HK1097770A - Methods of using and compositions comprising thalidomide for treatment, modification and management of fibromyalgia - Google Patents

Abstract

Methods of treating, preventing, modifying and/or managing fibromyalgia and related conditions are disclosed. Specific embodiments encompass the administration of thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with a second active agent and/or physical ox psychological therapy. Pharmaceutical compositions, single unit dosage forms, and kits suitable for use in the methods of the invention are also disclosed.

Description

Methods and compositions comprising thalidomide for the treatment of fibromyalgia

1. Field of the invention

The present invention relates to methods of treating, preventing, ameliorating and/or managing fibromyalgia and related syndromes comprising the administration of thalidomide, either alone or in combination with known therapies. The invention also relates to pharmaceutical compositions and dosage regimens. In particular, the invention encompasses the use of thalidomide in combination with physical or psychological therapy and/or other standard therapies for fibromyalgia and related syndromes.

2. Background of the invention

Thalidomide is under the trade name Thalomid^®Racemic compounds are sold under the chemical name α - (N-phthalimide) glutarimide or 2- (2, 6-dioxo-3-piperidyl) -1H-isoindole-1, 3(2H) -dione. The compounds have structure I:

thalidomide was originally developed in the 50's of the 20 th century for the treatment of vomiting of pregnancy, but was no longer used due to its teratogenic effects. Thalidomide has been approved in the united states for the acute treatment of skin symptoms of leprosy, leprosy erythema nodosum, Physicians' Desk Reference, 1153-. The sale of thalidomide is strictly controlled (ibid.) because its administration to pregnant women can lead to birth defects. The role of thalidomide in the treatment of other diseases, such as chronic graft versus host disease, rheumatoid arthritis, sarcoidosis, some inflammatory diseases of the skin, and inflammatory bowel disease, has been studied. See generally Koch, h.p., prog.med.chem.22: 165-242(1985). See also Moller, d.r. et al, j.immunol.159: 5157-5161 (1997); vasiliauskas, e.a., et al, Gastroenterology 117: 1278-1287 (1999); ehrenpris, e.d. et al, Gastroenterology 117: 1271-1277(1999). Further, it is believed that thalidomide may be combined with other drugs to treat ischemia/reflexes (recursion) associated with coronary and cerebral obstructions. See U.S. patent No. 5,643,915, which is incorporated herein by reference.

More recently, thalidomide has been found to have immunomodulatory and anti-inflammatory effects in a variety of disease states, AIDS mental committee and AIDS opportunistic infections. In studies to identify physiological targets for thalidomide, it was discovered that the drug has a wide range of biological activities in addition to its sedative effects, including neurotoxicity, teratogenicity, inhibition of TNF- α production by monocytes/macrophages and concomitant inhibition of inflammatory toxicity associated with high levels of TNF- α, and inhibition of angiogenesis and neovascularization.

In addition, beneficial effects are found in various skin diseases, ulcerative colitis, Crohn's disease, Bechets's syndrome, systemic lupus erythematosus, oral ulcers, cancer, and lupus. The anti-angiogenic properties of thalidomide in an in vivo model have been reported. D' Amato et al, thalidosides Is An Inhibitor Of Angiogenesis, 1994, PNAS, USA 91: 4082-4085.

However, the activity range of thalidomide is not well characterized. Data obtained from in vitro studies and preliminary clinical trials indicate that the immune effects of the compound vary significantly under different conditions. They may be associated with the inhibition of the production of tumor necrosis factor-alpha (TNF-alpha) and the down-regulation of selected cell surface adhesion molecules involved in leukocyte migration.

2.1 Pathology of fibromyalgia

Fibromyalgia is a clinical syndrome of widespread pain, fatigue, poor sleep and multiregional chronic pain in the musculoskeletal system characterized by repeated, increased tenderness at specific sites. Bradley et al, Rheum Dis Clin North Am 1999, 25 (1): 56; and Pellegrino et al, Arch Phys MedRehabil, 1999, 70: 61. fibromyalgia is also known as FM, Fibromyalgia Syndrome (FMs), fibrositis, myofascial syndrome, and extensive chronic pain syndrome. Pellegrino et al, Arch PhysMed Rehabil, 1999, 70: 61. fibromyalgia can be secondary to trauma, rheumatic diseases such as rheumatoid arthritis and osteoarthritis, connective tissue diseases, hypothyroidism, malignant diseases and other diseases (supra). When not associated with any of these diseases, the fibromyalgia is primary (ibid).

In patients with fibromyalgia, pain radiates diffusely from the axial skeleton covering a large area of the body, primarily involving muscle, and is described as debilitating, burning, painful, or intolerable. The 1990 American College of Rheumatology (ACR) classification criteria diagnosis of fibromyalgia is: the presence of widespread pain is longer than 3 months, and pain, notTenderness alone, may be controlled by applying pressure at about 4kg/cm at 11 or more defined tender points²Is activated by artificial pressure. Bradley et al, Rheum Dis Clin NorthAm 1999, 25 (1): 56.

pain in patients with fibromyalgia is due in part to a decrease in the pain perception threshold, which is reflected in the ability to distinguish nociception from non-nociception (e.g., touch, warmth, cold); and a decrease in pain tolerance threshold occurs, which is reflected by a reluctance to receive a stronger stimulus. Bradley et al, Rheum Dis Clin North Am 1999, 25 (1): 59.

psychological distress plays an important role in the pain experience and onset of fibromyalgia patients. Bradley et al, Rheum Dis Clin North Am 1999, 25 (1): 59-60. Increased psychological distress is a common feature of fibromyalgia. In patients with fibromyalgia and the general population, psychological distress is closely related to the number of pressure pain points. High levels of anxiety and pain, low certainty of pain resolution, and history of trauma are predictors of whether a patient will progress from acute pain to chronic pain (ibid).

Although both men and women are affected, the above syndrome occurs more frequently in women than in men. Pellegrino et al, Arch Phys Med Rehabil, 1999, 70: 62. this syndrome may occur in any age group, including the pediatric population. Gedalia et al, Clinical and Experimental Rheumatology, 2000, 18: 415-419. The cause of fibromyalgia appears to be multifactorial. Various causative factors include, but are not limited to, biological variables such as genetics, abnormal sleep, trauma, tissue injury, malignant disease, depression, neuroendocrine and autonomic disorders, neurotransmitter abnormalities, neuronal activation leading to central sensitization, low calcium levels, low serotonin levels, elevated levels of substance P, elevated levels of cerebrospinal fluid (CSF) nerve growth factor, elevated levels of CSF dynorphin A, elevated levels of CSF calcitonin gene-related peptide and various other antinociceptive molecules, functional brain activity abnormalities (regional reduced blood flow in the thalamus and caudate nucleus), nerve-mediated hypotension, cognitive behavioral variables such as adverse experiences during childhood, learning behavior in children's life with parents having dysfunction or chronic disease, failure in target-directed behavior leading to lower sensation of self-potency, inability to achieve a target, metabolic syndrome, fear of failure, depression and anxiety, as well as environmental and socio-cultural variables including psychosocial experience during childhood and lack of spouse or family support. Bradley et al, Rheum Dis Clin NorthAm 1999, 25 (1): 61-70 and Pellegrino et al, Arch Phys Med Rehabil 1999, 70: 62.

