substituted heterocyclic ring, but refers to a dish, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, Substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Thioacyl" refers to the group consisting of HC (S) -, alkyl-C (S) -, substituted alkyl-C (S) (S) -, substituted alkynyl-C (S) -, cycloalkyl-C (S) -, substituted cycloalkyl- Substituted aryl-C (S) -, heteroaryl-C (S) -, substituted heteroaryl-C (S) Refers to a cyclic-C (S) - and a substituted heterocyclic-C (S) - group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cyclo Alkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

"Thiol " refers to a-SH group.

"Thiocarbonyl" refers to the divalent group -C (S) -, which is equivalent to -C (= S) -.

"Thion" refers to an atom (= S).

"Alkylthio" refers to an-S-alkyl group, wherein alkyl is as defined herein.

"Substituted alkylthio" refers to the group -S- (substituted alkyl), wherein substituted alkyl is as defined herein.

&Quot; Compound "or" compounds ", as used herein, are meant to include stereoisomers and tautomers of the indicated formulas.

"Stereoisomers" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereogenic centers. Stereoisomers include enantiomers and diastereomers.

"Tautomeric" is intended to encompass compounds of alternate forms in which the positions of the proton are different, such as enol-keto and imine-enamine tautomers or ring-NH-moieties and ring- Quot; refers to a tautomeric form of a heteroaryl group containing a ring atom attached to a benzene ring, a thiazole ring, a thiazole ring, a thiazole ring, a thiazole ring, a thiazole ring,

The term "phosphate ester ", as used herein, refers to any one of mono-, di-, or triphosphate esters of the Norbiggan phosphorus mono-, di- or triphosphate ester moiety, Of the 12-hydroxy group and / or the indole nitrogen.

The term "phosphate ester ", as used herein, refers to any one of mono-, di-, or triphosphate esters of the Norbiggan phosphorus mono-, di- or triphosphate ester moiety, Of the 12-hydroxy group and / or the indole nitrogen.

As used herein, the term "monophosphate" refers to the group -P (O) (OH) ₂ .

As used herein, the term "phosphate" refers to the group -P (O) (OH) -OP (O) (OH) ₂ .

The term "triphosphate " as used herein refers to the group -P (O) (OH) - (OP (O) (OH)) ₂ OH.

, The term "ester" as used herein, it is one-or triphosphate that due to refer to esters of a base, of an ester phosphate can be represented by the formula ^{-P (O) (OR 45)} 2 -, a , Wherein each R ⁴⁵ is independently hydrogen, C ₁ -C ₁₂ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 1 to 10 carbon atoms, and oxygen, nitrogen and sulfur Heteroaryl of 1 to 4 optionally oxidized heteroatoms selected from the group consisting of &lt; RTI ID = 0.0 &gt; R &lt; / ^RTI &gt; Likewise, exemplary esters of di- or triphosphates have the formula -P (O) (OR ⁴⁵ ) -OP (O) (OR ⁴⁵ ) ₂ and -P (O) (OR ⁴⁵ ) ⁴⁵ )) ₂ OR ⁴⁵ , wherein R ⁴⁵ is as defined above.

As used herein, the term "hydrolyzable group" refers to a group that can be hydrolyzed to liberate a free hydroxy group under hydrolysis conditions. Examples of hydrolyzable groups include, but are not limited to, those defined for R above. Preferred hydrolyzable groups include carboxyl esters, phosphates and phosphate esters. Hydrolysis can be carried out by chemical reaction conditions such as base hydrolysis or acid hydrolysis, or can be done in vivo by being catalyzed by biological processes, such as phosphatase. Non-limiting examples of hydrolyzable groups include ester linkers (-C (O) O- or -OC (O) -), amide linkers (-C (O) NR ^46- or -NR ⁴⁶ C (O) (OR ⁴⁶ ) -O-, -OP (S) (OR ⁴⁶ ) -O-, -OP (S) (SR ⁴⁶ ) -O-, -SP ^{) (OR 46) -O-, -OP} (O) (OR 46) -S-, -SP (O) (OR 46) -S-, -OP (S) (OR 46) -S-, -SP ^{(S) (OR 46) -O-} , -OP (O) (R 46) -O-, -OP (S) (R 46) -O-, -SP (O) (R 46) -O-, ^{-SP (S) (R 46)} -O-, -SP (O) (R 46) includes an associated and -S-, or ^{-OP (S) (R 46)} -S-), wherein R ⁴⁶ is hydrogen Or alkyl.

As described above, The substituted groups do not include polymers obtained by an infinite chain of substituted groups. At most, any substituted group may be substituted up to 5 times.

"Norbiggan" refers to the following compounds as well as to derivatives thereof, or pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof:

It is to be understood that the term "norbornene " is referred to herein, and that at least one polymorph of norbornene can be used and assumed. In some embodiments, the Norwegian phosphorus is a glucuronide of Norwegian.

Norbigovine can be prepared by demethylation of naturally occurring ibocaine:

It is isolated from Tabernanth iboga , a shrub in West Africa. Demethylation can be accomplished by conventional techniques such as conventional tablets followed by reaction with boron tribromide / methylene chloride at room temperature. See, for example, Huffman, et al., J. Org. Chem. 50: 1460 (1985). Norbyborgins are described, for example, in U.S. Patent Nos. 2013/0165647, 2013/0303756 and 2012/0253037, International Patent Publication WO 2013/040471 (including the description of the manufacture of polymorphs of Norbig) , And U.S. Patent Application No. 13 / 593,454, each of which is incorporated herein by reference in its entirety.

"Norbigovane derivatives" refers, without limitation, to esters or O -carbamates of norbornene, or their respective pharmaceutically acceptable salts and / or solvates. Also included within the present invention are derivatives of Norbiggan which serve as prodrugs of Noribogane. Prodrugs are pharmaceutical substances that are administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolized in vivo into the active metabolite. Norbigovane derivatives include, without limitation, those described in U.S. Patent Nos. 6,348,456 and 8,362,007; As well as U.S. Patent Application No. 13 / 165,626; And U.S. Patent Application Publication No. 2013/0131046; U.S. Patent No. 2013/0165647; U.S. Patent No. 2013/0165425; And corresponding compounds set forth in U.S. Patent No. 2013/0165414; All of which are incorporated herein by reference. Non-limiting examples of derivatives of norbornene that are included by the present invention are provided in more detail in the "Composition" section below.

In some embodiments, the method of the present disclosure details the administration of a prodrug of a Norwegian bovine to provide serum levels that are the desired maximum serum concentration and efficacious mean Norwich score. The prodrug of Norwegian boron refers to a compound that metabolizes in vivo Norviga phosphorus. In some embodiments, the prodrug is selected such that it is readily cleavable by a truncated link arm or by cleavage of the prodrug entity so that the Norviga is produced in vivo. In one preferred embodiment, the prodrug moiety facilitates binding to the mu and / or kappa receptors in the brain by facilitating passage across the blood brain barrier or by targeting brain receptors other than mu and / or kappa receptors . An example of a Norwegian prodrug is provided in U.S. Patent Application No. 13 / 165,626, the disclosure of which is incorporated herein by reference.

The present invention is not limited to any particular chemical form of the Norvigene or Norviga derivative, and the drug may be provided to the patient as a free base, as a solvate or as a pharmaceutically acceptable acid addition salt. In the latter case, hydrochloride is generally preferred, but other salts derived from organic or inorganic acids may also be used. Examples of such acids include, but are not limited to those described below as "pharmaceutically acceptable salts" and the like.

"Pharmaceutically acceptable composition" refers to a composition suitable for administration to a mammal, preferably a human. Such compositions include various excipients, diluents, carriers, and other inert agents well known to those skilled in the art.

"Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt comprising a pharmaceutically acceptable partial salt of a compound, which salt is derived from a variety of organic and inorganic counter-ions well known in the art, By way of example only, mention may be made of the hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, phosphoric, nitric, perchloric, acetic, tartaric, lactic, succinic, citric, malic, maleic, aconitic, salicylic, Sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like when the molecule contains an acidic functional group.

&Quot; Pharmaceutically acceptable solvate "or" hydrate "of the present invention means a solvate or hydrate complex that is pharmaceutically acceptable and has the desired pharmaceutical activity of the parent compound, and includes one or more solvent or water molecules, Or from 1 to about 100, or from 1 to about 10, or from 1 to about 2, 3, or 4 solvent or water molecules, and a compound of the present invention.

The term "solvate " as used herein is taken to mean a solid form of a compound that forms a crystal with one or more molecules of an internally entrapped solvent. Some solvates which can be used to produce a solvate such as a pharmaceutically acceptable solvate include water, methanol, ethanol, isopropanol, butanol, generally C ₁ -C ₆ alcohol (and optionally substituted), tetra But are not limited to, hydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, water and solvent mixtures thereof. Other such biocompatible solvents that can assist in preparing pharmaceutically acceptable solvates are well known in the art and are applicable to the present invention. In addition, various organic and inorganic acids and bases may be added, or even used alone as a solvent to produce the desired solvate. Such acids and bases are known in the art. When the solvent is water, the solvate may be referred to as a hydrate. In addition, by remaining in the atmosphere or recrystallizing, the compounds of the invention can absorb moisture and the present invention can include one or more water molecules in the crystals formed, and thus become hydrates. Even when such hydrates are formed, they are included in the term "solvate &quot;. Solvates are also meant to include such compositions when other compounds or complexes are co-crystallized with the compound of interest. The term "solvate" as used herein refers to a complex with a solvent in which the norbornene is reacted or in which the norbigene is precipitated or crystallized. For example, a complex with water is known as "hydrate &quot;. The solvates of the norbornene are within the scope of the present invention. It will be appreciated by those skilled in the art of organic chemistry that a plurality of organic compounds may exist in more than one crystalline form. For example, the crystalline form may vary based on the solvate employed. Thus, all crystalline forms of norbobene or a pharmaceutically acceptable solvate thereof are within the scope of the present invention.

A "therapeutically effective amount" or "therapeutic amount ", when administered to a patient suffering from a condition, is an amount sufficient to achieve the intended therapeutic effect, e. G., To alleviate, ameliorate, alleviate or eliminate one or more symptoms of the condition Or the amount of the agent. The therapeutically effective amount will vary depending on the subject and the condition being treated, the body weight and age of the subject, the severity of the condition, the salt, solvate or derivative of the active drug moiety selected, the particular composition or excipient selected, the subsequent dosage regimen, All of which can be readily determined by those skilled in the art. A complete therapeutic effect is not necessarily caused by the administration of one dose, but may only occur after administration of a series of doses. Thus, a therapeutically effective amount can be administered in one or more administrations. For example, without limitation, a therapeutically effective amount of a noribogan is administered for at least 2 hours beyond the control (placebo), for at least about 5 hours beyond the control, and preferably during the treatment of the opioid- Refers to the amount of the norbornene that attenuates the dependence and / or symptoms of acute withdrawal symptoms for at least 10 hours. For example, without limitation, a therapeutically effective amount of an agent, such as a Norbitogorin, may be used to treat and / or ameliorate dependence and / or to provide statistically significant risk of relapse of nicotine use Refers to the amount of the formulation. For example, without limitation, a therapeutically effective amount of a Norvigagen may be administered for at least 2 hours beyond the control (placebo), at least about 5 hours beyond the control, and preferably at least 10 hours beyond the control Quot; refers to the amount of the norbornene that attenuates the dependence and / or symptoms of acute withdrawal symptoms over time. For example, without limitation, a therapeutically effective amount of a norbobigain may be administered for at least 2 hours beyond the control (placebo), at least about 5 hours beyond the control, and preferably at least 10 hours beyond the control Quot; refers to the amount of the norbornene that attenuates the dependence and / or symptoms of acute withdrawal symptoms over time. For example, without limitation, a therapeutically effective amount of Norbiggan refers to an amount of Norbigovin that re-sensitizes a patient to an opioid analgesic regimen in connection with controlling opioid analgesic tolerance.

The therapeutically effective amount of the compound may be higher or lower depending on the route of administration employed. For example, when direct blood administration (e. G., Sublingual, pulmonary and intranasal delivery) is used, lower doses of the compound may be administered. In one aspect, the therapeutically effective amount of the norbornene or derivative is from about 50 ng to less than 100 μg / kg body weight. When other routes of administration are used, higher doses of the compound may be administered. In one embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 8 mg / kg body weight per day.

"Therapeutic level" of a drug is sufficient to treat the symptoms of a disease or disorder or disease or disorder, or to treat, prevent, or attenuate the symptoms of the disease or disorder or disease or disorder, The amount of the derivative or its pharmaceutical salt or solvate of the norbornene which is not sufficiently high enough to be raised. The therapeutic level of the drug may be determined by testing to determine the actual concentration of the compound in the blood of the patient. This concentration is referred to as "serum concentration ". When the serum concentration of the norbornene is mentioned, it is to be understood that the term "noribogain" includes any form of the noribogain containing a derivative.

The "sub-therapeutic level" of the norbobene or its pharmaceutical salts and / or solvates is less than the therapeutic levels described above. For example, the sub-therapeutic level of the Norvigor phosphorus may be 80% of a therapeutically effective amount (e.g., 120 mg) of any lower value or subrange, for example, 70%, 60%, 50%, 40%, 30%, 20% or less than 10%. The sub-therapeutic level of the norbornene phosphorus is consistent with the "retention capacity" of the norbornene which is less than the therapeutically effective amount which provides some attenuation and / or prevention of post-acute withdrawal symptoms in the patient. The maintenance dose of the compound is expected to be less than the therapeutically effective dose since the level of inhibition need not be elevated in patients who are no longer physically addicted to the opioid or opioid-like drug.

A "prophylactically effective amount " of a drug, as defined herein, is an amount that is typically less than a therapeutically effective amount to provide for the attenuation and / or prevention of the disease or disorder or symptoms of the disease or disorder in the patient. For example, a prophylactically effective amount of a compound is such that the level of inhibition does not need to be elevated in a patient who no longer has the disease or disorder or the symptoms of the disease or disorder (e.g., is no longer physically addicted to nicotine) And therefore is expected to be less than a therapeutically effective amount. For example, a prophylactically effective amount is preferably less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% of the therapeutically effective amount. However, a prophylactically effective amount may be equal to a therapeutically effective amount, for example, when a patient physically poisoned with nicotine is administered a norfubgerine to weaken craving for a period of time when nicotine use is not feasible . A prophylactically effective amount may vary for different diseases or disorders or for the symptoms of different diseases or disorders.

A "retention dose" of a drug or agent as defined herein is typically an amount less than a therapeutically effective amount that provides attenuation and / or prevention of the syndrome, disease or disorder or symptom of the disease or disorder in the patient. The maintenance dose of the compound is expected to be less than the therapeutically effective dose since the level of inhibition does not need to be elevated in patients in whom the disease or disorder or the symptoms of the disease or disorder are no longer physically present. For example, the sustained release preferably amounts to at least 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% It is a subrange.

The terms " treating ", "treating" and "treating" refer to the treatment of a disease, disorder, or condition by an agent, such as a norebgen, to reduce or ameliorate the harmful or any other unwanted effect , &Lt; / RTI &gt; a disorder or condition. "Treatment ", as used herein, encompasses the treatment of a human patient and includes (a) reducing the risk of a condition in a patient determined to be predisposed to the condition but not yet diagnosed as having the condition; Delaying the onset of the condition, and / or (c) eliminating the condition, i. E., Inhibiting the condition and / or eliminating one or more symptoms of the condition. &Quot; Treating "or" treating "a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results, such as symptom reduction. For the purposes of the present invention, beneficial or desired outcomes include nicotine addiction treatment; Prevention, and / or attenuation of craving for nicotine; And prevention of recurrence of nicotine use. This includes reducing or eliminating smoking in the patient and / or reducing or eliminating withdrawal symptoms, craving, and the like. For some purposes of the present invention, beneficial or desired clinical results include treatment of substance addiction; Treatment, prevention and / or attenuation of acute withdrawal symptoms; Treatment, prevention and / or attenuation of prolonged (post-acute) withdrawal symptoms; And prevention of recurrence of substance use. For the purposes of certain aspects of the present invention, beneficial or desired clinical outcomes include classification of pain relief and pain in all categories; Treatment, mitigation and / or prevention of acute and / or chronic pain; Treatment, alleviation and / or prevention of skin, bodily, visceral and / or neurogenic pain; And prevention of recurrence of long-term pain.

As used herein, the term "patient" refers to mammals and includes human and non-human mammals.

As used herein, the term "opiate " refers to a naturally occurring alkaloid found in poppy. These include codeine, morphine, orifibin, pseudomorphine, and tebine. Also included are opium, poppy, poppy straw and their extracts and concentrates.

As used herein, the term "opioid" refers to naturally occurring opiate and synthetic or semisynthetic opioids with psychotropic effects. Non-limiting examples include, but are not limited to, acetyl-alpha-methylpentanyl, acetylmetallol, alpentanyl, allylprodine, alpha-cetylmetatol, alpha metadol, alpha-methylpentanyl, alpha-methylthiopentanyl, Beta-hydroxypentanyl, beta-hydroxypentanyl, beta-hydroxypentanyl, beta-hydroxypentanyl, beta-hydroxypentanyl, beta-hydroxypentanyl, But are not limited to, but not limited to, hydroxy-3-methylpentanyl, betameprodine, betametallone, betafodine, benzisuramide, buprenolpine, butorphanol, carpentanyl, clonitazene, codeine, desomorphin, dextromora Diethanolamine, dimethoxyethane, dimethoxyethane, dimethoxyethane, dimethoxyethane, dimethoxyethane, dimethoxyethane, dimethoxyethane, dimethoxyethane, dimethoxyethane, dimethoxyethane, - thiambutene, dioxaphetyl butyrate, diphenoxylate But are not limited to, ethoxycinnamic acid, succinic acid, succinic acid, succinic acid, succinic acid, succinic acid, succinic acid, succinic acid, But are not limited to, lactose, morpholine, hydroxyphetidine, isomethadone, ketobemidone, levo-alpha-cetylmethanole, levomethorphan, levorphanol, levophenacylmorphan, levomoramide, rofentanil, Methylpiperidine, methadzinol, metazocine, methadone, 3-methylpentanyl, 3-methylthiopentanyl, methopone, morphine, morpyridine, MPPP (1-methyl- Dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, dexamethasone, (1 - (- 2-pentyl) -4-phenyl-4-acetoxypiperidine), pentazocine, phenadoxine, penamycin A prodrug thereof, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, A salt of any of the foregoing, any of the foregoing, or a mixture of any of the foregoing, or a salt of any of the foregoing. Derivatives and the like. The term opioid may also be selected from the group consisting of 4-cyano-2-dimethylamino-4,4-diphenylbutane, 2-methyl-3-morpholino-1,1-diphenylpropane- Methyl-4-phenylpiperidine, ethyl-4-phenylpiperidine-4-carboxylate and 1-methyl-4-phenylpiperidine-4-carboxylic acid. Many opioids are Schedule I or Schedule II drugs in the United States. Specific preferred examples of opioids include, without limitation, buprenorphine, codeine, heroin, hydrocodone, oxycodone, morphine, tbain and derivatives thereof, which will be well known to those skilled in the art.

As used herein, the term "opioid-like drug" refers to any inducing drug that binds to one or more opioid receptors and causes opioid-like poisoning. Acute and prolonged withdrawal symptoms from discontinuation of these medications may be similar to withdrawal symptoms from the interruption of opioids. Opioid-like drugs include amphetamine, methamphetamine, ketamine, and cocaine.

As used herein, the term "QT interval" refers to the time measurement between the beginning of a Q wave and the end of a T wave in the electrical cycle of the heart. An extension of the QT interval refers to an increase in the QT interval.

The term "addicted "," abuse ", and "dependency ", as used herein, refers to an opioid or opioid-like drug, nicotine, alcohol, Quot; is used interchangeably to refer to the inability of the patient to stop using the &lt; / RTI &gt; The DSMIV-TR criteria for dependence include:

Dependent or significant disability or suffering caused by more than three of the following during a 12-month period:

One. A markedly reduced efficacy by tolerance of the substance or by the continued use of a significantly increased amount or the same amount of material to achieve the desired effect;

2. The use of certain substances to avoid withdrawal symptoms or withdrawal symptoms;

3. The use of substances that are larger or longer than intended;

4. Sustained or unsuccessful efforts to reduce or control substance use;

5. The involvement of chronic behavior to obtain a substance, use a substance, or restore its effect;

6. Reduction or abandonment of social, occupational or leisure activities resulting from the use of materials;

7. Use of a substance, even if there is a continuing or recurrent physical or psychological problem that may be caused or exacerbated by the substance.

As used herein, the term "nicotine addicted to remission" refers to any patient who ceases to use nicotine for a period of time. As used herein, a remission nicotine addict may be administered in any form including, but not limited to, a cigarette, an electronic cigarette or a vaporizer ("biping"), a chewing tobacco, a cigar, a snort, a pipe, And any person previously poisoned with nicotine. The nicotine addict with remission stops using nicotine, so the time may be short, for example from one day to a few days or longer, for example months or years. Preferably, the patient ceases using nicotine long enough that the physical symptoms of nicotine addiction are no longer present. Patients may exhibit psychological symptoms of nicotine addiction. In some embodiments, the patient does not exhibit psychological symptoms of nicotine addiction.

The terms "addictive substance "," drug ", "addictive drug ", and the like, as used herein, refer to drugs and other substances that cause addiction in at least a subset of the individuals using them. The addictive substance may be selected from the group consisting of benzodiazepines (chlorodiazepoxide, chlorazepate, diazepam, flurazepam, halazepam, prazemph, lorazepam, lorometazepam, oxazepam, themejempam, clonazepam, Naproxenimide and synthetic cannabinoids, stimulants (such as amphetamine, methylphenylacetamid, ampicillin, ampicillin, ampicillin, But are not limited to, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, methionine, dodecylphenidate, dextromethorphanamine, dextromethamine, mixed amphetamine salts, dextromethamphetamine, lysedecamphetamine, modafinil, adapinyl, Aminobutyronitrile, aminobutyric acid, pyro-valerone, mephedron, phenylpropanolamine, propylhexadrine, pseudoephedrine and khat), barbiturates Such as gamma-hydroxybutyrate (GHB), ketamine, opiate, opioid, opioid-like drug, PCP, dextrose (including but not limited to penal, barbiturate, bralovarbital, pentobarbital, phenobarbital and secobarbital) But are not limited to, methorine (DXM), lysergic diethylamide (LSD), mescaline, anabolic steroids, and derivatives of each of these. Addictive substances can be illegal drugs, prescription drugs that tend to abuse, or legitimate drugs that tend to abuse.

Obsessive-compulsive disorder (OCD) refers to repetitive and persistent thoughts, thoughts, and impulsions that are ego-dystonic and / or repetitive, purposeful, and intentional (coercive) Or image (obsession) (American Psychiatric Association, 1994a). Compulsive or impulsive causes significant pain, and is time-consuming and / or significantly hinders social or direct function.

Panic disorder is characterized by an unexpected panic attack recurring and related worries about additional seizures, worries about the effects or consequences of seizures, and / or significant changes in behavior related to seizures (American Psychiatric Association, 1994a). Panic attacks are defined as a discontinuous period of intense fear or anxiety, in which 4 (or more) of the following symptoms occur suddenly and reach a peak within 10 minutes: (1) palpitations, heart beats or accelerated heart rate; (2) sweating; (3) trembling or agitation; (4) feeling of choking or choking; (5) a feeling of choking; (6) chest pain or discomfort; (7) zone or abdominal pain; (8) dizziness, instability, feeling of slight dizziness or stunning; (9) loss of realism (impractical feeling) or self-confidence (feeling separated from oneself); (10) fear of loss of self-control; (11) fear of death; (12) sensory abnormality (numbness or numbness); (13) Chills or fever. Panic disorder may or may not be associated with agoraphobia or irrational and often with a disability fear of being in the presence of a person.

Social anxiety disorders, referred to as social phobia, are characterized by a marked and persistent fear of one or more social or performance situations that are exposed to as rigorous investigations as possible by persons not familiar with the individual or by others (American Psychiatric Association, 1994a). Exposure to a fearful situation almost invariably leads to anxiety, which can approximate the intensity of a panic attack. Dreadful situations can be avoided or lead to long periods of strong anxiety or suffering. The avoidance of fearful situation (s), the distress of an anticipated or fearful situation (s) has significant distress about the normal routine, occupational or academic functioning of a person or social activity or relationship, or having phobia . Fewer performance anxiety or shyness generally does not require psychopharmacological treatment.

Generalized anxiety disorders are characterized by excessive anxiety and worry (worrying expectation) that persist for at least 6 months and are difficult for individuals to control (American Psychiatric Association, 1994a). It should be associated with at least three of the following six symptoms: unsettling or feeling tense or restless, easily fatigued, difficulty concentrating or emptying the pubes, inability, muscle tension and sleeping disorders. Diagnostic criteria for this disorder are described in further detail in DSM-IV, incorporated herein by reference (American Psychiatric Association, 1994a).

Impulse control disorders are a class of psychiatric disorders involving disability in resisting temptation, desire or impulse (impulsivity), where such impulses are potentially harmful to the patient and / or others. DSM-5 (May 2013) of the American Psychiatric Association includes impulse control disorders characterized by the problem of emotional and behavioral self-regulation. These include, but are not limited to, borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), asthma, mood disorder, morbidity, morbidity, intermittent explosive disorder, pathological wall, sexual impulse, , Morbid skin tearing and obsessive shopping. Impulse control disorders can be associated with anxiety disorders and / or OCD.

Violence and anger are associated with a large number of mental disorders, especially when they are in excess of the consequences of irritation and / or pathological anger. These include regurgitant disorders, attention deficit / hyperactivity disorder and behavioral disorders (in children and adults), psychotic disorders, bipolar disorders, antisocial, borderline, paranoid and narcissistic personality disorders, concomitant disorders with concomitant disorders and intermittent explosive disorders do. Pathological anger and violence constitute a significant part of the range of violence, including many eye-catching crimes involving multiple victims. Highly anxious individuals are overrepresented in the US prison system.

As used herein, the term "pain" refers to all categories and categories of pain summarized below for illustrative purposes. First, skin pain is caused by damage to the skin or epidermal tissue. Skin invasive receptors terminate just below the skin and produce a well defined, localized pain of short duration due to the high concentration of nerve endings. Exemplary impairments that cause skin sores include scarring, weak burns (e.g., 1 degree burns), and shallow laceration.

Second, the somatization tube is derived from the ligaments, tendons, bones, blood vessels and even the nerves of its own, and is detected by somatization receptors. In this area, the deficiency of the intoxicating receptors produces sharp, tingling pain of a longer duration than skin pain and is somewhat less localized. Examples include ankle sprains and fractures.

Third, internal pain originates from the body organs. The built-in immune receptors are located in the body organs and lumens. Body Passage Similarly, in these areas, the deficiency of the intoxicating receptors usually picks up more and produces a longer duration of pain than the soma. Visceral pain may be more difficult to localize. Damage to visceral tissue may indicate a localized "affinity" of the sensation to an area not completely associated with the damaged area. Myocardial ischaemia (i. E., Loss of blood flow to a part of the heart muscle tissue) is an example of an affliction; Sensation can occur as a feeling of limited pain in the upper chest or on the left shoulder, arm or hand. Another example of an affinity is a fantasy channel. A fantasy tongue is a pain sensation from a limb where the individual no longer has a body signal or the individual no longer receives a body signal. This illusion - also known as centripetal blockade - is almost universal in people who have undergone arm trimming surgery and in patients with limb paralysis.

Fourth, neurogenic pain (e. G., "Neuralgia") can occur as a result of damage or disease to the neural tissue itself. Damage or disease can destroy the ability of the sensory nerve to convey accurate information about the thalamus or cortex. As a result, the brain interprets painful stimuli in spite of the presence of unclear or unreported physiological causes of pain.

Other pain classifications include acute pain and chronic pain. Acute pain is defined as short-term pain or pain with an easily identifiable cause. Acute pain is the damage or disease to the tissue, and can lead to "painful" pain after "quick" and "sharp" pain. Acute pain is concentrated on one area before it spreads somewhat. Acute pain generally responds well to medicines (eg, morphine).

Chronic pain can be medically defined as pain that lasts for more than six months. This persistent or intermittent pain often lasted longer than his purpose because it does not help the body to prevent damage. This is more difficult to treat than acute pain. Management of specialists is generally necessary to treat any chronic pain. In addition, stronger medicines are typically used for a long period of time in an attempt to control pain. This can lead to drug dependence. For example, opioids are used for a long period of time in some cases to control chronic pain. Drug tolerance, chemical dependency and even psychological addiction can occur.

"Acromegaly pain" refers to the pain sensed by a nociceptor, a nerve that senses and responds to a part of the body that is suffering from damage. Infiltration receptors can transmit tissue stimulation, imminent damage, or signals of actual damage. When activated, they transmit pain signals to the brain (through the spinal cord as well as the peripheral nerves). Acupuncture pain is typically well localized, constant, and often has tingling or throbbing. The subtypes of pain receptive pain include visceral pain, the internal organs include internal pain, and are involved with internal organs. Internal pain is episodic and tends to be localized poorly. Pain intoxication may be time-limited; When tissue damage is cured, pain is typically resolved. However, pain receptive pain associated with arthritis or cancer may not be time-limited. Acquired analgesic pain tends to respond to treatment with opiate analgesics such as, for example, buprenorphine, codeine, hydrocodone, oxycodone, morphine, and the like. Examples of painful aching pain include, but are not limited to, pain from sprains, inflammatory pain from fractures, burns, bumps, bruises, infections or joint disorders, pain from occlusion, cancer pain and muscle fascia pain associated with abnormal muscle stress, It is not limited.

&Lt; Desc / Clms Page number 2 &gt; "Acromegaly pain" often refers to chronic pain due to tissue damage. Neurogenic pain is usually caused by damage or destruction of nerve fibers. This may include a burnout or "coldness ", a" feeling down "sensation, numbness and / or itching. This may be continuous and / or episodic. Neurogenic pain is difficult to treat except for opioids, including, but not limited to, methadone, tramadol, tapentadol, oxycodone, methadone, morphine, levorphanol and the like. The causes of neurogenic pain are alcoholism; cut; Back, leg and hip problems; Chemotherapy; diabetes; Facial nerve problems; HIV / AIDS; Multiple sclerosis; Shingles; Spinal surgery; Trigeminal neuralgia; Fibromyalgia, and the like. In some cases, the cause of neurogenic pain may be unclear or unknown.

"Addiction" refers to a compound that, when administered to a mammal over a period of time, produces a dependence on that compound in the mammal. Dependency may be physiological and / or psychological. The therapeutic effect of a poisoning compound on a mammal can be reduced as the administration of a poisoning compound, a non-limiting example of physiological dependence, is prolonged. When administered to a mammal, the addictive compound may also produce a desire for it, which is a non-limiting example of psychological dependence in mammals. Examples of addictive compounds include, without limitation, addictive opioids and the like.

