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WO2010026487A1 - Méthodes et compositions thérapeutiques - Google Patents

Méthodes et compositions thérapeutiques Download PDF

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Publication number
WO2010026487A1
WO2010026487A1 PCT/IB2009/006953 IB2009006953W WO2010026487A1 WO 2010026487 A1 WO2010026487 A1 WO 2010026487A1 IB 2009006953 W IB2009006953 W IB 2009006953W WO 2010026487 A1 WO2010026487 A1 WO 2010026487A1
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Prior art keywords
boldine
pharmaceutically acceptable
derivative
acceptable salt
subject
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English (en)
Inventor
Alvaro F. Luzio
Luis G. Aguayo
Jorge P. Fuentealba
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Universidad de Concepcion
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Universidad de Concepcion
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Publication of WO2010026487A1 publication Critical patent/WO2010026487A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention relates generally to methods for treating a sexual dysfunction that include administration of boldine, a derivative or a pharmaceutically acceptable salt thereof such that the sexual dysfunction is treated (e.g., reduced, eliminated and/or prevented).
  • the present invention relates generally to methods for stimulating erectile response that include administration of boldine, a derivative or a pharmaceutically acceptable salt thereof such that the erectile response is stimulated (e.g., by the upregulation or downregulation of a physiological pathway).
  • the present invention relates generally to methods for enhancing erectile function that includes administration of boldine, a derivative or a pharmaceutically acceptable salt thereof such that the erectile function is enhanced (e.g., ability of a male subject to penetrate his partner, the ability of a male subject to maintain an erection during intercourse, erectile function, orgasmic function, sexual desire, intercourse satisfaction, completion of intercourse with ejaculation or orgasm, satisfaction with the hardness of a male subject's erection and overall sexual satisfaction).
  • the present invention also relates generally to methods for treating Parkinson's disease that include administration of boldine administration of boldine, a derivative or a pharmaceutically acceptable salt thereof such that the Parkinson's disease is treated (e.g., reduced, eliminated and/or prevented).
  • the present invention further relates generally to methods for inducing emesis that include administration of administration of boldine, a derivative or a pharmaceutically acceptable salt thereof such that emesis is induced.
  • Boldo (Peumus boldus Molina) is a tree native to the central region of Chile.
  • the leaves of the boldo tree have been traditionally used in South America in medicinal teas and alcoholic tinctures as a digestive aid and a sedative.
  • Chemical analysis of the leaves and bark of boldo has demonstrated that they contain a variety of flavonols, terpenoids and alkaloids.
  • An alkaloid present in the leaves and bark of boldo is boldine, which has been found to have anti-oxidative properties, as well as pharmacological activities that include the stimulation of the production of bile and its secretion from the gall bladder, the stimulation of the gastric juices, mild diuretic activity, mild hypnotic activity and the stimulation of uric acid excretion, (see “Medicinal Plants” B. -E. van Wyk and M. Wink (2004) p. 236). As with many traditional medicines, the potential healing ability of boldo leaves and the alkaloid boldine is being investigated.
  • the present invention is based, at least in part, on the discovery that administration of boldine, a derivative or a pharmaceutically acceptable salt thereof may be used to treat sexual dysfunction in a subject. Accordingly, in one aspect, the present invention provides methods for sexual dysfunction in a subject by administering to a subject in need thereof an effective amount of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the sexual dysfunction is a male sexual dysfunction, e.g., erectile dysfunction.
  • the present invention provides methods for stimulating an erectile response in a male mammal by administering to the mammal in need thereof an effective amount of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile response is stimulated substantially at the same time as the administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile response is stimulated within at least 1 hour, within at least 4 hours or within at least 24 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the present invention provides methods for enhancing erectile function in a male mammal in need thereof by administering to the mammal an effective amount of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • enhancing erectile function comprises enabling a male mammal to achieve an erection or maintain an erection.
  • the male mammal may achieve an erection within at least 1 hour, within at least 4 hours, within at least 12 hours or within at least 24 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the present invention provides methods for treating Parkinson's disease in a subject by administering to a subject in need thereof an effective amount of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the present invention at least in part, provides methods for inducing emesis in a subject by administering to the subject an effective amount of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the effective amount is an amount effective to induce emesis within at least 20 minutes, within at least 10 minutes or within at least 5 minutes after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof to the subject.
  • the effective amount is an amount that does not increase abdominal pressure prior to or during emesis.
