Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-03-23
2002-06-25
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S274000
Reexamination Certificate
active
06410554
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides combination therapy for the treatment of benign prostatic hyperplasia. More particularly, the combination comprises an alpha-1a adrenergic receptor antagonist with an endothelin antagonist, and optionally a 5a-reductase inhibitor, for relief of lower urinary tract symptoms in patients with symptomatic prostatism or benign prostatic hyperplasia.
BACKGROUND OF THE INVENTION
Benign prostatic hyperplasia, also known as benign prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
Bladder outlet obstruction (BOO) in BPH patients results from a static component of increased prostatic mass which physically impinges on the urethra and a dynamic component of increased contractile tone of the prostatic-urethral smooth muscle. Standard treatment of BPH involves surgical or pharmacological intervention. Surgical intervention, either by removal of the prostate via radical prostatectomy or removing the prostatic adenoma via transurethral resection of the prostate alleviates both the static and dynamic components of BOO since the entire prostate or the majority of the prostatic smooth muscle is removed. Although these procedures result in the most marked improvement in symptoms, there is the possibility of mortality and morbidity since these are invasive surgical procedures. Many patients suffer incontinence and retrograde ejaculation as a consequence of these surgical procedures. Because of the chances for morbidity and mortality, these procedures are not optimum for patients with mild to moderate symptoms in a disease which is not life-threatening.
Pharmacological treatment with 5a-reductase inhibitors such as finasteride reduces the size of the prostate, thereby alleviating the static component of BOO. However, the symptomatic improvement following this therapy is significantly less than that following surgery. The lesser efficacy is likely mechanism-based in that 5a-reductase inhibitors decrease the size of the prostate by reducing the amount of epithelial tissue without affecting the smooth muscle, therefore the dynamic component of BOO may still be present.
Another pharmacological therapy involves the administration of subtype nonselective alpha-1 adrenergic receptor antagonists. These agents relax the prostatic-urethral smooth muscle by blocking endogenous sympathetic tone hence affecting the dynamic component of BOO. However, these agents were originally developed to treat hypertension and have effects on the cardiovascular system which include decreasing blood pressure and causing orthostatic hypotension. The efficacy of this therapy is also significantly less than that following surgery. Efficacy of these agents may be limited by dose-related cardiovascular side-effects, the remaining static component of BOO, and/or because another endogenus substance contributes to the dynamic prostatic-urethral tone.
The predominant alpha-1 adrenergic receptor subtype responsible for alpha 1 agonist mediated contraction of human prostatic-urethral smooth muscle is the alpha-1a subtype. Animal studies suggest that the alpha-1a receptor is not involved in normal blood pressure regulation, therefore selective alpha-1a receptor antagonists may not have the dose-limiting side-effects of subtype nonselective antagonists. The only other substances identified to potently contract human prostate tissue are endothelins (ET) via both the ET-A and ET-B receptors. Endothelin-1 is found in very high concentrations in the prostate and appears to be produced locally in the epithelial tissue in the prostate (Langenstroer, et al 1993 J. of Urology 149:495-99). Alpha adrenergic tone is known to be involved in the dynamic component of BPH based on the efficacy of the subtype nonselective compounds approved for clinical use. The role of ET in BPH is unknown at this time.
It is therefore an object of the invention to find an improved therapy for treating benign prostatic hyperplasia. It is a further object of the invention to find improved methods for relaxing lower urinary tract tissue in patients in need of such treatment. Still a further object of the present invention is to improve lower urinary tract symptoms which include increasing urine flow rate, decreasing residual urine volume and improving overall obstructive and irritative symptoms in patients with benign prostatic hyperplasia or symptomatic prostatism.
It has now been found that combination therapy with an alpha-1a antagonist and an endothelin antagonist, preferably a mixed ET-A/ET-B antagonist, is useful for treating benign prostatic hyperplasia, for relaxing lower urinary tract tissue, and for improving lower urinary tract symptoms which include increasing urine flow rate, decreasing residual urine volume and improving overall obstructive and irritative symptoms in patients with benign prostatic hyperplasia or symptomatic prostatism. The advantage of the combined administration of an alpha-1a antagonist and an ET-A/ET-B antagonist is that two putative components which determine the dynamic prostatic tone would be inhibited without the dose-limiting side-effects observed with subtype non selective alpha-1 antagonists.
SUMMARY OF THE INVENTION
The present invention provides a composition comprising an alpha-1a adrenergic receptor antagonist and an endothelin antagonist, and pharmaceutically acceptable salts thereof.
In one embodiment of the instant invention is the composition of an alpha-1a adrenergic receptor antagonist and an endothelin antagonist wherein the alpha-1a adrenergic receptor antagonist is a selective alpha-1a adrenergic receptor antagonist; and the pharmaceutically acceptable salts thereof.
In a class of the embodiment is the composition comprising a selective alpha-1a adrenergic receptor antagonist and an endothelin antagonist wherein the selective alpha-1a adrenergic receptor antagonist is selected from Compound A, Compound C, Compound D, Compound E, KMD-3213, tamsulosin, REC 15/2739 or A131701; and the pharmaceutically acceptable salts thereof.
In a subclass of the embodiment is the composition mentioned above wherein the selective alpha-1a adrenergic receptor antagonist is Compound A.
In another subclass of the embodiment is the composition mentioned above wherein the selective alpha-1a adrenergic receptor antagonist is Compound C.
In another subclass of the embodiment is the composition mentioned above wherein the selective alpha-1a adrenergic receptor antagonist is Compound D.
In another subclass of the embodiment is the composition mentioned above wherein the selective alpha-1a adrenergic receptor antagonist is Compound E.
In a second class of the embodiment is the composition comprising an alpha-1a adrenergic receptor antagonist and an endothelin antagonist wherein the endothelin antagonist is a subtype non-selective endothelin antagonist; and the pharmaceutically acceptable salts.
In a subclass of the second class of the embodiment is the composition wherein the subtype non-selective endothelin antagonist is selected from Compound B, bosentan, SB217242, SB209670, A 127722 or A 182086.
Illustrating the subclass is the composition wherein the subtype non-selective endothelin antagonist is Compound B.
Illustrating the embodiment is the composition comprising a selective alpha-1a adrenergic receptor antagonist and an endothelin antagonist wherein the selective alpha-1a adrenergic receptor antagonist is Compound A, Compound D, Compound E, or a pharmaceutically acceptable salt thereof; and the endothe
Broten Theodore P.
Nichtberger Steven A.
Siegl Peter K. S.
Brown Baerbel R.
Criares Theodore J.
Fitch Catherine D.
Kim J.
Merck & Co. , Inc.
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