Compositions and methods for the treatment of anorectal disorders

Abstract

Compositions and methods for the treatment of anorectal disorders are provided in which certain combinations of NO donors, PDE inhibitors, superoxide (O2−) scavengers, β-adrenergic agonists, cAMP-dependent protein kinase activators, α1-adrenergic antagonists, L-type Ca2+ channel blockers, estrogens, ATP-sensitive K+ channel activators and smooth muscle relaxants are used.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. 119(e) of U.S. Patent Application No. 60 / 222,267, filed Jul. 31, 2000. This application also is a Continuation-In-Part and claims priority to U.S. patent application Ser. No. 09 / 460,306, filed Dec. 13, 1999; U.S. patent application Ser. No. 09 / 595,390 filed on Jun. 14, 2000; and U.S. patent application Ser. No. 09 / 769,621 filed Jan. 23, 2001 which each claim priority from U.S. Provisional Application No. 60 / 112,325, filed Dec. 14, 1998; U.S. Provisional Application No. 60 / 139,916, filed Jun. 17, 1999 and U.S. Provisional Application No. 60 / 155,318, filed Sep. 21, 1999. The disclosure of each of the above priority documents is incorporated herein by reference in its entirety.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] This invention was made with government support under Grant Number 1 R43 DK 56563-01 awarded by the National Institute...

AI Technical Summary

Benefits of technology

[0034] As noted above, methods of treating anorectal disorders are also provided herein. The methods of the invention comprise administering to a subject a suitable formulation of one or more of the c

Problems solved by technology

While hemorrhoids and anal fissures do not garner the attention given to life threatening diseases, they are responsible for considerable suffering and disability, affecting over 26 million people in the U.S., Europe, and Japan.

Commonly, internal hemorrhoidal tissue bulges into the anal canal during defecation and results in bleeding and pain.

As the tissue enlarges, further bleeding, pain, prolapse and thrombosis can ensue.

The thrombosis of hemorrhoids is yet another cause of bleeding and pain.

Post-hemorrhoidectomy pain is severe, disproportionate to the surgery itself, and requires the use of narcotic analgesics, which unfortunately complicate recovery by causing constipation.

Others have reported that the addition of lateral internal sphincterotomy to routine hemorrhoidectomy is unnecessary and carries the added risk of incontinence (Mathai, V. et al., Br J Surg.

However, ATP and VIP, either separately or together, could not account for all inhibitory neurotransmission in gastrointestinal smooth muscle, and their roles have not been established in man (Burleigh, D. E. et al., Gastroenterology 77(3): 484-90 (1979); Burleigh, D. E., J Pharm Pharmacol 35(4):258-60 (1983); Brookes, S. J., J Gastroenterol Hepatol 8(6):590-603 (1993).

However, the development of adverse side effects such as the development of headaches has limited the use of NO donors in stand alone therapy, especially at higher doses.

One problem associated with topical nitroglycerin therapy, which may limit its effectiveness, is the incidence of headache, particularly at higher doses (Palazzo, F. F. et al., J R Coll Surg Edinb 45(3): 168-70 (2000)).

The headache is presumably due to systemic effects of nitroglycerin and is generally transient, but can affect patient compliance.

A second potential problem of nitrates is the development of drug tolerance, a problem well documented for nitrate therapy in cardiovascular disease (Fung, H. L., et al., Cardiovasc Drugs Ther 8(3):489-99, (1994)).

Tolerance, if present, would limit the ability of nitroglycerin to produce a sustained relaxation of the LAS, which may be necessary for healing particularly refractant chronic anal fissures.

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