  • the effective amount is an amount that does not induce discomfort, agitation or muscle weakness in the subject. In some embodiments, the effective amount is an amount that does not substantially increase said subject's heart rate. In some embodiments, the effective amount is an amount that sustains or decreases the subject's blood pressure. In some embodiments, the effective amount is between about 0.1 mg/kg and about 40 mg/kg.
  • the present invention provides pharmaceutical compositions of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises boldine, a derivative or a pharmaceutically acceptable salt thereof in an amount effective to treat a sexual dysfunction in a subject, in an amount effective to stimulate an erectile response in a male mammal, in an amount effective to enhance erectile function in a male mammal, in an amount effective to treat Parkinson's disease in a subject or in an amount effective to induce emesis in a subject.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • boldine, a derivative or a pharmaceutically acceptable salt thereof is administered intranasally, orally, transdermally, bucally, parenterally, intramuscularly, via inhalation or sublingually.
  • boldine, a derivative or a pharmaceutically acceptable salt thereof is substantially pure. In some embodiments, boldine, a derivative or a pharmaceutically acceptable salt is substantially enantiomerically pure. In some embodiments, boldine is S-(+)-boldine. In some embodiments, boldine is R-(-)-boldine. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.
  • the subject is a mammal, e.g., a human or a domestic animal, for example, a dog.
  • the male mammal is a male human or a male domestic animal, e.g., a dog.
  • Figure 1 is a graph depicting the effect of boldine and several control compounds on the heart rate of dogs upon injection.
  • Figure 2 is a graph depicting the effect of boldine and controls on the mean arterial blood pressure of dogs upon injection.
  • boldine as described in more detail herein, is efficacious for the use in the treatment of certain disorders, e.g., sexual dysfunction; and for the stimulation of erectile response; for the enhancement of erectile function; and for the induction of emesis. It is believed that boldine may also be efficacious in treating Parkinson's disease. Accordingly, it is expected that compositions including sufficient amounts of boldine, a derivative or a pharmaceutically acceptable salt thereof, will effectively treat a subject that may be in need of treatment for a sexual dysfunction or Parkinson's disease; or a subject that may be in need of stimulation of erectile response or enhancement of erectile function or that may be in need for the inducement of emesis.
  • boldine does not increase a subject's heart rate upon administration to the subject.
  • boldine sustains or slightly decreases a subject's blood pressure upon administration to the subject.
  • boldine may act as an agonist of the dopamine receptor. Accordingly, boldine may bind to a dopamine receptor to trigger the production of dopamine.
  • the present invention is generally directed to methods for treating sexual dysfunction in a subject by administering to the subject an effective amount of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • treatment refers to the application or administration of boldine or a derivative or a pharmaceutically acceptable salt thereof to a subject who has a disease or a disorder, e.g., a sexual dysfunction or Parkinson's disease, as described herein, with the purpose to cure, heal, alleviate, delay, relieve, alter, remedy, ameliorate, improve or affect the disease or disorder, or symptoms of the disease or disorder.
  • treatment or “treating” is also used herein in the context of administering boldine, a derivative or a pharmaceutically acceptable salt thereof prophylactically.
  • sexual dysfunction refers to disorders that affect a subject's ability to achieve or sustain an aroused state.
  • sexual dysfunction also refers to disorders that affect a subject's ability to engage in sexual activity or that do not permit satisfactory sexual performance by a subject.
  • sexual dysfunctions include, but are not limited to, male sexual dysfunctions, such as erectile dysfunction, and female sexual dysfunctions, such as, for example, female arousal disorder.
  • erectile dysfunction refers to the persistent inability of a male mammal to attain and/or maintain an erection adequate to permit satisfactory sexual performance in a male subject.
  • female arousal disorder refers to a disorder that is characterized by the persistent or recurrent inability in a female subject to attain or to maintain until completion of sexual activity an adequate response (e.g., lubrication or swelling) of sexual excitement in a female subject.
  • SEP Sexual Encounter Profile
  • IIEF International Index of Erectile Function
  • the sexual dysfunction is a male sexual dysfunction, such as erectile dysfunction.
  • the present invention is generally directed to methods for stimulating an erectile response in a male mammal by administering to the mammal in need thereof an effective amount of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the term “erectile response” refers to the reaction of the physiological pathway that causes the penis to achieve an erection.
  • the term “stimulating an erectile response” includes inducing the penis to achieve an erection by upregulation or downregulation of the physiological pathway that leads to an erectile response.