"Analgesic" and "analgesic" refer to compounds that are capable of inhibiting and / or reducing pain in mammals. Pain can be inhibited and / or reduced in the mammal by binding of the opioid analgesic agent to the mu receptor. When painlessness is achieved through the mu receptor, the analgesic agent is referred to as a mu receptor agonist. Certain analgesic agents may inhibit infiltration and / or neurogenic pain including morphine, codeine, hydro morphone, oxycodone, hydrocodone, buprenorphine, and the like.

The term " tolerance " as used herein refers to a psychological and / or physiological process by which a patient controls the frequent presence of a substance so that a high dose of substance is required to achieve the same effect. Tolerance can occur at different times for different effects of the same drug (for example, analgesic effects on side effects). Although the mechanism of tolerability is not fully understood, they may include receptor down-regulation or desensitization, up-regulation of inhibition pathways, increased metabolism and / or changes in receptor processing (eg, phosphorylation).

The term "dosage" refers to a range of Norvigor derivatives, or pharmaceutical salts or solvates thereof, that provide a therapeutic serum level of Norviga phosphorus when provided to a patient in need of treatment. The dose is quoted in the range of, for example, about 20 mg to about 120 mg, and may be expressed as milligrams or as mg / kg body weight. The physician in charge will select the appropriate dose from a range based on the patient's weight, age, degree of addiction, health status, and other appropriate factors, all of which are within the skill of the art.

The term "unit dose" refers to the dose of drug given to a patient to provide treatment results independent of the patient &apos; s body weight. In this example, unit doses are available in standard form (e.g., 20 mg tablets). The unit dose may be administered as a single dose or as a sub-dose of continuous. In some embodiments, the unit dose provides a standardized level of drug to the patient, independent of the patient &apos; s body weight. Many medicines are marketed on a therapeutic basis to all patients based on therapeutic doses. In such a case, it is not necessary to titrate the dose based on the patient's body weight.

II. Composition

As will be apparent to those of ordinary skill in the art upon reading this disclosure, the present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of at least one compound selected from the group consisting of Norbogoglyph, Norbogophane derivatives, Norbogogene prodrugs, and their respective pharmaceutically acceptable salts and / There is provided a composition for treating or preventing a disease or disorder or symptom of a disease or disorder as described herein. The present invention provides a method of treating or ameliorating a symptom of a disease or disorder as described herein, comprising a Norbitogen, a Norbitogen derivative, a prodrug of Norbitogen, their respective pharmaceutically acceptable salts and / or solvates, Or &lt; RTI ID = 0.0 &gt; preventing &lt; / RTI &gt;

In some embodiments, the composition is formulated for oral, transdermal, intravenous, pulmonary, rectal, nasal, vaginal, tongue, intravenous, intraarterial, intramuscular, intraperitoneal, intradermal or subcutaneous delivery. In one embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 4 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.5 mg to about 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 4 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.5 mg to about 4 mg / kg body weight per day. The range includes not only the extremes but also any subranges therebetween.

In one embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 8 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 7 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 6 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 5 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 4 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.5 mg to about 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.7 mg to about 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 2 mg to about 4 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 2 mg to about 3 mg / kg body weight per day.

In one embodiment, the therapeutically effective amount of the compound is about 8 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 7 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 6 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 5 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 4 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 3 mg / kg body weight / day. In one embodiment, the therapeutically effective amount of the compound is about 2 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1 mg / kg body weight per day.

In one embodiment, the therapeutically effective amount of the compound is about 4 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 3 mg / kg body weight / day. In another embodiment, the therapeutically effective amount of the compound is about 2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.7 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.5 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1 mg / kg body weight per day.

In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a norbogen and a pharmaceutically acceptable excipient, wherein the therapeutically or prophylactically effective amount of the norbobigain is from about 50 ng to 10 μg / Kg body weight / day of the total amount of phosphorus. In some aspects, a therapeutically or prophylactically effective amount of a norbobigain is an amount that delivers a total amount of norbobene of from about 50 ng to about 5 μg / kg body weight per day. In some aspects, a therapeutically or prophylactically effective amount of Norbitcogen is an amount that delivers a total amount of Noribucogloin from about 50 ng to about 1 μg / kg body weight per day. In some aspects, the composition is formulated for administration once per day. In some aspects, the composition is formulated for administration two or more times per day.

In some embodiments, the composition is formulated for sublingual, intranasal, or intrapulmonary delivery. In one aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of a norbogen and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of the norbobigain is less than 50 ng / 100 g / kg body weight per day The amount to deliver the total amount. In some aspects, a therapeutically effective amount of Norbigovan is an amount that delivers a total amount of Norviga phosphorus of 50 ng to 50 μg / kg body weight per day. In some aspects, a therapeutically effective amount of Noribucogloin is an amount that delivers a total amount of Noribucogloin of 50 ng to 10 [mu] g / kg body weight per day. In some aspects, a therapeutically effective amount of Norbigovan is an amount that delivers a total amount of 50 ng to 1 [mu] g / kg body weight per day. In some aspects, the composition is formulated for administration once per day. In some aspects, the composition is formulated for administration two or more times per day. The range includes both extremes as well as any subranges therebetween.

In another embodiment, the therapeutically effective amount of the compound is from 1.3 mg to 4 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 1.5 mg to 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is 1.7 mg to 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 2 mg to 4 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 2 mg to 3 mg / kg body weight per day.

The compound used

In one embodiment, the Norvigor derivative is represented by the formula (I) or a pharmaceutically acceptable salt and / or solvate thereof:

,

,

Wherein R is hydrogen or a hydrolyzable group, such as a hydrolyzable ester of about 1 to 12 carbons.

Generally, in the above formula, R is hydrogen or a group of the formula:

Wherein X is an unsubstituted or substituted C ₁ -C ₁₂ group. For example, X may be a linear alkyl group such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, Or n-dodecyl, or branched alkyl groups such as i-propyl or sec-butyl. Also, X may be a phenyl group or a benzyl group, one of which may be substituted with a lower alkyl group or a lower alkoxy group. Generally, lower alkyl and / or alkoxy groups have from 1 to about 6 carbons. For example, the R group can be acetyl, &lt; RTI ID = 0.0 &gt; morpholinyl, &lt; / RTI &gt; However, these groups are merely illustrative.

Generally, for all X groups, they may be unsubstituted or substituted with lower alkyl or lower alkoxy groups. For example, the substituted X may be an o-, m- or p-methyl or methoxybenzyl group.

C ₁ -C ₁₂ group comprising an C ₁ -C ₁₂ alkyl, C ₃ -C ₁₂ cycloalkyl, C ₆ -C ₁₂ aryl, C ₇ -C ₁₂ arylalkyl, C _x is a group that contains x carbon atoms . Lower alkyl refers to C ₁ -C ₄ alkyl, and lower alkoxy refers to C ₁ -C ₄ alkoxy.

In one embodiment, the Norvigor derivative is represented by the formula (II) or a pharmaceutically acceptable salt and / or solvate thereof:

Wherein,

은 단일 또는 이중 결합이고;

Is a single or double bond;

R ¹ is halo, OR ² , or C ₁ -C ₁₂ alkyl optionally substituted with 1 to 5 R ¹⁰ ;

R ² is a hydrogen as possible, or ^{-C (O) R x, -C} (O) OR x , and ^{-C (O) N (R y} ) singer is selected from the group consisting of _two decomposition group, each R ^x is C ₁ -C ₆ alkyl optionally substituted with one to five R ¹⁰ , each R ^y is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl optionally substituted with 1 to 5 R ¹⁰ , 1 to a 5 to R ^10, optionally substituted C ₆ -C ₁₄ aryl, optionally substituted with one to five R _¹⁰ C ₃ -C ¹⁰ cycloalkyl, 1-4 while having a hetero atom with 1 to 5 R ¹⁰ optionally substituted C ₁ -C ₁₀ while having a heteroaryl, 1 to 4 heteroatoms independently selected from 1 to 5 R ¹⁰ and optionally a C ₁ -C ₁₀ group consisting of heterocyclic substituted with, where Each R ^y , together with the nitrogen atom to which it is attached, has 1 to 4 heteroatoms, with 1 to 5 R &lt; ¹⁰ &gt; Optionally form a substituted C ₁ -C ₆ heterocyclic, or optionally substituted 1, while having one to four heteroatoms in one to five R ¹⁰ C ₁ -C ₆ heteroaryl, and;

R ³ is hydrogen, 1 to 5 R ¹⁰ and optionally substituted C ₁ -C ₁₂ alkyl, with 1 to 5 R ¹⁰ optionally substituted aryl, -C (O) substituted with a R ^6, -C (O) NR ⁶ R ^6, and -C (O) is selected from the group consisting of OR ^6;

R ⁴ is _{hydrogen, - (CH 2) m OR} 8, -CR 7 (OH) R 8, - (CH 2) m CN, - (CH 2) m COR 8, - (CH 2) m CO 2 R 8 _{, - (CH 2) m C} (O) NR 7 R 8, - (CH 2) m C (O) NR 7 NR 8 R 8, - (CH 2) m C (O) NR 7 NR 8 C (O ) R ⁹ and - (CH ₂ ) _m NR ⁷ R ⁸ ;

m is 0, 1 or 2;

L is a bond or C ₁ -C ₁₂ alkylene;

R ⁵ is hydrogen, a 1 to 5 R ¹⁰ substituted C ₁ -C ₁₂ alkyl, with 1 to 5 R ¹⁰ substituted C ₁ -C ₁₂ ^{alkenyl, -X 1 -R 7, - (} X 1 - _{^{Y) n -X 1 -R 7,}} -SO 2 NR 7 R 8, -OC (O) R 9, -C (O) OR 8, -C (O) NR 7 R 8, -NR 7 R 8, -NHC (O) R ^9, and -NR ⁷ C (O) R ⁹ ;

Each R ⁶ is independently selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, C ₆ -C ₁₀ aryl, C ₁ -C ₆ hetero Aryl, and C ₁ -C ₆ heterocycle having 1 to 4 heteroatoms, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 R ¹⁰ , Substituted;

X &lt; ¹ &gt; is selected from the group consisting of O and S;

Y is selected from C ₁ -C ₄ alkylene or C ₆ -C ₁₀ arylene or combinations thereof;

n is 1, 2 or 3;

R ⁷ and R ⁸ are hydrogen, 1 to 5 R ¹⁰ and optionally substituted C ₁ -C ₁₂ alkyl, while having 1 to 4 heteroatoms, 1 to 5 R ¹⁰ optionally substituted with a C ₁ -C ₆ optionally substituted with heterocycle, with 1 to 5 R ¹⁰ and optionally a C ₃ -C ₁₀ cycloalkyl, one optionally substituted with 1 to 5 R _¹⁰ C ₆ -C ¹⁰ aryl and substituted by 1 to 5 R ¹⁰ a is independently selected from the group consisting of C ₁ -C ₆ heteroaryl group having 1 to 4 heteroatoms;

R ⁹ is optionally substituted C ₁ -C ₁₂ alkyl, while 1 to 4 have the heteroatom one to five R ¹⁰ and optionally substituted C ₁ -C ₆ heterocyclic, one with 1 to 5 R ¹⁰ with 1 to 5 R ¹⁰ and optionally substituted C ₃ -C ₁₀ cycloalkyl, one optionally substituted with 1 to 5 R _¹⁰ C ₆ -C ¹⁰ aryl, and 1 to 4 heteroatoms, while having 1 to 5 R optionally substituted with ¹⁰ C ₁ -C ₆ are selected from the heteroaryl group consisting of;

R ¹⁰ is selected from the group consisting of C ₁ -C ₄ alkyl, phenyl, halo, -OR ¹¹ , -CN, -COR ¹¹ , -CO ₂ R ¹¹ , -C (O) NHR ¹¹ , -NR ¹¹ R ¹¹ , ^{NR 11 R 11, -C (O} ) NHNHR 11, -C (O) NR 11 NHR 11, -C (O) NR 11 NR 11 R 11, -C (O) NHNR 11 C (O) R 11, - C (O) NHNHC (O) R 11, -SO 2 NR 11 R 11, -C (O) consisting of ^{NR 11 NR 11 C (O)} R 11 and ^{-C (O) NR 11 NHC (} O) R 11 &Lt; / RTI &gt; And

R ¹¹ is independently hydrogen or C ₁ -C ₁₂ alkyl;

only,

When L is a bond, R &lt; ⁵ &gt; is not hydrogen;

이 이중 결합일 때, R¹은 에스터 가수분해가능한 기이고, R³ 및 R⁴가 둘 다 수소라면, -L-R⁵는 에틸이 아니며;

When this double bond is R ¹ is an ester hydrolyzable group and R ³ and R ⁴ are both hydrogen, then -LR ⁵ is not ethyl;

이 이중 결합이고, R¹이 -OH, 할로 또는 1 내지 5개의 R¹⁰으로 선택적으로 치환된 C₁-C₁₂ 알킬일 때, R⁴는 수소이며; 그리고

Is a double bond, R ¹ is -OH, halo, or a 1 to 5 R ¹⁰ and optionally substituted C ₁ -C ₁₂ alkyl, when one, R ⁴ is hydrogen; And

이 이중 결합이고, R¹은 OR²이며, R⁴는 수소이고, -L-R⁵는 에틸일 때, R²는 에스터, 아마이드, 탄산염 및 카밤산염으로 이루어진 군으로부터 선택되는 가수분해가능한 기가 아니다.

Is a double bond, R ¹ is OR ² , R ⁴ is hydrogen, and -LR ⁵ is ethyl, and R ² is not a hydrolyzable group selected from the group consisting of an ester, an amide, a carbonate and a carbamate.

In one embodiment, the Norvigor derivatives are represented by the following formula III or a pharmaceutically acceptable salt and / or solvate thereof:

Wherein,

은 단일 또는 이중 결합이고;

Is a single or double bond;

R ¹² is halo, -OH, -SH, -NH ₂ , -S (O) ₂ N (R ¹⁷ ) ₂ , -R ^z -L ¹ -R ¹⁸ , -R ^z -L ¹ -R ¹⁹ , -R ^z -L ¹ -R ²⁰ or -R ^z -L ¹ -CHR ¹⁸ R ¹⁹ , wherein R ^z is O, S or NR ¹⁷ ;

L ¹ is alkylene, arylene, -C (O) -alkylene, -C (O) -arylene, -C (O) O) NR ²⁰ - alkylene, -C (O) NR ²⁰ - ^{arylene, -C (NR 20) NR 20} - alkylene or -C (NR ²⁰⁾ NR ²⁰ - are the arylene, L ¹ is -OL ¹ -R ¹⁸ is -OC (O) - alkylene -R ^18, -OC (O) O- arylene -R ^18, -OC (O) O- alkylene -R ^18, -OC (O) - aryl alkylene ^{-R 18, -OC (O) NR} 20 - alkylene ^{-R 18, -OC (O) NR} 20 - arylene ^{-R 18, -OC (NR 20)} NR 20 - alkylene -R ¹⁸ or -OC (NR ²⁰ ) NR ²⁰ -arylene-R ¹⁸ , wherein the alkylene and arylene are optionally substituted with one to two R ¹⁶ ;

R ¹³ is ^{_{hydrogen, -S (O) 2 OR 20}} , -S (O) 2 R 20, -C (O) R 15, -C (O) NR 15 R 15, -C (O) OR 15, 1 to 5 R ¹⁶ and optionally substituted C ₁ -C ₁₂ alkyl, with 1 to 5 R ¹⁶ to alkenyl optionally substituted with C ₁ -C ₁₂ alkenyl, or 1 to 5 R ¹⁶ with optionally substituted aryl and ;

R ¹⁴ is hydrogen, halo, -OR ¹⁷ , -CN, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, aryl, or aryloxy wherein alkyl, alkoxy, ¹⁶ ;

Each R ¹⁵ is independently selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, aryl, heteroaryl and heterocycle, Alkynyl, aryl, heteroaryl and heterocycle are optionally substituted with 1 to 5 R &lt; ^{16 &} gt ;;

R ¹⁶ is phenyl, halo, -OR ¹⁷ , -CN, -COR ¹⁷ , -CO ₂ R ¹⁷ , -NR ¹⁷ R ¹⁷ , -NR ¹⁷ C (O) R ¹⁷ , -NR ¹⁷ SO ₂ R ¹⁷ , -C ^{(O) NR 17 R 17,} -C (O) NR 17 NR 17 R 17, -SO 2 NR 17 R 17 and ^{-C (O) NR 17 NR 17} C (O) is selected from the group consisting of R ^17;

Each R ¹⁷ is independently an optionally substituted C ₁ -C ₁₂ alkyl from hydrogen or from one to three halo;

R ¹⁸ is hydrogen, -C (O) R ²⁰ , -C (O) OR ²⁰ , -C (O) N (R ²⁰ ) _2, or -N (R ²⁰ ) C (O) R ²⁰ ;

R ¹⁹ is _{^{hydrogen, -N (R 20) 2,}} -C (O) N (R 20) 2, -C (NR 20) N (R 20) 2, -C (NSO 2 R 20) N (R 20 ^{_{) 2, -NR 20 C (O}} ) N (R 20) 2, -NR 20 C (S) N (R 20) 2, -NR 20 C (NR 20) N (R 20) 2, -NR 20 C (NSO ₂ R ²⁰ ) N (R ²⁰ ) ₂ or tetrazole;

Each R ²⁰ is independently selected from hydrogen, C ₁ -C ₁₂ group consisting of alkyl and aryl,

only,

이 이중 결합이고 R¹³ 및 R¹⁴는 수소일 때, R¹²는 하이드록시가 아니며;

It is a double bond and R ¹³ and R ^14, when a hydrogen, R ¹² is not a hydroxy;

가 이중 결합이고, R¹⁴는 수소이며, R¹²는 -O-L¹-R¹⁸, -O-L¹-R¹⁹, -O-L¹-R²⁰이고, L¹은 알킬렌일 때, -O-L¹-R¹⁸, -O-L¹-R¹⁹, -O-L¹-R²⁰은 메톡시가 아니고;

Is a double bond, R ¹⁴ is hydrogen, R ¹² is ^{-OL 1 -R 18, -OL 1 -R} 19, -OL 1 and -R ^20, L ¹ is, -OL ¹ -R ¹⁸ when renil alkyl, -OL ¹ -R ¹⁹ , -OL ¹ -R ²⁰ is not methoxy;

가 이중 결합이며, R¹⁴는 수소이고, R^z는 O이며, L¹은 -C(O)-알킬렌, -C(O)-아릴렌, -C(O)O-아릴렌, -C(O)O-알킬렌, -C(O)NR²⁰-알킬렌 또는 -C(O)NR²⁰-아릴렌일 때, R¹⁸, R¹⁹ 또는 R²⁰ 중 어떤 것도 수소가 아니다.

Is a double bond, R ¹⁴ is hydrogen, R and ^z is O, L ¹ is -C (O) - alkylene, -C (O) - arylene, -C (O) O- arylene, -C (O) O-alkylene, -C (O) NR ²⁰ -alkylene or -C (O) NR ²⁰ -arylene, none of R ¹⁸ , R ¹⁹ or R ²⁰ is hydrogen.

In one embodiment, the norbigene derivative is represented by the formula (IV) or a pharmaceutically acceptable salt and / or solvate thereof:

Wherein,

R ²¹ is selected from the group consisting of hydrogen, -C (O) R ²³ , -C (O) NR ²⁴ R ²⁵ and -C (O) OR ²⁶ , wherein R ²³ is Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl, and R ²⁴ and R ²⁵ are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl Substituted alkyl, alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; and R ²⁶ is selected from the group consisting of alkyl, , Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that R ²¹ is selected from the group consisting of sugars or oligosaccharides Not;

L &lt; ² &gt; is selected from the group consisting of a covalent bond and a cleavable linker group;

R ²² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, Cyclic and substituted heterocyclic, with the proviso that R is not a sugar or an oligosaccharide;

With the proviso that when L ² is a covalent bond and R ²² is hydrogen, R ²¹ is selected from the group consisting of -C (O) NR ²⁴ R ²⁵ and -C (O) OR ²⁶ ; And

In addition, when R ²¹ is hydrogen or -C (O) R ²³ and L ² is a covalent bond, R ²² is not hydrogen.

In one embodiment, the Norvigor derivative is represented by the following formula V, or a pharmaceutically acceptable salt and / or solvate thereof:

Wherein,

는 단일 또는 이중 결합을 지칭하며, 단,

이 단일 결합일 때, 화학식 V는 대응하는 다이하이드로 화합물을 지칭하고;

Quot; refers to a single or double bond,

When this is a single bond, the formula V refers to the corresponding dihydro compound;

R ²⁷ is hydrogen or SO ₂ OR ²⁹ ;

R ²⁸ is hydrogen or SO ₂ OR ²⁹ ;

R ²⁹ is hydrogen or C ₁ -C ₆ alkyl;

Provided that at least one of R ²⁷ and R ²⁸ is not hydrogen.

In one embodiment, the Norvigor derivative is represented by the following formula VI: or a pharmaceutically acceptable salt and / or solvate thereof:

Wherein,

는 단일 또는 이중 결합을 지칭하며, 단,

가 단일 결합일 때, 화학식 VI는 대응하는 인접한 다이하이드로 화합물을 지칭하고;

Quot; refers to a single or double bond,

Is a single bond, then the formula VI refers to the corresponding adjacent dihydro compound;

R ³⁰ is hydrogen, monophosphate, diphosphate or triphosphate;

R ³¹ is hydrogen, monophosphate, diphosphate or triphosphate;

Provided that R &lt; ³⁰ &gt; and R &lt; ³¹ &gt; are not both hydrogen;

One or more phosphate, triphosphate and triphosphate groups of R &lt; ³⁰ &gt; and R &lt; ³¹ &gt; are optionally esterified by one or more C ₁ -C ₆ alkyl esters.

Norbybogain as used herein can be replaced by a solvate of a Norbigene derivative or a salt or a Norbigene derivative of Norbigain or a derivative of each of the foregoing.

In a preferred embodiment, the compounds used herein are Norbiggan or salts thereof. In a more preferred embodiment, the compound used herein is a Norbigovine.

III. The method of the present invention

As will be clear to those skilled in the art upon reading this disclosure, the present invention provides a method of treating a subject suffering from a disease or disorder, comprising administering to the subject a dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof There is provided a method of treating a treatable disease by administering a Noriboggen as described in the specification.

Nicotine addiction

As will be apparent to those skilled in the art upon reading this disclosure, the present invention provides a method for treating a patient in need of such treatment, comprising administering to a patient in need of such treatment a therapeutically effective amount of a norbogen, a norbobagene derivative, a norbigene prodrug, A method of treating nicotine addiction in a subject, comprising the step of administering a salt. The present invention further provides a method of treating, alleviating or preventing a patient in need of such treatment, prophylactic or preventive treatment comprising administering a therapeutically or prophylactically effective amount of a norbobagene, a norbobagene derivative, a noribogan prodrug, or a respective pharmaceutically acceptable salt thereof, To treat, attenuate or prevent nicotine craving in a subject.

In some embodiments, the invention provides a method of treating nicotine addiction in a subject, comprising administering to a patient in need of such treatment a therapeutically effective amount of a Norbogorgen, a Norbogophore derivative, or a respective pharmaceutically acceptable salt thereof . &Lt; / RTI &gt;

The subject or patient may be any patient using nicotine in any form including cigarettes, electronic cigarettes or vaporizers ("vaping"), chewing tobacco, cigar, snuff, pipe, hooker, In some embodiments, the patient is addicted to nicotine. In some embodiments, the patient is physically addicted to nicotine. In some embodiments, the patient is psychologically addicted to nicotine.

In some embodiments, the therapeutically effective amount of the compound is from about 50 ng to less than 10 μg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 5 μg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 [mu] g / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 [mu] g / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 500 ng to less than 10 [mu] g / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1 [mu] g to less than 10 [mu] g / kg body weight per day. In another embodiment, a therapeutically effective amount of a compound is administered at a dose of about 50 ng, about 100 ng, about 150 ng, about 200 ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng, about 500 ng, , About 700 ng, about 750 ng, about 800 ng, about 850 ng, about 900 ng, about 950 ng, about 1 μg, about 2 μg, about 3 μg, about 3 μg, about 4 μg, about 5 μg, About 8 μg, about 9 μg, about 10 μg / kg body weight per day. A therapeutically effective amount of a compound can be any amount within any of these ranges, including the end point.

In some embodiments, a therapeutically effective amount of a norbobene, derivative, prodrug, or salt thereof is administered once a day. In some embodiments, the therapeutically effective amount is administered twice per day. In some embodiments, the therapeutically effective amount is administered more than twice per day.

When a therapeutically effective amount is administered more than once per day, some of the total therapeutically effective amount is administered hourly. For example, a 90 kg patient taking 1 노 nigobook / kg body weight / day takes 90 1 once a day, 45 2 twice a day or 30 3 three times a day.

In some embodiments, a therapeutically effective amount of a norbobene, derivative, prodrug, or salt thereof is administered to a subject in need thereof, for example, when a patient has a desire for nicotine or has a craving for nicotine as described herein And is expected to be administered once.

 In some embodiments, the derivative wherein the Norbogophane or Norbogophage is administered is administered sublingually, intracorally or intranasally. These routes of administration are discussed in further detail in the sub-section below titled "Dosage and Administration Route ".

Prevention of recurrence of nicotine use

In some embodiments, the invention provides a method for treating, preventing or attenuating a neurological disorder in a subject, comprising administering to a subject in need thereof a therapeutically, prophylactically, or attenuating amount of a prophylactically effective amount of a noribogan derivative, or a respective pharmaceutically acceptable salt thereof, Thereby providing a method of treating, preventing or attenuating nicotine craving. In some embodiments, the invention provides a method of treating a relapse of nicotine addiction in a subject, comprising administering to a subject in need thereof a prophylactically effective amount of a noribogan, a noribogan derivative, or a respective pharmaceutically acceptable salt thereof, Of the &lt; / RTI &gt;

In some situations, patients who have not stopped using nicotine nevertheless can not use nicotine for a long period of time. For example, most planes no longer allow smoking, and vaporizers and e-cigarettes are similarly prohibited. Other places and situations where the use of nicotine is not feasible or difficult can be avoided in cinemas, other entertainment venues (including theaters, opera, concerts, etc.), and even in workplaces, especially in hospitals and schools where smoking is unacceptable anywhere . In some embodiments, a prophylactically effective amount of a noribogan derivative, or a pharmaceutically acceptable salt thereof, is administered prior to and / or during a period of time when the patient is expected to be unable to use nicotine , Norbyborin, derivatives, or salts thereof prevent, halt, or attenuate craving for nicotine. In some embodiments, the nicotine craving is attenuated, stopped or prevented for at least 2, 3, 4, 5, 6, 7, 8, 10, 15 or 24 hours.

In some embodiments, the Norwegian phosphorus is administered according to the criteria required by the patient. In some embodiments, the Norwegian phosphorus can be administered before the nicotine cravings occur. For example, a patient may take the dose of Norbigovin in the anticipation of cravings, for example, before the intake of alcohol, before a stress situation occurs, or when it contacts another trigger for nicotine use. In some embodiments, the patient takes the dose of Norviga phosphorus, for example, during cravings, after nicotine craving has occurred to reduce or eliminate craving. In some embodiments, the dose of Norwegian phosphorus is low enough that the patient can take one dose before the craving occurs, and then on the same day if he / she feels another hunger or anticipates.

In one embodiment, the prophylactically effective amount of the compound is from about 50 ng to less than 10 μg / kg body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 5 μg / kg body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 1 [mu] g / kg body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 500 ng to less than 10 [mu] g / kg body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 1 μg to less than 10 μg / kg body weight per day. A prophylactically effective amount of a compound can be any amount within any of these ranges including endpoints.

In some embodiments, a prophylactically effective amount of a noribogan, derivative, prodrug, or salt thereof is administered once daily. In some embodiments, the prophylactically effective amount is administered twice daily. In some embodiments, a prophylactically effective amount is administered more than 2 times per day.

When a prophylactically effective amount of Norbigovan is administered more than once per day, some of the total prophylactically effective amount is administered every hour. For example, a 90 kg patient taking 1 노 nigobook / kg body weight / day takes 90 1 once a day, 45 2 twice a day or 30 3 three times a day.

In some embodiments, the derivative wherein the Norbogophane or Norbogophage is administered is administered sublingually, intracorally or intranasally. These routes of administration are discussed in further detail in the sub-section below titled "Dosage and Administration Route ".

Opioid or opioid-like drug addiction

In one aspect, the present invention provides a method of treating acute withdrawal from an opioid or opioid-like drug in a poisoning patient, comprising administering a therapeutically effective amount of a noribogan derivative, or a pharmaceutically acceptable salt or solvate thereof, &Lt; / RTI &gt;

In one aspect, the invention provides a method of treating a patient in need of such treatment comprising administering to a patient a dosage of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt or solvate thereof, which provides a mean serum concentration of from about 50 ng / ml to about 180 ng / Like substance abuse in a poisoning patient, wherein said concentration is sufficient to inhibit or improve said abuse while maintaining a QT interval of less than about 500 ms during said treatment .

In one aspect, the invention provides a method of treating a patient in need of such treatment comprising administering to a patient a dosage of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt or solvate thereof, which provides a mean serum concentration of from about 80 ng / ml to about 100 ng / A method for attenuating withdrawal symptoms in a human patient susceptible to withdrawal symptoms due to opioid or opioid-like drug intoxication comprising the steps of: Lt; RTI ID = 0.0 &gt; QT &lt; / RTI &gt; In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, withdrawal symptoms are acute withdrawal symptoms.

In one embodiment, the QT interval does not extend beyond about 50 ms. In one embodiment, the QT interval does not extend beyond about 40 ms. In one embodiment, the QT interval does not extend beyond about 30 ms. In one embodiment, the QT interval does not extend beyond about 20 ms. In one embodiment, the QT interval does not extend beyond about 10 ms. In one embodiment, the prolongation of the QT interval is less than the extension observed for methadone-treated patients.

In one aspect, the invention provides a method of treating a patient in need of such treatment comprising administering to a patient a dosage of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt or solvate thereof, which provides a mean serum concentration of from about 60 ng / ml to about 180 ng / A method for attenuating withdrawal symptoms in a human patient susceptible to withdrawal symptoms due to opioid or opioid-like drug intoxication comprising the steps of: Lt; RTI ID = 0.0 &gt; QT &lt; / RTI &gt; In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, withdrawal symptoms are acute withdrawal symptoms.

In one embodiment, the average serum concentration of the Noriboglobin is from about 50 ng / ml to about 180 ng / ml, or from about 60 ng / ml to about 180 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is from about 50 ng / ml to about 150 ng / ml, or from about 60 ng / ml to about 150 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is from about 50 ng / ml to about 100 ng / ml, or from about 60 ng / ml to about 100 ng / ml. In one embodiment, the average serum concentration of the norbobene phosphorus is from about 80 ng / ml to about 150 ng / ml. In one embodiment, the average serum concentration of the norbobene phosphorus is from about 80 ng / ml to about 100 ng / ml. The range includes both extremes as well as any subranges therebetween.