2.2 treatment of fibromyalgia

To date, there is little effective treatment for fibromyalgia and related syndromes. In some cases, physical therapy is used. Physical therapy for fibromyalgia includes massage and graded aerobic exercises such as low intensity aerobic exercise, walking, aerobic exercise in water, swimming, and stationary bicycles. Gedalia et al, Clinical and Experimental Rheumatology, 2000, 18: 418. however, excessive reliance on physical therapy and physiotherapy by others may tire patients efforts to achieve self-efficacy in pain management.

Current medications used to treat fibromyalgia include anxiolytics, hypnotics, muscle relaxants, non-narcotic analgesics, opioid analgesics, antidepressants, anticonvulsants, and antihypertensives. Gedalia et al, Clinical and Experimental Rheumatology, 2000, 18: 418. however, these drugs hardly provide complete pain relief. Thus, there remains a need for safe and effective methods of treating and controlling fibromyalgia.

3. Summary of the invention

The invention encompasses methods of treating or preventing fibromyalgia comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The invention also encompasses methods of ameliorating or managing fibromyalgia comprising administering to a patient in need of such management a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Another specific embodiment of the invention comprises the use of thalidomide in combination with other therapeutic agents currently used for the treatment or prevention of fibromyalgia, including, but not limited to, antidepressants, antihypertensives, anxiolytics, hypnotics, anticonvulsants, calcium channel blockers, muscle relaxants, non-narcotic analgesics, opioid analgesics, alpha-adrenoceptor agonists or antagonists, anti-inflammatory agents, cox-2 inhibitors, immunomodulators, immunosuppressants, hyperbaric oxygen, JNK inhibitors or corticosteroids.

Another specific embodiment of the invention comprises the use of thalidomide in combination with conventional therapies for the treatment, prevention, amelioration, or management of fibromyalgia, including, but not limited to, surgery, interventional procedures (e.g., nerve block), physiotherapy, and psychotherapy.

The invention further encompasses pharmaceutical compositions, single unit dosage forms, and kits suitable for treating, preventing, ameliorating, and managing fibromyalgia, which comprise thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

4. Detailed description of the invention

The present invention is based, in part, on the following perspectives: the compounds of the present invention can act alone or in combination with other agents to effectively treat, prevent, ameliorate and/or control different types and severity of fibromyalgia. Without being limited by theory, the compounds of the present invention may act as analgesics, but this is not required. In particular, since certain compounds can surprisingly affect the production of cytokines (e.g., TNF- α), they are believed to have "anti-hyperalgesia" and/or "neuromodulator" function by restoring the baseline or normal pain domain in the injured animal or human to which they are administered. Thus, the compounds of the present invention may exert a different effect than analgesics, which typically only reduce the stimulus-induced response, while the compounds of the present invention may alter a patient's ability to tolerate such a response by inhibiting pain-related distress, or by directly reducing the responsiveness of nociceptors. Furthermore, because certain compounds of the present invention are believed to act by a unique mechanism, they are believed to relieve or reduce pain without the typical adverse effects (e.g., anesthetic effects) of certain analgesics (e.g., opioids) even when used systemically.

A first embodiment of the invention encompasses a method of treating, preventing, ameliorating or managing fibromyalgia, which comprises administering to a patient in need thereof a prophylactically or therapeutically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

As used herein, the terms "fibromyalgia," "fibromyalgia syndrome," and "myofascial syndrome" and "fibromyalgia and related syndromes" refer to chronic pain conditions characterized by one or more of the following: pain, including allodynia (producing a painful response to a stimulus that is usually not painful) and hyperalgesia (producing an exaggerated response to a stimulus that is usually only mildly painful); a range of regional pain, such as non-cardiac chest pain, dyspepsia, headache, abdominal cramps (irritable bowel syndrome), temporal mandibular pain and chronic pelvic pain; stiffness; chronic pain in the musculoskeletal system in multiple zones; debilitation; poor sleep; a tender point; cognitive difficulties with attention and memory; body weight fluctuations; allergic symptoms (e.g., nasal congestion); environmental stimuli (e.g., odor, light, loud voice noise) and drug oversensitivity; syncope; shortness of breath; and frequent and urgent urination.

Another specific embodiment of the invention encompasses methods of modifying or modulating the threshold, progression, and duration of pain comprising administering to a patient in need of such modification or modulation a prophylactically or therapeutically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.

Another embodiment of the invention encompasses a pharmaceutical composition suitable for treating, preventing, ameliorating or managing fibromyalgia, the composition comprising thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and an optional carrier.

The invention also encompasses a single unit dosage form suitable for treating, preventing, ameliorating or managing fibromyalgia, which comprises thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and an optional carrier.

Another embodiment of the invention encompasses a kit suitable for treating, preventing, ameliorating, or managing fibromyalgia, which comprises a pharmaceutical composition comprising thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The invention further includes kits comprising a single unit dosage form.

Without being limited by theory, it is believed that thalidomide and other agents used to treat symptoms of fibromyalgia may act in a complementary or synergistic manner in the treatment, prevention, amelioration, or control of fibromyalgia. Accordingly, a particular embodiment of the invention encompasses methods of treating, preventing, ameliorating and/or managing fibromyalgia, which comprise administering to a patient in need thereof a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a therapeutically or prophylactically effective amount of a second active agent.

Examples of second active agents include, but are not limited to, antidepressants, antihypertensives, anxiolytics, hypnotics, anticonvulsants, calcium channel blockers, muscle relaxants, non-narcotic analgesics, opioid analgesics, alpha-adrenoceptor agonists or antagonists, anti-inflammatory agents, cox-2 inhibitors, immunomodulators, immunosuppressants, hyperbaric oxygen, JNK inhibitors, corticosteroids, and others such as those described inPhysician’s Desk Reference(2003) The medicament of (1).

The invention also encompasses pharmaceutical compositions, single unit dosage forms, and kits comprising thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active agent. For example, the kit may contain thalidomide and an antidepressant, antihypertensive, anxiolytic, hypnotic, anticonvulsant, calcium channel blocker, muscle relaxant, non-narcotic analgesic, opioid analgesic, alpha-adrenergic receptor agonist or antagonist, anti-inflammatory agent, cox-2 inhibitor, immunomodulator, immunosuppressant, hyperbaric oxygen, JNK inhibitor, corticosteroid, or other drug capable of reducing or alleviating the symptoms of fibromyalgia.

Further, it is believed that thalidomide can reduce or eliminate the adverse effects associated with therapeutic agents used to treat fibromyalgia, thereby allowing patients to be administered larger amounts of the agent and/or improving patient compliance. Accordingly, another specific embodiment of the invention encompasses methods of reversing, alleviating or avoiding an adverse effect associated with the administration of a second active agent in a patient suffering from fibromyalgia, which comprises administering to a patient in need thereof a prophylactically or therapeutically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. Examples of such adverse effects include, but are not limited to, emesis, insomnia, and diarrhea.

As described elsewhere in this specification, the symptoms of fibromyalgia can be treated with physiotherapy and psychotherapy. Without being limited by theory, it is believed that these conventional therapies in combination with thalidomide may provide a uniquely effective treatment for fibromyalgia. Accordingly, the invention encompasses methods of treating, preventing, ameliorating and/or managing fibromyalgia, which comprise administering thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, to a patient (e.g., a human) before, during, or after physical therapy, psychological therapy, or other non-pharmaceutical conventional fibromyalgia therapy.