  • the erectile response may be stimulated in a male mammal that may not be able to achieve an erection.
  • the erectile response may be stimulated in a male mammal that can achieve an erection but is not satisfied with the ability to penetrate his partner, the ability to maintain an erection during intercourse, erectile function, orgasmic function, sexual desire, intercourse satisfaction, completion of intercourse with ejaculation and/or orgasm, satisfaction with the hardness of a male subject's erection or overall sexual satisfaction.
  • the erectile response may be stimulated by the administration of boldine, a derivative or a pharmaceutically acceptable salt thereof alone.
  • the erectile response may be stimulated by the administration of boldine, a derivative or a pharmaceutically acceptable salt thereof in combination with external stimuli (e.g., visual, physical and/or emotional stimuli).
  • the erectile response is stimulated substantially at the same time as the administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the term "substantially at the same time” refers to the stimulation of an erectile response that occurs immediately or almost immediately upon administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile response is stimulated within at least one hour and within at least 24 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile response is stimulated within at least one hour after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile response is stimulated within at least two hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least three hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least four hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least five hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least six hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile response is stimulated within at least seven hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least eight hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least nine hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least ten hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least 11 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile response is stimulated within at least 12 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least 13 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least 14 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least 15 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least 16 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile response is stimulated within at least 17 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least 18 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least 19 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least 20 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least 21 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile response is stimulated within at least 22 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least 23 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile response is stimulated within at least 24 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the present invention is generally directed to methods for enhancing erectile function in a male mammal by administering to the mammal in need thereof an effective amount of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • enhancing erectile function refers to the intensification or the improvement in the performance of the erection of a male mammal.
  • the erectile function may be enhanced in a male mammal that can achieve an erection but is not satisfied with the ability to penetrate his partner, the ability to maintain an erection during intercourse, erectile function, orgasmic function, sexual desire, intercourse satisfaction, completion of intercourse with ejaculation and/or orgasm, satisfaction with the hardness of a male subject's erection or overall sexual satisfaction.
  • the erectile function may be enhanced by the administration of boldine, a derivative or a pharmaceutically acceptable salt thereof alone.
  • erectile function may be enhanced by the administration of boldine, a derivative or a pharmaceutically acceptable salt thereof in combination with external stimuli (e.g., visual, physical and/or emotional stimuli).
  • external stimuli e.g., visual, physical and/or emotional stimuli.
  • enhancing erectile function includes enabling a male mammal to achieve an erection.
  • enhancing erectile function includes enabling the male mammal to maintain an erection.
  • erectile function is enhanced substantially at the same time as the administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the term "substantially at the same time” refers to the enhancement of erectile function that occurs immediately or almost immediately upon administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile function is enhanced within at least one hour and within at least 24 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile function is enhanced within at least one hour after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile function is enhanced within at least two hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least three hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least four hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least five hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least six hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile function is enhanced within at least seven hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least eight hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least nine hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least ten hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least 11 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile function is enhanced within at least 12 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least 13 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least 14 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least 15 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least 16 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile function is enhanced within at least 17 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, erectile function is enhanced within at least 18 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least 19 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least 20 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least 21 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • the erectile function is enhanced within at least 22 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least 23 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the erectile function is enhanced within at least 24 hours after administration of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • boldine, a derivative or pharmaceutically acceptable salt thereof may be administered alone or in combination with one or more additional therapeutic agents that treat erectile dysfunction, stimulate erectile response or enhance erectile function.
  • additional therapeutic agents include, but are not limited to, phoshodiesterase inhibitors (e.g., PDE5 inhibitors, such as vardenafil (Levitra ® ), sildenafil (Viagra ® ), tadalafil (Cialis ® ), alprostadil (e.g., Befar), naltrexone, bremelantide, melanotan II, gene therapy (e.g., hMaxi-K), herbal agents (e.g., ginseng) and prelox.
  • PDE5 inhibitors e.g., PDE5 inhibitors, such as vardenafil (Levitra ® ), sildenafil (Viagra ® ), tadalafil (Cialis ®
  • in combination with refers to the administration of boldine, a derivative or pharmaceutically acceptable salt thereof with one or more additional therapeutic agent at substantially the same time, the administration of boldine, a derivative or pharmaceutically acceptable salt thereof first followed by subsequent administration of the additional therapeutic agent, or the administration of the additional therapeutic agent first, followed by subsequent administration of boldine, a derivative or pharmaceutically acceptable salt thereof.
