Methods of treating or preventing restless leg syndrome using sibutramine metabolites

Abstract

Methods are disclosed for the treatment and prevention of disorders and conditions such as, but are not limited to: eating disorders; weight gain; obesity; irritable bowel syndrome; obsessive-compulsive disorders; platelet adhesion; apnea; affective disorders such as attention deficit disorders, depression, and anxiety; male and female sexual function disorders; restless leg syndrome; osteoarthritis; substance abuse including nicotine and cocaine addiction; narcolepsy; pain such as neuropathic pain, diabetic neuropathy, and chronic pain; migraines; cerebral function disorders; chronic disorders such as premenstrual syndrome; and incontinence. Pharmaceutical compositions and dosage forms are also disclosed which comprise a racemic or optically pure sibutramine metabolite and an optional additional pharmacologically active compound.

What is claimed is:  
     
         1 . A method of treating or preventing sexual dysfunction which comprises administering to a patient in need of such treatment or prevention therapeutically or prophylactically effective amounts of a sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, and a phosphodiesterase inhibitor.  
     
     
         2 . The method of  claim 1  wherein the sibutramine metabolite is optically pure.  
     
     
         3 . The method of  claim 2  wherein the sibutramine metabolite is (R)-desmethylsibutramine, (S)-desmethylsibutramine, (R)-didesmethylsibutramine, or (S)-didesmethylsibutramine.  
     
     
         4 . The method of  claim 1  wherein the phosphodiesterase inhibitor is a PDE5 or PDE6 inhibitor.  
     
     
         5 . The method of  claim 4  wherein the phosphodiesterase inhibitor is sildenophil, desmethylsildenophil, vinopocetine, milrinone, amrinone, pimobendan, cilostamide, enoximone, peroximone, vesnarinone, rolipram, R020-1724, zaprinast, dipyridamole, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, prodrug, optically and pharmacologically active stereoisomer, or a pharmacologically active metabolite thereof.  
     
     
         6 . The method of  claim 1  wherein the amount of sibutramine metabolite administered is from about 0.1 mg to about 60 mg/day.  
     
     
         7 . The method of  claim 6  wherein the amount of sibutramine metabolite administered is from about 2 mg to about 30 mg/day.  
     
     
         8 . The method of  claim 7  wherein the amount of sibutramine metabolite administered is from about 5 mg to about 15 mg/day.  
     
     
         9 . The method of  claim 1  wherein the sibutramine metabolite and/or the phosphodiesterase inhibitor is administered transdermally or mucosally.  
     
     
         10 . The method of  claim 1  wherein the patient is male.  
     
     
         11 . The method of  claim 10  wherein the sexual dysfunction is erectile dysfunction.  
     
     
         12 . The method of  claim 1  wherein the patient is female.  
     
     
         13 . A method of treating or preventing a cerebral function disorder which comprises administering to a patient in need of such treatment or prevention therapeutically or prophylactically effective amounts of a sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, and a phosphodiesterase inhibitor.  
     
     
         14 . The method of  claim 13  wherein the cerebral function disorder is senile dementia, Alzheimer's type dementia, memory loss, amnesia/amnestic syndrome, disturbance of consciousness, coma, lowering of attention, speech disorders, Parkinson's disease, Lennox syndrome, autism, epilepsy, hyperkinetic syndrome, or schizophrenia.  
     
     
         15 . The method of  claim 13  wherein the sibutramine metabolite is optically pure.  
     
     
         16 . The method of  claim 15  wherein the sibutramine metabolite is (R)-desmethylsibutramine, (S)-desmethylsibutramine, (R)-didesmethylsibutramine, or (S)-didesmethylsibutramine.  
     
     
         17 . The method of  claim 13  wherein the phosphodiesterase inhibitor is a PDE5 or PDE6 inhibitor.  
     
     
         18 . The method of  claim 17  wherein the phosphodiesterase inhibitor is sildenophil, desmethylsildenophil, vinopocetine, milrinone, amrinone, pimobendan, cilostamide, enoximone, peroximone, vesnarinone, rolipram, R020-1724, zaprinast, dipyridamole, or a pharmaceutically acceptable salt, solvate, hydrate clathrate, prodrug, optically and pharmacologically active stereoisomer, or a pharmacologically active metabolite thereof.  
     