In one embodiment, the dosage of a Norbitogen, a Norbitogor derivative, or a pharmaceutically acceptable salt or solvate thereof provides a serum concentration of from about 1000 ng * hr / ml to about 6000 ng * hr / ml. In one embodiment, the dosage of a Norbitogen, Norbigor derivative, or a pharmaceutically acceptable salt or solvate thereof provides a serum concentration of from about 1200 ng * hr / ml to about 5800 ng * hr / ml. In one embodiment, the dosage of a Norvigor, Norbigor derivative, or a pharmaceutically acceptable salt or solvate thereof provides a serum concentration of about 1200 ng * hr / ml to about 5500 ng * hr / ml. The range includes both extremes as well as any subranges therebetween.

In one embodiment, the dosage of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, provides a maximum serum concentration (Cmax) of less than about 250 ng / ml. In one embodiment, the dosage of a Norbitogen, Norbigor derivative, or a pharmaceutically acceptable salt or solvate thereof, provides a Cmax of from about 40 ng / ml to about 250 ng / ml. In a preferred embodiment, the dosage of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, provides a Cmax of about 60 ng / ml to about 200 ng / ml. In one embodiment, the dosage of a Norbitogen, Norbigor derivative, or a pharmaceutically acceptable salt or solvate thereof, provides a Cmax of from about 100 ng / ml to about 180 ng / ml.

In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 1 mg / kg to about 4 mg / kg body weight per day. The total dosage is the total amount of the combined dose, for example, a norbyborne derivative, or a pharmaceutically acceptable salt or solvate thereof, administered over a period of 24 hours, with a smaller amount of more than once per day . In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 1.3 mg / kg to about 4 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 1.3 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of a Norvigor, Norvigor derivative, or a salt or solvate thereof, is from about 1.3 mg / kg to about 2 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 1.5 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or a salt or solvate thereof, is from about 1.7 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 2 mg / kg to about 4 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 2 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 2 mg / kg body weight. The range includes both extremes as well as any subranges therebetween.

In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 4 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 3 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 2 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 1.9 mg / kg body weight per day. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or salt or solvate thereof is about 1.8 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 1.7 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 1.6 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 1.5 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 1.4 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 1.3 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 1.2 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 1.1 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 1 mg / kg body weight per day.

In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 70 mg to about 150 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 75 mg to about 150 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 80 mg to about 140 mg. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or a salt or solvate thereof, is from about 90 mg to about 140 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 90 mg to about 130 mg. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or a salt or solvate thereof, is from about 100 mg to about 130 mg. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or a salt or solvate thereof, is from about 110 mg to about 130 mg.

In another embodiment, a unit dose of a Norvigor derivative, or salt or solvate thereof, of about 120 mg / dose of Norviga is provided. The term "unit dose" should be understood to mean a dose sufficient to provide a therapeutic result whether provided all at once or continuously over a period of time.

In some embodiments, the patient is administered an initial dose of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses. In one embodiment, such a dosing regimen provides a mean serum concentration of Norvigovin from about 50 ng / ml to about 180 ng / ml. In one embodiment, the one or more additional doses maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml over a period of time.

In some embodiments, the initial dose of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 60 mg to about 120 mg. In one embodiment, the initial dose is about 75 mg. In one embodiment, the initial dose is about 80 mg. In one embodiment, the initial dose is about 85 mg. In one embodiment, the initial dose is about 90 mg. In one embodiment, the initial dose is about 95 mg. In one embodiment, the initial dose is about 100 mg. In one embodiment, the initial dose is about 105 mg. In one embodiment, the initial dose is about 110 mg. In one embodiment, the initial dose is about 115 mg. In one embodiment, the initial dose is about 120 mg.

In some embodiments, the at least one additional capacity is lower than the initial capacity. In one embodiment, the at least one additional dose is from 5 mg to 50 mg. In one embodiment, the one or more additional doses may or may not include a norovogen derivative, or a salt or solvate thereof, wherein the same amount of Norbig is present. In one embodiment, the at least one additional dose is about 5 mg. In one embodiment, the at least one additional dose is about 10 mg. In one embodiment, the at least one additional dose is about 15 mg. In one embodiment, the at least one additional dose is about 20 mg. In one embodiment, the at least one additional dose is about 25 mg. In one embodiment, the at least one additional dose is about 30 mg. In one embodiment, the at least one additional dose is about 35 mg. In one embodiment, the at least one additional dose is about 40 mg. In one embodiment, the at least one additional dose is about 45 mg. In one embodiment, the at least one additional dose is about 50 mg.

In one embodiment, one or more additional doses are administered periodically. In one embodiment, one or more additional doses are administered every 4 hours. In one embodiment, at least one additional dose is administered every 6 hours. In one embodiment, at least one additional dose is administered every 8 hours. In one embodiment, at least one additional dose is administered every 10 hours. In one embodiment, at least one additional dose is administered every 12 hours. In one embodiment, at least one additional dose is administered every 18 hours. In one embodiment, at least one additional dose is administered every 24 hours. In one embodiment, at least one additional dose is administered every 36 hours. In one embodiment, at least one additional dose is administered every 48 hours.

In some embodiments, a therapeutic dose of Norbiga, a Norbogophore derivative, or a salt or solvate thereof, is administered to a patient over a period of time during which the patient is detoxified without suffering significant acute withdrawal symptoms, for example, Is decreasing. Without being constrained by theory, it is believed that diminishing is allowing the full therapeutic effect of the Norwegian phosphorus by extending the QT interval to a lesser extent. The diminution is accompanied by one or more subsequent lower doses of the Norwegian boron over time. For example, in some embodiments, the first gradually decreasing dose is from 50% to 95% of the first or original dose. In some embodiments, the second gradually decreasing dose is between 40% and 90% of the first or original dose. In some embodiments, the third gradually diminishing capacity is between 30% and 85% of the first or original capacity. In some embodiments, the fourth gradually decreasing dose is 20% to 80% of the first or the original dose. In some embodiments, the fifth gradually decreasing dose is between 10% and 75% of the first or the original dose.

In some embodiments, a first gradually decreasing capacity is provided after the first capacity of the Norwegian phosphorus. In some embodiments, a first gradually decreasing capacitance is provided after the second, third, or subsequent capacitances of the NOR gate. The first gradually decreasing dose can be administered at any time after the previous dose of the Norwegian phosphorus. The first gradually decreasing capacity may be provided once, followed by a subsequent incrementally decreasing capacity, or may be followed by a further, decreasing capacity (e.g., second, third, 4, or the like), or can be provided in multiple circuits without increasingly shrinking capacitances, for example, increasingly shrinking capacities can be provided over a single circuit or multiple doses. In some embodiments, the first gradually decreasing dose is administered at about 1 hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours or more after the previous dose of Norwegian phosphorus. Similarly, the gradually decreasing capacity of the second, third, fourth, etc., if provided, is about 1 hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours As shown in FIG.

In some embodiments, a gradually decreasing dose is provided to achieve the desired lower therapeutic dose. In some embodiments, two diminishing doses are provided to achieve the desired lower therapeutic doses. In some embodiments, three gradually decreasing doses are provided to achieve the desired lower therapeutic doses. In some embodiments, four or more gradually decreasing doses are provided to achieve the desired lower therapeutic dose. Decreasing dosing decisions, the number of shrinking doses, and the like, can easily be achieved by qualified clinicians.

In some embodiments, the patient is administered periodically, for example once, twice, three times, four times, or five times a day, for example, with a Norbigand, a Norbigor derivative, or a pharmaceutically acceptable salt or solvate thereof do. In some embodiments, the administration is once a day or once every two days, once every three days, three times a week, twice a week, or once a week. The dosage and frequency of administration depend, without limitation, on the route of administration, the dosage, the age and weight of the patient, and the condition of the patient. Determination of the dosage and frequency appropriate for this technique can be readily made by a qualified clinician.

A norbyborg derivative, or a pharmaceutically acceptable solvate or salt thereof, which is suitable for administration in accordance with the methods provided herein, includes oral, transdermal, sublingual, buccal, intrapulmonary or intranasal delivery, But not limited to, a variety of delivery schemes. Compositions suitable for the body, lung, rectal, nasal, vaginal, tongue, intravenous, intraarterial, intramuscular, intraperitoneal, intradermal and subcutaneous routes may also be used. Possible formulations include tablets, capsules, pills, powders, aerosols, suppositories, parenteral, and oral liquids (including suspensions, solutions and emulsions). Sustained-release formulations may also be used. All formulations can be prepared using methods that are standard in the art (see, for example, Remington ' s Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa., 1980).

In a preferred embodiment, the Norvigor, Norbogar derivative, or a pharmaceutically acceptable salt or solvate thereof is administered orally, which may conveniently be provided in the form of tablets, dragees, sublingual, liquid or capsules. In certain embodiments, the Noriboggen is provided as HCl with Norbig, and the dosage is reported as the amount of free base Norbigene. In some embodiments, the HCl, which is a Norbiter, is provided as a hard gelatin capsule containing only HCl, which is a no-booster, without an excipient.

The patient may suffer from an addiction to any opioid or opiate or opioid-like drug. In a preferred embodiment, the opioid or opioid-like drug is selected from the group consisting of heroin, cocaine, opiate, methadone, morphine, codeine, oxycodone, hydrocodone, and methamphetamine. In one embodiment, the opioid or opioid-like drug is heroin. In one embodiment, the opioid or opioid-like drug is methadone. In one embodiment, the opioid or opioid-like drug is a morphine.

In one aspect, the present invention provides a method for the treatment of post-acute withdrawal from an opioid or opioid-like drug in a poisoning patient using a Norwegian, nordogene derivative, or a sustained amount of a pharmaceutically acceptable salt or solvate thereof Or weakening.

In some aspects, the present invention is directed to a method of preventing the recurrence of opioid or opioid-like drug abuse in a poisoned patient being treated to improve abuse, said method comprising administering to said patient a maintenance dose of Norviga phosphorus periodically .

In some embodiments, the subject suffers from prolonged (e.g., one year or longer) treatment with a retention dose of a Norwegian, Norwegian derivative, or salt or solvate thereof. In some embodiments, the patient is treated for acute withdrawal symptoms using a therapeutic dose of a Norwegian bovine as described above, and then the amount of Norwegian phosphorus is maintained at a maintenance level after the acute withdrawal symptoms are expected to settle . Although acute withdrawal symptoms can last as long as one week or more, acute withdrawal symptoms are most evident in the first 48 to 72 hours after withdrawal of the addictive drug.

In some embodiments, the patient is administered a high (therapeutic) dose of a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, for a period of time to ameliorate the most significant withdrawal symptoms, and then (Maintenance) dose is administered to prevent recurrence of opioid or opioid-like drug use. In some embodiments, the patient is administered a therapeutically effective amount of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, for a period of time to improve the most significant withdrawal symptoms, , Or a pharmaceutically acceptable salt and / or solvate thereof, wherein the amount of the norbigene derivative is reduced (diminishing) with time until reaching a predetermined level

In some embodiments, the retention capacity of the Noribogloin, Norbigor derivative, or a pharmaceutically acceptable salt or solvate thereof is 70% of the therapeutic dose. In some embodiments, the retention volume is 60% of the therapeutic volume. In some embodiments, the retention volume is 50% of the therapeutic volume. In some embodiments, the retention volume is 40% of the therapeutic volume. In some embodiments, the retention capacity is 30% of the therapeutic dose. In some embodiments, the retention volume is 20% of the therapeutic volume. In some embodiments, the retention volume is 10% of the therapeutic volume.

In some embodiments, the sustained average serum level of the Noribucogloin is about 70% of the therapeutic average serum level of Noribucoglobin. In some embodiments, the maintenance average serum level of the Noribucogloin is about 60% of the therapeutic average serum level of the Noriboglobin. In some embodiments, the sustained average serum level of the Noribucogloin is about 50% of the therapeutic average serum level of Noribucoglobin. In some embodiments, the maintenance average serum level of the Noribucogloin is about 40% of the therapeutic average serum level of the Noriboglobin. In some embodiments, the sustained average serum level of the Noribucogloin is about 30% of the therapeutic average serum level of Noribucoglobin. In some embodiments, the sustained average serum level of the Noribucogloin is about 20% of the therapeutic average serum level of Noribucoglobin. In some embodiments, the sustained average serum level of the Noribucogloin is about 10% of the therapeutic average serum level of Noribucoglobin.

In some embodiments, the retention Cmax of the Norwegian phosphorus is 70% of the therapeutic Cmax of the Norwegian phosphorus. In some embodiments, the maintenance Cmax of the Norwegian phosphorus is 60% of the therapeutic Cmax of the Norwegian phosphorus. In some embodiments, the retention Cmax of the Norwegian phosphorus is 50% of the therapeutic Cmax of the Norwegian phosphorus. In some embodiments, the maintenance Cmax of the Norwegian phosphorus is 40% of the therapeutic Cmax of the Norwegian phosphorus. In some embodiments, the maintenance Cmax of the Norwegian phosphorus is 30% of the therapeutic Cmax of the Norwegian phosphorus. In some embodiments, the retention Cmax of the Norwegian phosphorus is 20% of the therapeutic Cmax of the Norwegian phosphorus. In some embodiments, the maintenance Cmax of the Norwegian phosphorus is 10% of the therapeutic Cmax of the Norwegian phosphorus.

In some embodiments, the sustained AUC / 24 hr of Norvigovin is about 70% of the therapeutic AUC / 24 hr of Norvigovin. In some embodiments, the sustained AUC / 24 hr of Norvigovin is about 60% of the therapeutic AUC / 24 hr of Norvigovin. In some embodiments, the sustained AUC / 24 hours of Noribogloin is about 50% of the therapeutic AUC / 24 hours of Norwegian phosphorus. In some embodiments, the sustained AUC / 24 hours of Norvigovin is about 40% of the therapeutic AUC / 24 hours of Norvigans. In some embodiments, the sustained AUC / 24 hr of Norvigovin is about 30% of the therapeutic AUC / 24 hr of Norvigovin. In some embodiments, the sustained AUC / 24 hr of Norvigovin is about 20% of the therapeutic AUC / 24 hr of Norvigovin. In some embodiments, the sustained AUC / 24 hours of the Norbigovsin is about 10% of the therapeutic AUC / 24 hours of the Norbigovan.

In one embodiment, the therapeutic dose is gradually reduced until the desired retention capacity is reached. For example, in some embodiments, the first gradually decreasing dose is from 50% to 95% of the therapeutic dose. In some embodiments, the second, gradually decreasing dose is between 40% and 90% of the therapeutic dose. In some embodiments, the third gradually decreasing dose is from 30% to 85% of the therapeutic dose. In some embodiments, the fourth gradually decreasing dose is 20% to 80% of the therapeutic dose. In some embodiments, the fifth gradually decreasing dose is from 10% to 75% of the therapeutic dose. In some embodiments, a gradually decreasing capacity is provided to achieve a retention capacity. In some embodiments, two increasingly reduced capacities are provided to achieve the retention capacity. In some embodiments, three increasingly reduced capacities are provided to achieve the retention capacity. In some embodiments, four or more gradually decreasing capacities are provided to achieve the retention capacity. Decreasing dosing decisions, the number of shrinking doses, and the like, can easily be achieved by qualified clinicians.

In one embodiment, the QT interval does not extend beyond about 30 ms. In a preferred embodiment, the QT interval does not extend beyond about 20 ms. In one embodiment, the QT interval does not extend beyond about 10 ms.

In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 10 mg to about 100 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 20 mg to about 100 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 30 mg to about 100 mg. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or salt or solvate thereof is from about 40 mg to about 100 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 50 mg to about 100 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 60 mg to about 100 mg. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or a salt or solvate thereof, is from about 60 mg to about 90 mg. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or a salt or solvate thereof, is from about 60 mg to about 80 mg. In one embodiment, the dosage or total dosage of a Noriborgen, Norbigor derivative, or a salt or solvate thereof, is from about 60 mg to about 70 mg.

In some embodiments, the patient is dosed periodically, such as once, twice, three times, four times, or five times a day, or a pharmaceutically acceptable salt or solvate thereof, with a Norbitogen, a Norbitogor derivative, or a pharmaceutically acceptable salt or solvate thereof . In some embodiments, the administration is once a day or once every two days, once every three days, three times a week, twice a week, or once a week. The dosage and frequency of administration depend, without limitation, on the route of administration, the content of the composition, the age and weight of the patient, and the condition of the patient. Determination of the appropriate dose and frequency for this technique can be easily made by a qualified clinician.

A norbyborg derivative, or a pharmaceutically acceptable salt or solvate thereof, suitable for administration in accordance with the methods provided herein may be administered orally, transdermally, sublingually, buccally, intrapulmonary or intranasally And may be suitable for a variety of delivery schemes including. Compositions suitable for the body, lung, rectal, nasal, vaginal, tongue, intravenous, intraarterial, intramuscular, intraperitoneal, intradermal and subcutaneous routes may also be used. Possible formulations include tablets, capsules, pills, powders, aerosols, suppositories, parenteral and oral liquids (including suspensions, solutions and emulsions). Sustained-release formulations may also be used. All formulations can be prepared using methods that are standard in the art (see, for example, Remington ' s Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa., 1980).

In a preferred embodiment, the Norvigene, Norbigor derivative, or a pharmaceutically acceptable salt or solvate thereof is conveniently orally administered in the form of tablets, dragees, sublingual, liquid or capsules. In a particular embodiment, Norbigophane is provided as Hb in which the free base Norbig is phosphorus using reported doses as the amount of phosphorus. In some embodiments, the HCl, which is a Norbiter, is provided as a hard gelatin capsule containing only HCl, which is a no-booster, without an excipient.

The patient may suffer addiction to any opioid or opiate, or opioid-like drug. In a preferred embodiment, the opioid or opioid-like drug is selected from the group consisting of heroin, cocaine, opiate, methadone, morphine, codeine, hydrocodone, oxycodone and methamphetamine. In one embodiment, the opioid or opioid-like drug is heroin. In one embodiment, the opioid or opioid-like drug is methadone. In one embodiment, the opioid or opioid-like drug is a morphine.

Alcohol dependence

In one aspect, the present invention provides a method of treating acute withdrawal symptoms from alcohol in a patient suffering from an alcohol dependency comprising the administration of a therapeutically effective amount of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt and / or solvate thereof, .

In one aspect, the invention provides a method of treating a patient, comprising administering to a patient a dosage of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, which provides a mean serum concentration of about 50 ng / ml to about 850 ng / Wherein said concentration is sufficient to inhibit or improve said abuse while maintaining a QT interval of less than about 500 ms during said treatment.

In one aspect, the invention provides a method of treating a patient in need of such treatment comprising administering to a patient a dosage amount of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, which provides an average serum concentration of from about 60 ng / ml to about 400 ng / A method of attenuating withdrawal symptoms in a human patient susceptible to withdrawal caused by alcohol dependence comprising administering to said patient a therapeutically effective amount of a compound of formula I, Enough to keep it. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, withdrawal symptoms are acute withdrawal symptoms.

In one aspect, the invention provides a method of treating a patient in need thereof comprising administering to the patient a dosage amount of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, which provides a mean serum concentration of about 50 ng / ml to about 400 ng / A method of attenuating withdrawal symptoms in a human patient susceptible to withdrawal caused by alcohol dependence comprising administering to said patient a therapeutically effective amount of a compound of formula I, Enough to keep it. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, withdrawal symptoms are acute withdrawal symptoms.

In one embodiment, the average serum concentration of the norbornene phosphorus is from about 50 ng / ml to about 800 ng / ml, or from about 60 ng / ml to about 800 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is from about 50 ng / ml to about 700 ng / ml, or from about 60 ng / ml to about 700 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is from about 50 ng / ml to about 600 ng / ml, or from about 60 ng / ml to about 600 ng / ml. In a preferred embodiment, the average serum concentration of the Noriboglobin is from about 50 ng / ml to about 500 ng / ml, or from about 60 ng / ml to about 500 ng / ml. In one embodiment, the average serum concentration of the Noriboglobin is from about 50 ng / ml to about 400 ng / ml, or from about 60 ng / ml to about 400 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is from about 50 ng / ml to about 300 ng / ml, or from about 60 ng / ml to about 300 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is from about 50 ng / ml to about 200 ng / ml, or from about 60 ng / ml to about 200 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is from about 50 ng / ml to about 100 ng / ml, or from about 60 ng / ml to about 100 ng / ml. The range includes both extremes as well as any subranges therebetween.

In one embodiment, the dosage or total dosage amount of a Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 1 mg / kg to about 8 mg / kg body weight per day. The total dosage is the total amount of the combined dose, for example, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the Norvigor is administered over a 24 hour period, and a smaller amount is administered once per day Lt; / RTI &gt; In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is from about 1.3 mg / kg to about 7 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is from about 1.3 mg / kg to about 6 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is from about 1.3 mg / kg to about 5 mg / kg body weight. In a preferred embodiment, the dosage or total dosage of the Norboghorn, Norbogar derivative, or a salt and / or solvate thereof is from about 1.3 mg / kg to about 4 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is from about 1.3 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is from about 1.3 mg / kg to about 2 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is from about 1.5 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is from about 1.7 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is from about 2 mg / kg to about 4 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is from about 2 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is about 2 mg / kg body weight. The range includes both extremes as well as any subranges therebetween.

In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is about 8 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is about 7 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is about 6 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is about 5 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is about 4 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is about 3 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is about 2 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is about 1.7 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is about 1.5 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is about 1.3 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is about 1 mg / kg body weight per day.

In one aspect, the invention provides a method of treating a condition selected from the group consisting of alcoholism, and / or withdrawal from withdrawal symptoms in addiction patients by administering a sustained dose of a Norwegian, Norwegian derivative, or a pharmaceutically acceptable salt and / To the treatment or attenuation of post-acute withdrawal symptoms.

In some aspects, the present invention is directed to a method of preventing the recurrence of alcohol abuse and / or use in a poisoned patient being treated to ameliorate said abuse, said method comprising administering to said patient a therapeutically effective amount of a compound of the formula And a pharmaceutically acceptable salt and / or solvate thereof.

In some embodiments, the patient is treated for a prolonged period of time (e.g., 1 month, 3 months, 6 months, 1 year or more) with a retention dose of a Norwegian, Norwegian derivative, or salt and / Suffer. In some embodiments, the patient is treated for acute withdrawal symptoms using a therapeutic dose of a Norwegian bovine as described above, and then the amount of Norwegian phosphorus is maintained at a maintenance level after the acute withdrawal symptoms are expected to settle . Although acute withdrawal symptoms can last as long as six weeks or more, acute withdrawal symptoms are most common in the first week after discontinuation of alcohol use.

In some embodiments, the patient is administered a high (therapeutic) dose of a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, for a period of time to ameliorate the most significant withdrawal symptoms, and then , Lower (sustained) doses are administered to prevent recurrence of drug use. In some embodiments, the patient is administered a therapeutically effective amount of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, for a period of time to improve the most significant withdrawal symptoms, , Or a pharmaceutically acceptable salt and / or solvate thereof, wherein the amount of the norbigene derivative is reduced (diminishing) with time until reaching a predetermined level

Drug addiction

In one aspect, the present invention provides a method of treating acute withdrawal from a poisoning substance in a poisoning patient, comprising administering a therapeutically effective amount of a norbyborg derivative, or a pharmaceutically acceptable salt and / or solvate thereof, .

In one aspect, the present invention provides a method of treating a condition comprising administering a dose of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, which provides an average serum concentration of 50 ng / ml to 180 ng / Wherein the concentration is sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.

In one aspect, the invention provides a method of treating a patient comprising administering to a patient a dosage of a Norbitcogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, which provides a mean serum concentration of about 80 ng / ml to 180 ng / Comprising administering a therapeutically effective amount of a QT interval of less than about 500 ms during said treatment while maintaining said QT interval less than about 500 ms during said treatment, . In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, withdrawal symptoms are acute withdrawal symptoms.

In one aspect, the invention provides a method of treating a patient in need of such treatment comprising administering to a patient a dosage of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, which provides a mean serum concentration of 50 ng / ml to 180 ng / A method of attenuating withdrawal symptoms in a human patient susceptible to withdrawal symptoms resulting from substance abuse, said attenuating said condition while maintaining a QT interval of less than about 500 ms during said treatment . In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, withdrawal symptoms are acute withdrawal symptoms.

In one embodiment, the average serum concentration of the norbornene phosphorus is between 50 ng / ml and 180 ng / ml or between 60 ng / ml and 180 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphor is from 50 ng / ml to 150 ng / ml or 60 ng / ml to 150 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is between 50 ng / ml and 100 ng / ml or between 60 ng / ml and 100 ng / ml. In one embodiment, the average serum concentration of the norbobene phosphorus is between 80 ng / ml and 150 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is between 80 ng / ml and 100 ng / ml. The range includes both extremes as well as any subranges therebetween.

The patient may suffer from addiction to any addictive drug or substance. In a preferred embodiment the drug is selected from the group consisting of benzodiazepines, cannabinoids and synthetic cannabinoids, stimulants, barbiturates, gamma-hydroxybutyrate (GHB), ketamine, PCP, dextromethorphan (DXM) (LSD), mescaline, anabolic steroids, and derivatives of each of these.

In one aspect, the present invention provides post-acute &lt; RTI ID = 0.0 &gt; (e. G., &Lt; / RTI &gt; post-acute &lt; RTI ID = Treatment or withdrawal of withdrawal symptoms.

In some aspects, the present invention is directed to a method of preventing the recurrence of drug abuse in a poisoned patient being treated to ameliorate said abuse, said method comprising administering to said patient a therapeutically effective amount of a compound selected from the group consisting of Norvigor, Norvigor, And periodically administering a sustained dosage of an acceptable salt and / or solvate.

ache

As will be apparent to those skilled in the art upon reading this disclosure, the present invention encompasses administering to a patient a dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt and / or solvate thereof A method of treating pain in a patient by alleviating and / or inhibiting pain in the patient.

In one aspect, the present invention is directed to the treatment of pain in a patient suffering from pain comprising the administration of a therapeutically effective amount of a noribogan derivative, or a pharmaceutically acceptable salt and / or solvate thereof, .

In one aspect, the invention provides a method of treating a patient in need of such treatment comprising administering to a patient a dose of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, which provides a mean serum concentration of from 20 ng / ml to 180 ng / Wherein the concentration is sufficient to inhibit or improve the pain while maintaining a QT interval of less than about 500 ms during the treatment. In one embodiment, the concentration is sufficient to inhibit or improve the pain while maintaining a QT interval of less than about 20 ms during the treatment.

In one aspect, the invention provides a method of treating a patient in need of such treatment comprising administering to a patient a dose of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, which provides a mean serum concentration of from 20 ng / ml to 180 ng / And wherein the concentration is sufficient to attenuate the condition while maintaining a QT interval of less than about 500 ms during the treatment. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during the treatment. Preferably, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during the treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during the treatment.

In one aspect, the invention provides a method of treating a patient in need of such treatment comprising administering to a patient a dosage of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, which provides a mean serum concentration of 50 ng / ml to 180 ng / Wherein the concentration is sufficient to attenuate the condition while maintaining a QT interval of less than about 500 ms during the treatment. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during the treatment. Preferably, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during the treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during the treatment.

In one aspect, the invention provides a method of treating a patient in need of such treatment comprising administering to a patient a dosage of a norbyborg derivative, or a pharmaceutically acceptable salt and / or solvate thereof, that provides a mean serum concentration of 80 ng / ml to 100 ng / Wherein the concentration is sufficient to attenuate the condition while maintaining a QT interval of less than about 500 ms during the treatment. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during the treatment. Preferably, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during the treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during the treatment.

In one embodiment, the average serum concentration of Norvigovin is 50 ng / ml to 180 ng / ml or 20 ng / ml to 180 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is between 50 ng / ml and 150 ng / ml or between 20 ng / ml and 150 ng / ml. In one embodiment, the average serum concentration of Norvigovin is between 50 ng / ml and 100 ng / ml or between 20 ng / ml and 100 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is between 80 ng / ml and 100 ng / ml. The range includes both extremes as well as any subranges therebetween.

In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt and / or solvate thereof is from 0.1 mg / kg to 4 mg / kg body weight per day. The total dosage is the total amount of the combined dose, for example, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the Norvigor is administered over a 24 hour period, and a smaller amount is administered once per day Lt; / RTI &gt; In another embodiment, the therapeutically effective amount of the compound is from 0.1 mg to 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.1 mg to 2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.1 mg to 1.5 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.1 mg to 1 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 1.5 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 1.3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 1.2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 1.1 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 1 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.7 mg to 1.5 mg / kg body weight / day. The range includes both extremes as well as any subranges therebetween.

In one embodiment, the therapeutically effective amount of the compound is about 3 mg / kg body weight / day. In one embodiment, the therapeutically effective amount of the compound is about 2 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.5 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.4 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.3 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.2 mg / kg body weight / day. In one embodiment, the therapeutically effective amount of the compound is about 1.1 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.9 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.8 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.7 mg / kg body weight / day. In one embodiment, the therapeutically effective amount of the compound is about 0.6 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.5 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.4 mg / kg body weight / day. In one embodiment, the therapeutically effective amount of the compound is about 0.3 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.2 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.1 mg / kg body weight per day.

In one embodiment, the dosage or total dosage of the norbobene or salt or solvate thereof is from 60 mg to 150 mg. In one embodiment, the dosage or total dosage of the norbobene or salt or solvate thereof is from 70 mg to 150 mg. In one embodiment, the dosage or total dosage of the norbobene or salt or solvate thereof is 80 mg to 140 mg. In one embodiment, the dosage or total dosage of the norbyborin or salt or solvate thereof is from 90 mg to 140 mg. In one embodiment, the dosage or total dosage of the norbobene or salt or solvate thereof is from 90 mg to 130 mg. In one embodiment, the dosage or total dose of the norbobene or salt or solvate thereof is from 100 mg to 130 mg. In one embodiment, the dosage or total dosage of the norbobene or salt or solvate thereof is from 110 mg to 130 mg.

In another embodiment, a unit dose of Norvigor or a salt or solvate thereof of about 120 mg per dose is provided. The term "unit dose" should be understood to mean a dose sufficient to provide a therapeutic result, whether delivered sequentially or over a period of time.

In one embodiment, the dosage or total dosage of the norbobene phosphorus or salt or solvate thereof is 10 mg to 100 mg. In one embodiment, the dosage or total dosage of the norbobene or salt or solvate thereof is from 50 mg to 100 mg. In one embodiment, the dosage or total dosage of the norbicycin or its salt or solvate is from 60 mg to 100 mg. In one embodiment, the dosage or total dosage of the norbobene or salt or solvate thereof is 60 mg to 90 mg. In one embodiment, the dosage or total dosage of the Norbigovs phosphorus or salt or solvate thereof is 60 mg to 80 mg. In one embodiment, the dosage or total dosage of the norbyborin or salt or solvate thereof is from 60 mg to 70 mg.