  • the present invention is generally directed to methods for treating Parkinson's disease in a subject by administering to the subject in need thereof an effective amount of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • Parkinson's disease refers to a neurological disorder characterized by muscle rigidity, tremor, bradykinesia, and akinesia that is caused by the decreased stimulation of the motor cortex by the basal ganglia due to insufficient formation and action of dopamine on the dopamine receptors in the brain.
  • Parkinson's disease includes chronic progressive parkinsonism, primary parkinsonism, idiopathic parkinsonism, secondary parkinsonism induce by drugs, trauma or other medical disorders and Parkinson-plus syndromes (e.g., multiple symptom atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and olivopontocerebellar atrophy).
  • the present invention is generally directed to methods for inducing emesis in a subject in need thereof by administering to the subject in need thereof an effective amount of boldine, a derivative or a pharmaceutically acceptable salt thereof.
  • emesis refers to the act of vomiting (e.g., expulsion of the contents of the stomach through the mouth and/or nose), either voluntary or involuntarily.
  • inducing emesis refers to causing a subject to vomit upon the administration of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof.
  • emesis occurs within at least about 20 minutes after administration of boldine, a derivative thereof, or a pharmaceutically acceptable salt thereof to the subject.
  • emesis occurs within at least about 15 minutes after administration of boldine, a derivative thereof, or a pharmaceutically acceptable salt thereof to the subject.
  • emesis occurs within at least about 10 minutes after administration of boldine, a derivative thereof, or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, emesis occurs within at least about 5 minutes after administration of boldine, a derivative thereof, or a pharmaceutically acceptable salt thereof to the subject.
  • subject refers to animals such as mammals, including, but not limited to humans, primates, and domestic animals (e.g., cows, sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent or murine species).
  • subject also includes both male and female members of the species.
  • the subject is human, a male mammal, such as a male human, or a domestic animal, such as a dog.
  • boldine refers to a compound comprising formula I:
  • boldine, a derivative thereof or a pharmaceutically acceptable salt thereof is substantially pure.
  • the term "substantially pure” denotes boldine, a derivative or a pharmaceutically acceptable salt thereof that is separated from and/or free of contaminants that are typically associated with the production (e.g., chemical synthesis or biosynthesis) of boldine, a derivative or pharmaceutical salt thereof.
  • boldine, a derivative or a pharmaceutically acceptable salt thereof is about 80% pure, about 85% pure, about 90% pure, about 91% pure, about 92% pure, about 93% pure, about 94% pure, about 95% pure, about 96% pure, about 97% pure, about 98% pure, about 99% pure or about 100% pure.
  • boldine, a derivative or pharmaceutical salt thereof may be substantially free of other isomers (e.g., as a pure or substantially pure optical isomer having a specified activity), or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention may have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • boldine is substantially enantiomerically pure.
  • substantially enantiomerically pure denotes an enantiomer of boldine, a derivative or a pharmaceutically acceptable salt thereof that is separated from and/or free of the other enantiomers of boldine or a derivative thereof.
  • the S-(+)-enantiomer of boldine may be substantially free of or separated from the (R)-(-)-enantiomer of boldine.
  • the R- (-) -enantiomer of boldine may be substantially free of or separated from the S-(+)-enantiomer of boldine.
  • boldine is about 80% enantiomerically pure, about 85% enantiomerically pure, about 90% enantiomerically pure, about 91% enantiomerically pure, about 92% enantiomerically pure, about 93% enantiomerically pure, about 94% enantiomerically pure, about 95% enantiomerically pure, about 96% enantiomerically pure, about 97% enantiomerically pure, about 98% enantiomerically pure, about 99% enantiomerically pure or about 100% enantiomerically pure.
  • boldine may be the S-(+)-enantiomer, as shown in the formula II:
  • boldine may be the R-(-)-enantiomer, as shown in formula III:
  • derivative refers to a chemical compound that is structurally related to boldine and may be derived from boldine by one or more chemical reactions.
  • phrases “pharmaceutically acceptable salt,” as used herein is art recognized and refers relatively non-toxic, inorganic and organic addition salts of boldine or a derivative thereof.
  • boldine or a derivative thereof may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like, ⁇ see, e.g., Berge et al. (1977) "Pharmaceutical Salts", /. Pharm. ScL. 66:1-19).