Compounds useful in the invention include racemic thalidomide, stereoisomerically enriched or stereoisomerically pure thalidomide, and pharmaceutically acceptable salts, solvates, hydrates, clathrates, or prodrugs thereof.

The term "stereomerically pure" as used herein, unless otherwise specified, refers to a composition that contains one stereoisomer of a compound and is substantially free of other stereoisomers of the compound. Typical stereomerically pure compounds include greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound; more preferably, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound; more preferably, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound; and most preferably comprises greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.

The term "stereoisomerically enriched" as used herein, unless otherwise indicated, means that a composition contains greater than about 60% by weight of one stereoisomer of a compound, preferably greater than about 70% by weight, more preferably greater than about 80% by weight of one stereoisomer of a compound.

The term "enantiomerically pure" as used in the present invention, unless otherwise specified, denotes a stereochemically pure composition of a compound having one chiral center. Similarly, the term "enantiomerically enriched" refers to a composition that is stereomerically enriched in a compound having one chiral center.

Thalidomide may be obtained commercially (from Celgene, New Jersey) or prepared according to known methods. See, e.g.The Merck IndexPage 9182 (11 th edition; 1989) and references disclosed therein. Known resolving agents or chiral columns and other standards may be usedThe synthetic organic chemistry techniques of (a) yield enantiomerically pure thalidomide. See, e.g., Blaschke, Arzneimitelforschung 29: 1640-1642 (1979); shealy et al, chem.indes.1030 (1965); and Casini et al, Faramco Ed. Sci.19: 563(1964).

The term "pharmaceutically acceptable salt" as used herein includes, but is not limited to, salts of the acidic or basic moiety of thalidomide, unless specifically stated otherwise. The basic moiety is capable of forming various salts with various inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of these basic compounds are those which form non-toxic acid addition salts, i.e., salts which contain a pharmaceutically acceptable anion. Suitable organic acids include, but are not limited to, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, acetic acid, formic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, cinnamic acid, oleic acid, tannic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, gluconic acid, glucuronic acid, saccharic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, or pamoic acid (i.e., 1' -methylene-bis (2-hydroxy-3-naphthoic acid)). Suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, or nitric acid. In addition to the acids described above, the compounds containing an amino moiety may form pharmaceutically acceptable salts with various amino acids.

Naturally occurring acidic compounds are capable of forming salts with various pharmaceutically acceptable bases. The bases which can be used for the preparation of pharmaceutically acceptable base addition salts of such acidic compounds are those which form non-toxic base addition salts, that is, salts containing a pharmaceutically acceptable cation, such as, but not limited to, alkali metal or alkaline earth metal salts, especially calcium, magnesium, sodium, potassium salts. Suitable organic bases include, but are not limited to, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine, and procaine.

Unless otherwise indicated, as used in the present inventionThe term "prodrug" refers to a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide the compound. Examples of prodrugs include, but are not limited to, thalidomide derivatives containing biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Other examples of prodrugs include those containing-NO, -NO₂-ONO or-ONO₂Part of a thalidomide derivative. Prodrugs can generally be prepared by well-known methods, such as those described in Burger's medicinal Chemistry and Drug Discovery, 172-178, 949-982 (edited by Man. Wolff, 5 th edition 1995) and Design of Prodrugs (edited by H. Bundgaand, Elselvier, New York 1985).

As used herein, unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide", "biohydrolyzable phosphate" refer to an amide, ester, carbamate, carbonate, ureide, or phosphate, respectively, of a compound having the following properties: 1) does not interfere with the biological activity of the compound, but may confer advantageous properties to the compound in vivo, such as absorption, duration of action or onset of action; or 2) is biologically inactive, but is converted in vivo to a biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acyloxyalkyl esters (e.g., acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters), lactonyl esters (e.g., phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (e.g., methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl, and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylaminoalkyl esters (e.g., acetamidomethyl esters). Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, alpha-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

4.1. A second active agent

A second active ingredient or agent may be used in the methods and compositions of the present invention with thalidomide. In preferred embodiments, the second active agent is capable of relieving pain, inhibiting an inflammatory response, providing sedation or an anti-neuropathic effect, or ensuring patient comfort.

Examples of second active agents include, but are not limited to, opioid analgesics, non-narcotic analgesics, anti-inflammatory agents, cox-2 inhibitors, alpha-adrenoceptor agonists or antagonists, ketamine, anesthetics, NMDA antagonists, immunomodulators, immunosuppressive agents, antidepressants, hypnotics, anticonvulsants, antihypertensive agents, anxiolytic agents, calcium channel blockers, muscle relaxants, corticosteroids, hyperbaric oxygen, JNK inhibitors, other drugs known to alleviate pain, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, prodrugs, and pharmacologically active metabolites thereof.

Opioids can be used to treat severe pain. Examples of opioid analgesics include, but are not limited to: oxycodone (OxyContin)^®) Morphine sulfate (MS Continu)^®、Duramorph^®、Astramorph^®) Piperidine (Demerol)^®) Fentanyl transdermal patch (Duragesic)^®) And other known conventional drugs; see, for example, Physicians' Desk Reference, 2834, 2851 and 2991 (57 th edition, 2003). Oxycodone (OxyContin)^®) Is a long-acting form of opioids, often used in patients with fibromyalgia. Morphine sulfate is used to treat analgesia because of its reliable and predictable action, safety, and ease of use to abolish its effect with naloxone, see, e.g., Physicians' Desk Reference, 2834 (57 th edition, 2003).

Antihypertensive agents may be used to control withdrawal symptoms during periods of gradual withdrawal of opioids. Clonidine (Catapres)^®) Stimulation of alpha-2 adrenoreceptors in the brainstem activates inhibitory neurons, which in turn lead to a decrease in sympathetic output. See, e.g., Physicians' Desk Reference, 1033 (eds 57, 2003).

Pain is preferably treated during pregnancy and lactation with non-narcotic analgesics and anti-inflammatory agents. Anti-inflammatory agents such as non-steroidal anti-inflammatory agents (NSAIDs) and cox-2 inhibitors generally inhibit inflammatory responses and pain by decreasing the activity of the cyclooxygenase enzyme responsible for prostaglandin synthesis. NSAIDs can relieve pain early in the symptoms of pain. Examples of such anti-inflammatory agents include, but are not limited to: acetylsalicylic acid (Aspirin)^®) Acetaminophen (Tylenol)^®、Feverall^®、Tempra^®Anacin without aspirin^®) Ibuprofen (Motrin)^®、Advil^®) Ketoprofen (Oruvail)^®) Rofecoxib (Vioxx)^®) Naproxen sodium (Anaprox)^®、Naprelan^®、Naprosyn^®) Ketorolac (Acular)^®) And other known conventional drugs. A specific cox-2 inhibitor is celecoxib (Celebrex)^®). See, e.g., Physicians' Desk Reference, 1065, 1903, 1910, and 2891 (57 th edition, 2003); physicians' Desk Reference for Nonpreparation drug and diet Supplements, 511, 667 and 773 (23 rd edition, 2002).