Migraine treatment

In some embodiments, the invention provides a method of treating a migraine headache and / or a migraine headache in a subject, comprising administering to a patient in need of such treatment a therapeutically effective amount of a Norbitogen, a Norbitogen derivative, or a respective pharmaceutically acceptable salt thereof. Thereby providing a method for treating the symptoms thereof. In one embodiment, the method further comprises administering at least one agent known to treat or prevent migraine and / or its symptoms. In a preferred embodiment, treatment with a Norbigophane and / or agent does not result in a QT interval extension of greater than about 50 ms. It should be understood that although the norbogenin is discussed throughout this disclosure, such agents may optionally be administered (e.g., before, after, or concurrently) with a norbogen or derivative.

The subject or patient may be any patient exhibiting migraine headache and / or symptoms thereof. In a preferred embodiment, the patient has a migraine headache. In one embodiment, the patient has chronic migraine. Chronic migraine is characterized by a headache (tension and / or migraine) of more than 15 days per month for at least 3 months (migraine and / or migraine), at least 8 days of migraine per month (no aura) (or successful treatment of expected symptoms).

In one aspect, the invention provides a method of treating a patient in need of such treatment comprising administering to a patient a dosage of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt or solvate thereof, which provides a mean serum concentration of from about 50 ng / ml to about 180 ng / Wherein the concentration is sufficient to maintain the QT interval of less than about 500 ms during the treatment while treating the migraine headache and / or symptoms.

In some embodiments, the concentration is sufficient to maintain a QT interval of less than about 470 ms during treatment while treating the patient. Preferably, the concentration is sufficient to maintain a QT interval of less than about 450 ms during treatment while treating the patient. In one embodiment, the concentration is sufficient to maintain the QT interval of less than about 420 ms during treatment while being sufficient to treat the patient.

In one embodiment, the QT interval does not extend beyond about 50 ms. In one embodiment, the QT interval does not extend beyond about 40 ms. In one embodiment, the QT interval does not extend beyond about 30 ms. In one embodiment, the QT interval does not extend beyond about 20 ms. In one embodiment, the QT interval does not extend beyond about 10 ms.

In one embodiment, the dosage of a Norbitogen, a Norbitogor derivative, or a pharmaceutically acceptable salt or solvate thereof provides a serum concentration of from about 1000 ng · hr / ml to about 6000 ng · hr / ml. In one embodiment, the dosage of a Norvigor, Norbigor derivative, or a pharmaceutically acceptable salt or solvate thereof, provides a serum concentration of from about 1200 ng · hr / ml to about 5800 ng · hr / ml. In one embodiment, the dosage of a Norbitogen, Norbigor derivative, or a pharmaceutically acceptable salt or solvate thereof, provides a serum concentration of about 1200 ng · hr / ml to about 5500 ng · hr / ml. The range includes both extremes as well as any subranges therebetween.

In one embodiment, the dosage of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, provides a maximum serum concentration (Cmax) of less than about 250 ng / ml. In one embodiment, the dosage of a Norbitogen, Norbigor derivative, or a pharmaceutically acceptable salt or solvate thereof, provides a Cmax of from about 40 ng / ml to about 250 ng / ml. In a preferred embodiment, the dosage of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, provides a Cmax of about 60 ng / ml to about 200 ng / ml. In one embodiment, the dosage of a Norbitogen, Norbigor derivative, or a pharmaceutically acceptable salt or solvate thereof, provides a Cmax of from about 100 ng / ml to about 180 ng / ml.

In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 1 mg / kg to about 4 mg / kg body weight per day. The total dosage is the total amount of the combined doses, for example, a norbyborne derivative, or a pharmaceutically acceptable salt or solvate thereof, administered over a 24 hour period, with a smaller amount of more than once per day Lt; / RTI &gt; In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 1.3 mg / kg to about 4 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 1.3 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of a Norvigor, Norvigor derivative, or a salt or solvate thereof, is from about 1.3 mg / kg to about 2 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 1.5 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or a salt or solvate thereof, is from about 1.7 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 2 mg / kg to about 4 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 2 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is about 2 mg / kg body weight. The range includes both extremes as well as any subranges therebetween.

In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 70 mg to about 150 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 75 mg to about 150 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 80 mg to about 140 mg. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or a salt or solvate thereof, is from about 90 mg to about 140 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from about 90 mg to about 130 mg. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or a salt or solvate thereof, is from about 100 mg to about 130 mg. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or a salt or solvate thereof, is from about 110 mg to about 130 mg.

In some embodiments, the therapeutically effective amount of the compound is from about 50 ng to about 10 μg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 5 μg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 [mu] g / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 [mu] g / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 500 ng to 10 μg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1 [mu] g to less than 10 [mu] g / kg body weight per day. In another embodiment, a therapeutically effective amount of a compound is administered at a dose of about 50 ng, about 100 ng, about 150 ng, about 200 ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng, about 500 ng, , About 700 ng, about 750 ng, about 800 ng, about 850 ng, about 900 ng, about 950 ng, about 1 μg, about 2 μg, about 3 μg, about 3 μg, about 4 μg, about 5 μg, , About 8 μg, about 9 μg, or about 10 μg / kg body weight per day. A therapeutically effective amount of a compound can be any amount within any of these ranges, including the end point.

In some embodiments, a therapeutically effective amount of a norbobene, derivative, prodrug, or salt thereof is administered once daily. In some embodiments, the therapeutically effective amount is administered twice daily. In some embodiments, a therapeutically effective amount is administered more than twice a day.

When a therapeutically effective amount is administered more than once a day, some of the total therapeutically effective amount is administered every hour. For example, a 90 kg patient taking 1 μg Norwegian phosphorus / kg body weight / day will take 90 μg once a day, 45 μg twice a day, or 30 μg three times a day.

In some embodiments, a therapeutically effective amount of a norbobene, derivative, prodrug, or salt thereof is administered to a subject when needed, for example, when the patient has migraine or symptoms thereof or is expected to have a migraine Predisposes or experiences a trigger, or has a symptom or prognosticator).

In some embodiments, the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof is administered to a patient periodically, such as once, twice, three, four or five times a day . In some embodiments, the administration is once a day or once every two days, once every three days, three times a week, twice a week, or once a week. The dosage and frequency of administration depend, without limitation, on the route of administration, the content of the composition, the age and weight of the patient, and the condition of the patient. Determination of the appropriate dose and frequency for this technique can be easily made by a qualified clinician.

In some embodiments, a derivative wherein the Norbigovorin or Norbigovan is administered is administered sublingually, intrapulmonary, buccally or intranasally. These routes of administration are discussed in further detail in the sub-section below titled "Dosage and Administration Route ".

Prevention of migraine

In some embodiments, the invention provides a method of treating migraine headaches in a subject, comprising administering to a patient in need of such prevention or attenuation a prophylactically effective amount of a Norbogovir, a Norbogar derivative, or a respective pharmaceutically acceptable salt thereof. / RTI &gt; and / or a method of preventing or attenuating the symptoms thereof. In some embodiments, the invention provides a method of preventing or treating a migraine headache comprising administering to a patient in need of such prevention or attenuation a prophylactically effective amount of a noribogan derivative, or a respective pharmaceutically acceptable salt thereof, A method of preventing or attenuating a migraine headache and / or a symptom thereof in a subject, comprising administering the agent together with the agent. It is to be understood that the norbornene is discussed throughout this disclosure and that such agents may optionally be administered (e.g., before, after, concurrently or substantially concurrently) with the norbogen or derivative.

In some embodiments, the Norwegian phosphorus is administered according to the criteria required by the patient. In some embodiments, the Noriboglobin can be administered prior to the onset of migraine and / or its symptoms. For example, a patient may take the dose of a Norwegian phoenix in the anticipation of a symptom (e.g., after a migraine trigger, at the same time or at the same time, when one or more symptoms are experienced; In some embodiments, a prophylactically effective amount of Norbiggan may be administered on a regularly scheduled basis (e. G., Daily, every two days, weekly, etc.) to prevent migraine.

In one embodiment, the prophylactically effective amount of the compound is up to about 90% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 80% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 70% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 60% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 50% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 40 therapeutic doses. In one embodiment, the prophylactically effective amount of the compound is up to about 30% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 20% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 10% of the therapeutic amount.

In one embodiment, the prophylactically effective amount of the compound is from about 50 ng to less than 10 [mu] g / kg body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 5 μg / kg body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 1 [mu] g / kg body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 500 ng to less than 10 μg / kg body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 1 μg to less than 10 μg / kg body weight per day. A prophylactically effective amount of a compound can be any amount within any of these ranges, including endpoints.

In one embodiment, the QT interval does not extend beyond about 30 ms. In a preferred embodiment, the QT interval does not extend beyond about 20 ms. In one embodiment, the QT interval does not extend beyond about 10 ms.

In some embodiments, a prophylactically effective amount of a noribogan, derivative, prodrug, or salt thereof is administered once daily. In some embodiments, the prophylactically effective amount is administered twice daily. In some embodiments, a prophylactically effective amount is administered more than 2 times per day.

When a prophylactically effective amount of Norbigovan is administered more than once per day, some of the total prophylactically effective amount is administered every hour. For example, a 90 kg patient taking 1 μg Norwegian phosphorus / kg body weight / day will take 90 μg once a day, 45 μg twice a day, or 30 μg three times a day.

In some embodiments, the patient is administered periodically, e.g., once, twice, three times, four times, or five times a day, with a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof . In some embodiments, the administration is once a day, once every two days, once every three days, three times a week, twice a week, or once a week. The dosage and frequency of administration depend, without limitation, on the route of administration, the content of the composition, the age and weight of the patient, and the condition of the patient. Determination of the appropriate dose and frequency for this technique can be easily made by a qualified clinician.

In some embodiments, derivatives wherein the Norbogophyllin or Norbogog is administered are administered orally, sublingually, intrapulmonally, buccally or intranasally. These routes of administration are discussed in further detail in the sub-section below titled "Dosage and Administration Route ".

In some embodiments, the sustained average serum level of the norbornene phosphorus is from about 10% to about 80% of the therapeutic average serum level of the norbornene phosphorus. In some embodiments, the sustained average serum level of the Noribucogloin is about 70% of the therapeutic average serum level of Noribucoglobin. In some embodiments, the maintenance average serum level of the Noribucogloin is about 60% of the therapeutic average serum level of the Noriboglobin. In some embodiments, the sustained average serum level of the Noribucogloin is about 50% of the therapeutic average serum level of Noribucoglobin. In some embodiments, the maintenance average serum level of the Noribucogloin is about 40% of the therapeutic average serum level of the Noriboglobin. In some embodiments, the sustained average serum level of the Noribucogloin is about 30% of the therapeutic average serum level of Noribucoglobin. In some embodiments, the sustained average serum level of the Noribucogloin is about 20% of the therapeutic average serum level of Noribucoglobin. In some embodiments, the sustained average serum level of the Noribucogloin is about 10% of the therapeutic average serum level of Noribucoglobin.

Reduction of analgesic tolerance

In one aspect of the invention, the patient is treated with an additive opioid analgesic to alleviate the patient &apos; s pain. The pain can be of any type and can originate from any source. In one embodiment, the patient is treated for acute pain. In one embodiment, the patient is treated for chronic pain. In one embodiment, the patient is treated for intractable pain. In one embodiment, the patient is treated for neurogenic pain. In some embodiments, the pain is caused by surgery, diabetes, trigeminal neuralgia, fibromyalgia, cancer, central pain syndrome, tissue damage, body injury, and the like. In some embodiments, the pain source is not known or is unclear.

In one aspect, the present invention is directed to a method of modulating tolerability to an opioid analgesic in a patient suffering from opioid analgesic therapy, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of Norviga, which provides an average serum concentration of about 50 ng / ml to about 180 ng / Or a pharmaceutically acceptable salt or solvate thereof, at the same time as or simultaneously with the opioid analgesic agent, wherein the concentration is sufficient to re-sensitize the patient to the opioid as an analgesic agent, While maintaining a QT interval of less than about 500 ms.

In one embodiment, the average serum concentration of the norbornene phosphorus is between 50 ng / ml and 180 ng / ml or between 60 ng / ml and 180 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphor is from 50 ng / ml to 150 ng / ml or 60 ng / ml to 150 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is between 50 ng / ml and 100 ng / ml or between 60 ng / ml and 100 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is between 80 ng / ml and 100 ng / ml. The range includes both extremes as well as any subranges therebetween.

In one embodiment, the dosage or total dosage of a Norvigor, Norvigor derivative, or a salt or solvate thereof, is from 10 mg to 100 mg. In one embodiment, the dosage or total dosage of a Norvigor, Norvigor derivative, or a salt or solvate thereof, is from 20 mg to 100 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is 30 mg to 100 mg. In one embodiment, the dosage or total dosage of a Norvigor, Norbigor derivative, or a salt or solvate thereof, is from 40 mg to 100 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is from 50 mg to 100 mg. In one embodiment, the dosage or total dosage amount of the Norvigor, Norvigor derivative, or salt or solvate thereof is 60 mg to 100 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is 60 mg to 90 mg. In one embodiment, the dosage or total dosage of a Norvigor, Norvigor derivative, or a salt or solvate thereof, is from 60 mg to 80 mg. In one embodiment, the dosage or total dosage of the Norvigor, Norvigor derivative, or salt or solvate thereof is 60 mg to 70 mg.

The patient may receive any additive opioid analgesic for the treatment of pain. In a preferred embodiment, the opioid analgesic is selected from the group consisting of pentanil, hydrocodone, hydro morphone, morphine, oxycodone, buprenorphine, codeine, heroin, tbain, buprenorphine, methadone, meperidine, tramadol, Pentanol, pentanol, pentanoxine, oxymorphone, and derivatives thereof, respectively.

depression

As will be apparent to those of ordinary skill in the art upon reading this disclosure, the present invention provides a method of treating a patient, comprising administering to a patient a therapeutically effective amount of a norbyeene, a derivative thereof, or a pharmaceutically acceptable salt and / Or PTSD in a patient in need of such treatment. In a preferred embodiment, the patient is not addicted to cocaine or opiate. Norbigovane derivatives include, but are not limited to, the compositions described in the "Composition of the Invention" section above.

The following description of depressive disorder and PTSD is provided for the purpose of facilitating an understanding of the utility of the compounds and compositions of the present invention. Definitions of depressive disorders and PTSD provided below are listed in the American Psychiatric Association, 1994a or the American Psychiatric Association, 1987. Further information on these disorders can be found in this reference as well as in other references listed below, all of which are incorporated herein by reference.

In some embodiments, the compounds of the present invention are expected to be effective in treating depression in patients diagnosed with depression based on administration of any of the following tests: Hamilton Depression Rating Scale (HDRS) , Hamilton Depressed mood item, Clinical Global Impression (CGI) - Severity of illness. It is further contemplated that the compounds of the present invention are effective in improving certain factors measured in the HDRS sub-factor scores, including depressive mood items, sleep disturbance and anxiety factors, and CGI-severity of disease severity . The compounds of the present invention are also expected to be effective in preventing the recurrence of major depressive episodes.

The invention provides, in certain embodiments, a method of treating a patient suffering from a major depressive disorder, comprising administering a therapeutically effective amount of any compound as used herein effective to treat a subject major depressive disorder do.

The present invention also relates to the use of a compound of formula I in the manufacture of a medicament for the treatment of depressive disorder, bipolar I or II disorder, schizophrenia disorder, cognitive disorder with depressed mood, personality disorder, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, And provides a method of treating the recipient.

The compounds used in the present invention are expected to be effective in treating PTSD in patients diagnosed with PTSD based on the administration of any of the following tests: Clinical-administered PTSD Scale Part 2 (CAPS), Event Scale Patient-grade effect (IES). The compounds described herein are further contemplated to be effective in inducing an improvement in CAPS, IES, CGI-disease severity or CGI-overall improvement test scores. It is also contemplated that the compounds described herein will be effective in preventing recurrence of PTSD.

The present invention provides a method of treating a post-traumatic stress disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any of the present invention to treat a post-traumatic stress disorder of the subject.

Another aspect of the present invention provides a method of treating depression and / or PTSD in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of a Norbitogen, a Norbitogor derivative, or a pharmaceutically acceptable salt and / Cargo, wherein the amount of the derivative wherein the Norbogophane or Norbogophage is sufficient to treat depression and / or PTSD in the patient.

In a preferred embodiment, the invention provides a method of treating depression and / or depression in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a nordoborgene derivative, or a pharmaceutically acceptable salt and / or solvate thereof, / Or a post-traumatic stress disorder, wherein the patient is not intoxicated with cocaine or opiate, and, further, a therapeutically effective amount provides a serum level of from 50 to 800 ng / ml of an average Norberger. In some embodiments, the serum level is less than about 50 ng / ml, wherein the average Norwich is provided by the dosage. In one embodiment, the therapeutically effective amount is from 0.5 mg to 4 mg / kg body weight. In one embodiment, the therapeutically effective amount is between 50 ng and less than 100 [mu] g / kg body weight. In one embodiment, depression is treated. In one embodiment, post-traumatic stress disorder is treated. In one embodiment, the Norvigor, Norbigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery.

In some embodiments, the composition is administered via sublingual, intranasal, or intrapulmonary delivery. In one aspect, the invention provides a pharmaceutical composition comprising a pharmaceutical composition comprising a pharmaceutically effective amount of a norbogen and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of norbobigain is less than 50 ng to less than 100 μg / kg The amount of weight / day that the Norwegian Boy delivers the total amount of phosphorus. In some aspects, a therapeutically effective amount of Norbigovan is an amount that delivers a total amount of Norviga phosphorus of 50 ng to 50 μg / kg body weight per day. In some aspects, a therapeutically effective amount of Noribucogloin is an amount that delivers a total amount of Noribucogloin of 50 ng to 10 [mu] g / kg body weight per day. In some aspects, a therapeutically effective amount of Noribucogloin is an amount that delivers a total amount of Norwegian phosphorus of 50 ng to 1 [mu] g / kg body weight per day. In some aspects, the composition is administered once per day. In some aspects, the composition is administered more than once per day. In some embodiments, the composition is administered less than once per day, for example once every two days, once every three days, once every four days, once a week, and the like.

In some embodiments, the composition is administered via oral, transdermal, intravenous, pulmonary, rectal, nasal, vaginal, tongue, intravenous, intraarterial, intramuscular, intraperitoneal, intradermal or subcutaneous delivery. In one embodiment, the dosage or total dosage of the compound is 0.5 mg to 4 mg / kg body weight per day. The total dosage is the total amount of the combined doses, for example, the norbobogain or its pharmaceutically acceptable salts and / or solvates administered over a 24 hour period, with smaller doses administered more than once per day. In one embodiment, the dosage or total dosage of the compound is from 1 mg to 4 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is from about 1 mg to 3 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is from 1 mg to 2 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is from 1.5 mg to 3 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is 1.7 mg to 3 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is from 2 mg to 4 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is from 2 mg to 3 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is about 2 mg / kg body weight per day.

In one embodiment, the dosage or total dosage of the compound is about 4 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is about 3 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is about 2 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is about 1.7 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is about 1.5 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is about 1.3 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is about 1 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the compound is less than about 1 mg / kg body weight per day.

In certain preferred embodiments of the present invention, the Norbitogen, the Norbitogen derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered at a dose of 50 ng / ml to 180 ng / ml or 60 ng / ml to 180 ng / Administered in an amount that provides an average serum concentration of phosphorus. In one embodiment, the average serum concentration of the norbornene phosphor is from 50 ng / ml to 150 ng / ml or 60 ng / ml to 150 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is between 50 ng / ml and 100 ng / ml or between 60 ng / ml and 100 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is between 80 ng / ml and 100 ng / ml. The range includes both extremes as well as any subranges therebetween.

In some embodiments, the patient is administered periodically, e.g., once, twice, three times, four times, or five times, with a Norbitogen, a Norbitogen derivative, or a salt and / or solvate thereof. In some embodiments, the administration is once a day, once every two days, once every three days, three times a week, twice a week, or once a week. The dosage and frequency of administration depend, without limitation, on the route of administration, the content of the composition, the age and weight of the patient, and the condition of the patient. Determination of the appropriate dose and frequency for this technique can be easily made by a qualified clinician.

In one aspect, the invention provides a method of treating a human being, comprising administering to a patient a dosage of a norbobene or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of from about 50 ng / ml to about 180 ng / Wherein the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 500 ms during the treatment. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment.

In one embodiment, the QT interval does not extend beyond about 50 ms. In one embodiment, the QT interval does not extend beyond about 40 ms. In one embodiment, the QT interval does not extend beyond about 30 ms. In a preferred embodiment, the QT interval does not extend beyond about 20 ms. In one embodiment, the QT interval does not extend beyond about 10 ms.

Norvigornine, Norbigovane derivatives, or pharmaceutically acceptable salts and / or solvates thereof may also be in the form of pharmaceutical preparations such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, Can be used with any vehicle and excipient conventionally used in non-aqueous solvents, oils, paraffin derivatives, glycols and the like. Coloring agents and flavoring agents may also be added to the formulation, especially for oral administration. The solution may be prepared using water or a physiologically compatible organic solvent such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerin and the like. Parenteral compositions containing the norbornene phosphorus may be prepared using conventional techniques, including sterile saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, .

Anxiety, etc.

As will be apparent to those of ordinary skill in the art upon reading this disclosure, the present invention provides a method of treating a patient, comprising administering to a patient a therapeutically effective amount of a norbyeene, a derivative thereof, or a pharmaceutically acceptable salt and / A method of treating anxiety disorder, impulse control disorder, anger / violence-related disorder, or modulation of food intake in a patient in need of such treatment. In a preferred embodiment, the patient is not addicted to cocaine or opiate. Norbigovane derivatives include, but are not limited to, the compounds described in the "Composition of the Invention" section above.

The following description of anxiety disorders and impulse control disorders is provided for the purpose of facilitating an understanding of the utility of the compounds and compositions of the present invention. Disorders related to violence and / or anger are included in these descriptions. Definitions of anxiety disorders and impulse control disorders provided below are listed in the American Psychiatric Association, 2013, American Psychiatric Association, 1994a, or the American Psychiatric Association, 1987. Further information on these disorders can be found in this reference as well as in other references listed below, all of which are incorporated herein by reference.

Anxiety disorders include panic disorder, agoraphobia with or without a history of panic disorder, specific phobias, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, and generalized anxiety disorder. The compounds of the present invention are expected to be effective in treating these patients in patients diagnosed with this disorder.

The present invention provides a method of treating a patient suffering from anxiety, comprising administering to the patient an amount of any of the compounds described herein effective to treat anxiety in the subject.

It is contemplated that the compounds described herein may be effective in treating obsessive-compulsive disorders based on the administration of appropriate tests, including, but not limited to, any of the following: Yale Brown Obsessive Compulsive Scale (YBOCS) ), The US National Institute of Mental Health Overall OCD Scale (NIMH GOCS), and CGI-severity scale. In addition, the compounds described herein are expected to be effective in inducing an improvement in the reduction of some of the scores in a particular score, such as the YBOCS total score, measured in these tests. It is also contemplated that the compounds described herein will be effective in preventing the recurrence of impulsive impulsive disorder.

The present invention provides a method of treating obsessions and impulses in a patient having an obsessive-compulsive disorder comprising administering to the patient an effective amount of a compound of any of the present invention effective to treat obsessive-compulsive disorder of the subject.

The compounds described herein are expected to be effective in treating panic disorders in patients diagnosed with a panic disorder based on the frequency of recurrence of a panic attack or by a measure of severity of CGI-disease. In addition, the compounds described herein may be used to improve certain factors measured in these assessments, such as a reduction in frequency or elimination of panic attacks, a severity scale of CGI-disease or an improvement in CGI-overall improvement score of 1 (very much improved) (Much improved) or 3 (least improved). It is also contemplated that the compounds described herein will be effective in preventing the recurrence of panic disorders.

The present invention provides a method of treating panic disorder with or without agoraphobia in a subject comprising administering to the patient a therapeutically effective amount of a compound of any of the present invention for treating a panic disorder of the subject .

It is contemplated that the compounds described herein may be effective in treating social anxiety disorders diagnosed as having a social anxiety disorder based on administration of any of the following tests: Levovitz Social Anxiety Scale (LSAS), CGI-Disease The Hamilton Rating Scale for Depression (HAM-D), the Hamilton Rating Scale for Depression (HAM-D), the V-axis Social and Vocational Function Assessment Scale for DSM-IV, the II Axis (ICD-10) (WHOQOL-100), which is incorporated herein by reference in its entirety, as well as the information provided in the book &apos; Disability Assessment, Schedule 2 (DAS-2), Easy Disability Scale, Schneider Disability Profile, Other tests such as bars. In addition, the compounds described herein may be used in a variety of forms, such as those from the Levobitsu Social Anxiety Inventory (LSAS), or from the CGI-Overall Improvement Score 1 (very much improved), 2 (much improved), or 3 It is assumed that it will be effective in inducing the improvement measured by the test. It is also contemplated that the compounds described herein will be effective in preventing the recurrence of social anxiety disorder.

The present invention provides a method of treating a social anxiety disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any of the present invention for treating a social anxiety disorder of the subject.

It is contemplated that the compounds used in the present invention may be effective in treating generalized anxiety disorders in patients diagnosed with a generalized anxiety disorder based on the diagnostic criteria described in DSM-IV or DSM-5. In addition, the compounds used in the present invention are expected to be effective in reducing the symptoms of this disorder, such as: excessive anxiety and anxiety, difficulty in controlling anxiety, lack of calm or tension, feeling of restlessness, Difficulty in getting, concentrating or emptying the pubes, infertility, muscle tension and sleep disorders. It is also contemplated that the compounds described herein will be effective in preventing recurrence of generalized anxiety disorders.

The invention provides a method of treating a generalized anxiety disorder in a subject comprising administering to the patient an amount of any of the compounds described herein effective to treat a generalized anxiety disorder of the subject.

Impulse control disorders include pathological gambling (PG), pathologic wall wall, TTM, intermittent explosive disorder (IED), and pathological arson. Impulse control disorders may also be associated with a variety of conditions, including PSP, impulsive behavior, impulsive purchasing (CB), conduct disorder, antisocial personality disorder, rebellious personality disorder, borderline personality disorder, attention deficit / hyperactivity disorder , ADHD including ADD), asthma, mood disorders, sexual arousal, and Internet addiction. Symptoms of impulse control disorder include repetitive participation in behavior despite reduced adverse outcomes, reduced control of behavior, impulsive / obsessive-related behaviors, and good feeling during participation in behavior.

It is contemplated that the compounds used in the present invention may be effective in treating impulse control disorders in patients with at least one impulse control disorder based on the diagnostic criteria described in DSM-IV or DSM-5. In addition, the compounds used in the present invention are expected to be effective in reducing the symptoms of this disorder, including impulsivity or lack of self-regulation. It is also contemplated that the compounds described herein will be effective in preventing recurrence of impulse control disorders.

It is contemplated that the compounds used in the present invention may be effective in treating ADHD or ADD in patients with a disorder based on the diagnostic criteria described in DSM-IV or DSM-5. In addition, the compounds used in the present invention are expected to be effective in reducing the symptoms of this disorder, including impulsivity or lack of self-regulation. It is also contemplated that the compounds described herein will be effective in preventing recurrence of ADD or ADHD.

It is contemplated that the compounds used in the present invention may be effective in treating asthma in patients with a disorder based on the diagnostic criteria described in DSM-IV or DSM-5. Chorea is characterized by delusions, hallucinations, broken language and behavior, and other symptoms that cause social or occupational dysfunction. In addition, the compounds used in the present invention are expected to be effective in reducing the symptoms of this disorder. It is also contemplated that the compounds described herein will be effective in preventing recurrence of asthma.

The compounds described herein may be used in patients diagnosed with this disorder based on the expression of a patient with a symptom involving intentional tissue damage without suicidal will (e.g., amputation, burn, intoxication or self-harm) It is expected to be effective in treating impairment disorders. In addition, the compounds described herein are contemplated to be effective in inducing an improvement in certain of these factors, such as the frequency of self-injury or a reduction in elimination. It is also contemplated that the compounds described herein may be effective in preventing the recurrence of non-suicidal autoimmune disorders.

The invention provides a method of treating a non-suicidal self-injury disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any of the invention, for treating a non-suicidal self- &Lt; / RTI &gt;

It is contemplated that the compounds described herein will be most effective in treating muhnhausen syndrome based on the patient's tendency to most illness, illness, or psychological trauma leading to attention, empathy, or reassurance of the patient herself. Symptoms include frequent hospitalizations, knowledge of some diseases, frequent requests for medications (eg, analgesics), no need for large-scale surgery, little or no visitors during hospitalization, and exaggerated or fictional stories about various medical problems . In addition, the compounds described herein are contemplated to be effective in inducing improvements in certain of these factors, e. G., Reducing or eliminating the frequency of one or more symptoms. It is also contemplated that the compounds described herein will be effective in preventing the recurrence of the Munich Hausen syndrome. Münhausen syndrome also includes Münhausen syndrome by an agent, in which the caregiver exaggerates, fakes, or induces someone's illness in his / her care.

The present invention provides a method of treating muhnhausen syndrome in a subject comprising administering to the patient a therapeutically effective amount of a compound of any of the present invention for treating a subject's muchnhausen syndrome.

The compounds described herein are believed to be effective in treating destructive mood disorders in patients diagnosed with this disorder based on mood and recurrent mood explosive, irritation or exaggerated compared to the situation as well as persistent irritability / do. In addition, the compounds described herein are contemplated to be effective in inducing improvements in certain of these factors, such as reducing or eliminating the frequency of property explosions and / or improving mood. It is also contemplated that the compounds described herein will be effective in preventing the recurrence of a destructive mood-control disorder.

The present invention provides a method of treating a destructive mood disorder disorder in a subject comprising administering to the subject a therapeutically effective amount of a compound of any of the present invention for treating a disorder of a disorder of the mood of the subject .

It is contemplated that the compounds used in the present invention may be effective in reducing the frequency, intensity and duration of anger and / or violence in individuals who are prone to one or both of anger or violence. Anger and violence disorders other than those associated with other disorders (e. G., As described above) are not outlined in DSM IV or DSM 5, but many health professionals recognize that such disorders are associated with significant dysfunction. Anger management training and other psychosocial treatments are often used in an effort to treat these individuals.

It is contemplated that the compounds used in the present invention may be effective in controlling food intake and / or modulating food intake in a patient in need of food control or reduction. In some embodiments, the patient is overweight. In some embodiments, the subject is obese. In some embodiments, the patient is suffering from overweight / obesity, such as coronary heart disease, hypertension, stroke, type 2 diabetes, abnormal levels of blood fat, metabolic syndrome, cancer, osteoarthritis, sleep apnea, Represents the comorbidity involved.