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • boldine or the derivative thereof may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • These salts can likewise be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine
  • the term "effective amount” refers to that amount of boldine, a derivative thereof, or a pharmaceutically acceptable salt thereof, that is amount to achieve or at least partially achieve a desired effect (e.g., treating the disorder, disease or symptom of the disease or disorder).
  • therapeutically effective amount is defined as an amount sufficient to cure or at least partially arrest the disorder, disease or symptom of interest and its complications in a subject already suffering from the disorder, disease or symptom of the disease or disorder.
  • actual dosage levels of boldine, a derivative thereof or a pharmaceutically salt thereof may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level may also depend upon a variety of factors including the activity of the particular compound of the present invention employed or the salt or derivative thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of boldine, a derivative thereof or a pharmaceutically salt thereof required.
  • the physician or veterinarian could start doses of boldine, a derivative thereof or a pharmaceutically salt thereof at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, doses of the compounds of this invention for a patient will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 1.0 to about 100 mg per kg per day.
  • An effective amount is that amount that treats one or more symptoms of erectile dysfunction or Parkinson's disease; stimulates an erectile response; enhances erectile function or induces emesis.
  • boldine, a derivative thereof or a pharmaceutically salt thereof is administered on demand.
  • the term "on demand" refers to the intermittent administration of boldine, a derivative thereof or a pharmaceutically salt thereof only when the therapeutic effect is desired.
  • a subject may administer boldine, a derivative thereof or a pharmaceutically salt thereof only upon the desire to engage in sexual activities or upon the need for emesis.
  • the effective daily dose of boldine, a derivative thereof or a pharmaceutically salt thereof may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • an effective amount of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof is that amount effective to treat a sexual dysfunction in a subject (e.g., an amount effective to allow a subject to achieve or sustain an aroused state; an amount effective to allow a subject to engage in sexual activity or an amount effective to permit a subject satisfactory performance).
  • an effective amount of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof is that amount effective to treat Parkinson's disease in a subject.
  • an effective amount of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof is that amount effective to stimulate erectile response in a subject.
  • an effective amount of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof is that amount effective to enhance erectile function in a subject. In some embodiments, an effective amount of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof is that amount effective to induce emesis in a subject. In some embodiments, the effective amount is an amount effective to induce emesis within at least 20 minutes of administration of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the effective amount is an amount effective to induce emesis within at least 15 minutes of administration of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof.
  • the effective amount is an amount effective to induce emesis within at least 10 minutes of administration of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the effective amount is an amount effective to induce emesis within at least 5 minutes of administration of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the effective amount is an amount that does not increase abdominal pressure prior to or during emesis.
  • the effective amount is an amount that does not increase discomfort, agitation or muscle weakness in the subject upon administration of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the effective amount is an amount that does not substantially increase a subject' s heart rate upon administration of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the effective amount is an amount that sustains or slightly decreases a subject's blood pressure upon administration of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof to the subject.
  • the decrease in a subject's blood pressure may not be more than a 1% decrease, a 2% decrease, a 3% decrease, a 4% decrease, a 5% decrease, a 6% decrease, a 7% decrease, an 8% decrease, a 9% decrease or a 10% decrease in either or both of the systolic and diastolic pressure.
  • an effective amount of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof that is effective to treat one disease, disorder or symptom of one disease or disorder may not be effective for the treatment of a second disease, disorder or symptom of the second disease or disorder.
  • the effective amount of boldine is between about 0.1 mg/kg and about 40 mg/kg. In some embodiments, the effective amount is about 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 3.0 mg/kg, 4.0 mg/kg, 5.0 mg/kg, 6.0 mg/kg, 7.0 mg/kg, 8.0 mg/kg, 9.0 mg/kg, 10.0 mg/kg, 11.0 mg/kg, 12.0 mg/kg, 13.0 mg/kg, 14.0 mg/kg, 15.0 mg/kg, 16.0 mg/kg, 17.0 mg/kg, 18.0 mg/kg, 19.0 mg/kg, 20.0 mg/kg, 21.0 mg/kg, 22.0 mg/kg, 23.0 mg/kg, 204.0 mg/kg, 25.0 mg/kg, 26.0 mg/kg, 27.0 mg/kg, 28.0 mg
  • the present invention is generally directed to pharmaceutical compositions comprising boldine, a derivative thereof of a pharmaceutically acceptable salt there in an amount effective stimulate an erectile response in a male mammal.