Antidepressants increase synaptic concentrations of serotonin and/or norepinephrine in the CNS by inhibiting their uptake by presynaptic neuronal membranes. Examples of antidepressants include, but are not limited to, ketamine, nortriptyline (Pamelor)^®) Amitriptyline (Elavil)^®) Imipramine (Tofranil)^®) Sanoping (Sinequan)^®) Clomipramine (Anafranil)^®) Fluoxetine (Prozac)^®) Sertraline (Zoloft)^®) Naphazolone (Serzone)^®) Venlafaxine (Effexor)^®) Trazodone (Desyrel)^®) Anfil, amKetone (Welbutrin)^®) And other known conventional drugs. See, for example, Physicians' desk reference, 329, 1417, 1831 and 3270 (57 th edition, 2003).

Anticonvulsants may also be used in embodiments of the present invention to treat chronic pain in fibromyalgia and related syndromes. They may also alleviate depression and anxiety associated with pain. Examples of anticonvulsants include, but are not limited to, carbamazepine (Tegretol)^®) Oxcarbazepine (Trileptal)^®) Gabapentin (Neurontin)^®) Phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine, zonisamide, and tiagabine. See, for example, Physicians' Desk Reference, 2323 (57 th edition, 2003).

Anxiolytics and hypnotics are useful for reducing anxiety and pain, and as sleep-aids, as poor sleep is almost common in fibromyalgia. They also have antinociceptive effects in chronic pain patients. Anxiolytics are sometimes used in combination with antidepressants and antiepileptics. Alprazolam (Xanax)^®) Lorazepam (Ativan)^®) Clonazepam (Klonopin)^®) Buspirone (Buspar)^®) Trazodone (Desyrel)^®) Zolpidem (Ambien)^®) And temazepam (Restoreil)^®) Can be used in combination with thalidomide. See, for example, Physicians' Desk Reference, 1280, 2517, and 2794 (57 th edition, 2003).

Skeletal muscle relaxants (e.g. cyclobenzaprine (Flexenl)^®) Or carpriptan (Soma)^®) Can be used as an adjunct treatment to nociceptive pain associated with muscle strain. See, for example, Physicians' Desk Reference, 1897 and 3254 (57 th edition, 2003).

Corticosteroids (e.g., prednisone, dexamethasone, or hydrocortisone), orally active class Ib antiarrhythmics (e.g., mexiletine), calcium channel blockers (e.g., nifedipine), beta-blockers (e.g., propranolol), alpha-blockers (e.g., phenoxybenzylamine), and alpha 2-adrenergic agonists (e.g., clonidine) may be used in combination with thalidomide. See, for example, Physicians' Desk Reference, 1034, 1979, 2190, and 3404 (57 th edition, 2003).

Specific second active agents for use in the present invention include, but are not limited to, acetylsalicylic acid (Aspirin)^®) Acetaminophen (Tylenol)^®) Celecoxib (Celebrex)^®)、Enbrel^®Ketamine, gabapentin (Neurontin)^®) Dilantin (Dilantin)^®) Carbamazepine (Tegretol)^®) Oxcarbazepine (Trileptal)^®) Valproic acid (Depakene)^®) Morphine sulfate, hydromorphone, prednisone, griseofulvin, penthonium, alendronic acid, dyphenhydramide, guanethidine, ketorolac (Acula)^®) Thyrocalcitonin, dimethyl sulfoxide (DMSO), clonidine (Cataprress)^®) Brombenzylamine, ketanserin, reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine, acetaminophen, nortriptyline (Pamelor)^®) Amitriptyline (Elavil)^®) Imipramine (Tofranil)^®) Sanoping (Sinequan)^®) Clomipramine (Anafranil)^®) Fluoxetine (Prozac)^®) Sertraline (Zoloft)^®) Naphazolone (Serzone)^®) Venlafaxine (Effexor)^®) Trazodone (Desyrel)^®) Bupropion (Wellbutrin)^®) Mexiletine, nifedipine, propranolol, tramadol, lamotrigine, ziconotide, ketamine, dextromethorphan, benzodiazepines, baclofen, tizanidine, phenoxybenzamine, alprazolam (Xanax)^®) Lorazepam (Ativan)^®) Clonazepam (Klonopin)^®) Buspirone (Buspar)^®) Trazodone (Desyrel)^®) Zolpidem (Ambien)^®) Temazepam (Restoreil)^®) Cyclobenzaprine (Flexeril)^®) And carisoprodol (Sorma)^®)。

4.2 methods of treatment and control

The methods of the present invention include methods of preventing, treating, ameliorating and/or managing various types of fibromyalgia and related syndromes. The term "preventing fibromyalgia" as used herein includes, but is not limited to, inhibiting or lessening the severity of one or more symptoms associated with fibromyalgia, unless specifically stated otherwise. Symptoms associated with fibromyalgia include, but are not limited to: pain, including allodynia (producing a painful response to a stimulus that is usually not painful) and hyperalgesia (producing an exaggerated response to a stimulus that is usually only mildly painful); a range of regional pain, such as non-cardiac chest pain, dyspepsia, headache, abdominal cramps (irritable bowel syndrome), temporal mandibular pain and chronic pelvic pain; debilitation; poor sleep; a tender point; cognitive difficulties with attention and memory; body weight fluctuations; allergic symptoms (e.g., nasal congestion); oversensitivity to environmental stimuli (e.g. smell, light, loud noise) and therapy; syncope; shortness of breath; and urinary frequency and urgency; autonomic imbalance; depression; and anxiety.

As used herein, unless otherwise specifically indicated, the term "treating fibromyalgia" refers to the administration of thalidomide or other additional active agent after the onset of symptoms of fibromyalgia, while "preventing" refers to the administration prior to the onset of symptoms, particularly to patients at risk for fibromyalgia. Examples of patients at risk of fibromyalgia include, but are not limited to, patients who have experienced trauma, neurological disorders, myocardial infarction, musculoskeletal disease, rheumatic disease, connective tissue disease, hypothyroidism, and malignant disease. Patients with a family history of fibromyalgia and related syndromes are also preferred candidates for prophylactic regimens.

Unless otherwise indicated, the term "ameliorating fibromyalgia" as used herein includes modulating the domain, progression and duration of pain, or altering the way a patient responds to pain. Without being bound by theory, it is believed that the compounds of the present invention may act as anti-hyperalgesics and/or neuromodulators. In one embodiment of the invention, "ameliorating fibromyalgia" includes eliminating the patient's exaggerated pain response (i.e., the patient experiences a level of pain greater than normal pain in response to a particular stimulus) and returning the human or animal system to the normal pain domain. In another embodiment, "ameliorating fibromyalgia" includes reducing the pain response of a patient to a stimulus of a particular intensity. In another specific embodiment, "ameliorating fibromyalgia" comprises increasing the pain threshold of a patient relative to the patient's pain threshold prior to such amelioration.

The term "managing fibromyalgia" as used herein, unless otherwise indicated, includes preventing the recurrence of fibromyalgia in a patient suffering from fibromyalgia, and/or prolonging the time in remission in a patient suffering from fibromyalgia.

The present invention includes methods for treating, preventing, ameliorating and managing fibromyalgia and related syndromes in patients at various stages and in specific types of diseases, including but not limited to FM, fibromyalgia syndrome (FMS), fibrositis, myofascial syndrome and extensive chronic pain syndrome, chronic fatigue syndrome, radiculopathy and other painful neurological disorders, such as diabetic neuropathy. The invention further includes methods of treating patients who have previously received fibromyalgia therapy but not responded to standard therapy, as well as patients who have not previously received fibromyalgia therapy. Because patients with fibromyalgia have different clinical manifestations and different clinical outcomes, the treatment given to a patient may be different depending on his/her prognosis. The specific ancillary agents, as well as the types of physical therapies that are effective for treating an individual patient, can be readily determined by the skilled clinician without undue experimentation.