In a preferred embodiment, the invention provides a method of treating anxiety disorders in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a norbobagene derivative, or a pharmaceutically acceptable salt and / or solvate thereof, , A method of treating impulse control disorder, OCD, and / or an anxiety / violence-related disorder, or a food intake and / or treatment, wherein the patient is not addicted to cocaine or opiate, Effective amounts provide serum levels of about 50 to about 180 ng / ml of an average norbid. In some embodiments, the serum level is less than about 50 ng / ml, wherein the average Norberger is provided by the dosage. In one embodiment, the therapeutically effective amount is from about 1 mg to about 4 mg / kg body weight. In one embodiment, the therapeutically effective amount is from about 50 ng to about 100 μg / kg body weight. In one embodiment, an anxiety disorder is treated. In one embodiment, the OCD is treated. In one embodiment, impulse control disorders are treated. In one embodiment, the anger-related disorder is treated. In one embodiment, the violence-related disorder is treated. In one embodiment, anger symptoms are reduced or eliminated. In one embodiment, violent ejection is reduced or eliminated. In one embodiment, the food intake is regulated. In one embodiment, the meals are weakened. In one embodiment, the Norvigor, Norbigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery.

Dosage and route of administration

In some embodiments, the composition is administered via sublingual, intranasal, or intrapulmonary delivery. In one aspect, the invention provides a pharmaceutical composition comprising a pharmaceutical composition comprising a pharmaceutically effective amount of a norbogen and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of the norbomene is from about 50 ng to about 100 μg / Kg body weight / day of Norwegian boron. In some aspects, a therapeutically effective amount of Norbitcogen is an amount that delivers a total amount of Norbitcine phosphorus of from about 50 ng to about 50 μg / kg body weight per day. In some aspects, a therapeutically effective amount of Norbogophane is an amount that delivers a total amount of Norbogophane of about 50 ng to about 10 μg / kg body weight per day. In some aspects, a therapeutically effective amount of Norbitcogen is an amount that delivers a total amount of Noribucogloin from about 50 ng to about 1 μg / kg body weight per day. In some aspects, the composition is administered once per day. In some aspects, the composition is administered more than once per day. In some embodiments, the composition is administered less than once per day, for example once every two days, once every three days, once every four days, once a week, and the like.

In some embodiments, the composition is administered via oral, buccal, transdermal, intravenous, pulmonary, rectal, nasal, vaginal, tongue, intravenous, intraarterial, intramuscular, intraperitoneal, intradermal or subcutaneous delivery.

In one embodiment, the dosage or total dosage of the compound is from about 1 mg to about 4 mg / kg body weight per day. The total dosage is the total amount of the combined dose, for example, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the Norvigor is administered over a 24 hour period, and a smaller amount is administered once per day Lt; / RTI &gt;

In some embodiments, the patient is administered periodically, e.g., once, twice, three times, four times, or five times, with a Norbitogen, a Norbitogen derivative, or a salt and / or solvate thereof. In some embodiments, the administration is once a day, once every two days, once every three days, three times a week, twice a week, or once a week. The dosage and frequency of administration depend, without limitation, on the route of administration, the content of the composition, the age and weight of the patient, and the condition of the patient. Determination of the appropriate dose and frequency for this technique can be easily made by a qualified clinician.

In another embodiment, unit doses of a Norbigand derivative, or a salt or solvate thereof, wherein the Norbiga is from about 50 mg to about 200 mg per dose, are provided. In one embodiment, the unit dose is from about 50 to about 120 mg per dose. In one embodiment, the unit dose is about 120 mg per dose. The term "unit dose" should be understood to mean a dose sufficient to provide a therapeutic result either once or continuously over a period of time.

In one aspect, the invention provides a method of treating a patient comprising administering to a patient a dosage of a norbobene or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of from about 50 ng / ml to about 180 ng / ml A method of attenuating the symptoms of anxiety disorders, impulse control disorders, or anger and / or violence-related disorders in a human patient, wherein the concentration attenuates the symptoms while a QT interval of less than about 500 ms Lt; / RTI &gt; In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during the treatment. Preferably, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during the treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during the treatment.

In one aspect, the invention provides a method comprising administering to a patient a dosage of a Norbitogen or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of from about 50 ng / ml to about 400 ng / ml , A method of attenuating a sextant in a human patient, said concentration being sufficient to attenuate said craving while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate the craving while maintaining a QT interval of less than about 470 ms during the treatment. Preferably, the concentration is sufficient to attenuate the craving while maintaining a QT interval of less than about 450 ms during the treatment. In one embodiment, the concentration is sufficient to attenuate the craving while maintaining a QT interval of less than about 420 ms during the treatment.

In one embodiment, the QT interval does not extend beyond about 50 ms. In one embodiment, the QT interval does not extend beyond about 40 ms. In one embodiment, the QT interval does not extend beyond about 30 ms. In a preferred embodiment, the QT interval does not extend beyond about 20 ms. In one embodiment, the QT interval does not extend beyond about 10 ms.

Norvigornine, Norbigovane derivatives, or pharmaceutically acceptable salts and / or solvates thereof may also be in the form of pharmaceutical preparations such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, Can be used with any vehicle and excipient conventionally used in non-aqueous solvents, oils, paraffin derivatives, glycols and the like. Coloring agents and flavoring agents may also be added to the formulation, especially for oral administration. The solution may be prepared using water or a physiologically compatible organic solvent such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerin and the like. Parenteral compositions containing the norbornene phosphorus may be prepared using conventional techniques, including sterile saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, .

Continuous treatment

As will be clear to those skilled in the art upon reading this disclosure, one aspect of the present invention provides a method of treating a condition in a patient, wherein the condition is selected from the group consisting of a Norbitogen, a Norbitogen derivative, Salt or solvate thereof, wherein the method comprises administering to the patient a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a therapeutically effective amount of a non- Acceptable salt or solvate thereof, followed by an at least one additional dose of a norbyeene, a norbyeene derivative, or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, the invention provides a method of treating a condition in a patient that can be treated with a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, while maintaining an acceptable QT interval prolongation in the patient , Said method comprising the steps &lt; RTI ID = 0.0 &gt;

a) Or a pharmaceutically acceptable salt or solvate thereof, wherein said unit dose comprises a therapeutically effective amount of a therapeutically effective amount of a compound of formula &lt; RTI ID = 0.0 &gt; Providing an average serum concentration of 180 ng / ml; And

b) Wherein the at least one additional dose is at least one additional dose of Norviga so as to maintain an average serum concentration of between about 50 ng / ml and about 180 ng / ml during treatment, or a pharmaceutically acceptable salt or solvate thereof &Lt; / RTI &gt; wherein said serum concentration is maintained;

The additional dose or doses continue if necessary to treat the condition.

In an aspect, the serum concentration provides a maximum QT interval of less than about 500 ms during the treatment. In some embodiments, the serum concentration provides a maximum QT interval of less than about 470 ms during the treatment. Preferably, the serum concentration provides a maximum QT interval of less than about 450 ms during the treatment. In one embodiment, the serum concentration provides a maximum QT interval of less than about 420 ms during the treatment.

In one embodiment, the QT interval does not extend beyond about 50 ms. In one embodiment, the QT interval does not extend beyond about 40 ms. In one embodiment, the QT interval does not extend beyond about 30 ms. In one embodiment, the QT interval does not extend beyond about 20 ms. In one embodiment, the QT interval does not extend beyond about 10 ms.

In one embodiment, the average serum concentration of the norbornene phosphorus is between 50 ng / ml and 180 ng / ml or between 60 ng / ml and 180 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphor is from 50 ng / ml to 150 ng / ml or 60 ng / ml to 150 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is between 50 ng / ml and 100 ng / ml or between 60 ng / ml and 100 ng / ml. In one embodiment, the average serum concentration of the norbobene phosphorus is between 80 ng / ml and 150 ng / ml. In one embodiment, the average serum concentration of the norbornene phosphorus is between 80 ng / ml and 100 ng / ml. In some aspects of the invention, lower serum concentrations may be therapeutic for a given condition. In one embodiment, the therapeutic serum concentration is from 1 ng / ml to 10 ng / ml. By way of non-limiting example, the therapeutic serum concentration for the treatment of nicotine addiction is believed to be lower than for addiction to opioids. The range includes both extremes as well as any subranges therebetween. In some embodiments, the initial unit dose of the Norvigor, Norvigor derivative, or salt or solvate thereof is 50 mg to 120 mg. In one embodiment, the initial dose is about 50 mg. In one embodiment, the initial dose is about 55 mg. In one embodiment, the initial dose is about 60 mg. In one embodiment, the initial dose is about 65 mg. In one embodiment, the initial dose is about 70 mg. In one embodiment, the initial dose is about 75 mg. In one embodiment, the initial dose is about 80 mg. In one embodiment, the initial dose is about 85 mg. In one embodiment, the initial dose is about 90 mg. In one embodiment, the initial dose is about 95 mg. In one embodiment, the initial dose is about 100 mg. In one embodiment, the initial dose is about 105 mg. In one embodiment, the initial dose is about 110 mg. In one embodiment, the initial dose is about 115 mg. In one embodiment, the initial dose is about 120 mg.

In some embodiments, the initial unit dose of the Norbitcogen, a derivative thereof, or a salt or solvate thereof, wherein the total dose is a unit dose, is administered as a sub-dose. In some embodiments, the initial unit dose is administered as a sub-unit dose continuously administered until a unit dose level is achieved, wherein the total sub-unit dose provides an initial unit dose and further provides a therapeutic average serum concentration . In some embodiments, the total dose provides a therapeutic serum concentration of 80 ng / ml to 150 ng / ml. In some embodiments, the lower dose is administered every 15 minutes to 6 hours until a unit dose is achieved. In some embodiments, the sub-dose is administered every 15 minutes, every 30 minutes, every hour, every 2 hours, every 3 hours, every 4 hours, every 5 hours, or every 6 hours until a unit dose is achieved. The range includes both extremes as well as any subranges therebetween.

In some embodiments, the at least one additional capacity is lower than the initial capacity. In one embodiment, the at least one additional dose is from 5 mg to 75 mg. In one embodiment, the one or more additional doses may or may not include a Norvigor derivative, or a salt or solvate thereof, wherein the same amount of Norvig is present. In one embodiment, the at least one additional dose is about 5 mg. In one embodiment, the at least one additional dose is about 10 mg. In one embodiment, the at least one additional dose is about 15 mg. In one embodiment, the at least one additional dose is about 20 mg. In one embodiment, the at least one additional dose is about 25 mg. In one embodiment, the at least one additional dose is about 30 mg. In one embodiment, the at least one additional dose is about 35 mg. In one embodiment, the at least one additional dose is about 40 mg. In one embodiment, the at least one additional dose is about 45 mg. In one embodiment, the at least one additional dose is about 50 mg. In one embodiment, the at least one additional dose is about 55 mg. In one embodiment, the at least one additional dose is about 60 mg. In one embodiment, the at least one additional dose is about 65 mg. In one embodiment, the at least one additional dose is about 70 mg. In one embodiment, the at least one additional dose is about 75 mg. The range includes both extremes as well as any subranges therebetween.

In one embodiment, one or more additional doses are administered periodically. In one embodiment, one or more additional doses are administered every 4 to 48 hours. In a preferred embodiment, one or more additional doses are administered every 6 hours to 24 hours. In one embodiment, one or more additional doses are administered every 4 hours. In one embodiment, at least one additional dose is administered every 6 hours. In one embodiment, at least one additional dose is administered every 8 hours. In one embodiment, at least one additional dose is administered every 10 hours. In one embodiment, at least one additional dose is administered every 12 hours. In one embodiment, at least one additional dose is administered every 18 hours. In one embodiment, at least one additional dose is administered every 24 hours. In one embodiment, at least one additional dose is administered every 36 hours. In one embodiment, at least one additional dose is administered every 48 hours. The range includes both extremes as well as any subranges therebetween. In some embodiments, a therapeutic dose of a Norbitogen, a Norbitogor derivative, or a salt or solvate thereof, is administered to a patient over a period of time, e.g., without suffering from significant acute withdrawal symptoms, Is decreasing. Without being constrained by theory, it is believed that diminishing is allowing the full therapeutic effect of the Norwegian phosphorus by extending the QT interval to a lesser extent. The diminution is accompanied by the administration of one or more successively less doses of Norvigovin, depending on time. For example, in some embodiments, the first gradually decreasing dose is from 50% to 95% of the initial or at least one additional dose. In some embodiments, the second gradually decreasing dose is between 40% and 90% of the initial or at least one additional dose. In some embodiments, the third gradually decreasing dose is between 30% and 85% of the initial or at least one additional dose. In some embodiments, the fourth gradually decreasing dose is between 20% and 80% of the initial or at least one additional dose. In some embodiments, the fifth gradually decreasing dose is between 10% and 75% of the initial or at least one additional dose.

 In some embodiments, a first gradually decreasing capacity is provided after the first capacity of the Norwegian phosphorus. In some embodiments, a first gradually decreasing capacitance is provided after the second, third, or subsequent capacitances of the NOR gate. The first gradually decreasing dose can be administered at any time after the previous dose of the Norwegian phosphorus. The first gradually decreasing capacity may be provided once, for example, a subsequent additional increasingly decreasing capacity may be provided, or a subsequent further decreasing capacity may be provided (e.g., second, third, fourth, etc.) With or without increasingly shrinking capacity, and, for example, an increasingly shrinking dose can be provided over a single circuit or multiple doses. In some embodiments, the first gradually decreasing dose is administered at about 1 hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours or more after the previous dose of Norwegian phosphorus. Similarly, the gradually decreasing capacity of the second, third, fourth, etc., if provided, is about 1 hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours As shown in FIG.

In some embodiments, the capacity begins to decrease from 12 to 96 hours after the initial dose. In some embodiments, the capacity begins to decrease at 12 hours after the initial dose. In some embodiments, the capacity begins to decrease at 18 hours after the initial dose. In some embodiments, the capacity begins to decrease at 24 hours after the initial dose. In some embodiments, the capacity begins to decrease at 30 hours after the initial dose. In some embodiments, the capacity begins to decrease at 36 hours after the initial dose. In some embodiments, the capacity begins to decrease at 42 hours after the initial dose. In some embodiments, the capacity begins to decrease at 48 hours after the initial dose. In some embodiments, the capacity begins to decrease at 54 hours after the initial dose. In some embodiments, the capacity begins to decrease at 60 hours after the initial dose. In some embodiments, the capacity begins to decrease at 66 hours after the initial dose. In some embodiments, the capacity begins to decrease at 72 hours after the initial dose. In some embodiments, the capacity begins to decrease at 78 hours after the initial dose. In some embodiments, the capacity begins to decrease at 84 hours after the initial dose. In some embodiments, the capacity begins to decrease at 90 hours after the initial dose. In some embodiments, the capacity begins to decrease at 96 hours after the initial dose.

In some embodiments, the at least one additional dose is administered between 4 hours and 24 hours after the initial unit dose. In some embodiments, the additional dose is administered between 4 hours and 24 hours after the previous dose. In some embodiments, the dose is administered every 4 to 24 hours. In some embodiments, the dose is administered as needed. The dosage and frequency of administration depend, without limitation, on the route of administration, the content of the composition, the age and weight of the patient, and the condition of the patient. Determination of the appropriate dose and frequency for this technique can be easily made by a qualified clinician.

In some embodiments, the dose is administered at various time points. That is, each dose need not be administered at the same interval as the previous dose. In some embodiments, additional doses are administered more frequently at the beginning of treatment and less frequently after a certain time. For example and without limitation, withdrawal symptoms are most severe in the first 72 hours after the last dose of the addiction medication. Norbigovir, Norbigovir derivatives, or a pharmaceutically acceptable solvate or salt thereof may be administered, for example, every 4 to 12 hours for the first 72 hours and then less frequently (for example, 12 hours To 24 hours).

In some embodiments, the Norvigor, Norvigor, or a pharmaceutically acceptable salt or solvate thereof is administered for an indefinite period of time (e.g., up to the life of the patient for months or years).

In some embodiments, the subject may suffer long-term (e. G., One year or longer) treatment with a retention dose of the Norbigand, Norbogor derivative, or salt or solvate thereof. In some embodiments, the patient is first treated for an acute symptom with a therapeutic dose of a Norbogophane as described above, and then the amount of Norbogophane is administered, e.g., after the acute symptom is expected to settle, And is reduced to the holding capacity. This is particularly appropriate for the treatment of drug addiction, since acute withdrawal symptoms can last as long as one week, but acute withdrawal symptoms are most pronounced during the first 48 to 72 hours after the withdrawal of addiction drugs in general.

Patient pre-screening and monitoring

Monitoring of the patient during pre-treatment and / or treatment with a Norbitogen derivative, or a pharmaceutically acceptable salt and / or solvate thereof, of a pre-treatment patient with a Norbitogarin, May be necessary to ensure that For example, a QT interval of greater than about 500 ms may account for the risk to an individual patient. Pre-screening and / or monitoring may be essential for treatment with high levels of Norvasc.

In a preferred embodiment, a patient receiving a therapeutic dose of Norbigovirus is monitored in a clinical setting. Monitoring may be necessary to ensure that the QT interval is not extended to an unacceptable degree. "Clinical situation" refers to an outpatient condition (e.g., an inpatient clinic, hospital rehabilitation facility) or an outpatient condition due to frequent and regular monitoring (e.g., ). Monitoring includes monitoring of the QT interval. Methods for monitoring the QT interval are well known in the art, for example by ECG.

In one embodiment, a patient receiving a retention dose of a Norwegian phosphorus is not monitored in a clinical setting. In one embodiment, a patient receiving a retention dose of a Norwegian phosphorus is administered periodically, e. G. Daily, weekly, monthly or occasionally.

In one aspect, the invention provides a method of treating a patient in need of such treatment comprising administering to a patient a dosage of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt or solvate thereof, which provides a mean serum concentration of from about 50 ng / ml to about 180 ng / Prevention or attenuation of a disease or disorder or a symptom of a disease or disorder as described herein pre-screened to assess a patient &apos; s anticipated tolerability for prolongation of the QT interval, comprising the steps of: Is sufficient to inhibit or improve abuse or symptoms while maintaining a QT interval of less than about 500 ms during the treatment. In some embodiments, the concentration is sufficient to attenuate the abuse or symptom while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to weaken the abuse or symptom while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the abuse or symptom while maintaining a QT interval of less than about 420 ms during treatment.

In one embodiment, pre-screening of a patient includes confirming that treatment with Norbigbore does not result in a maximum QT interval over approximately 500 ms. In one embodiment, the pre-screening of the patient includes confirming that the treatment in which the Norwegian boron does not result in a maximum QT interval over about 470 ms. In one embodiment, the pre-screening comprises confirming that the treatment in which the Norwegian bone does not result in a maximum QT interval over about 450 ms. In one embodiment, the pre-screening comprises verifying that the treatment in which the Nyborg does not result in a maximum QT interval over about 420 ms. In one embodiment, the pre-screening comprises determining a pre-treatment QT interval of the patient.

The patient can be selected based on any criteria as determined by a skilled clinician, if the patient is about pre-selection or pre-selection. These criteria include, by way of non-limiting example, a pre-treatment QT interval, a pre-existing cardiac condition, a risk of a cardiac condition, age, sex, The following are examples of selection criteria for limiting the dose of Norvigovin that does not tolerate or is administered to a patient: a high QT interval before treatment (e.g., To be at risk of QT interval); Congenital long QT syndrome; Bradycardia; Hypokalemia or hypomagnesemia; Recent acute myocardial infarction; Non-affective heart failure; And other medications that increase QT interval. In some embodiments, the method may comprise selecting and / or administering / providing a Norviga phosphorus to a patient without one or more of these criteria.

In one embodiment, the invention relates to preselecting a patient to determine whether the patient is at risk for prolongation of the QT interval above a safe level. In one embodiment, a patient at risk of prolongation of the QT interval above a safe level is not administered with Norwegian phosphorus. In one embodiment, a patient at risk of prolonging the QT interval above a safe level is administered a Norwegian bovine with a limited dosage.

In one embodiment, the present invention is directed to monitoring a patient to which a therapeutic dose of Noribogloin has been administered. In one embodiment, if the patient has severe adverse side effects, the dose of Norvigulin is reduced. In one embodiment, if the patient has severe adverse side effects, the treatment with Norbigovan is discontinued. In one embodiment, the adverse side effect is a QT interval that extends beyond a safe level. The determination of the safe level of extension is within the skills of a qualified clinician.

In an aspect, the invention includes selecting a patient exhibiting symptoms of a preselected anxiety disorder, an impulse control disorder, or an anger / violence-related disorder to assess a patient &apos; s anticipated tolerability for prolongation of the QT interval Or a pharmaceutically acceptable salt and / or solvate thereof, to a patient in need thereof, wherein the medicament is administered to a patient in an amount effective to provide a mean serum concentration of from about 50 ng / ml to about 850 ng / A method of treating or ameliorating anxiety disorders, impulse control disorders, or anger / violence-related disorders in a subject, and / or treating or ameliorating symptoms thereof, wherein said concentration inhibits or ameliorates said disorder or condition, Is sufficient to maintain a QT interval of less than about 500 ms during the treatment. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment.

In one aspect, the invention includes selecting a preselected overweight or obese patient to assess a patient &apos; s anticipated tolerability for prolongation of the QT interval, wherein the patient is administered an average of about 50 ng / ml to about 180 ng / Administering a dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the Norbitogen is at least one selected from the group consisting of: Wherein said concentration is sufficient to inhibit or ameliorate said disorder or condition while maintaining a QT interval of less than about 500 ms during said treatment.

Kit Parts

An aspect of the present invention relates to a kit component for treating a condition in a patient treatable with a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, Or a salt or solvate thereof, and means for administering the composition to a patient in need thereof. Means for administration to a patient can be, for example, a pharmaceutically acceptable formulation, including, for example, a nordoborgain, or a nordoborgain derivative, or a pharmaceutically acceptable salt or solvate thereof (For example, without limitation, an IV bag comprising a syringe, a needle, a composition, a vial containing the composition, a composition, or the like) for preparing and / or administering a formulation, Included inhaler Etc.). &Lt; / RTI &gt; In one embodiment, the kit component further comprises instructions for dosing and / or administration of the composition.

In some aspects, the present invention is directed to a kit component for administration of a Norwegian phosphorus, wherein the kit comprises a plurality of delivery vehicles and includes a dosing treatment schedule with selectively readable media, Of the norbornene phosphorus, and, further, each delivery vehicle is identified by the amount of Norwegian phosphorus provided to it. In some embodiments, the medication treatment schedule includes providing the amount of Norvigli phosphor needed to achieve each average serum level. In some embodiments, the kit part comprises a medication treatment schedule that provides the physician with the ability to select a dosing regimen of the Norwegian population based on the patient's sex, the patient &apos; s body weight, and the serum level to be achieved by the clinician . In some embodiments, the medication treatment schedule further provides information corresponding to the patient's blood volume based on the patient's body weight (or weight) and gender. In an embodiment, the storage medium may contain similar recorded information accompanied by a unit volume form in the accompanying pamphlet or kit. In an embodiment, the storage medium may comprise electronic, optical or other data storage, such as non-volatile memory, for example to store a digitally-encrypted machine-readable representation of such information.

The term "delivery vehicle " as used herein refers to any formulation that can be used for the administration of a Norwegian phosphorus to a patient. Non-limiting, exemplary delivery vehicles include dragees, pills, capsules, tablets, powders, liquids or any other form in which the drug can be administered. The delivery vehicle may be intended for administration by oral, inhalation, insufflation, or by any other means.

The term "readable medium" as used herein refers herein to a representation of data that can be read, for example, by a human or by a machine. Non-limiting examples of human-readable forms include pamphlets, inserts, or other written forms. Non-limiting examples of machine-readable forms include any machine that provides (i.e., stores and / or delivers) information in a form readable by a machine (e.g., computer, tablet and / or smartphone) . For example, the machine-readable medium may comprise read only memory (ROM); Random access memory (RAM); Magnetic disk storage media; Optical storage media; And a flash memory device. In one embodiment, the machine-readable medium is a CD-ROM. In one embodiment, the machine-readable medium is a USB drive. In one embodiment, the machine-readable medium is a Quick Response Code (QT code) or other matrix bar code.

In some aspects, the machine-readable medium includes software that contains information about a dosing schedule for a unit dosage form of Norwegian boron and optionally other drug information. In some embodiments, the software may be interactive so that the attending physician or other medical professional may enter patient information. In a non-limiting example, the medical professional may enter the weight and gender of the patient to be treated, and the software program provides the recommended medication therapy based on the input information. The amount and time of the recommended norbyborin to be delivered will be within a dosage that results in a serum concentration as provided herein.

In some embodiments, kit parts include multiple delivery vehicles with various dosage options. For example, the kit part may contain tablets or tablets at various dosages such as 120 mg, 90 mg, 60 mg, 30 mg, 20 mg, 10 mg, and / or 5 mg of noriboglobin per tablet. Each pellet is labeled so that the medical professional and / or patient can easily distinguish between different dosages. Labeling may be based on printing or incidence on the pill, the shape of the pill, the color of the pill, the location of the pellets within the separate labeled pellets within the kit, and / or other distinctive features of the pellet. In some embodiments, all delivery vehicles in the kit are intended for one patient. In some embodiments, the delivery vehicle in the kit is intended for multiple patients.

An aspect of the invention relates to kit parts for the treatment, prevention, or attenuation of the disease or disorder or disorder or disorder described herein, the kit comprising a Norbitogen, a Norbitogen derivative, or a salt or solvent thereof It includes unit type of cargo. The unit dosage form provides the patient with an average serum level of Norvibogulin from about 50 ng / ml to about 180 ng / ml, or from about 60 ng / ml to about 180 ng / ml. The unit dosage form provides the patient with an average serum level of Norvibogloin from about 50 ng / ml to about 800 ng / ml, or from about 60 ng / ml to about 800 ng / ml. In one embodiment, the unit dosage form provides a patient with an average serum level of about 50 ng / ml to about 400 ng / ml, or about 60 ng / ml to about 400 ng / ml of Norvigl. In one embodiment, the unit dosage form provides the patient with an average serum level of Norvigovin from 80 ng / ml to 100 ng / ml.

In some embodiments, the unit dose of a Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof is from 20 mg to 120 mg. In one embodiment, the unit dose is 20 mg. In one embodiment, the unit dose is 30 mg. In one embodiment, the unit dose is 40 mg. In one embodiment, the unit dose is 50 mg. In one embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is 70 mg. In one embodiment, the unit dose is 80 mg. In one embodiment, the unit dose is 90 mg. In one embodiment, the unit dose is 100 mg. In one embodiment, the unit dose is 110 mg. In one embodiment, the unit dose is 120 mg.

In some embodiments, the unit dosage form is a multi-dose dose to be administered periodically, such as once, once, twice, three, four or five times by a Norwegian or prodrug thereof. In some embodiments, the administration is once a day, once every two days, once every three days, three times a week, twice a week, or once a week. The dosage and frequency of administration depend, without limitation, on the route of administration, the content of the composition, the age and weight of the patient, the condition of the patient, the sex of the patient, as well as the severity of the poisoning. Determination in the form of a unit dose that provides an appropriate dosage and frequency for a given patient can be readily made by a qualified clinician.

In some embodiments, the initial unit dose and one or more additional doses of a Norbitogen, a Norbitogen derivative, or a salt or solvate thereof, is administered once, once, or once per day by a Norbitogen or prodrug thereof, Such as once, twice, three times, four times, or five times per day. In some embodiments, the administration is once a day, once every two days, once every three days, three times a week, twice a week, or once a week. The dosage and frequency of administration depend, without limitation, on the route of administration, the content of the composition, the age and weight of the patient, the condition of the patient, the sex of the patient, as well as the severity of the poisoning. Determination in the form of a unit dose that provides an appropriate dosage and frequency for a given patient can be readily made by a qualified clinician.

In one aspect, a kit component is provided herein that comprises at least two doses of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein at least two doses are administered to the patient Or a pharmacologically acceptable salt or solvate thereof, wherein the pharmacologically acceptable salt thereof is at least one pharmacologically acceptable salt thereof, wherein the pharmacologically acceptable salt or solvate thereof is sufficient to maintain a serum concentration of 50 ng / ml to 180 ng / ml.

In one embodiment, one dose is an initial dose of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, sufficient to achieve a therapeutic serum concentration when administered to said initial dose patient ); And

At least one additional dose (said additional dose being sufficient to maintain a therapeutic serum concentration when administered to a patient), wherein the therapeutic serum concentration is from 50 ng / ml to 180 ng / ml. In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg.

These dosage ranges can be achieved by transdermal, oral, or parenteral administration of a Norbitcogen, a derivative thereof, or a pharmaceutically acceptable salt or solvate thereof, in unit dosage form. Such unit dosage forms can conveniently be provided in the form of transdermal patches, tablets, dragees, liquids or capsules. In certain embodiments, the Noriboggen is provided as HCl with Norbig, and the dosage is reported as the amount of the free base Norbigene. In some embodiments, the HCl, which is a Norbiter, is provided as a hard gelatin capsule containing only HCl, which is an excipient free norbober. In some embodiments, the Noribucogloin is provided in saline for intravenous administration.

Formulation

The present invention further relates to a pharmaceutically acceptable formulation comprising a unit dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the amount of Norbitogin is administered to the patient To about 50 ng / ml to about 180 ng / ml. In a preferred embodiment, the amount of Norviga phosphorus is sufficient to provide an average serum concentration of from about 80 ng / ml to about 100 ng / ml when administered to a patient. In one embodiment, the amount of the Norvigor, the Norvigor derivative, or a pharmaceutically acceptable salt thereof is an amount that delivers a total amount of Norvigovine of about 50 ng to about 10 μg / kg body weight / day.

In some embodiments, the unit dose of Norvigovin is administered in one or more dosages. The present invention further relates to a pharmaceutically acceptable formulation comprising a unit dose of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the amount of Norbitogin is administered to the patient And is sufficient to provide and / or maintain an average serum concentration of about 50 ng / ml to about 180 ng / ml. In a preferred embodiment, the amount of Norviga phosphorus is sufficient to provide and / or maintain an average serum concentration of 80 ng / ml to 100 ng / ml when administered to a patient.

In some embodiments, the unit dose of Norvigovin is administered in one or more dosages.

 In one embodiment, the amount of noribogan phosphorus is sufficient to provide an average serum concentration of norbobene from 50 ng / ml to 180 ng / ml or 60 ng / ml to 180 ng / ml. In one embodiment, the amount of Norvigov phosphorus is sufficient to provide an average serum concentration of norbobene from 50 ng / ml to 150 ng / ml or 60 ng / ml to 150 ng / ml. In one embodiment, the amount of Norviga phosphorus is sufficient to provide a mean serum concentration of Norvigans from 50 ng / ml to about 120 ng / ml, or from about 60 ng / ml to about 120 ng / ml. In one embodiment, the amount of Norviga phosphorus is sufficient to provide an average serum concentration of Norvigovane from about 50 ng / ml to about 100 ng / ml, or from about 60 ng / ml to about 100 ng / ml. In one embodiment, the amount of Noribucogloin is sufficient to provide an average serum concentration of Noribucogloin from about 50 ng / ml to about 120 ng / ml, or from about 60 ng / ml to about 120 ng / ml. In one embodiment, the amount of Norviga phosphorus is sufficient to provide an average serum concentration of Norvigovane from about 50 ng / ml to about 100 ng / ml, or from about 60 ng / ml to about 100 ng / ml. In one embodiment, the amount of noribogan phosphorus is sufficient to provide an average serum concentration of the norbobene of from about 80 ng / ml to about 100 ng / ml. The range includes both extremes as well as any subranges therebetween.