  • the present invention is generally directed to pharmaceutical compositions comprising boldine, a derivative thereof of a pharmaceutically acceptable salt there in an amount effective to enhance erectile function in a male mammal. In some aspects, the present invention is generally directed to pharmaceutical compositions comprising boldine, a derivative thereof of a pharmaceutically acceptable salt there in an amount effective to treat Parkinson's disease in a subject.
  • the present invention is generally directed to pharmaceutical compositions comprising boldine, a derivative thereof of a pharmaceutically acceptable salt there in an amount effective to induce emesis in a subject.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • pharmaceutical composition refers to preparations of boldine, a derivative thereof, or a pharmaceutically acceptable salt thereof that is suitable for administration to a subject, e.g., a mammal, for example, a male or female human, primate or domestic animal.
  • a subject e.g., a mammal
  • the compounds of the present invention are administered as pharmaceuticals to subjects, e.g., a mammal, they can be administered per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of boldine, a derivative or pharmaceutically acceptable salt thereof is formulated as a controlled release pharmaceutical composition.
  • controlled release refers to a formulation that delivers an agent at a specified rate for an extended period of time.
  • the pharmaceutical composition of boldine, a derivative or pharmaceutically acceptable salt thereof is formulated as a sustained release pharmaceutical composition.
  • sustained release refers to a formulation that provides a required dosage initially and maintains or repeats the dosage at a desired interval.
  • pharmaceutically acceptable carrier includes a pharmaceutically acceptable material, composition or vehicle, suitable for administration of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof.
  • the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, ⁇ -tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
  • boldine, a derivative thereof or a pharmaceutically acceptable salt thereof may be administered intranasally, orally, parenterally, transdermally, buccally, parenterally, intramuscularly, via inhalation or sublingually.
  • the aforementioned formulations may be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof which may be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • Methods of preparing these formulations or compositions include the step of bringing into association boldine, a derivative thereof or a pharmaceutically acceptable salt thereof with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association boldine, a derivative thereof or a pharmaceutically acceptable salt thereof with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • Boldine, a derivative thereof or a pharmaceutically acceptable salt thereof may also be administered as a bolus, electuary or paste.
  • solid dosage forms of the invention for oral administration capsules, tablets, pills, powders, granules and the like
  • boldine, a derivative thereof or a pharmaceutically acceptable salt thereof is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as par
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices
  • compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • Boldine, a derivative thereof or a pharmaceutically acceptable salt thereof may also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluent commonly used in the art, such as, for example, water or other solvent
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to boldine, a derivative thereof or a pharmaceutically acceptable salt thereof, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdermal administration of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • Boldine, a derivative thereof or a pharmaceutically acceptable salt thereof may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to boldine, a derivative thereof or a pharmaceutically acceptable salt thereof, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to boldine, a derivative thereof or a pharmaceutically acceptable salt thereof, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. Sprays also can be delivered by mechanical, electrical, or by other methods known in the art.
  • Transdermal patches have the added advantage of providing controlled delivery boldine, a derivative thereof or a pharmaceutically acceptable salt thereof to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • parenteral administration and “administered parenterally” refers to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, administration via spinal tap, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • compositions of this invention suitable for parenteral administration comprise boldine, a derivative thereof or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • microorganisms Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial, antiparasitic and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.
  • agents which delay absorption such as aluminum monostearate and gelatin.
  • a derivative thereof or a pharmaceutically acceptable salt thereof it is desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof then depends upon its rate of dissolution. Alternatively, delayed absorption of a parenterally-administered drug form may be accomplished by dissolving or suspending boldine, a derivative thereof or a pharmaceutically acceptable salt thereof in an oil vehicle.
  • the compositions also may be formulated such that its elimination is retarded by methods known in the art.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of boldine, a derivative thereof or a pharmaceutically acceptable salt thereof to polymer, and the nature of the particular polymer employed, the rate of release may be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly( anhydrides). Depot injectable formulations are also prepared by entrapping boldine, a derivative thereof or a pharmaceutically acceptable salt thereof in liposomes or microemulsions which are compatible with body tissue.