The invention encompasses methods comprising administering thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, to a patient (e.g., a human) suffering from, or likely to suffer from, fibromyalgia.

In a particular embodiment of the invention, thalidomide may be administered orally in a single or divided daily dose of about 50 mg/day to about 1,500 mg/day, preferably about 50 mg/day to about 1,000 mg/day, and more preferably about 100 mg/day to about 400 mg/day (e.g., about 300 mg/day). In a specific embodiment, thalidomide is administered orally to a patient with fibromyalgia in a single or divided daily dose of about 100 mg/day to about 400 mg/day. In another specific embodiment, thalidomide is administered every other day, several times per week, or at other intervals.

In another embodiment, the present invention relates to a method of treating, preventing, managing and/or ameliorating fibromyalgia associated with planned surgery (i.e., planned trauma) comprising administering to a patient in need thereof an effective amount of thalidomide. In this particular embodiment, thalidomide may be administered before, during, and/or after the planned surgery. In particular embodiments, thalidomide is administered to a patient from about 1 mg/day to about 200 mg/day, from about 1 mg/day to about 100 mg/day, from about 1 mg/day to about 75 mg/day, from about 1 mg/day to about 50 mg/day, from about 5 mg/day to about 40 mg/day, from about 5 mg/day to about 25 mg/day, or from about 5 mg/day to about 10 mg/day before and/or after about 1-21 days of a planned surgery. In another specific embodiment, the patient is administered about 10 mg/day thalidomide before about 1-21 days and/or after 1-21 days of the planned surgery.

4.2.1 combination therapy with a second active agent

Particular methods of the invention comprise administering thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in combination with a second active agent or ingredient. Examples of second active agents are also disclosed herein (see, e.g., section 4.1).

The administration of thalidomide and the second active agent to the patient may be performed simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without breaking down before entering the bloodstream) and the disease being treated. A preferred route of administration of thalidomide is oral. Preferred routes of administration for the second active agent or component of the invention are known to those of ordinary skill in the art. See, for example, the Physicians' Desk Reference, 594-.

In a specific embodiment, the second active agent is administered orally, intravenously, intramuscularly, subcutaneously, mucosally, or transdermally, in an amount of from about 1mg to about 3,500mg, from about 5mg to about 2,500mg, from about 10mg to about 500mg, or from about 25mg to about 250mg, once or twice daily.

The specific dosage of the second active agent described above will depend upon the specific agent used, the type of fibromyalgia being treated or controlled, the severity and stage of fibromyalgia, and the amount of thalidomide and any optional other active agents concurrently administered to the patient. In particular embodiments, the second active agent is IMiDs^TM、SelCIDs^TMAcetylsalicylic acid (Aspirin)^®) Acetaminophen (Tylenol), celecoxib (Celebrex)^®)、Enbrel^®Ketamine, gabapentin (Neurontin)^®) Dilantin (Dilantin)^®) Carbamazepine (Tegretol)^®) Oxcarbazepine (Trileptal)^®) Valproic acid (Depakene)^®) Morphine sulfate, hydromorphone, prednisone, griseofulvin, penthonium, alendronic acid, dyphenhydramide, guanethidine, ketorolac (Acula)^®) Thyrocalcitonin, dimethyl sulfoxide (DMSO), clonidine (Cataprress)^®) Brombenzylamine, ketanserin, reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine, acetaminophen, nortriptyline (Pamelor)^®) Amitriptyline (Elavil)^®) Imipramine (Tofranil)^®) Sanoping (Sinequan)^®) Clomipramine (Anafranil)^®) Fluoxetine (Prozac)^®) Sertraline (Zoloft)^®) Naphazolone (Serzone)^®) Venlafaxine (Effexor)^®) Trazodone (Desyrel)^®) Bupropion (Wellbutrin)^®) Mexiletine, nifedipine, propranolol, tramadol, lamotrigine, ziconotide, ketamine, dextromethorphan, mexiletine, propranolol, tramadol, and the like,Benzodiazepines, baclofen, tizanidine, phenoxybenzamine, alprazolam (Xanax)^®) Lorazepam (Ativan)^®) Clonazepam (Klonopin)^®) Buspirone (Buspar)^®) Trazodone (Desyrel)^®) Zolpidem (Ambien)^®) Temazepam (Restoreil)^®) Cyclobenzaprine (Flexeril)^®) Carisoprodol (Soma)^®) Or a combination thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, prodrug, or pharmacologically active metabolite thereof.

Hydromorphone (dilaudi)^®) Moderate to severe pain is preferably controlled orally in a primary dose of about 2mg or intravenously in a primary dose of about 1 mg. See, for example, Physicians' desk reference, 441-. Morphine sulfate (Duramorph)^®、Astramorph^®、MS Contin^®) Preferably, administration is at an initial dose of about 2mg IV/SC/IM, depending on whether the patient has taken narcotic analgesics. See, for example, the Physicians' Desk Reference, 594-. Morphine sulfate may also be an immediate release or timed release oral formulation. The long acting oral form may be taken twice a day. An immediate release form may be required at the time of a pain outbreak and the dosage depends on the previous dose. Oxycodone (OxyContin)^®) Is a long-acting form of opioids and can be used in the early and late stages of the pain syndrome. Oxycodone (OxyContin)^®) Preferably, it is administered in an amount of about 10-160mg twice daily. See, for example, Physicians' Desk Reference, 2851 (57 th edition, 2003). Pethidine (Demerol)^®) PO/IV/IM/SC is preferably administered in an amount of about 50-150mg once every 3-4 hours. A typical dose for pediatric use is 1-1.8mg/kg (0.5-0.8mg/lb) every 3-4 hours. See, for example, Physicians' Desk Reference, 2991 (57 th edition, 2003).

Non-narcotic analgesics and anti-inflammatory agents such as NSAIDs and cox-2 inhibitors are useful in treating patients with mild to moderate pain. Ibuprofen (Motrin)^®、Advil^®) Administered orally at 400-800mg 3 times per day. Referring to the description of the preferred embodiment,for example, Physicians' Desk Reference, 1900 (57 th edition, 2003); physicians' Desk Reference for NPRefraction Drugs and Dietarysupplements, 511, 667, 773 (23 rd edition, 2002). Naproxen sodium (Anaprox)^®、Naprelan^®、Naprosyn^®) Also preferred for the relief of mild to moderate pain is an amount of about 275mg 3 times per day, or about 550mg twice per day. See, for example, Physicians' Desk Reference, 2891 (57 th edition, 2003). Acetaminophen (Tylenol)^®、Feverall^®、Tempra^®Aspirin-free Anacin^®) It can be preferably used for pain of patients allergic to aspirin or NSAID in an amount of about 325-650mg every 4-6 hours, or about 1000mg every 3 to 4 times a day. See, for example, the Physicians' Desk Reference, 1910-.

Antidepressants, e.g. nortriptyline (Pamelor)^®) Embodiments of the invention may also be used to treat chronic and/or neuropathic pain patients. The oral dosage for adults is generally about 25-100mg, and preferably does not exceed 200 mg/day. A typical initial dose in children is about 0.1mg/kg PO, which if tolerated may be increased to about 0.5-2 mg/day. Amitriptyline (Etrafon)^®) Preferably for the treatment of neuropathic pain, the adult dose is about 10-100mg PO. See, for example, Physicians' Desk Reference, 329, 1417, 1831 and 3270 (57 th edition, 2003).