In some embodiments, the initial unit dose of a Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof is from about 50 mg to about 120 mg. In one embodiment, the unit dose is about 50 mg. In one embodiment, the unit dose is about 55 mg. In one embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is about 65 mg. In one embodiment, the unit dose is about 70 mg. In one embodiment, the unit dose is about 75 mg. In one embodiment, the unit dose is about 80 mg. In one embodiment, the unit dose is about 85 mg. In one embodiment, the unit dose is about 90 mg. In one embodiment, the unit dose is about 95 mg. In one embodiment, the unit dose is about 100 mg. In one embodiment, the unit dose is 105 mg. In one embodiment, the unit dose is about 110 mg. In one embodiment, the unit dose is about 115 mg. In one embodiment, the unit dose is about 120 mg.

In some embodiments, the at least one additional dose of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof is from 5 mg to 75 mg. In one embodiment, the unit dose is 5 mg. In one embodiment, the unit dose is 10 mg. In one embodiment, the unit dose is 15 mg. In one embodiment, the unit dose is 20 mg. In one embodiment, the unit dose is 25 mg. In one embodiment, the unit dose is 30 mg. In one embodiment, the unit dose is 35 mg. In one embodiment, the unit dose is 40 mg. In one embodiment, the unit dose is 45 mg. In one embodiment, the unit dose is 50 mg. In one embodiment, the unit dose is 55 mg. In one embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is 65 mg. In one embodiment, the unit dose is 70 mg. In one embodiment, the unit dose is 75 mg.

In some embodiments, the formulation comprises a delivery vehicle as described above. In one embodiment, the delivery vehicle comprises a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the dose is 5 mg to 120 mg of Norviga.

In some embodiments, the formulation is a controlled release formulation. The term " controlled release formulation "includes sustained release and time-release formulations. Controlled release formulations are well known in the art. These include excipients that enable continuous, periodic, pulsed or delayed release of the drug. Controlled-release formulations include, but are not limited to, the incorporation of a drug into a substrate; Enteric coating; Microcapsules; Gels and hydrogels; Implants; Transdermal patch; And any other formulations that enable controlled release of the drug.

In one embodiment, the amount of Norviga phosphorus is sufficient to provide an average serum concentration of Norviborgans of about 50 ng / ml to about 180 ng / ml, or about 60 ng / ml to about 180 ng / ml. In one embodiment, the amount of Norviga phosphorus is sufficient to provide an average serum concentration of Norviborgans of about 50 ng / ml to about 150 ng / ml, or about 60 ng / ml to about 150 ng / ml. In one embodiment, the amount of Noribucogloin is sufficient to provide an average serum concentration of Noribucogloins from about 50 ng / ml to about 120 ng / ml, or from about 60 ng / ml to about 120 ng / ml. In one embodiment, the amount of Noribucogloin is sufficient to provide an average serum concentration of Noribucogloins from about 50 ng / ml to about 100 ng / ml, or from about 60 ng / ml to about 100 ng / ml. In one embodiment, the amount of noribogan phosphorus is sufficient to provide an average serum concentration of from about 80 ng / ml to about 100 ng / ml of the norbornene phosphorus. The range includes both extremes as well as any subranges therebetween.

In some embodiments, the unit dose of the Norvigor, Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof is from about 20 mg to about 120 mg. In one embodiment, the unit dose is about 20 mg. In one embodiment, the unit dose is about 30 mg. In one embodiment, the unit dose is about 40 mg. In one embodiment, the unit dose is about 50 mg. In one embodiment, the unit dose is about 60 mg. In one embodiment, the unit dose is about 70 mg. In one embodiment, the unit dose is about 80 mg. In one embodiment, the unit dose is about 90 mg. In one embodiment, the unit dose is about 100 mg. In one embodiment, the unit dose is about 110 mg. In one embodiment, the unit dose is about 120 mg.

The present invention further relates to a pharmaceutically acceptable formulation comprising a unit dose of a Norvigor, a Norvigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the amount of Norvigain is administered to the patient Is sufficient to provide an average serum concentration of from about 50 ng / ml to about 850 ng / ml. In a preferred embodiment, the amount of noribogloin is sufficient to provide an average serum concentration of from about 50 ng / ml to about 400 ng / ml when administered to a patient.

In one embodiment, the amount of Norviga phosphorus is sufficient to provide an average serum concentration of Norvigovane from about 50 ng / ml to about 800 ng / ml, or from about 60 ng / ml to about 800 ng / ml. In one embodiment, the amount of Norviga phosphorus is sufficient to provide an average serum concentration of Norvigovane from about 50 ng / ml to about 700 ng / ml, or from about 60 ng / ml to about 700 ng / ml. In one embodiment, the amount of Noribucogloin is sufficient to provide an average serum concentration of Noribucogloins from about 50 ng / ml to about 600 ng / ml, or from about 60 ng / ml to about 600 ng / ml. In a preferred embodiment, the amount of Noribucogloin is sufficient to provide an average serum concentration of Noribucogloin from about 50 ng / ml to about 500 ng / ml, or from about 60 ng / ml to about 500 ng / ml. In one embodiment, the amount of Norviga phosphorus is sufficient to provide an average serum concentration of Norviborgans of about 50 ng / ml to about 400 ng / ml, or about 60 ng / ml to about 400 ng / ml. In one embodiment, the amount of Norviga phosphorus is sufficient to provide an average serum concentration of Norviborgans of about 50 ng / ml to about 300 ng / ml, or about 60 ng / ml to about 300 ng / ml. In one embodiment, the amount of Noribucogloin is sufficient to provide an average serum concentration of Noribucogloin from about 50 ng / ml to about 200 ng / ml, or from about 60 ng / ml to about 200 ng / ml. In one embodiment, the amount of Noribucogloin is sufficient to provide an average serum concentration of Noribucogloins from about 50 ng / ml to about 100 ng / ml, or from about 60 ng / ml to about 100 ng / ml. The range includes both extremes as well as any subranges therebetween.

In some embodiments, the formulations comprise a cyclic administration, such as once, twice, three, four or five times daily with a Norwegian, Norwegian derivative, or a pharmaceutically acceptable salt or solvate thereof . In some embodiments, the administration is once a day, once every two days, once every three days, three times a week, twice a week, or once a week. The dosage and frequency of administration depend, without limitation, on the route of administration, the content of the composition, the age and weight of the patient, and the condition of the patient. Determination of the dosage and frequency appropriate for this technique can be easily made by a qualified clinician.

In some embodiments, formulations designed for administration in accordance with the methods provided herein may be suitable for a variety of delivery routes, including, without limitation, oral, transdermal, sublingual, buccal, intrapulmonary or intranasal delivery. Formulations suitable for the body, lung, rectal, nasal, vaginal, tongue, intravenous, intraarterial, intramuscular, intraperitoneal, intradermal and subcutaneous routes may also be used. Possible formulations include tablets, capsules, pills, powders, aerosols, suppositories, parenteral and oral liquids (including suspensions, solutions and emulsions). Sustained-release formulations may also be used. All formulations can be prepared using methods that are standard in the art (see, for example, Remington ' s Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa., 1980).

In a preferred embodiment, the formulations are designed for oral administration which may conveniently be presented in tablet, dragee, sublingual, liquid or capsule form. In certain embodiments, the Noriboggen is provided as HCl with Norbig, and the dosage is reported as the amount of free base Norbigene. In some embodiments, the HCl, which is a Norbiter, is provided as a hard gelatin capsule containing only HCl, which is a no-booster, without an excipient.

Norvigorine or Norvigor derivatives are commonly used in pharmaceutical preparations such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or nonaqueous solvents, oils, paraffin derivatives, glycols and the like Lt; RTI ID = 0.0 &gt; vehicle &lt; / RTI &gt; Coloring agents and flavoring agents may also be added to the formulation, especially for oral administration. The solution may be prepared using water or a physiologically compatible organic solvent such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerin and the like. Parenteral compositions containing the norbornene phosphorus may be prepared using conventional techniques, including sterile saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, .

The compositions used herein may be formulated, particularly for aerosol administration to the respiratory tract and including intrapulmonary or intranasal administration. The compound will generally have a small particle size, for example, on the order of 5 microns or less. Such particle size can be obtained by means known in the art, for example by micronization. The active ingredient may be a pressurized pack with a suitable propellant such as chlorofluorocarbon (CFC), (e.g. dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane), carbon dioxide or other suitable gas . &Lt; / RTI &gt; Aerosols may also conveniently contain surfactants such as lecithin. The dose of the drug can be controlled by a metering valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose and polyvinylpyrrolidone . In some embodiments, the powder carrier will form a gel in the nasal cavity. The powder compositions may be presented in unit dose form, for example as capsules or cartridges, gelatin or blister packs, and the powders from them may be administered by inhaler.

The compositions used herein can be formulated for sublingual administration, for example, as sublingual tablets. The sublingual tablets are designed to dissolve very quickly. The formulations of these tablets contain, in addition to the drug, a limited number of soluble excipients, usually lactose and powdered sucrose, but sometimes dextrose and mannitol.

It has been found that Norwegian boron has a bitter taste for at least some patients. Thus, compositions for oral use (including sublingual, inhalation and other oral formulations) may be formulated using a taste masking technique. Addition of sugars, flavors, sweeteners or coatings; The use of lipid proteins, small spores, and / or liposomes; Granulation; Microencapsulation; Tidal paralysis; Multiple emulsion; Variation of viscosity; Prodrug or salt formation; Encapsulated or molecular complexes; Ion exchange resins; And solid dispersions, are well known in the art. Any method for determining the bitter taste of the compounds of the present invention may be used.

Example

The following examples are intended to further illustrate specific embodiments of the disclosure and are not intended to limit its scope.

Example  1. In humans Norwegian  Pharmacokinetics and Pharmacodynamics

Enrolled and completed 36 healthy, drug-free male volunteers from 18 to 55 years of age. This was a single elevated dose, placebo-controlled, randomized, double-blind, parallel group study. The mean (SD) age was 22.0 (3.3), the mean (SD) elongation was 1.82 (0.08) and the mean (SD) body weight was 78.0 (9.2) kg. 26 subjects were white, 3 were Asian, 1 was Maori, 1 was Pacific Islander, and 5 were guitar. The protocol for this study was approved by the Lower South Regional Ethics Committee (LRS / 12/06/015) and the study was approved by the Australian New Zealand Clinical Trial Registry (ACTRN12612000821897) . All subjects provided prior written consent before signing up and assessed their adequacy for participation based on a review of medical history, physical examination, safety laboratory tests, vital signs and ECG.

Within each dose level, six participants randomized to receive Norwegian boys and three receive placebo based on computer-generated randomized codes. The lowest Norwegian doses started dosing and the follow-up cohort received the highest dose after reviewing the safety, tolerability, and blind pharmacokinetics of the complete cohort and approval of dose-elevation by an independent data safety review committee. After at least 10 hours of overnight fasting, the blind study drug was administered as a capsule with 240 ml of water. Participants did not receive any food for at least 5 hours after dosing. Participants were confined to the study site from 12 hours before drug administration to 72 hours after dosing and there was follow-up outpatient evaluation by 216 hours after dosing.

0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, and 12 before the dosing for pharmacokinetic evaluation , 14, 18, 24, 30, 36, 48, 60, 72, 96, 120, 168 and 216 hours. Samples were centrifuged and plasma was stored at -70 C until analysis. A 30-hour urine collection was obtained after study drug administration for the 30 and 60 mg cohorts. The aliquots were frozen at -20 &lt; 0 &gt; C until analysis.

Pulse oximetry and capnography data were obtained using the GE Carescape B650 monitoring system from 2 hours before dosing and up to 6 hours after dosing and at 12, 24, 48 and 72 hours after dosing &Lt; / RTI &gt; Additional oximetry data were collected at 120, 168, and 216 hours. The pupil diameter was evaluated by pupil measurement. The dark-adapted pupil diameter was measured using a Neuroptics PLR-200 pupil under standardized light intensity (<5 lux) before dosing and at 2, 4, 6, 12, 24, 48, 72, 96, 120, And the measurement was repeated three times using a measuring instrument.

Plasma Norbogophore concentrations were determined in the 3 mg to 10 mg dose group using an effective, sensitive LCMSMS method. Sample preparation was accomplished by double extraction of the basicized plasma sample with tert-butyl methyl ether, drying of the sample under nitrogen flow, acetonitrile: BP water (5:95, v) containing 0.1% (v / v) / v). &lt; / RTI > Compounds were separated by a 150 × 2.0 mm Luna 5 μm C18 column and detected using a triple-quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization and multi-reaction monitoring in positive mode. It was used for the beams noreuyi -d ₄ as standard body. The precursor-product ion transfer value for the norbornene phosphorus was m / z 297.6 -> 122.3 and 301.1 -> 122.2 for -d ₄ m / z, which is the standard norbornene in the body. Analyst (R) software was used for data acquisition and processing. The maximum area ratio of -d _{4 in} the Norwegian standard of Norwegian boron is used for calibration and measurement of unknown concentrations of Norwegian boron. The lower limit of quantification (LLOQ) was 0.025 ng / ml Norwegian. The calibration curve was 0.025 to 25.600 ng / ml Norviga. Mobile phase A is acetonitrile: BP water (5:95, v / v) containing 0.1% (v / v) formic acid and mobile phase B is acetonitrile Water (95: 5, v / v). Total run time was 6 minutes. Binary flow: the initial concentration is 8% mobile phase B; Maintained at 8% mobile phase B for 0.5 min and linearly increased to 90% mobile phase B over 1.5 min; Held at 90% mobile phase B for 1 minute and then dropped again to 8% mobile phase B over 0.01 minutes. Equilibration system for 3 minutes. Total run time was 6 minutes. The precision of analysis between date and date was less than 9%, and the accuracy of analysis between dates and dates was less than 9%.

Plasma Norbogophore concentrations were determined in the 30 mg to 60 mg dose group using an effective, sensitive LCMSMS method. Sample preparation entailed dilution of samples using protease and 0.1% (v / v) formic acid in plasma samples using acetonitrile. Compounds were separated by a 150 x 2.0 mm column or a 5 μm C18 column and detected using a triple-quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization and multi-reaction monitoring in positive mode. It was used for the beams noreuyi -d ₄ as standard body. The precursor-product ion transfer value for the norbornene phosphorus was m / z 297.6 -> 122.3 and 301.1 -> 122.2 for -d ₄ m / z, which is the standard norbornene in the body. Analyst (R) software was used for data acquisition and processing. The maximum area ratio of -d _{4 in} the Norwegian standard of Norwegian boron is used for calibration and measurement of unknown concentrations of Norwegian boron. LLOQ was 0.50 ng / ml Norviga. The calibration curve was from 0.50 to 256.00 ng / ml Norviga. The mobile phase was the same as Method A and the binary flow was also the same as Method A. Analysis accuracy between dates and dates was less than 9%, and analysis accuracy between dates and between dates was less than 9%.

Glucuronide concentrations were determined in the 30 mg to 60 mg dose group using the effective sensitive LCMSMS method. Sample preparation was carried out using a sample of acetonitrile-based plasma sample, drying of the sample under a nitrogen stream and acetonitrile: BP water (5: 95, v / v) containing 0.1% (v / v) formic acid . Compounds were separated by a 150 x 2.0 mm column or a 5 μm C18 column and detected using a triple-quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization and multi-reaction monitoring in positive mode. It was used for the beams noreuyi -d ₄ as standard body. The precursor-product ion transfer value for the glucoside of norbornene was m / z 472.8 -> 297.3 and 301.1 -> 122.2 for -d ₄ m / z, which is the standard norbornene in the body. Analyst (R) software was used for data acquisition and processing. The maximum area ratio of the di-glucononide to the in-house standard norbigene-d ₄ was used for the calibration and measurement of unknown concentrations of glucuronides in the presence of Norbig. The LLOQ was 0.050 ng / ml Norwegian glucuronide. The calibration curve was glucuronide with 0.050 to 6.400 ng / ml of norbornene. The mobile phase was the same as in Method A. Binary flow: The initial concentration is 6% mobile phase B; Maintained at 6% mobile phase B for 0.5 min and linearly elevated to 90% mobile phase B over 2 min; Held at 90% mobile phase B for 1 min, then dropped again to 6% mobile phase B over 0.01 min. Balance maintenance system for 3.5 minutes. The total run time was 7 minutes. The accuracy of analysis between dates and dates was less than 11%, and the accuracy of analysis between dates and between dates was less than 10%.

The concentration of glucuronide in urine Norbigone and Norwegian boron was determined in the 30 mg to 60 mg dose group using the effective sensitive LCMSMS method. Sample preparation involved the dilution of the sample using protease and 0.1% (v / v) formic acid in a urine sample using acetonitrile. Compounds were separated by a 150 x 2.0 mm column or a 5 μm C18 column and detected using a triple-quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization and multi-reaction monitoring in positive mode. It was used for the beams noreuyi -d ₄ as standard body. The precursor-product ion transfer values for the norbornene phosphorus were m / z 297.6 -> 122.3, glucuronide m / z 472.8 -> 297.3 and 301.1 -> 122.2 for -d ₄ m / z, . Analyst (R) software was used for data acquisition and processing. Noreuyi beams and the beams of noreuyi glucuronic arsenide for a standard body noreuyi maximum area of the beams -d ₄ ratio was used for the calibration and the measurement of the unknown concentration of cyanide in the glucuronic noreuyi beams and the beams and their noreuyi . The analytical LLOQ was 20.0 ng / ml for Norbybogin and 2.0 ng / ml for glucoside with Norbig. The calibration curve was glucuronide with 20.0 to 5120.0 ng / ml Norviga and 2.0 to 512.0 ng / ml Norbigon. The mobile phase was as described in Method A and the binary flow was as in Method C. Analysis accuracy between dates and dates was less than 13% and analysis accuracy between dates and between dates was less than 12%.

Pharmacokinetic parameters using model-independent methods were calculated using glucuronide concentrations of Norwegian and Norwegian over the limit of quantitation. The maximum plasma concentration (Cmax) and the time to maximum plasma concentration (Tmax) were observed values. After the distribution step of the plasma concentration-time plot, the data were fitted using linear regression for the formula lnC = lnCo-t.Kel, where Co was the zero point slice at the extrapolation final step and Kel was the final removal rate constant Respectively. The half-life (t _1/2 ) was determined using the equation t _1/2 = 0.693 / Kel. The area under the concentration-time curve from point 0 to the final concentration-time point (tf) after the distribution step was calculated using the trapezoidal formula. The area under the curve from the final concentration-time point (Ctf) to infinity time after the distribution step was calculated from AUC _{t -∞} = Ctf / Kel. The concentration used for Ctf was the final determination of LLOQ over time. The total AUC _0-∞ was obtained by adding AUC _tf and AUC _{t -∞} . Noreuyi beams of the apparent clearance (CL / F) of formula CL / F = dose / AUC _{0 -∞} × 1000 to determine the formula for the apparent volume (Vd / F) of distribution Vd using the / F = (CL / F) / Kel. &Lt; / RTI &gt; The total urine Norwegian phosphorus was the sum of both analytes.

Summary statistics (mean, standard deviation and coefficient of variation) were determined for each dose group for safety and safety laboratory, ECG and pharmacokinetic parameters and pharmacokinetic parameters. Categorical variables were analyzed by using coefficients and percentages. The dose-proportions of AUC and Cmax were evaluated using linear regression. The dose effect on the pharmacokinetic parameter values over time was evaluated using the two-factor analysis of variance (ANOVA). Using a least squares estimate obtained from ANOVA using SAS Proc Mixed (SAS version 6.0), a pairwise comparison between each dose group and placebo (using Tukey-Kramer control) .

result

Pharmacokinetics: The mean plasma concentration-time plot of Norvigovin is shown in Figure 1, and the average pharmacokinetic parameters are shown in Table 1.

Norvigorine was rapidly absorbed and reached its maximum concentration in 2 to 3 hours after oral administration. Variations in the individual distribution-step concentration-time profiles may indicate the possibility of long-term recirculation (highlighted individual 4-8 hour profile in FIG. 1, illustration). Both Cmax and AUC were linearly increased with dose (Table 1, top panel). An average half-life estimate of 28 to 50 hours was observed according to the dose group for the Norwegian phosphorus. The distribution volume was extensive (1417 to 3086 liters, depending on the dose group).

Glucuronide concentration-time plots, in which mean plasma norbornene for 30 mg to 60 mg dose groups are shown in Figure 2, and mean pharmacokinetic parameters are shown in Table 1, lower panel. Glucuronides of Norviga were detected in all subjects for up to 0.75 hours, with maximal concentrations occurring in 3 to 4 hours after Norvibor medication. An average half-life of 21-23 hours was estimated for glucuronide with plasma norbober. The ratio of glucuronide Cmax and AUC, which is a Norwegian boron to the norbornene phosphorus, was 3 to 4% for both dose groups. Total urine Norbigophyllin removal was 1.16 mg to 0.82 mg for the 30 mg to 60 mg dose group, representing 3.9% and 1.4% of the dose administered, respectively.

The mean serum levels of the subject were plotted over time for free bases free of Norbig from a single dose of free base with 3 mg of Norbig under fasting conditions. The mean C _{max of} 5.2 ng / ml was observed at 1.9 hours after administration and the mean AUC / 24 hr of 3.1 ng / ml was observed.

The mean serum levels of the subject were plotted over time for the free base in which the free base was from a single dose of free base with 10 mg of Norviga under fasting conditions. The mean C _{max of} 14.5 ng / ml was observed at 2.9 hours after administration and the average AUC / 24 hr of 10.6 ng / ml was observed.

The mean serum levels of the subject were plotted over time for the free base in which the free base was from a single dose of the free base of 30 mg Norviga under fasting conditions. The mean C _{max of} 55.9 ng / ml was observed at 1.75 hours after administration and the mean AUC / 24 hr of 29.2 ng / ml was observed.

The mean serum level of the subject was plotted over time for the free base in which the free base was Norvig from a single dose of free base with 60 mg of Norviga under fasting conditions. Mean C _{max of} 116 ng / ml was observed at 1.75 hours after administration and mean AUC / 24 ng / ml 61 was observed.

The mean serum levels of the subjects were plotted over time for free bases in which all four cohorts were free of Norberg. Extrapolated doses of the free base wherein the free base is required to provide a C _max in the range of about 5.2 ng / ml to about 1980 ng / ml, and an AUC / 24 hr of about 3.1 ng / ml to about 1100 ng / ml were determined.

Pharmacokinetics: There was no evidence of pupil contraction in subjects dosing Norbyborg. There was no difference in pupil diameter between dose groups over time. After adjustment for baseline difference, the comparison of each dose group with placebo by ANOVA showed no statistically significant difference (p> 0.9).

The treatment with Norbogoggi did not show the analgesic effect in the cold pressor test. The analgesic effect was assessed based on the duration of handwashing in ice water and the visual analog scale (VAS) pain score at the time of hand removal from the bath. After adjustment for baseline differences, ANOVA showed a statistically significant difference (p> 0.9) between each dose group and placebo during the duration of handwashing. Similarly, for the VAS pain scores, after adjustment for baseline difference, the comparison of placebo with each dose group by ANOVA showed no statistically significant difference (p = 0.17).

Example  2. In healthy humans Norwegian  Safety and Tolerance

The safety and tolerability of Norovigrin was tested in the applicant group from Example 1. Cold stress was performed in water at 1 ° C after dosing 6, 24, 48, 72 and 216 hours before dosing according to the method of Mitchell ( J Pain 5: 233-237, 2004) and the like. Safety assessments included clinical monitoring, recording of adverse events (AE), safety laboratory tests, vital signs, telemetry from -2 to 6 hours after dosing, and 12-lead electrocardiogram (ECG) up to 216 hours after dosing.

result

A total of 13 adverse events were reported by 7 participants (Table 2). Six adverse events were reported by three participants in the placebo group and five adverse events were reported by two subjects in the 3 mg dose group and one adverse event was reported in a single subject in the 10 mg to 30 mg dose group Respectively. The most common adverse events were headache (4 reports) and non bleeding (2 reports). All adverse events were of mild to moderate severity and were all resolved before the study was completed. There was no change in vital signs or safety laboratory test tokens. In particular, there was no change in oxygen measurement or capnography or change in respiration rate. There was no QTcF value exceeding 500 msec at any time point. One subject dosed with 10 mg of Noribogain had a single increase in QTcF over 60 msec at 24 hours after dosing.

Example  3. In opioid-addicted humans Norwegian  safety, Tolerance  And efficacy

This example demonstrates that Norvasc can be administered at a therapeutic dose while maintaining an acceptable QT interval. The therapy used is for opioid-dependent participants in a randomized, placebo-controlled, double-blind trial, but the results indicate that the therapeutic window can be established for the Norwegian bovine.

The efficacy of Norovigrin in humans was evaluated in opioid-dependent participants in a randomized, placebo-controlled, double-blind trial. The patient received methadone therapy as an opioid replacement therapy, but switched to morphine therapy before the administration of Norviga. This was done to avoid in vivo Norviba-in-methadone interaction that was not observed between Norviga and Morphin. 14 / 214,157, filed March 14, 2014, and 14 / 346,655, filed March 21, 2014, all of which are incorporated herein by reference in their entirety.

Three cohorts were evaluated for tolerability, pharmacokinetics, and efficacy, nine (9) subjects (6 in each cohort receiving Norwegian and 3 in placebo). Cohort 1 received a single dose of 60 mg Norwegian or placebo. Cohort 2 received a single dose of 120 mg Norwegian or placebo. Cohort 3 received a single dose of either 180 mg Norwegian or placebo. Therapy was administered 2 hours after the final morphine dose and the time to re-consumption of morphine (opioid replacement therapy, OST) was determined. Side effects of Norovigrin were rarely observed in any participant, including no hallucinogenic effects. Table 3 reports adverse events for each treatment that do not contribute to withdrawal symptoms from opioids. Headache was frequent in placebo and 60 mg Norviga treatment, but was attenuated in the 120 mg to 180 mg dose group.

Figure 3 shows the mean serum norbornene concentration over time after administration of Norvigans to each cohort (60 mg, diamond; 120 mg, square; or 180 mg, triangle). Additional results are detailed in U.S. Provisional Patent Application No. 62 / 023,100, filed July 10, 2014, entitled " METHODS FOR ACUTE AND LONG-TERM TREATMENT OF DRUG ADDICTION ", which is incorporated herein by reference in its entirety It is included as a reference.

result

The pharmacokinetic results for each cohort are provided in Table 4. The serum concentration (Cmax) of the maximum Norwichian phosphorus was increased in a dose-dependent manner. The time (Tmax) for Cmax was similar in all three cohorts. The mean half-life of serum Norvigrin was similar to that observed in healthy patients.

Figure 4 shows the time to re-consumption of morphine for patients treated with placebo (circles), 60 mg Norwegian (square), 120 mg Norwegian (triangle), and 180 mg Norwegian (inverted triangle) OST). Patients who received a single 120 mg dose of Norwegian Bogin showed an average time to reuse of more than 20 hours of cucumber. Patients receiving a single 180 mg dose of Norwegian Bone showed the mean time to reuse of cucumber similar to placebo. This demonstrates that increasing the dose of Norovigrin to 180 mg leads to a shorter time for OST re-consumption than observed in patients receiving 120 mg Norvigor. The time for re-consumption of OST after treatment with 180 mg was still longer than in patients treated with non-treated patients (7 hours, untreated) or 60 mg Norwegian Phosphorus.

(COWS), the target opiate withdrawal symptom scale (SOWS), and the objective opiate withdrawal symptom scale (COWS) over a period of time between the administration of the Norvigor (or placebo) OOWS) scoring system. These scales are outlined in the Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence, World Health Organization, Geneva (2009), Annex 10, which is incorporated herein by reference in its entirety. The scale measures the severity of withdrawal symptoms based on clinical, objective, and objective indicators.

Figure 5 shows the COWS score at the reuse time of the OST for each cohort. Box contains values representing 25% to 75% quartiles. Diamond = median; Crossbar in box = average; Whisker = medium - the value within the standard deviation of the quartiles. There are no anomalies. A highly variable COWS score across each cohort and in each cohort indicates that the patient consumes apiate regardless of the withdrawal symptom severity. It also reflected the SOWS and OOWS scores at the reuse time of the OST.

Figure 6A shows the mean change in total COWS score over the first 6 hours after dosing and before re-consumption of the OST. Figure 6B shows the mean AUC (0-6 hours) of COWS total score change from baseline. Figure 7A shows the mean change in total OOWS score over the first 6 hours after dosing and before re-consumption of the OST. Figure 7B shows the mean AUC (0-6 hours) of the OOWS total score change from the baseline. Figure 8A shows the mean change in total SOWS score over the first 6 hours after dosing and before re-consumption of the OST. Figure 8B shows the mean AUC (0-6 hours) of the SOWS total score change from the baseline. These data indicate that withdrawal symptoms worsen over time after discontinuation of the OST, and patients receiving placebo generally experience worsened withdrawal symptoms over the period of time. Patients receiving 120 mg Norbygovine did not experience withdrawal symptoms much less than other patients, regardless of the scale used. Patients receiving placebo generally experienced more withdrawal symptoms than patients treated with Norwegian Phosphorus.

Patients' QT intervals were evaluated at regular intervals throughout the study. Figure 9A shows the mean change in QT interval (ΔQTcl, ie QT interval extension) over the first 24 hours following Norwegian injection (or placebo). FIG. 9B shows the estimated correlation between the concentration of Norbit and the change in QT interval. There was a dose-dependent increase in the QT interval prolongation correlated with the serum concentration of Norbycognathia.

Based on this data, it is believed that the therapeutic window for the dose of single Bolus nobilis phosphorus bounds at an upper limit of as low as 50 mg and less than 180 mg. In particular, the therapeutic serum concentration in vivo appears to be about 50 ng / ml to about 180 ng / ml.

 The inventors contemplate that this can eliminate the current bc updated result and is included in the "other" example 3 above.

Example  4. In humans Norwegian Multiple  dosage

The multidrug dose efficacy of Norovigrin in humans was evaluated in opioid-dependent participants in a randomized, placebo-controlled, double-blind trial. The patient received methadone therapy as an opioid replacement therapy, but switched to a morphine treatment before the administration of Norvigarin.

The patient is treated with an initial unit dose of 80 mg of Noribucoglobin, followed by 15 to 20 mg of Norbigbore every 6 to 12 hours as shown in Table 5.

