Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-12-29
2000-05-16
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514878, 514906, A01N 4340
Patent
active
060637927
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to methods for treating urinary incontinence, such as incontinence caused by bladder detrusor muscle instability, and to pharmaceutical compositions for such treatment.
BACKGROUND OF THE INVENTION
Urinary incontinence is a prevalent problem that affects people of all ages and levels of physical health, both in healthcare settings and in the community at large. At present, urinary incontinence afflicts 15-30% of elderly people living at home, one-third of those living in acute-care settings, and at least one-half of those in long-term care institutions (R. M. Resnick, Lancet 346:94 (1995)). Medically, it predisposes persons to urinary tract infections, pressure ulcers, perineal rashes, and urosepsis. Psychosocially, urinary incontinence is associated with embarrassment, social stigmatization, depression, and with the risk of institutionalization (Herzo et al., Annu. Rev. Gerontol. Geriatr., 9:74 (1989)). Economically, the costs are great; in the United States alone, over $10 billion is spent per annum managing incontinence.
Treatments for incontinence include drugs with bladder relaxant properties, i.e., which help to control bladder detrusor muscle overactivity. Such drugs are effective in 80 to 85% of patients with uninhibited bladder contractions, with anticholinergic medications representing the mainstay of this type of treatment. For example, anticholinergics such as propantheline bromide, and combination smooth muscle relaxant/anticholinergics such as racemic oxybutynin and dicyclomine, have been used to treat urge incontinence. (See, e.g., A. J. Wein, Urol. Clin. N. Am., 22:557-77 (1995).)
No treatment for incontinence, including existing drug therapies, has achieved complete success with all classes of incontinent patients, and without significant side effects. For example, adverse effects, such as drowsiness, dry mouth, constipation, blurred vision, headaches, and cardiac arrhythmia which are related to the anticholinergic activity of drugs such as racemic oxybutynin, occur frequently and can be sufficiently troublesome to necessitate discontinuing treatment in up to 25% of patients, depending on the dosage. Yet, despite the occurrence of unwanted anticholinergic effects in many patients, and an apparent lack of efficacy in the elderly institutionalized population, racemic oxybutynin nevertheless is considered the drug of first choice in patients with bladder detrusor muscle hyperactivity when pharmacological therapy is indicated (cf. Yarllur et al., Drugs Aging, 6:243 (1995)).
Trihexyphenidyl, 3-(1-piperidyl)-1-cyclohexyl-1-propanol, a synthetic antispasmotic drug, is described as being useful in treating parkinsonism, and has been used in muscarinic receptor binding studies (Lambrecht et al., Eur. J. Pharmacol., 155:167-170 (1988); Waelbroeck et al., Brit. J. Pharmacol., 109:360-370 (1993)). Similar adverse effects to those for anticholinergic drugs may result with the use of trihexyphenidyl (cf.Physician's Desk Reference, 50th Edition, page 1368 (1996)).
SUMMARY OF THE INVENTION
The present invention provides methods and compositions for treatment of urinary incontinence, including, e.g., bladder detrusor muscle instability incontinence, stress incontinence, urge incontinence, overflow incontinence, enuresis, and post-prostectomy incontinence, with (S)-trihexyphenidyl. The methods of the present invention provide for treatment of incontinence with fewer adverse effects than occur upon administration of racemic trihexyphenidyl.
One aspect of the present invention relates to methods for treating urinary incontinence by administration to a subject in need thereof a therapeutically effective amount of enantiomerically enriched (S)-trihexyphenidyl, or a pharmaceutically acceptable salt thereof. In a preferred embodiment of this method, the enantiomerically enriched (S)-trihexyphenidyl, or a pharmaceutically acceptable salt thereof, is substantially free of (R)-trihexyphenidyl.
The present invention also relates to methods for treating bladde
REFERENCES:
patent: 4945097 (1990-07-01), Olney
Chemical Abstract 121:292670, "Antagonism by (R)-and (S)-trihexyphenidyl of Muscarinic Stimulation of Adenyl Cyclase . . . ", Mar. 1994.
Chemical Abstract 89:99555g, "The Fate of Prindol in the Organism: Pharmacokinetics and Distribution in Animals", Apr. 1978.
Poyurovsky, M. et al., "Trihexyphenidyl as a possible therapeutic option in clozapine-induced nocturnal ensuresis," Int'l Clin Psychopharm, 11:61-63 (1996).
Foote, J. et al., "Neurogenic Dysfunction of the Urinary Bladder in Parkinson's Disease," Primary Care 4:463-473 (1977).
Waelbrocck, M. et al., "Stereoselective interaction of procyclidine, hexahydro-difenidol, hexbutinol and oxyphencyclimine, and of related antagonists, with four muscarinic receptors," European Journal of Pharmacology --Molecular Pharmacology Section, 227:33-42 (1992).
Armstrong, D. et al., "Separation of Drug Stereoisomers by the Formation of .beta.-Cyclodextrin Complexes," Science, 232:1132-1135 (1986).
Fabiano Vincent L.
McCullough John R.
Krass Frederick
Sepracor Inc.
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