Anticonvulsants such as gabapentin (Neurontin)^®) Can also be used for treating chronic and neuropathic pain patients. Gabapentin is preferably administered orally 3 times per day in an amount of about 100-. See, for example, Physicians' Desk Reference, 2563 (57 th edition, 2003). Carbamazepine (Tegretol)^®) Is used for treating pain associated with trigeminal neuralgia. The initial oral dose for adults is typically about 100mg, twice daily, and may be increased to about 2,400 mg/day if tolerated. See, for example, Physicians' Desk Reference, 2323-25 (57 th edition, 2003).

Anxiolytics and hypnotics such as alprazolam (Xanax)^®) Lorazepam (Ativan)^®) Clonazepam (Klonopin)^®) Buspirone (Buspar)^®) Trazodone (Desyrel)^®) Zolpidem (Ambien)^®) And temazepam (Restoreil)^®) Can be used in a daily sub-dose of about 0.25-300mg for reducing pain, anxiety and distress in a patient suffering from fibromyalgia, the disease being useful as a sleep aid. See, for example, Physicians' Desk Reference, 1280, 2571, and 2794 (57 th edition, 2003).

Skeletal muscle relaxants may be used as an adjunct to the treatment of pain associated with muscle strain. Cyclobenzaprine (Flexeril)^®) Can be administered orally in divided doses of about 20-40mg per day. Carisoprodol (Soma)^®) May be administered orally in divided doses of about 350mg per day. See, for example, Physicians' Desk Reference, 1897 and 3254 (57 th edition, 2003).

4.2.2 use in combination with Physiotherapy or psychotherapy

In another embodiment, the invention encompasses methods of treating, preventing, ameliorating and/or managing fibromyalgia, which comprise administering thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in combination with physical therapy or psychotherapy.

Benefits of exercise to a patient with fibromyalgia include improved subjective and objective perception of pain and improved overall sensation of recovery. Many chronic pain patients get worse because they fear that activity will worsen their pain and weakness. Therefore, physical therapy (e.g., low-intensity aerobics, walking, aerobics in water, swimming, and stationary bicycles) can play an important role in functional recovery.

It is believed that the combined use of thalidomide and physical therapy may provide a unique treatment regimen with unexpected effects in certain patients.

It is believed that the combined use of thalidomide and psychotherapy can provide a unique treatment regimen with unexpected effects in certain patients. Without being bound by theory, it is believed that thalidomide may provide additive or synergistic effects when administered concurrently with psychotherapy, including, but not limited to, biofeedback, relaxation training, active pacing, visual imagery, distraction strategies, cognitive behavioral therapy, and individual or family psychotherapy.

Thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, is administered before, during, or after physical therapy or psychotherapy. In particular methods, a second active agent can also be administered to the patient.

4.3 pharmaceutical compositions and Single Unit dosage forms

The pharmaceutical compositions may be formulated for use in a single unit dosage form. Pharmaceutical compositions and dosage forms of the invention comprise thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The pharmaceutical compositions and dosage forms of the present invention may also comprise one or more excipients.

The pharmaceutical compositions and dosage forms of the invention may also comprise one or more additional active ingredients. Accordingly, pharmaceutical compositions and dosage forms of the invention comprise an active ingredient (e.g., thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, and a second active agent) as described herein. Examples of optional additional active ingredients are disclosed in this specification (see e.g. section 4.1).

The single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular or intraarterial), transdermal or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: a tablet; a caplet; capsules, such as elastic soft gelatin capsules; a cachet; keeping in mouth; a lozenge; a dispersant; suppositories; a powder agent; aerosols (e.g., nasal sprays or inhalants); gelling agent; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

The composition, shape and type of dosage form of the present invention will vary depending on its use. For example, a dosage form for the acute treatment of a disease may contain an amount of one or more active ingredients that is greater than the amount contained in a dosage form for the chronic treatment of the same disease. Similarly, a parenteral dosage form will contain an amount of one or more active ingredients that is less than the amount contained in an oral dosage form used to treat the same disease. The manner in which these particular dosage forms of the invention are contained, as well as other manners, will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18 th edition, Mack Publishing, Easton PA (1990).

Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those of ordinary skill in the pharmaceutical arts, and non-limiting examples of suitable excipients are provided in the present specification. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the route by which the dosage form is administered to a patient. For example, oral dosage forms (e.g., tablets) may contain excipients that are not suitable for use in parenteral dosage forms. The suitability of a particular excipient may depend on the particular active ingredient in the dosage form. For example, some excipients (e.g., lactose), or when exposed to water, may accelerate the decomposition of some active ingredients. Active ingredients containing primary or secondary amines are particularly sensitive to this accelerated decomposition. Thus, the invention includes pharmaceutical compositions and dosage forms that contain little, if any, lactose or other mono-or disaccharides. In the present invention, the term "lactose-free" is used to indicate that the amount of lactose, if any, is insufficient to substantially accelerate the rate of degradation of the active ingredient.

Lactose-free compositions of the invention may contain excipients well known in the art, such as those listed in, for example, the United States Pharmacopeia (USP)25-NF20 (2002). Typically, lactose-free compositions contain pharmaceutically compatible and pharmaceutically acceptable amounts of active ingredient, binder/filler and lubricant. Preferably, the lactose-free dosage form contains the active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

The present invention also includes anhydrous pharmaceutical compositions and dosage forms containing the active ingredient, as water promotes the degradation of certain compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine properties of the formulation over time, such as shelf life or stability. See, e.g., Jens t. carstensen, "drug stability: principles and practices (drug stability: Principles & Practice), second edition, Marcel Dekker, NY, NY, 1995, pages 379-80. In fact, water and heat will accelerate the decomposition of some compounds. Thus, the effect of water on the formulation is very significant, as moisture and/or humidity is often encountered during manufacture, handling, packaging, storage, shipment, and use of the formulation.

The anhydrous pharmaceutical compositions and dosage forms of the invention can be manufactured with anhydrous or low moisture content ingredients and under low humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active agent comprising a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity is expected during manufacture, packaging, and/or storage.

Anhydrous pharmaceutical compositions should be prepared and stored in a manner that maintains their anhydrous nature. Accordingly, anhydrous compositions are preferably packaged with materials known to prevent exposure to water, so that they can be packaged in a suitable kit. Examples of suitable packaging include, but are not limited to, sealed films, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

The invention also includes pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate of decomposition of the active ingredient. Such compounds are referred to herein as "stabilizers" and include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers, or salt buffers.

As with the amount and type of excipient, the type and amount of a particular active ingredient in a dosage form may vary depending upon a variety of factors including, but not limited to, the route of administration. However, a typical dosage form of the invention contains thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in an amount of from about 50mg to about 1,500 mg. Typical dosage forms contain thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof in an amount of about 50mg, 100mg, 200mg, 300mg, or 400 mg. Typical dosage forms contain the second active ingredient in an amount of about 1mg to about 3,500mg, about 5mg to about 2,500mg, about 10mg to about 500mg, about 25mg to about 250 mg. The specific amount of the second active agent will, of course, depend on the specific agent used, the type of fibromyalgia being treated or controlled, and the amount of thalidomide and any optional additional active agents concurrently administered to the patient.