The patient is treated with an initial unit dose of 80 mg of Norvigovin, which is administered as a 20 mg dose at 2 hours and 4 hours after the lower dose of 40 mg. The initial unit dose is followed by a dose of 15 mg to 20 mg of norbornene per 6 to 12 hours, as shown in Table 6.

Example  5. Opioids in humans Tolerance  For conditioning Norwegian  efficacy

A 59-year-old female patient who received opioid analgesic treatment for chronic abdominal pain was treated with a dose of about 2 mg / kg of opioid with hydrochloride of norbornene. The amount of opioid needed to treat her abdominal cavity at the same level as before treatment is determined after treatment with Norvig.

Example  6. Sprague  Dolly In the rat  For nicotine dependence Norwegian  effect

animal

Fourteen adult male Sprague Dawley rats (300 to 325 g) from Harlan were used in this study. The rats received catheter surgery and nicotine self-administration training.

Upon arrival, a unique identification number (tail mark) was assigned to the rat. Animals were housed in two to three animals per us in a tethered polycarbonate rat with a filter paper covering mesh shelf and acclimated for up to 7 days. All rats were tested, treated and weighed prior to initiation of the study to ensure appropriate health conditions and fitness. During the course of the study, 12/12 persons / cancer cycles were maintained. The room temperature was 20 to 23 ° C, and the relative humidity was maintained at 30 to 70%. Water was optionally provided for continued research. After surgery (in 14 nicotine-training rats), all rats were housed single and left single housed throughout the duration of the study.

Test compound

(Converted to free base capacity using 12.5, 25 and 50 mg / kg, correction factor 1.12) was dissolved in 35% of 0.5% Tween 80 of total required volume in 5% dextrose. The suspension was stirred for at least 30 minutes. 1.5% methylcellulose was added to make up 65% of the total volume, and then the suspension was stirred again for at least 30 minutes. As a result, a dose of 12.5 mg / kg and 25 mg / kg was a clear solution, and 50 mg / kg was a slightly turbid suspension.

A mixture of 0.5% Tween 80 in 5% dextrose (35% of total volume) and 1.5% methylcellulose solution (65% of total volume) was used as the compound vehicle treatment group.

Vehicle and Norbybogen were orally administered 2 hours before the test at a dose volume of 5 ml / kg.

Barrenicin (1.7 mg / kg) was dissolved in saline (0.9% NaCl) and then administered intraperitoneally 30 minutes before the test. The volume capacity of barrenicin was 1 ml / kg. The formulation of barrenicin (1.7 mg / kg) was a clear solution.

Nicotine self-administration study

Apparatus: Intravenous drug self-administration and testing were carried out in a laboratory chamber in a cubicle for behavioral experiments with an exhaust fan (Med Associates, Vermont, USA). Each chamber contained two reaction levers located on one wall of the chamber. The stimulating light was placed on each lever and the receiving light was placed on top of the opposite wall. The drug solution was delivered via Tygon tubing connected to a single channel fluid swivel mounted on a balance arm on the operating chamber with an infusion pump mounted on each chamber. The product of the liquid swivel was attached to the outer end of the intravenous catheter.

Food training and surgery : Before intravenous catheterization, animals were trained in lever presses for food. After lever-press reaction rats were obtained, they were prepared using an intravenous catheter. After one week, it is possible to self-administer a nicotine solution (0.03 mg in 0.1 ml over a period of 0.8 s under fixed-ratio 3 (FR3)) by pressing the food-pair lever previously in response to the delivery of the drug solution Respectively. In this study, four weeks of manipulative training were required to obtain adequate nicotine infusion (defined as less than 20% variation in mean number of consolidations obtained with more than six injections and one hour of training over three consecutive days).

Self-administration procedure : Animals were first trained to respond to nicotine (0.03 mg / kg / injection) under FR3, a 20-second time-out schedule of enrichment. After completion of the training and evaluation of the appropriate criteria, the effect of Norvigovin was assessed. (Defined as a change of less than 20% of the average number of enhancements obtained with one hour of training over six injections and the last three consecutive non-drug test days), Norbybogain or &lt; RTI ID = 0.0 &gt; Only the reference compound barrenicin (nicotine acetylcholine receptor partial agonist) was administered. The baseline levels of self-administration behavior were assumed to be Tuesday and Thursday, and compound testing was conducted on Wednesday and Friday.

Research design and data analysis

The design in each object received by each rat was applied using a Latin square test schedule. The six treatment groups that were blinded to the experimenter were:

One. Saline solution

2. Barrenicin 1.7 mg / kg

3. The vehicle (5% dextrose and 35% 0.5% Tween-80 in 65% 1.5% methylcellulose)

4. 12.5 mg / kg &lt; / RTI &gt;

5. Norvigovin 25 mg / kg

6. Norvigovin 50 mg / kg

Data from the nicotine infusion obtained during the test period were analyzed following repeated measures ANOVA followed by Fisher LSD post-mortem comparisons where appropriate. The percentage of inactive lever presses was also analyzed by repeated measures ANOVA for nonspecific behavioral effects. P <0.05, the effect was considered significant. Data are presented as mean and standard error (s.e.m.) for the mean. Statistical anomalies belonging to above average +/- (2 x standard deviation) were removed from the analysis. By this criterion, 0 to 2 or more points were removed from the different measurements.

result

The effect of noribogain and barrenicin on nicotine infusion is shown in Figure 10A. Repeated measures ANOVA found a significant primary effect of treatment [F (5,58) = 29.708, P <0.001]. Post-test comparisons showed that barrenicin and Norbogolin significantly stunted nicotine infusion at both 25 and 50 mg / kg ( P s <0.001). The stagnation trend of nicotine infusion was also found at a dose of 12.5 mg / kg ( P < 0.10). The data represent the mean + sem.

The effect of noriboglobin and barrenicin against inactive lever press during nicotine self-administration is shown in Figure 10B. Repeated measures of ANOVA did not find significant significant effects of treatment. [F (5,54) = 0.356, P > 0.05]. These results suggest that the effect of the test compound on nicotine infusion was not compromised by nonspecific inactive lever pressing.

Example 7: Low dose of Norbiggan effect in smoking cessation in humans

Nonsmokers of Norwegian boron hydrocarbons were absorbed into the nasal passages of female smokers. During a period of time, any craving for smoking was stopped, and only then was resumed. The patient did not know any nicotine or smoking cravings during the period.

Example 8: Norvigene effect on withdrawal symptoms from alcohol in humans

In a randomized, placebo-controlled, double-blind trial, 6 patients received a single dose of 2 mg / kg Norwegian phosphorus, and 3 patients received placebo. All patients were alcohol dependent. Treatment was administered at least 2 hours after the last alcohol use. Patients who have received a Norwegian boson determined by a self-assessment (eg questionnaire) and clinical observation show less severe symptoms than those who have no or withdrawal alcohol withdrawal symptoms.

Example 9: Effect of Noribogaine in the Treatment of Substance Dependence

Evaluate the efficacy of Norwegian boron in substance-dependent participants in randomized, placebo-controlled, double-blinded trials. Patients were administered 60 mg or 120 mg of compound followed by QT interval.

Example 10: Effect of Norbiggan on the treatment of pain in humans

A 57-year-old female patient with a chronic diverticulum is treated with approximately 2 mg / kg of Norvigor Hydrochloride. Her pain is weakened by self-assessment and clinical assessment.

Example 11: Effect of Noriboglobin on chronic migraine in humans

A 25-year-old female patient with recurrent migraine without recurrent withdrawal symptoms from an opioid is treated with a dose of about 1.5 mg / kg of hydrobromide of Norviga. During periods of several hours determined by self-assessment and clinical assessment, her migraine symptoms are attenuated.

Example 12. Forced Swim Test (FST) using a rat

Animals : Male Sprague Dawley rats (Taconic Farms, New York) are used in all experiments. Rats are housed in 5 animals per group, and then maintained in a 12: 12-h contrast cycle. Treat the rats for 1 minute daily for 4 days before the behavioral test.

Drug administration : Animals are given a single intraperitoneal injection of vehicle (2.5% EtOH / 2.5% Tween-80), imipramine (positive control; 60 mg / kg), or test compound 60 min before the start of the 5 min test period Randomly assigned. All injections are provided using a 1 cc tubercular syringe with 26 3/8 gauge needles (Becton-Dickinson, VWR Scientific, Bridgeport, NY). The injection volume is 1 ml / Kg.

Experimental design : The procedure used in this study is to use a water depth of 31 cm. Deeper depths in this test prevent the rats from supporting them by striking the cylinder bottom with their feet. The swimming period is carried out by placing the rats in individual plexiglass cylinders (46 cm length and 20 cm diameter) containing water at 23 to 25 ° C. The swimming test was always carried out at 9:00 to 17:00 hours, followed by an initial 15 minute conditioning test 24 hours later to a subsequent 5 minute test. 5 minutes Drug therapy is given 60 minutes before the test period. After all the swimming periods, the rats were removed from the cylinder, dried with a paper towel, placed in a raised temperature for 15 minutes, then returned to their home. All test periods are photographed using a color video camera and recorded for subsequent scoring.

Behavior scoring : The behavior of the rats was graded at 5 second intervals for 5 minutes by single subjects blinded to treatment conditions. The scored behavior is as follows: 1. Float-only movement required to keep the rat floating in the water without shaking and keeping his head on the water; 2. Climbing - The rat moves his paw actively in and out of the water, usually toward the wall; 3. Swimming - The rat has a swim movement that is more active than just needed to keep his head on the water, for example moving around the cylinder; And 4. Diving - The body of the rat is locked.

Data analysis : Perform a randomized, one-way ANOVA and post-test using the Newman-Keuls test on forced swimming test data (floating, swimming, climbing and diving). Data is analyzed using GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, Calif.).

Example 13. Forced swimming test (FST) using a mouse

Animals : DBA / 2 mice (Taconic Farms, New York) are used in all experiments. Animals are housed in a controlled environment under the 12:12 hour name: Cancer cycle with 5 animals per us. Treat rats for 1 minute daily for 4 days before animals are tested. This procedure involves mock gastroparesis using a 1.5 inch feeding tube.

Drug Administration : Animals were randomly assigned to receive a single dose of vehicle (5% EtOH / 5% Tween-80), test compound or imipramine (60 mg / kg) by oral gavage at 1 hour before the swim test.

Experimental design : The procedure for forced swimming test in mice is similar to that described above for rats, with the following variations. The cylinder used for the test is a 1 liter beaker (10.5 cm diameter and 15 cm height) filled to 800 ml (10 cm depth) of 23 to 25 ° C water. water. Only one 5-minute swim test is performed for each mouse between 13:00 and 17:00 hours. Medication is administered 30 to 60 minutes before the 5-minute study period. After every swim period, the mouse is removed from the cylinder, then dried with a paper towel and placed in a heated room for 15 minutes. All test periods are recorded using a Sony color video camera and recorded for subsequent scoring.

Behavior Scoring : Behavior for 2 to 5 minutes of the test is reproduced on a TV monitor and scored by the researcher. Record the time spent on the float (the animal's movement due to minimal movement to remain floating on the water) and the movement (swim and movement beyond what is required to remain floating on the water).

Data analysis : Perform a randomized, one-way ANOVA and post-test using the Newman-Kuels test on forced swimming data (time to float, movement time; seconds). Data is analyzed using GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, Calif.).

Example 14: Single dose toxicity in rats

The aim of this study was to determine the toxicity and toxicological profile of HCl, which is a Norwegian Bog after a single oral (gavage) method in Sprague-Dawley rats. 100, 300 and 800 mg / kg (achieved at a dose of 400 mg / kg, 3 h +/- 30 minutes apart, due to the limitation of maximum dose formulation concentration). Five male rats / group were used. All male rats died approximately 2 to 3 hours after administration of the second dose of 400 mg / kg in the 800 mg / kg group. Undergoing, vocalization, chewing motion, changes in respiration / posture, salivation, stimulation sensitivity, progression, convulsions and erections occurred before death. Overactivity, vocalization, salivary secretion, irritation sensitization, loss of limb function and lying down on the floor occurred on the treatment day and lasted from 3/5 to 2 days in rats given 300 mg / kg. Low dose rats treated with 100 mg / kg did not show any treatment related signs. No observed adverse effect level (NOAEL) was determined to be 100 mg / kg.

Example 15: Single dose toxicity in dogs

In the acute oral toxicity / TK study in dogs, death did not occur at a dose of 5 (n = 2) or 10 (n = 2) mg / kg. Other CNS-related clinical manifestations, including contractions, salivation, salivation, vocalization, ataxia, and underactivity, occurred at a dose of 10 mg / kg, started at 20 minutes after dosing and continued until 3 hours and 40 minutes of dosing . A 5 mg / kg dose was considered as a NOAEL because only a temporary reduction in food consumption in one dog occurred at that dose.

Example 16: Single dose toxicity in cynomolgus monkeys

The aim of the study was to determine the toxic and toxicological profile of noribogloin after oral (gut-guided nutrition) in cynomolgus monkeys. Each dose was followed by a 7 day washout period. The dose was staggered by 45 minutes. On the 15th day of the study, 80 mg / kg was administered to one animal and 160 mg / kg was administered to the other animals. The test items were administered as in Table 7 below:

Toxicity and Toxicity Profile in Cynomolgus Monkeys Treatment at study day Capacity level (mg / kg) Number of animals One 20 Two males 8 40 Two males 15 80 and 160 Two males

The parameters monitored in the study included: mortality, clinical signs and weight. Blood samples were collected for TK evaluation. Clinical signs of death and treatment were not noted for doses up to 160 mg / kg, including 160 mg / kg. Single dose maximum tolerated dose (MTD) was determined to be greater than 160 mg / kg based on parameters monitored during the study.

Example 17: 14 day repeated dose toxicity and toxicity in rats

This study was performed following the following Table 8 to evaluate the toxicity profile of Norbiggan-HCl after oral (gavage) administration to rats for 14 days:

Male and female Sprague Dawley rats (10 rats / sex / group) were administered HCl with 0, 25, 50 or 100 mg / kg Norviga daily by single oral gavage for 14 days. An additional 5 rats / gender / group in the 0 (control) and 100 mg / kg groups were maintained for a 28 day recovery period without drug administration. Six rats / sex / group (3 rats / gender control) were similarly dosed and then sampled on days 1 and 14 of the study for analysis of the noribogan phosphorus-HCl concentration in the blood. Hematology, clotting, clinical chemistry, urinalysis, gross autopsy, organ weight and histopathology (total tissue panel, + GFAP (pre-dose, 2 weeks and at the end of recovery), mortality, clinical signs, weight, food consumption, And immunocytochemistry of the five sections of the brain and spinal cord by staining for calvindin). There were no test-related effects on mortality, clinical signs, optometry, hematology, clinical parameters, clinical chemistry, urinalysis, gross autopsy or histopathology. Food consumption and body weight were slightly reduced in the high dose (100 mg / kg) group (food consumption: -4.7% in male and female; body weight: -5.5% in male and -2.6% in female). The slight increase in liver weight in the intermediate- and high-dose groups was not correlated with histopathological changes and was considered incidental. Therapeutic-related differences in the brain were not seen in the stained sections for GFAP or CalvinDin.

The NOAEL dose in this study is understood to be 100 mg / kg, and the highest dose tested in this study.

Example 18: 14 day repeated dose toxicity and toxicity in dogs

The purpose of this study was to determine the toxic profile of the given Norwegian HCl after oral (gavage) administration to dogs for 14 days according to Table 9 below:

Norvigin HCl was administered to groups of 4 males and 4 females by single oral gavage for 14 days at doses of 0, 0.5, 1.0, and 5.0 mg / kg / day. An additional group of 4 males and 4 females received either the vehicle control or 5.0 mg / kg / day for 14 days and received additional 28 days after discontinuation of the dose to assess recovery from any potential drug- Respectively. The study was conducted under the GLP guideline and included a comprehensive test of plasma analysis for clinical indications, body weight, clinical pathology parameter optometric testing, ECG recording and biometric assay at drug level at appropriate intervals during the study. At the end of the dosing phase and at the end of the recovery phase, all dogs underwent complete post-analysis tests, including histological testing of the total test of major organs and a vast list of tissues. Additional sections of the brain were obtained from the cerebrum, cerebellum, brain stem and spinal cord and histologically tested to assess the potential effects on brain histopathology. In addition, these sections were tested using immunohistological staining for calbindin for more comprehensive testing of GFAP and cerebellar Purkinje cells for evidence of gliosis. No side effects were observed in dogs from any treatment group during clinical or observation, weight, clinical pathology, optometric testing, ECG recording, or autopsy during the dosing or recovery phase in total lesions. The results of plasma drug level measurements on days 1 and 14 of the study are shown in the following table. Plasma concentrations gradually decreased over a period of up to 24 hours except that significant levels of Norvigovin in the male and female dogs of Group 4 were still detected at 24 hours after dosing at both the first and 14th day , The maximum plasma concentration of HbCl (C _max ) was reached at 0.5 to 0.9 hours after dosing.

The only target tissues identified in this study were dogs that received 5 mg / kg / day. Tear organ changes were characterized by slight to moderate atrophy and degeneration of the rearing cells accompanied by a slight to moderate accumulation of brown / yellow pigment and infiltration of mononuclear cells. There were associated mononuclear infiltrates in the submandibular submandibular lymph nodes in this dose group. Despite the apparent appearance of some of the isolated eyes in this high dose group, there was no clear association between these eye signs and the appearance of tear changes, which suggests that these morphological changes may be due to physical changes Lt; RTI ID = 0.0 &gt; of &lt; / RTI &gt; There was no accurate evidence of local irritation associated with drug treatment in these high dose dogs. No evidence of drug-induced effects was observed in any other tissues, including the vast majority of the brain evaluated by conventional histopathology or by immunohistochemistry. Animal testing in the recovery group showed clear evidence of regrowth of this tear organ change. After 28 days without drug, slight atrophy was still evident in spleen cells of the spleen, but there was no evidence of ongoing denaturation or cellular infiltration. In this study NOAEL was 1 mg / kg / day based on tear organ change at 5 mg / kg / day. The results are summarized in Tables 10 and 11.

Example  19. For depression in humans Norwegian  effect

A 55-year-old male patient suffering from depression unrelated to the use of any illegal substance is treated with a dose of about 1 mg / kg / day of hydrochloric acid for a period of 4 weeks. During the course of treatment, a change in his depressive symptoms and / or one or more of the following tests (HDRS, Hamilton Depression Inventory and CGI-disease severity) is determined.

Example 20. Social interaction test (SIT)

Animals : Male Albino Sprague Dawley rats (Taconic palms in New York State) are housed in pairs under a 12 hour light cycle (light for 0700 hours), and food and water access is free.

The rats are housed in animal care facilities for 5 days and then housed alone for 5 days before testing. Animals are treated for 5 minutes per day. On the day of testing, the same treatment was given to pairs of unfamiliar weight matching rats (+/- 5%) and then returned to their home. Animals were randomly divided into 5 treatment groups (5 pairs per group) and then i.p. (1, 2 or 4 mg / kg), vehicle (1 ml / kg) or chlorodiazepoxide (5 mg / kg). The dose is given 1 hour before the test. The rats are subsequently placed in a white perspex test box or stage (54 x 37 x 26 cm) for 15 minutes, the floor of which is divided into 24 identical dampings. Use the air conditioner to generate background noise and keep the room at approximately 74 ° F. The entire period is photographed using a JVC camcorder (Model GR-SZ1, Elmwood Park, New York) using TDK (HG top brand) or Sony 30 min video cassette. All periods are performed between 13:00 and 16:30 hours. Scoring with positive watches (Sportsline model number 226, 1/100 sec.) Distinguishes active social interactions that appear as hair trim, sniffing, biting, boxing, wrestling, do. The number of episodes of back-up (the animal raises his body completely on his hind legs), hair trim (body licking, biting, scraping), and facial stroking (ie, repeatedly moving his hand over his face) Scores the number of crossed dampings. Passive social interactions (animals lying next to each other or lying on top of each other) do not score. All behaviors are evaluated later by blind observers for each pair of treatments. At the end of each test, rub the box thoroughly with a wet paper towel.

Data analysis : Perform randomized, one-way ANOVA and post-test using the Student-Newman-Keuls test on social interaction data (time interaction, back-up and cross-contamination). The data are subjected to a normality test (Shapiro-Wilk test). Data is analyzed using the GBSTAT program, version 6.5 (Dynamics Microsystems, Inc., Silver Spring, Md., 1997).

Example 21: Effect of Noriboglobin on food consumption

The effect of noribogain and barrenicin on food consumption in food-holding reaction rats is shown in Figure 10A. Repeated measures ANOVA found a significant primary effect of treatment [F (5,33) = 16.905, P <0.001]. The post-mortem comparisons showed that the Norwegian bogs (25 and 50 mg / kg) significantly reduced food consumption (P <0.05 and P <0.001, respectively) compared to vehicle treatment. Naryobogain (12.5 mg / kg) and barrenicline (1.7 mg / kg) had no significant effect on this measurement.

The effect of noriboglobin and barrenicline on inactive lever responses in food-holding reaction rats is shown in Figure 10B. Repeated measures ANOVA found significant significant effects [F (5,31) = 7.583, P <0.001]. This main effect is distributed solely by the high doses (50 mg / kg) of Norwegian boron (P <0.001 compared to the vehicle treated group) as shown in the post-test comparison. This result suggests that high doses of Norovigor (50 mg / kg) for high-frequency lever-pressing in food tests may cause some behavioral disturbances.

At 12.5 mg / kg, Norbogophane showed no effect on food consumption. At 25 mg / kg, Norbogophane reduced food intake by 10% (P < 0.05). At At 50 mg / kg, the Norwegian phosphorus reduced food intake by 25% (P <0.001). In general, the percentage of inactive reactions was very low during food consumption under all treatments.

Example 22: Single dose toxicity in rats

The aim of this study was to determine the toxicity and toxicokinetic profile of HCl with Norviga after single oral (gavage) administration in Sprague Dawley rats. 100, 300, and 800 mg / kg single dose (achieved at 3 h +/- 30 minute intervals with 400 mg / kg dose due to limit of maximum dose formulation concentration). Five male rats / groups were used. All male rats died approximately 2 to 3 hours after administration of the second dose of 400 mg / kg in the 800 mg / kg group. Undergoing, vocalization, chewing motion, changes in respiration / posture, salivation, stimulation sensitivity, progression, convulsions and erections occurred before death. Overactivity, vocalization, salivary secretion, irritation sensitization, loss of limb function and lying down on the floor occurred on the treatment day and lasted from 3/5 to 2 days in rats given 300 mg / kg. Low dose rats treated with 100 mg / kg did not show any treatment related signs. The NOAEL was determined to be 100 mg / kg.

Example 23. Effect of Noribogensin on Anxiety Disorders in Humans

A 45-year-old male patient suffering from generalized anxiety disorder not associated with the use of any illegal substance is treated with hydrochloride at a dose of about 1 mg / kg / day for a period of 4 weeks. His generalized level of anxiety is determined by the patient's self-report of weakening of at least one of the following symptoms: feeling unsettled or feeling tense or restless, easily fatigued, difficulty concentrating or emptying, Muscle tension and sleep disorders.

Example  24. Anxiety-related At the end point  Expressed by In zebra fish  Effect of Noriboglobin on nicotine withdrawal symptoms

animal

A total of 60 adult wild short fins zebrafish (approximately 50:50 male: female ratio) were used in this study. Water rings were housed in groups of 20 to 30 fish per 40 l tank. The tank was filled with filtered water and then kept at 25 占 폚. Illumination (1000-1100 lx) was provided by ceiling mount fluorescence in a 12 hour period (On: 6.00 hours, Off: 18.00 hours) according to the zebra fish management standard. All the fish used in this study were experimentally naive and fed twice daily with Tetramin Tropical Flakes (Tetra USA, Blacksburg, Va.). After the behavioral test, animals were euthanized in 500 mg / L Tricaine (Sigma-Aldrich, St. Louis, MO) buffered to pH = 7.0. In this study, animal experiments faithfully followed national and institutional guidelines and regulations.

Test compound

A dose of 1 mg / l of Norvigor (DMXl) was selected based on pilot experiments, and the literature reports other similar compounds in an effective dose. Pilot experiments showed the quasi-maximal efficacy of Norwegian bovine at a dose of 1 mg / l, which does not promote any locomotor effect, which is likely to prove incorrect efficacy endpoints of interest in other protocols. Based on experience with a wide range of other neuroactive compounds and pilot studies, a standard 20-minute pretreatment time was chosen. This exposure time was also sufficient to stimulate the physiological (e.g., cortisol and c- fos ) responses of zebrafish to multiple drugs. Drug exposure was performed in this study by placing individual zebrafish in a 1 L plastic beaker for 20 minutes before testing. After each exposure, the solution is periodically changed to ensure that each fish is exposed to a constant concentration of phosphorus phosphorus. Control fish are exposed to water free of Norvigans for the same treatment time as described above.

Tests and Procedures

Apparatus: Behavioral tests were conducted at 11:00 to 15:00 using a tank adjusted to maintain room temperature (25 ° C) using water. The study used the New Tank Test (NTT) protocol. NTT represents one of the most commonly used neurophenotyping tests for adult zebrafish. To avoid test battery or conditioning effects, each analysis was performed once for each separate navy fish. Prior to testing, the water loops were individually exposed to one of the drug-treated or drug-free water in a 1 L plastic beaker for 20 minutes. During the test, zebrafish behavior was recorded by two blinded observers for treatment, who were followed by subsequent automation by Etovision XT8.5 software (Noldus IT, Glenning, The Netherlands) Analysis was used to manually score different behavior endpoints (in all experiments, between the evaluator and the evaluator> 0.85). The NTT used to evaluate zebrafish anxiety and movement was a 1.5-liter trapezoidal tank (15 cm high x 28 cm upper x 23 cm lower x 7 cm wide; aquatic hibitatsu (located in Apopka, Florida Aquatic Habitats), which are divided into two substantially identical horizontal sections by line marking the outer walls. The fish were individually exposed to water (water control), chronic nicotine (1 mg / l), repeated withdrawal symptoms from chronic (WD), repeated withdrawal symptoms + 20 minutes of nobilis (1 mg / l) , And a standard 5 minute NTT test.

Behavioral Analysis : The zebrafish behavior is recorded by the trained observer and the time spent waiting for the top half of the tank (s) to reach, the time consumed at the top (s), the number of transitions up to the top, Respectively. Freezing was defined as a lack of total movement except for gills and eyes for more than 2 seconds. The test was recorded on a computer using a USB webcam (2.0-megapixel, Gigaware, England) and subsequently analyzed by Ettovision XT 8.5 to determine the travel distance (m), velocity (m / s), and the meandering phenomenon end point. During manual observation, the video was recorded in MPEG1 format at a maximum sample rate of 30 fps during each test by an autofocus 2.0 MP USB webcam placed at 25 cm in front of the tank and attached to a laptop computer. Recorded video was analyzed using the Ettovision XT8.5 software. After calibrating all the environments for each area, the origin (0,0) was designed at the center of each tank by placing the calibration axis. The spatial pattern of the zebrafish swim was described by independently evaluating the criteria accorded by two trained observers blinded to the exported trace treatment.

RESEARCH DESIGN AND DATA ANALYSIS : The study showed that adult zebrafish (15 animals per group) was strongly (20 minutes) in water control, chronic nicotine, repeated nicotine withdrawal symptoms, and nicotine withdrawal symptoms + 1 mg / ), And tested on NTT for 5 min before euthanizing the fish. To generate graphs and descriptive statistics for manual and computer generated endpoints, raw data from manual and automatic endpoints were analyzed using a graph pad prism. The D'Agostino & Pearson omnibus normality K2 test was performed on the data group. When the control passed the normality test, the data groups were analyzed by Bennett's test or Bonferroni all-pair comparison test (ANOVA). Grouping and / or ranking was performed when the data were not of the following Gaussian distribution or were not suitable for the statistical approach described above and the data were processed in a discriminatory manner allowing for subgroup and / or category comparisons . Acceptable values for significance were P < 0.05 and indicated the higher significance to which it was applied. For illustrative purposes, the data analyzed by parametric statistics are presented as mean ± SEM, while nonparametric data are represented as scattered points or categorical subgrouping.

result

Figure 11 shows the effect of Norvigovin on zebrafish behavior, A to G, and Fig. 12, panels A to G, respectively. In chronic nicotine (Chr Nic) and nicotine withdrawal symptoms (Nic WD), zebrafish exhibited increased latency to the upper (s), while group withdrawal (Nic WD-DMX1) with withdrawal symptoms + 1 mg / Zebrafish showed a statistically significant decrease. Figure 11, panel A. Zebrafish of chronic nicotine (Chr Nic) and nicotine withdrawal symptoms (Nic WD) group also showed reduced migration to the upper, while withdrawal symptoms + 1 mg / l of Norwegian (Nic WD- DMX1) group showed a statistically significant increase. 11, panel B. Additionally, the zebrafish of the chronic nicotine (Chr Nic) and nicotine withdrawal symptoms (Nic WD) group exhibited normal habit patterns while the withdrawal symptoms + 1 mg / l of Norwegian (Nic WD-DMX1 ) Group of zebrafish reached a value equivalent to the control at 5 minutes. Figure 11, Panel C. A statistically significant increase in the duration of time consumed in the upper (s) of the tank area was associated with a withdrawal symptom plus one (1) compared to the control, chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) Gt; mg / l &lt; / RTI &gt; of zebrafish of the Norwegian (Nic WD-DMX1) group. 11, panel D. Furthermore, the zebrafish of the Nic WD-DMX1 group with withdrawal symptoms plus 1 mg / l of Norbogol had a significantly lower risk than the control, chronic nicotine (Chr Nic) and nicotine withdrawal symptoms (Nic WD) The duration of time consumed in the upper (s) portion of the upper portion and the mean duration of inflow in the upper portion. 11, panels E and F. The fish treated with Norwegian phosphorus consumed more than average time in their respective movements to the upper, suggesting the possibility of an anti-anxiety-like effect of Norwegian phosphorus. Fish treated with Norwegian bogin also showed increased mean duration of inflow compared to the control, chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups. 11, Panel G.

The total distance traveled in the tank was measured, and the zebrafish in the nicotine withdrawal group exhibited an increased anxiety-like response calibrated by treatment with Norbybogaine (Fig. 12, panel A). The average velocities of the zebrafish were also corrected by treatment with Norvig (Fig. 12, panel B). There were no observed differences in absolute changes in the zebrafish direction in any test group (FIG. 12, panel C). In addition, the zebrafish treated with Norbigbo treated showed a slight increase in the rotation rate of rotation for both chronic nicotine and nicotine withdrawal groups (Figure 12, Panel D). On the other hand, no change was observed in the relative change in direction between any groups or in the absolute change in the direction of movement per shift distance (Fig. 12, panels E and F). Reduced absolute changes in the direction of movement per shift distance observed in the nicotine withdrawal group were corrected by treatment with Norwegian phosphorus. (Fig. 12, panel G). These results suggest an anti-anxiety-like anti-withdrawal effect of treatment with Norvigor.