     
         19 . The method of  claim 13  wherein the amount of sibutramine metabolite administered is from about 0.1 mg to about 60 mg/day.  
     
     
         20 . The method of  claim 19  wherein the amount of sibutramine metabolite administered is from about 2 mg to about 30 mg/day.  
     
     
         21 . The method of  claim 20  wherein the amount of sibutramine metabolite administered is from about 5 mg to about 15 mg/day.  
     
     
         22 . A method of treating or preventing restless leg syndrome which comprises administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a racemic or optically pure sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.  
     
     
         23 . The method of  claim 22  wherein the sibutramine metabolite is optically pure.  
     
     
         24 . The method of  claim 23  wherein the sibutramine metabolite is (R)-desmethylsibutramine, (S)-desmethylsibutramine, (R)-didesmethylsibutramine, or (S)-didesmethylsibutramine.  
     
     
         25 . The method of  claim 22  which further comprises the administration of pergolide, carbidopa, levodopa, oxycodone, carbamazepine, or gabapentin, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, prodrug, optically and pharmacologically active stereoisomer, or pharmacologically active metabolite thereof.  
     
     
         26 . A pharmaceutical composition comprising a sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, and a phosphodiesterase inhibitor.  
     
     
         27 . The pharmaceutical composition of  claim 26  wherein the sibutramine metabolite is optically pure.  
     
     
         28 . The pharmaceutical composition of  claim 27  wherein the sibutramine metabolite is (R)-desmethylsibutramine, (S)-desmethylsibutramine, (R)-didesmethylsibutramine, or (S)-didesmethylsibutramine.  
     
     
         29 . The pharmaceutical composition of  claim 28  wherein the phosphodiesterase inhibitor is sildenophil, desmethylsildenophil, vinopocetine, milrinone, amrinone, pimobendan, cilostamide, enoximone, peroximone, vesnarinone, rolipram, R020-1724, zaprinast, dipyridamole, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, prodrug, optically and pharmacologically active stereoisomer, or a pharmacologically active metabolite thereof.  
     
     
         30 . The pharmaceutical composition of  claim 26  wherein the sibutramine metabolite is in an amount of from about 0.1 mg to about 60 mg.  
     
     
         31 . The pharmaceutical composition of  claim 30  wherein the sibutramine metabolite is in an amount of from about 2 mg to about 30 mg.  
     
     
         32 . The pharmaceutical composition of  claim 31  wherein the sibutramine metabolite is in an amount of from about 5 mg to about 15 mg.  
     
     
         33 . The pharmaceutical composition of  claim 26  wherein the phosphodiesterase inhibitor is in an amount of from about 0.5 mg to about 500 mg.  
     
     
         34 . The pharmaceutical composition of  claim 33  wherein the phosphodiesterase inhibitor is in an amount of from about 1 mg to about 350 mg.  
     
     
         35 . The pharmaceutical composition of  claim 34  wherein the phosphodiesterase inhibitor is in an amount of from about 2 mg to about 250 mg.  
     
     
         36 . The pharmaceutical composition of  claim 26  wherein the pharmaceutical composition is adapted for oral, mucosal, rectal, parenteral, transdermal, or subcutaneous administration.  
     
     
         37 . The pharmaceutical composition of  claim 36  wherein the pharmaceutical composition is adapted for oral, mucosal, or transdermal administration.  
     
     
         38 . A lactose-free pharmaceutical composition which comprises a sibutramine metabolite, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, a phosphodiesterase inhibitor, and a pharmaceutically acceptable excipient.  
     
     
         39 . The pharmaceutical composition of  claim 38  wherein the excipient is croscarmellose sodium, microcrystalline cellulose, pre-gelatinized starch, or magnesium stearate.  
     
     
         40 . The pharmaceutical composition of  claim 39  wherein said pharmaceutical composition is substantially free of mono- or di-saccharides.