4.3.1 oral dosage forms

Pharmaceutical compositions of the invention suitable for oral administration may be formulated in discrete dosage forms such as, but not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of the active ingredient and may be prepared by pharmaceutical methods well known to those of ordinary skill in the art. See generally, Remington's pharmaceutical sciences, 18 th edition, Mack Publishing, Easton PA (1990).

Typical oral dosage forms of the invention are prepared by intimately mixing the active agent with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients may take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules using solid excipients represent the most advantageous oral unit dosage form. If desired, the tablets may be coated using standard aqueous or non-aqueous techniques. Such dosage forms may be prepared by any pharmaceutical method. Pharmaceutical compositions and dosage forms are generally prepared by: the active agent is intimately mixed with a liquid carrier, a well-dispersed solid carrier, or both, and the product is then shaped as desired.

For example, tablets may be made by compression or molding. Compressed tablets may be manufactured by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with excipients. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Examples of excipients that may be used in the oral dosage forms of the present invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums (e.g., acacia), sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropylmethylcellulose (e.g., nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (available from FMC corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. One particular binder is a mixture of microcrystalline cellulose and sodium carboxymethylcellulose sold as AVICEL RC-581. Suitably anhydrousOr low moisture content excipients or additives including AVICEL-PH-103^TMAnd Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical compositions of the present invention is present in an amount of about 50% to about 99% by weight of the pharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to provide tablets that disintegrate upon exposure to an aqueous environment. Tablets containing too much disintegrant may disintegrate in storage, while tablets containing too little may not disintegrate at a desired rate or under desired conditions. Thus, a sufficient amount of disintegrant that does not significantly alter the release of the active agent, either too much or too little, should be used to form the solid oral dosage form of the present invention. The amount of disintegrant used varies with the type of formulation and is readily determined by one skilled in the art. Typical pharmaceutical compositions comprise from about 0.5% to about 15% by weight of disintegrant, preferably from about 1% to about 5% by weight of disintegrant

Disintegrants that can be used in the pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium carboxymethyl starch, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants useful in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other alcohols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Other lubricants include, for example, syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, MD), a solidified aerosol of synthetic silica (sold by Degussa Co. of Plano, TX), CAB-O-SIL (a sintered silica product sold by Cabot Co. of Boston, MA), and mixtures thereof. Lubricants, if used, are generally used in amounts less than about 1% by weight of the pharmaceutical composition or dosage form into which they are incorporated.

The solid oral dosage form of the present invention preferably contains thalidomide, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silicon dioxide, and gelatin. See, for example, U.S. patent application No. 10/608,077 filed on 30/6/2003, which is hereby incorporated by reference in its entirety.

4.3.2 delayed Release dosage forms

The active ingredients of the present invention may be administered by controlled release devices or by delivery devices well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in the following patents: U.S. Pat. nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms may be used for slow or controlled release of one or more active agents by using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, isotonic systems, multilayer coatings, microparticles, liposomes, microspheres or combinations thereof to produce the desired release profile in varying proportions. Suitable controlled release formulations are well known to those skilled in the art, including those disclosed herein, and are readily selected for use with the active agents of the present invention. Thus, the present invention encompasses single unit dosage forms suitable for controlled release and for oral administration, including but not limited to tablets, capsules, gelcaps, and caplets.

All controlled release drug products share the following common objectives: the therapeutic effect of the drug is enhanced over that achieved by its uncontrolled release product. Ideally, the use of optimally designed controlled release formulations in medical treatment is characterized by: the disease is cured or controlled in the shortest time with the least amount of medicine. Advantages of controlled release formulations include prolonged drug activity, reduced dosing frequency, and enhanced patient compliance. In addition, controlled release formulations may be used to affect the time of onset or other characteristics, such as blood levels of the drug, and thereby affect the incidence of side effects (e.g., adverse side effects).

Most controlled release formulations are designed to initially release an amount of the drug (active ingredient) that rapidly produces the desired therapeutic effect, and gradually and continuously release other amounts of the drug to maintain such therapeutic or prophylactic levels over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will compensate for the amount of drug that is metabolized and excreted from the body. Controlled release of the active agent can be stimulated by a variety of conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

4.3.3 parenteral dosage forms

Parenteral dosage forms can be administered to a patient by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Since their administration typically bypasses the natural defenses of the patient against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to use in the patient. Examples of parenteral dosage forms include, but are not limited to, solutions for injection, dry products dissolved or suspended in a pharmaceutically acceptable carrier for injection, suspensions for injection, and emulsions.

Suitable carriers for use in the parenteral dosage forms of the invention are well known to those of ordinary skill in the art. Examples include, but are not limited to: USP water for injection; aqueous vehicles such as, but not limited to, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated ringer's injection; water-miscible carriers such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the active agents disclosed herein can also be incorporated into the parenteral dosage forms of the invention. For example, cyclodextrins and their derivatives can be used to increase the solubility of thalidomide. See, for example, U.S. Pat. No. 5,134,127, which is incorporated herein by reference.

4.3.4 topical and mucosal dosage forms

Topical and mucosal dosage forms of the invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, or other forms known to those of ordinary skill in the art. See, e.g., Remington's pharmaceutical sciences, 16 and 18 th ed., Mack Publishing, Easton PA (1980 and 1990); and Introduction to Pharmaceutical dosage Forms (Introduction to Pharmaceutical Dose Forms), 4 th edition, Lea & Febiger, Philadelphia (1985). The preparation suitable for treating oral mucosa tissue can be made into collutory or oral gel.

Suitable excipients (e.g., carriers and diluents) and other materials that may be used in the topical and mucosal dosage forms of the invention are well known to those of ordinary skill in the pharmaceutical arts and depend on the particular tissue to which a given pharmaceutical composition or dosage form is administered. In fact, typical excipients include, but are not limited to, water, propanol, ethanol, ethylene glycol, propylene glycol, butane-1, 3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof, used to form non-toxic and pharmaceutically acceptable solutions, emulsions or gels. Wetting agents or humectants may also be added to the pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's pharmaceutical sciences, 16 and 18 th ed., Mack Publishing, Easton PA (1980 and 1990).

The pH of the pharmaceutical composition or dosage form may also be adjusted to facilitate delivery of the one or more active agents. Similarly, the polarity of the solvent carrier, its ionic strength, or tonicity can be adjusted to facilitate transport. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients to facilitate delivery. In this regard, stearates can be used as lipid carriers, emulsifiers or surface active agents, as well as delivery or penetration enhancers for the formulation. Different salts, hydrates or solvates of the active agent may also be used to adjust the properties of the resulting composition.

4.3.5 kits

It is generally preferred that the active agents of the invention not be administered at the same time or by the same route of administration. Thus, the present invention includes kits that, when used by medical personnel, can simplify the administration of an appropriate amount of an active agent to a patient.

A typical kit of the invention comprises a dosage form of thalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof. The kits of the invention may also contain other active ingredients or combinations thereof. Examples of other active ingredients include, but are not limited to: antidepressants, anticonvulsants, antihypertensives, anxiolytics, calcium channel blockers, muscle relaxants, non-narcotic analgesics, opioid analgesics, anti-inflammatory agents, cox-2 inhibitors, immunomodulators, immunosuppressants, corticosteroids or other treatments described herein (see, e.g., section 4.1).