Anxiety / fear responses were also tested by recording the frequency of frozen seizures and the duration of freezing. Figure 13. More frozen seizures and longer freezing duration indicate elevated anxiety and / or fear. (Nic WD + Cpd 1 mg / l) reaffirmed the high seizure (panel A) and duration of freezing (panels B and C) due to nicotine withdrawal symptoms at the control level.

We also detected the effect of treatment with Norvig-boy on motion mobility. Figure 14. The label "floating" was used to express the episode frequency with a degree of motion independent of spatial displacement (the duration of the flood). The label "Move" reflects the overall locomotive activity. "High-shift" reflects accelerated swim seizures (greater than 60% of the individual mean). While strong declines in immobility, migration, and high migra- tion events were observed in nicotine withdrawal symptoms zebrafish, the Norieboogin-treated zebrafish showed an increase in the number of high-mobility events. (Fig. 14, panel A). In addition, nicotine withdrawal symptoms reduced the mobility of fish and increased immobility, especially. The chronic nicotine treated fish exhibited a moderate increase in mobility and a moderate decrease in the immobility duration, while the Norwegian phosphorus-treated fish exhibited a control-equivalent value for migratory and immobile endpoints and a slight increase in high-mobility activity Respectively. (Fig. 14, panel B).

Argument

Analysis of the passive NTT end point was assessed by the longer time spent by the Norwegian in-treatment fish in the shorter wait time entering from the control and in the more avoidant upper (versus 'more protective' lower) compartment of the test As shown in Figure 11 (panel A and D), with statistically significant anti-anxiety-like effects of Norviga at 1 mg / l. The number of migrations from the top to the bottom (top inflow) also differed in the 1 mg / L Norwegian population of nicotine withdrawal fish, suggesting the general activation of inquiry as this dose. (Fig. 11, panel B). The frequency and duration of frozen seizures were increased in chronic nicotine and especially nicotine withdrawal. At 1 mg / l, Norvigovin reversed the effect of nicotine withdrawal fish and reaffirmed its level for the control fish group. (Fig. 13). All fish exhibited normal habit responses, assessed by the minute distribution of swimming activity in all passive parameters, which were generally normal and lacked behavioral abnormalities in the applied test conditions consistent with other published NTT studies Respectively. Analysis of the computer-generated NTT endpoints showed a constant pattern of unchanged locomotor activity (evaluated by distance and velocity measurements) at 1 mg / L of Norvigrin but activity was reduced in the WD group. (Fig. 12, panels A and B). The heading (moving direction index) and the average meandering phenomenon (straightness index) were similar in all groups. (Fig. 12, panels E and F).

In this study, whimsical movements were measured automatically using frequency of high mobility episodes. These end points are generally characterized by a higher anxiety state, but can be found when a characteristic state of the altered crust (eg, hallucinogen) is reached. In this experiment, no changes were seen in the treatment of chronic nicotine and nicotine withdrawal symptoms. (Fig. 14). We observed an increase in the duration and frequency of high mobility (approximately 2) in Noriboglofen-treated fish with nicotine withdrawal symptoms. The Norwegian boys did not cause any rounding behavior (referred to as unchanged rotational angle), which was common for strongly given anti-glutamic acid drugs. Movement mobility (migration frequency) and migration duration (the end point reflecting general mobilization activity and anxiety induction treatment) showed significant effects of treatment with chronic nicotine, nicotine withdrawal symptoms, and noroviga. (Fig. 14). The hypo-locomotive effect of nicotine withdrawal was observed (duration and frequency of mobility not only at end point but also at travel distance and end point of speed). (Fig. 14). The hyper-locomotive effects of chronic nicotine (as in the literature) were observed. (Fig. 14). At 1 mg / ℓ, Norvigovin reaffirmed the duration and frequency of mobility (migration and immobility) in nicotine-treated fish versus control values, suggesting that Norvigovin can obtain the effects of movement of nicotine withdrawal symptoms do. (Fig. 14).

conclusion

Norbyborg therapy can reverse the effects of nicotine withdrawal symptoms induced by nicotine withdrawal symptoms, in particular, both anxiety induction and exercise deterioration. The 1 mg / l dose of acute Norvigovin caused strong anxiolytic-like behavior in the repeated nicotine withdrawal symptoms zebrafish model without any apparent overactivity / underactivity compared to the control. Chronic nicotine, and in particular repeated WD, induced anxiety-inducing-like and locomotor effects in zebrafish, consistent with zebrafish and rodent literature. Repeated anxiety-induced similarity and movement effects of nicotine withdrawal symptoms were completely reversed by Norwich borne at a dose of 1 mg / l. Based on these results, the beneficial effects of Norvigovin in other behavioral paradigms are appropriate for nicotine abuse as well as other drug abuse-related models and can be expected at a potential dose of 1 mg / l.

Example  25. Anxiety-related At the end point  Expressed by From zebra fish Norwegian  effect

animal

A total of 60 adult wild short fins zebrafish (approximately 50:50 male: female ratio) were used in this study. Water rings were housed in groups of 20 to 30 fish per 40 l tank. The tank was filled with filtered water and then kept at 25 占 폚. Illumination (1000 to 1100 lx) was provided by ceiling mount fluorescence in a 12 hour period (On: 6.00 hours, Off: 18.00 hours) according to the zebra fish management standard. All of the fish used in this study were experimentally naive and fed two times a day with tetramine tropal flakes (Tetra USA, Blacksburg, Va.). After the behavioral test, the animals were euthanized in 500 mg / L tricine (Sigma-Aldrich, St. Louis, MO) buffered to pH = 7.0. In this study, animal experiments faithfully followed national and institutional guidelines and regulations.

Test compound

Pilot experiments performed at 1-, 5-, and 10-mg / ml indicated that the effect of the Norovigrin in the other protocol, at doses of 1 mg / l, which does not promote any effect of mobile movement, While the 5- and 10-mg / ℓ doses resulted in a decrease in selected swimming activity levels. As a result, a dose of 1 mg / l of Norbigov (DMX1 or Cpd) was selected. Based on experience with a wide range of other neuroactive compounds and pilot studies, a standard 20-minute pretreatment time was chosen. This exposure time was also sufficient to stimulate the physiological (e.g., cortisol and c- fos ) responses of zebrafish to multiple drugs. Drug exposure was performed in this study by placing individual zebrafish in a 1 L plastic beaker for 20 minutes before testing. After each exposure, the solution is periodically changed to ensure that each fish is exposed to a constant concentration of phosphorus phosphorus. Control fish are exposed to water free of Norvigans for the same treatment time as described above.

Tests and Procedures

Apparatus: Behavioral tests were conducted at 11:00 to 15:00 using a tank adjusted to maintain room temperature (25 ° C) using water. The study used the New Tank Test (NTT) protocol. NTT represents one of the most commonly used nerve phenotype tests for adult zebrafish. To avoid test battery or conditioning effects, each analysis was performed once for each separate navy fish. Prior to testing, the water rings were individually pre-exposed in a 1 L plastic beaker for 20 minutes in either Norwegian-treated or Norwegian-phosphorus free water. During the test, zebrafish behavior was recorded by two blinded observers for treatment, using follow-up automated analysis made by Etovision XT8.5 software (Noldus IT, Glenningen, The Netherlands) Different behavioral endpoints (in all experiments between the evaluators and the evaluator's confidence> 0.85) were manually scored. NTT used to assess zebrafish anxiety and movement was a 1.5-liter trapezoidal tank (15 cm high × 28 cm upper x 23 cm lower x 7 cm wide, Aquatic Hibitatsu, located in Apopka, Florida) And divided into two substantially identical horizontal portions by line marking the outer walls. The fish were individually exposed to water (water control) or noribogloin (1, 5 and 10 mg / l) for 20 min and tested at standard 5 min NTT.

Behavioral Analysis : The zebrafish behavior is recorded by the trained observer and the time spent waiting for the top half of the tank (s) to reach, the time consumed at the top (s), the number of transitions up to the top, Respectively. Freezing was defined as a lack of total movement except for gills and eyes for more than 2 seconds. The test was recorded on a computer using a USB webcam (2.0-megapixel, Gigaware, UK) and subsequently analyzed by Ettovision XT 8.5 to determine the travel distance (m), velocity (m / s) And the meandering phenomenon end point were evaluated. During manual observation, the video was recorded in MPEG1 format at a maximum sample rate of 30 fps during each test by an autofocus 2.0 MP USB webcam placed at 25 cm in front of the tank and attached to a laptop computer. Recorded video was analyzed using the Ettovision XT8.5 software. After calibrating all the environments for each area, the origin (0,0) was designed at the center of each tank by placing the calibration axis. Track data for each fish was sent as a raw data into a separate spreadsheet. The spatial pattern of the zebrafish swimming was described by evaluating independently of the criteria agreed by two trained observers blinded to the follow-up treatment that sent the tracing.

RESEARCH DESIGN AND DATA ANALYSIS : Studies have shown that adult zebrafish is strongly (20 min) immersed in water control (15 animals per group) and 3 volumes of Norwegian (1, 5 and 10 mg / And tested on NTT for 5 minutes before euthanizing the fish. To generate graphs and descriptive statistics for manual and computer generated endpoints, raw data from manual and automatic endpoints were analyzed using a graph pad prism. Dagostino and Pearson omnibus normality K2 tests were performed on data groups. When the control passed the normality test, the data groups were analyzed by Bennett's or Bonnieferney's all-pair comparison test (ANOVA). Grouping and / or ranking was performed when the data were not of the following Gaussian distribution or were not suitable for the statistical approach described above and the data were processed in a discriminatory manner allowing for subgroup and / or category comparisons . Acceptable values for significance were P &lt; 0.05 and indicated the higher significance to which it was applied. For illustrative purposes, the data analyzed by parametric statistics are presented as mean ± SEM, while the nonparametric data are presented as discrete points or categorical subgrouping.

result

Figure 16 shows the effect of Norvigovin on zebrafish behavior, A to G and Fig. 17, panels A to G, respectively. Zebrafish in each of the Noribogloin treated groups (1-, 5-, and 10-mg / l) showed a statistically significant reduction in waiting time for the upper half of the tank. Figure 16, Panel A. On the other hand, while none of the treatment groups exhibited statistically significant changes from the control group in migration to the upper half of the tank (Figure 16, panels B and C), in each treatment group The zebrafish showed a statistically significant increase in the duration of time spent in the defined upper portion of the tank (Fig. 16, panels D and E). Zebrafish treated with Norwegian phosphorus consumed more than average time in each of their movements to the top, and 2-3 fish in the 5- and 10-mg / l treatment groups had their entire time in the upper part of the tank (Fig. 16, panel F). The mean inflow duration in the Norbigovine phosphorus-treated zebra fish was higher than the first one minute and then steadily decreased for the remaining 2 to 5 minutes (Figure 16, Panel G).

The total distance and velocity moved in the tank was measured and in the Norwegian In-treatment group the zebra fish exhibited a modest, but not significant, decrease in travel distance (Figure 17, panel A) and velocity (Figure 17, panel B) . In addition, there was a trend for a decrease in the high rotational angle events (Fig. 17, panel C) and a significant turning / rotational speed reduction in the range of 10 mg / l capacity for the Norvigor phosphorus-treated zebra fish ). When observing relative changes in body direction, unchanged behavior was observed between the control and the Norwegian phosphorus-treated group (Figure 17, panel E). A statistically significant decrease in overall rotational speed and pattern (meandering) was observed in the 5- and 10-mg / l Norviga treated group (Figure 17, Panel F), but no difference in average meandering was observed 17, Panel G).

Anxiety / fear responses were also tested by recording the frequency of frozen seizures and the duration of freezing. Figure 18. More frozen seizures and longer freezing duration indicate elevated anxiety and / or fear. There was no difference in the frequency of frozen seizures (frequency per 5 minutes or frozen seizures) or duration of freezing (Figure 18, panels A and B).

We also detected the effect of treatment with Norvig-boy on motion mobility. 19. The label "floating" was used to express the episode frequency with a degree of motion independent of spatial displacement (the duration of the flood). The label "Move" reflects the overall locomotive activity. "High-shift" reflects accelerated swim seizures (greater than 60% of the individual mean). The subgroups were visible (35% to HF / ℓF thresholds) by the discriminatory nature of high frequency (HF) for low frequency (LF) zebrafish in each cohort. No difference in mean values per subgroup was observed. In addition, there was a dose-related loss of HF high-transfer events and a dose-related loss of LF immobilization events by treatment with Norbigovan. There was an overall redistribution of HF-floating and HF-migration events (Figure 19, panel A). The subgroups observed in each cohort were shown as normal (M) duration versus high (H) duration locomotor activity, with no difference in mean value per group in each subcategory (Figure 19, Panel B). Movement category was not affected. Contingency analysis by the medium (M) versus high (H) duration per category (threshold of 50 seconds) showed a dose-related increase in the H-immune category and a dose-related decrease in the M-high migra- tion category.

Argument

Analysis of the passive NTT endpoints showed that consumption of nutrients by in-treatment fish in the lower avoidance upper (even more 'protective' lower) compartment of the study and the lower waiting time to enter from the control (Figure 16, panel A) Like effects of the Norvigors at 1, 5 and 10 mg / l, as assessed by the longer duration of exposure (Fig. 16, panels D and E)). In addition, drug-treated zebrafish appears to be easier to capture by the net (data not shown), as noted independently by researchers during experiments that indirectly support reduced anxiety in these cohorts. The number of transitions from the top to the bottom (top inflow) was not different in the treatment group of 1 mg / l-nobilis, suggesting that there is no movement disorder in this dose (i. E., Unaltered ability to cross the water layer (Fig. 16, panels B and C). Two higher doses tended to slightly decrease the number of top deliveries from 10 (control) to approximately 7 for both doses (Fig. 16, panel B).

The frequency and duration of frozen seizures was unaffected and remained generally low during this study (Figure 18, panels A and B). This situation is not uncommon with zebrafish NTT studies in general and reflects the specific behavioral characteristics and reference files of the zebrafish cohort used. All fish exhibited normal habit responses, as generally assessed by the distribution of minutes of acceptance activity in all passive parameters, confirming the absence of behavioral abnormalities in application test conditions consistent with the standard and other published NTT studies . Analysis of the computer-generated NTT endpoints shows a constant pattern of unchanged locomotor activity (assessed by distance and velocity measurements) at 1 mg / L of Norvigrin (FIG. 17, panels A and B). (Fig. 17, panels A and B) the total distance moved at 5 and 10 mg / l compared to the control.

While the heading and the average gait (straightness index) are similar in all groups, the significant dose-dependent effect of the Norwegian boy in lowering total gait can be attributed to reduced anxiety and / (Fig. 17, panels E to G), which is relatively slow in the upper part of NTT as commonly occurs with anxiety serotonin agonists.

The volatile movement in this study was automatically assessed by measuring the frequency of high mobility episodes (Figure 19, panels A and B). These end points are generally characterized by a higher anxiety state, but can be found when a characteristic state of the altered crust (eg, hallucinogen) is reached. Fish usually make multiple turns / turns as part of the natural zebra fish anxiety-like arousal behavior and / or during certain hallucinogenic drug treatments. The Norwegian boys did not cause any rounding behavior (referred to as unchanged rotational angle), which was common for strongly given anti-glutamic acid drugs. In contrast, the Norwegian phosphorus resulted in a statistically significant dose-dependent reduction in turning / number of rotations, which could indicate an anti-anxiety effect and / or direct or indirect stimulation of, for example, NMDA function.

The movement mobility (movement frequency) and the duration of movement (the end point of which reflects general locomotor activity and anxiety inducing treatment) showed a statistically significant effect of treatment with Norwegian bone (Figure 19, panels A and B) . Subgroups were observed at these endpoints, and subgroups were assigned to the subgroups. We have observed a specific redistribution of the high-mobility duration swimming category to the benefits of the floating duration category without changing the normal mobility. Since 'mobility' (reflecting normal swimming) remained unaltered, the effect of Norwegian bogin did not appear to be associated with generalized motor impairment. However, redistribution of floating / high mobility suggests that typical fast-accelerated swimming episodes are reduced for anxious fish during irregular 'high-stress' swimming, where the Norwegian borealone can match the observed anxiolytic effect. Furthermore, dose-related loss of HF (high frequency) high-shift events by medication and loss of capacity of LF (low frequency) floating events with overall redistribution of HF- and HF- (Fig. 19, panel B). The final variance came from a specific subgroup of fish (roughly 50% of the population), which showed an average of more than 50% of the total event counts, the higher score of the total-coefficients being associated with the higher frequency of floating events. At 10 mg / ℓ, the fish had the lowest 'high shift' and duration (also highest in the more insecure control zebrafish cohort). A similar trend was observed for the 10 mg / l group, especially for reduced rotational parameters.

conclusion

Treatment with Norgibogg at 1 mg / l resulted in strong anxiolytic-like behavior without any apparent hyperactivity / hyperexcitation or swirling behavior in zebrafish. Under the tested control, higher doses of Norbogophane were no longer efficacious for the appropriate and sensitive indicators (time at the top, latency at the top) at the level of anxiety because the half- Mg / l. &Lt; / RTI &gt; At 5- and 10-mg / ml, the noribogans continued to induce anxiolytic-like effects, while their in vivo behavioral profiles showed a decrease in fast swim duration to 'more calmer' / slower upper swimming activity Connected.

Claims (41)

A method of treating opioid or opioid-like drug abuse in a human patient afflicted with an opioid or an opioid-like drug, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I, Or a pharmaceutically acceptable salt or solvate thereof, wherein said concentration inhibits or ameliorates said abuse, wherein said concentration is less than about 500 ms during said treatment A method for treating opioid or opioid-like substance abuse sufficient to maintain QT interval. The method according to claim 1,
a) administering a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose of Norviga provides an average serum concentration of from about 50 ng / ml to about 180 ng / ml; And
b) at least one additional dose of a norboboride such that at least one additional dose maintains an average serum concentration of from about 50 ng / ml to about 180 ng / ml for a period of time, or a pharmaceutically acceptable derivative thereof, Or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of opioid or opioid-like drug abuse. 6. The method of claim 1, further comprising the step of selecting pre-selected poisoned patients to assess tolerability to prolongation of the QT interval. 7. The method of claim 1, wherein the maximum serum concentration is from about 40 ng / ml to about 250 ng / ml. 4. The method of claim 1, wherein the serum concentration of the Norbitogloin is from about 1000 ng * hr / ml to about 5800 ng * hr / ml. A method of treating opioid or opioid-like drug abuse in a human patient afflicted with an opioid or an opioid-like drug, the method comprising administering to the patient a therapeutically effective amount of at least one compound selected from the group consisting of Norviga, Derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the concentration is sufficient to inhibit or ameliorate the abuse while maintaining a QT interval prolongation of less than about 20 ms during the treatment , Opioid or opioid-like substance abuse. A method of treating nicotine addiction in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a norbobagene, a noribogan derivative, or a pharmaceutically acceptable salt thereof, About 50 ng to less than 10 [mu] g / kg body weight per day. A method of preventing nicotine craving in a patient in need of prevention of nicotine craving, comprising administering to said patient a prophylactically effective amount of a noribogan, a noribogan derivative, or a pharmaceutically acceptable salt thereof, An effective effective amount is from about 50 ng to less than 10 μg / kg body weight per day for preventing nicotine craving. 9. The method of claim 8, wherein the patient is no longer physically addicted to nicotine. CLAIMS What is claimed is: 1. A method of treating alcohol dependence in a human patient suffering from alcoholism, comprising administering to said patient a Norbitogen, a Norbitogen, or a pharmaceutically acceptable salt thereof, which provides an average serum concentration of about 50 ng / ml to about 500 ng / Administering a dosage of an acceptable salt and / or solvate, wherein said concentration is sufficient to maintain said QT interval of less than about 500 ms during said treatment, while improving said dependency. 11. The method according to claim 10, wherein the total dose of the Noribogloin, Norbigor derivative, or a pharmaceutically acceptable salt and / or solvate thereof is from about 1.3 mg / kg to about 4 mg / kg / How to cure. WHAT IS CLAIMED IS: 1. A method of treating substance abuse in a human patient afflicted with a substance, the method comprising administering to the patient a therapeutically effective amount of a norbobagene derivative, or a pharmaceutically acceptable salt thereof, wherein the norbobagain provides an average serum concentration of 50 ng / ml to 180 ng / Administering a dose of a solvate, wherein said concentration is sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment. 13. The method of claim 12,
a) administering a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein an initial dose of Norviga provides an average serum concentration of 50 ng / ml to 180 ng / ml; And
b) at least one additional dose of the at least one norbye such that at least one additional dose maintains an average serum concentration of from about 50 ng / ml to about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt thereof, A method of treating substance abuse comprising administering a salt or solvate. WHAT IS CLAIMED IS: 1. A method of treating substance abuse in a human patient afflicted with a substance, the method comprising administering to the patient a therapeutically effective amount of a norbobene derivative, or a pharmaceutically acceptable salt thereof, wherein the norbobagain provides an average serum concentration of 50 ng / ml to 180 ng / Or a solvate, wherein said concentration is sufficient to inhibit or ameliorate said abuse while maintaining a QT interval prolongation of less than about 20 ms during said treatment. 15. The method of claim 14,
a) administering a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein an initial dose of Norviga provides an average serum concentration of 50 ng / ml to 180 ng / ml; And
b) an at least once additional dose of at least one additional dose of a norbober to maintain an average serum concentration of from about 50 ng / ml to about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt thereof Or a pharmaceutically acceptable salt, solvate, or solvate thereof. CLAIMS 1. A method of treating pain in a patient, the method comprising administering to the patient a therapeutically effective amount of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the Norbitogen is a Norbitogarin which provides an average serum concentration of 50 ng / ml to 180 ng / Wherein said concentration is sufficient to alleviate and / or inhibit said pain while maintaining a QT interval of less than about 500 ms during said treatment. 17. The method of claim 16,
a) administering a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein an initial dose of Norviga provides an average serum concentration of 50 ng / ml to 180 ng / ml; And
b) an at least once additional dose of at least one additional dose of a norbober to maintain an average serum concentration of from about 50 ng / ml to about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt thereof Or a pharmaceutically acceptable salt, solvate, or solvate thereof. CLAIMS 1. A method of treating pain in a patient, the method comprising administering to the patient a therapeutically effective amount of a Norbitogen, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the Norbitogen is a Norbitogarin which provides an average serum concentration of 50 ng / ml to 180 ng / Wherein said concentration is sufficient to alleviate and / or inhibit said pain while maintaining a QT interval of less than about 20 ms during said treatment. A method of treating a migraine headache and / or a symptom thereof in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a norbyborne, nordoborgene derivative, or a pharmaceutically acceptable salt thereof, And / or &lt; / RTI &gt; 20. The method of claim 19, wherein the therapeutically effective amount is from about 50 ng to about 10 μg / kg body weight per day. A method of preventing migraine and / or symptoms thereof in a patient in need of such treatment comprising administering to said patient a prophylactically effective amount of a norbyeene, a norbyeene derivative, or a pharmaceutically acceptable salt thereof, And / or preventing the symptoms thereof. 22. The method of claim 21, wherein the prophylactically effective amount is from about 50 ng to about 10 μg / kg body weight per day. A method of maintaining a tolerable QT interval prolongation in a patient while treating a condition in a patient treatable with a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof,
a) administering to the patient an initial unit dose of a Norbitogen, a Norbitogor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the unit dose is such that the serum concentration has an acceptable QT interval in the subject Lt; / RTI &gt; to 180 ng / ml; &lt; RTI ID = 0.0 &gt; And
b) an at least one additional dose of at least one additional noribogon such that an additional dose is maintained during treatment at an average serum concentration of from about 50 ng / ml to about 180 ng / ml, or a pharmaceutically acceptable salt or solvate thereof, Maintaining said serum concentration by administering a solvate periodically;
Wherein said additional capacity or capacities continue if necessary to treat said condition, and wherein said allowable QT interval is not longer than 500 ms. 25. The method of claim 24, wherein the QT interval is extended by less than 50 ms or less than 20 ms. A method of maintaining a tolerable QT interval prolongation in a patient while treating a condition in a patient treatable with a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt or solvate thereof,
a) administering to the patient an initial unit dose of a Norbitogen, a Norbitogor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the unit dose is such that the serum concentration has an acceptable QT interval in the subject Lt; / RTI &gt; to 180 ng / ml; &lt; RTI ID = 0.0 &gt; And
b) an at least one additional dose of at least one additional noribogon such that an additional dose is maintained during treatment at an average serum concentration of from about 50 ng / ml to about 180 ng / ml, or a pharmaceutically acceptable salt or solvate thereof, Maintaining said serum concentration by administering a solvate periodically;
Wherein the additional capacity or capacities continue if necessary to treat the condition, and wherein the allowable QT interval is not longer than 50 ms. 26. The method of claim 25, wherein the QT interval is extended to less than 20 ms. CLAIMS 1. A method of modulating tolerability to opioid analgesics in a patient suffering from opioid analgesic therapy comprising administering to a patient a therapeutically effective amount of a norbobene derivative, or a pharmaceutically acceptable salt thereof, wherein the norbornene provides an average serum concentration of 50 ng / ml to 180 ng / Or solvate of said opioid analgesic at the same time as or simultaneously with said opioid analgesic therapy, wherein said concentration is sufficient to re-sensitize said patient to said opioid as an analgesic agent while maintaining a QT interval Of opioid analgesics sufficient to maintain &lt; RTI ID = 0.0 &gt; a &lt; / RTI &gt; 28. The method of claim 27, further comprising ceasing the dose of the analgesic agent. 28. A method of modulating tolerability to an opioid analgesic agent, further comprising administering a therapeutically effective amount of a norbobagene derivative, or a pharmaceutically acceptable salt and / or solvate thereof, . CLAIMS 1. A method of modulating tolerability to opioid analgesics in a patient suffering from opioid analgesic therapy comprising administering to a patient a therapeutically effective amount of a norbobene derivative, or a pharmaceutically acceptable salt thereof, wherein the norbornene provides an average serum concentration of 50 ng / ml to 180 ng / And / or solvate of said opioid analgesic at the same time as or simultaneously with said opioid analgesic therapy, wherein said concentration is sufficient to re-sensitize said patient to said opioid as an analgesic agent while maintaining a QT interval Of opioid analgesics sufficient to maintain &lt; RTI ID = 0.0 &gt; a &lt; / RTI &gt; 32. A pharmaceutical composition according to any one of claims 27 to 30 wherein the opioid analgesic is selected from the group consisting of pentanil, hydrocodone, hydro morpholine, morphine, oxycodone, buprenorphine, codeine, tbaine, buprenorphine, methadone, Wherein the tolerance to an opioid analgesic is selected from the group consisting of tramadol, tamaptopir, levorphanol, sufentanil, pentazocine and oxymorphone. A method of treating a depressive and / or post-traumatic stress disorder in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a nordoborgain, a nordoborgain derivative, or a pharmaceutically acceptable salt and / or solvate thereof Wherein the patient is not intoxicated with cocaine or opiate and further wherein the therapeutically effective amount provides a serum level of efficacious mean Norvir of from about 50 ng / ml to about 180 ng / ml, Wherein the QT interval is less than about 500 ms during the treatment. A method of treating a depressive and / or post-traumatic stress disorder in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a nordoborgain, a nordoborgain derivative, or a pharmaceutically acceptable salt and / or solvate thereof Wherein the patient is not intoxicated with cocaine or opiate and further wherein the therapeutically effective amount provides a serum level of efficacious mean Norvir of from about 50 ng / ml to about 180 ng / ml, Wherein the treatment maintains a QT interval of less than about 20 ms during the treatment. A method of treating anxiety-related disorders in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt and / or solvate thereof Wherein the patient is not intoxicated with cocaine or opiate and further wherein the therapeutically effective amount provides a serum level of efficacious mean Norvir of from about 50 ng / ml to about 180 ng / ml, Maintaining a QT interval of less than 500 ms. A method of treating an impulse control disorder in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a norbobene, a derivative thereof, or a pharmaceutically acceptable salt and / or solvate thereof, , The patient is not intoxicated with cocaine or opiate and further wherein the therapeutically effective amount provides a serum level of efficacious mean Norvir of from about 50 ng / ml to about 180 ng / ml, while about 500 &lt; RTI ID = 0.0 &gt; Maintaining a QT interval of less than &lt; RTI ID = 0.0 &gt; ms. &Lt; / RTI &gt; A method of controlling and / or attenuating food intake in a patient in need of control of food intake and / or weakening of appetite, comprising administering to said patient a therapeutically effective amount of a norbobene, a derivative thereof, or a pharmaceutically acceptable salt thereof Wherein said patient is not intoxicated with cocaine or opiate and further wherein said therapeutically effective amount is from about 50 ng / ml to about 180 ng / ml efficacious average yolk Wherein the composition maintains a QT interval of less than about 500 ms during the treatment, while providing a serum level that is less than about 500 msec. A method of treating an anxiety-related disorder in a patient in need of such treatment comprising the step of administering to said patient a therapeutically effective amount of a Norbitogen, a Norbitogen derivative, or a pharmaceutically acceptable salt and / or solvate thereof Wherein the therapeutically effective amount provides a serum level of about 50 ng / ml to about 180 ng / ml of efficacious mean insulin, while maintaining an QT interval of less than about 500 ms during the treatment, How to treat a disorder. A method for screening opioid-addicted patients for determining a patient &apos; s tolerability to a therapeutic dose of a norbobene or a pharmaceutically acceptable salt and / or solvate thereof,
Measuring the pre-dose QT interval of the patient;
Administering to the patient a sub-therapeutic dose of a norbobene or a pharmaceutically acceptable salt thereof; And
And measuring the QT interval after administration of said patient. 39. The method of claim 38, further comprising one or more of the following steps:
Determining a first extension by determining a difference between a pre-administration QT interval and a post-administration QT interval;
Estimating a second prolongation based on the first prolongation, the second prolongation being an estimated QT interval prolongation expected to be observed in the patient at the time of administration of a therapeutic dose of Norbitcine;
Determining the patient &apos; s tolerability to the therapeutic dose of Norbogophane; And
Administering said therapeutic dose of Noribogloin or stopping treatment with Noribogloin to said patient wherein said second prolongation is estimated to be less than about 50 msec. . 40. The method of claim 39, wherein said therapeutic dose provides an average serum concentration of between 50 ng / ml and 180 ng / ml, said concentration inhibiting or ameliorating opioid poisoning, A method of screening patients for opioid-intoxication sufficient to effect. 40. The method of claim 39,
a) administering a Norvigor derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein an initial dose of Norviga provides an average serum concentration of 50 ng / ml to 180 ng / ml; And
b) an at least once additional dose of at least one additional dose of a norbober to maintain an average serum concentration of from about 50 ng / ml to about 180 ng / ml for a period of time, or a pharmaceutically acceptable salt thereof Or a pharmaceutically acceptable salt, solvate, or solvate thereof.

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