  • boldine, a derivative thereof or a pharmaceutically acceptable salt thereof which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Example 1 Administration ofBoldine to Induce Emesis All studies were carried out on a group consisting of 20 clinically healthy dogs of different ages and sexes. The health status of the animals was determined by clinical exams and complete blood analysis. The blood analysis was performed on samples obtained in a sterile tube containing the anticoagulant EDTA and sent to the clinical laboratory for analysis within 24 hours. Boldine hydrochloride was diluted to 10% in Tween 80. The solution was then incubated at 37°C for 10 minutes in a water bath and agitated for 1 minute. Precaution was taken so that no more than 1 ml/2 kg was applied per animal. Apomorphine 0.5% and domperidone 0.5% were used for comparison as a dopaminergic agonist and a D2 antagonist, respectively.
  • domperidone a selective D2 antagonist
  • domperidone a selective D2 antagonist
  • the canine subjects pre-treated with domperidone were administered a sodium chloride solution containing 40 mg/kg boldine hydrochloride. None of the dogs pre-treated with domeridone presented emesis. In contrast, 100% of dogs that were not pre-treated exhibited emesis after 20 minutes. The results of this assay indicate that the emetic effect of boldine may proceed through a D2 receptor signalling pathway.
  • dogs intramuscularly administered with boldine exhibited on a slight increase in heart rate.
  • Dogs administered with a 20 mg/kg dose of boldine (•) after 5 minutes, displayed an average increase in heart rate from about 80 beats per minute to about 100 beats per minute.
  • Dogs intramuscularly administered with a 40 mg/kg dose of boldine (A) exhibited a non- statistically significant increase in heart rate from a starting heart rate to 96 beats per minute after 5 minutes after administration. After 15 minutes, the average heart rate had dropped to the starting heart rate of 90 beats per minute.
  • the heart rate of dogs dosed with 40 mg/kg was similar to those dogs that were treated with the control Tween 80 solution ( ⁇ ).
  • Blood pressure was also measured in the canine test subjects, as shown in Figure 2.
  • Normal physiological range of blood pressure for dogs is about 80-120 mm Hg (Grosenbaugh and Muir, 1998).
  • Dogs intramuscularly administered a 40 mg/kg dose of boldine ( ⁇ ) resulted in a reduction on the blood pressure of 102 mm Hg to 94 mm Hg at 15 minutes and 93 mm Hg at 30 minutes.
  • Dogs intramuscularly administered a 20 mg/kg dose of boldine ( ⁇ ) demonstrated a similar blood pressure profile as those dogs administered with a 40 mg/kg dose.
  • dogs administered with a control solution of Tween ( ⁇ ) presented no change in blood pressure.
  • Example 2 Administration of Boldine to Induce Erection This Example describes an expanded study and analysis of the effectiveness of intramuscular boldine for the treatment of erectile dysfunction. The data was obtained from a group of 20 healthy male dogs.

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Abstract

L'invention porte sur des méthodes de traitement d'un dysfonctionnement sexuel ou de la maladie de Parkinson ; sur des méthodes d'amélioration de la fonction d'érection ; sur des méthodes de stimulation de réponse d'érection et sur des méthodes d'induction de vomissement qui impliquent l'administration de boldine, un dérivé ou un sel pharmaceutiquement acceptable de celle-ci dans une quantité efficace pour traiter un dysfonctionnement sexuel ou la maladie de Parkinson ; améliorer une fonction d'érection ; stimuler une réponse d'érection ou induire un vomissement.
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WO2013056386A1 (fr) * 2011-10-19 2013-04-25 Universidad De Santiago De Chile Utilisation d'un extrait de peumus boldus obtenu par culture in vitro, présentant des propriétés antibotricide, allélopathique et antioxydante
WO2021159011A1 (fr) * 2020-02-07 2021-08-12 United States Government As Represented By The Department Of Veterans Affairs Procédé de traitement de lésions du système nerveux avec de la boldine et des analogues de celle-ci
WO2024243339A3 (fr) * 2023-05-23 2025-05-08 Burrell Justin Boldine pour réduire l'atrophie musculaire et favoriser la récupération neuromusculaire

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WO2013056386A1 (fr) * 2011-10-19 2013-04-25 Universidad De Santiago De Chile Utilisation d'un extrait de peumus boldus obtenu par culture in vitro, présentant des propriétés antibotricide, allélopathique et antioxydante
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US11707459B2 (en) 2020-02-07 2023-07-25 United States Government As Represented By The Department Of Veterans Affairs Method for treating nervous system injuries using boldine and analogs thereof
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WO2024243339A3 (fr) * 2023-05-23 2025-05-08 Burrell Justin Boldine pour réduire l'atrophie musculaire et favoriser la récupération neuromusculaire

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