The kit of the invention may also comprise a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

The kits of the invention may further comprise a pharmaceutically acceptable carrier for administering one or more active ingredients. For example, if the active ingredient is in solid form and must be formulated for parenteral administration, the kit may comprise a sealed container containing a suitable carrier in which the active agent can be dissolved to form a sterile, particle-free solution suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: USP water for injection; aqueous vehicles such as, but not limited to, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated ringer's injection; water-miscible carriers such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

5. Examples of the embodiments

The following studies are intended to further illustrate the present invention without limiting its scope.

5.1 pharmacological Studies

One of the biological effects of thalidomide is the reduction of TNF- α synthesis. Thalidomide enhances the degradation of TNF-alpha mRNA. TNF-alpha may play a pathological role in neuropathic pain. It has been shown to be expressed in Schwann cells (Schwann cells) increased in human painful neurological conditions. The serum of a patient with allodynia has an increase in soluble TNF-alpha receptors compared to a patient with neuropathic pain in the absence of allodynia. This cytokine can induce aberrant activity of primary afferent nociceptors and is therefore a potential cause of hyperalgesia in neuropathic pain. One possible mechanism is that TNF- α can form active sodium ion channels in cells. The increased influx of sodium ions into nociceptors causes them to discharge abnormally. A pathological effect may be exerted if cytokines are activated at the site of nerve injury or dysfunction.

The inhibitory effect of thalidomide on the production of TNF- α by human PBMC following LPS stimulation was studied in vitro. IC for inhibition of TNF-alpha production by thalidomide on PBMC following LPS stimulation₅₀194 μ M (50.1 μ g/mL).

5.2 clinical Studies in patients with fibromyalgia

About 4kg/cm is applied manually at multiple anatomical sites of a patient with fibromyalgia²To evaluate pain and tenderness. A device that can be used to quantify pain sensitivity is a tonometer or a tonometer. The widespread reduction in pain perception thresholds and pain tolerance thresholds in patients with fibromyalgia and related syndromes has been demonstrated without doubt using this device or a variety of other laboratory procedures, such as the use of thermodes. This reflects an altered central nociceptive process and manifests itself in patients with allodynia and hyperalgesia.

Clinical studies were conducted in patients with fibromyalgia who did not respond to conventional physical therapy and suffered from the disease for at least 1 year. In one embodiment, thalidomide is administered to a fibromyalgia patient in an amount of 100-400mg per day for three months to one year. Baseline assessments were performed to assess the effect of drug treatment on pain intensity, the effect of pain on activities of daily living, and the consumption of other pain medications. Treatment with a continuous oral daily dose of 300mg is well tolerated. Studies in patients with fibromyalgia treated with thalidomide indicate that the drug has an analgesic effect in this disease.

The embodiments of the invention described herein are intended to be merely illustrative of the scope of the invention. The full scope of the invention will be better understood with reference to the appended claims. All references cited herein are incorporated herein by reference in their entirety. None of the references cited herein are admitted to constitute prior art.

Claims (14)

1. A method of treating, preventing, ameliorating or managing fibromyalgia, which comprises administering to a patient in need of such treatment, prevention, amelioration or management a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. A method of treating, preventing, ameliorating or managing fibromyalgia, which comprises administering to a patient in need of such treatment, prevention, amelioration or management a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a therapeutically or prophylactically effective amount of a second active agent.

3. The method of claim 2, wherein the second active agent is capable of reducing pain, depression, or anxiety.

4. The method of claim 2, wherein the second active agent is an antidepressant, anxiolytic, hypnotic, antihypertensive, anticonvulsant, calcium channel blocker, muscle relaxant, non-narcotic analgesic, opioid analgesic, alpha-adrenoceptor agonist, alpha-adrenoceptor antagonist, anti-inflammatory agent, cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent, hyperbaric oxygen, JNK inhibitor, or corticosteroid.

5. The method of claim 2, wherein the second active agent is acetylsalicylic acid, celecoxib, ketamine, gabapentin, carbamazepine, oxcarbazepine, phenytoin, sodium valproate, prednisone, nifedipine, clonidine, oxycodone, meperidine, morphine sulfate, hydromorphone, phenotanib, acetaminophen, ibuprofen, naproxen sodium, griseofulvin, amitriptyline, imipramine, doxepin, alprazolam, lorazepam, clonazepam, buspirone, trazodone, zolpidem, temazepam, cyclobenzaprine, or carisoprodol.

6. The method of claim 1 or 2, wherein the fibromyalgia is fibrositis, myofascial syndrome, extensive chronic pain syndrome, chronic fatigue syndrome, radiculopathy, or painful neuropathic disease.

7. The method of claim 1 or 2, wherein the thalidomide is enantiomerically pure.

8. A method of treating, preventing, ameliorating or managing fibromyalgia, which comprises administering to a patient in need of such treatment, prevention, amelioration or management a therapeutically or prophylactically effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, before, during or after physical therapy or psychotherapy to reduce or avoid the symptoms of fibromyalgia in the patient.

9. A method of reducing or avoiding an adverse effect associated with the administration of a second active agent in a patient suffering from fibromyalgia, which method comprises administering to a patient in need of such reduction or avoidance an effective amount of thalidomide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

10. The method of claim 9, wherein the second active agent is capable of reducing pain, depression, or anxiety.

11. The method of claim 9, wherein the second active agent is an antidepressant, anxiolytic, hypnotic, antihypertensive, anticonvulsant, calcium channel blocker, muscle relaxant, non-narcotic analgesic, opioid analgesic, alpha-adrenoceptor agonist, alpha-adrenoceptor antagonist, anti-inflammatory agent, cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent, hyperbaric oxygen, JNK inhibitor, or corticosteroid.

12. The method of claim 9, wherein the second active agent is acetylsalicylic acid, celecoxib, ketamine, gabapentin, carbamazepine, oxcarbazepine, phenytoin, sodium valproate, prednisone, nifedipine, clonidine, oxycodone, meperidine, morphine sulfate, hydromorphone, phenotanib, acetaminophen, ibuprofen, naproxen sodium, griseofulvin, amitriptyline, imipramine, doxepin, alprazolam, lorazepam, clonazepam, buspirone, trazodone, zolpidem, temazepam, cyclobenzaprine, or carisoprodol.

13. A pharmaceutical composition comprising thalidomide, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a second active agent, wherein the second active agent is an antidepressant, anxiolytic, hypnotic, antihypertensive, anticonvulsant, calcium channel blocker, muscle relaxant, non-narcotic analgesic, opioid analgesic, alpha-adrenoceptor agonist, alpha-adrenoceptor antagonist, anti-inflammatory agent, cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent, hyperbaric oxygen, JNK inhibitor, or corticosteroid.

14. The method of claim 13, wherein the second active ingredient is acetylsalicylic acid, celecoxib, ketamine, gabapentin, carbamazepine, oxcarbazepine, phenytoin, sodium valproate, prednisone, nifedipine, clonidine, oxycodone, meperidine, morphine sulfate, hydromorphone, phenotanib, acetaminophen, ibuprofen, naproxen sodium, griseofulvin, amitriptyline, imipramine, doxepin, alprazolam, lorazepam, clonazepam, buspirone, trazodone, zolpidem, temazepam, cyclobenzaprine, or carisoprodol.