Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-13
2002-05-28
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S273000, C514S353000, C514S309000, C514S422000
Reexamination Certificate
active
06395736
ABSTRACT:
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
This invention is directed to compositions and methods for treating anorectal disorders such as anal fissures, anal ulcer, hemorrhoidal diseases and levator spasm by administering to an appropriate anal area of a subject (for example, the internal anal canal) in need of such treatment an agent or combination of agents which relaxes the internal anal sphincter muscle. More specifically, this invention describes compositions and methods for treating anorectal disorders with agents which induce an increase in cyclic nucleotides in the anal sphincter muscle or mimics the actions of cyclic nucleotides or reduce intracellular calcium concentrations in the affected anal sphincter muscle tissue, thereby reducing anal sphincter hypertonicity and/or spasm in patients afflicted with such disorders.
In general, anal fissure (fissure-in-ano), anal ulcer, hemorrhoidal diseases, and levator spasm (proctalgia fugax) are relatively common benign conditions of the anorectal area which affect subjects, including humans, of all ages, races, and sexes. However, these conditions can be problematical and inconvenient to treat and painful to endure. An anal fissure or ulcer is a tear or ulcer of the mucosa or lining tissue of the distal anal canal. An anal fissure or ulcer can be associated with another systemic or local disease, but is more frequently present as an isolated finding. The typical idiopathic fissure or ulcer is confined to the anal mucosa and usually lies in the posterior midline, distal to the dentate line. An individual with an anal fissure or ulcer frequently experiences anal pain and bleeding, the pain being more pronounced during and after bowel movements.
Hemorrhoids are specialized vascular areas lying subjacent to the anal mucosa. Symptomatic hemorrhoidal diseases are manifested by bleeding, thrombosis and/or prolapse of the hemorrhoidal tissues. 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.
Levator spasm is a condition affecting women more frequently than men. This syndrome is characterized by spasticity of the levator ani muscle, a portion of the anal sphincter complex. The patient suffering from levator spasm may experience severe, episodic rectal pain. A physical exam may reveal spasm of the puborectalis muscle and pain may be reproduced by direct pressure on this muscle. Bleeding is normally not associated with this condition.
Sphincters are circular groups of smooth muscle that control the orifices of hollow organs. Sphincters present throughout the gastrointestinal (GI) tract control the passage of materials through this system of the body. When constricted, the sphincters close orifices leading to the hollow organs, such as the stomach, intestine, anus, etc. In order for the sphincter to open, the muscles must relax. The sphincter that closes the anus (sphincter ani) consists of two sphincter muscle groups. The external anal sphincter is a thin flat plane of striated muscle fibers adherent to the integument surrounding the margin of the anus. The internal anal sphincter (IAS) is a ring of smooth muscle which surrounds the lower extremity of the rectum and is formed by an aggregation of the involuntary smooth muscle fibers. Inflammation locally may cause sphincter spasm and pain.
Anal sphincter spasm is a condition in which the muscles of the internal anal sphincter are under abnormal tension. The strong contractions of the internal anal sphincter associated with sphincter spasm often give rise to painful linear ulcers or crack-like sores, known as rectal fissures, on the margin of the anus, especially after defecation. Anal sphincter spasm is also considered a cause of the pain following rectal surgery or thrombosed hemorrhoids. Current treatments of rectal fissures are directed at relieving sphincter spasm and include dilatation (under anesthesia) or cutting a part of the sphincter (lateral internal sphincterotomy). Applications of heat, cold, witch hazel, topical anesthetics, topical steroids, stool softeners, and bed rest have also been prescribed to treat rectal pain. However, none of these approaches significantly modifies the sphincter spasm itself.
The treatment of, for example, anal fissure has not changed significantly for over 150 years. Typically, non-surgical therapies involving bulk laxatives and/or sitz baths are used. Approximately 60% of the acute anal fissures heal within three weeks under this treatment regimen. Acute anal fissures which do not heal become chronic anal fissures or anal ulcers. The hypertonicity of the internal anal sphincter muscle, which is believed to be the main cause of anal fissures, can be relieved through surgical sphincterotomy. The Standards Task Force of the American Society of Colon and Rectal Surgeons recommends management of chronic anal fissures by “subcutaneous or open lateral internal sphincterotomy, posterior internal sphincterotomy with advanced flap, or manual dilatation”. Healing occurs following sphincterotomy in 95% of cases. Successful sphincterotomy (or anal dilatation) is associated with a significant decrease in intra-anal pressure. However, a number of patients experience incontinence following the surgical procedure.
A known moderator of sphincter tone is nitric oxide (NO). Nitric oxide has been shown to bring about a concentration-dependent reduction in the resting tension of internal sphincter smooth muscle strips in vitro (Rattan et al.,
Am. J Physiol
. 262:G107-112 (1992)), and NO donors, e.g. nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, reduce anal pressure in man. NO has also been shown to mediate adaptive relaxation of other sphincters in the gastrointestinal tract including the lower esophageal sphincter (Conklin et al.,
Gastroenterology
104:1439-1444 (1993); Tottrup et al.,
Br. J Pharmacol
. 104:113-116 (1991)), pyloric sphincter (Bayguinov et al.,
Am. J Physiol
. 264:G975-983 (1993), sphincter of Oddi (Mourelle et al.,
Gastroenterology
105:1299-1305 (1993)), and the ileocolic sphincter (Ward et al.,
Br. J. Pharmacol
. 105:776-782 (1992)). It is thought that NO or NO-like substances serve as important control mechanisms for the general phenomenon of gastrointestinal adaptive relaxation.
U.S. Pat. Nos. 5,504,117 and 5,693,676 describes the use of NO donors for the treatment of anorectal conditions. 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.
There is clearly a significant need for other non-surgical treatments of anorectal disorders, including, for example, anal fissures and other anorectal conditions caused by anal sphincter spasm and or hypertonicity, including acute hemorrhoidal diseases and proctalgia fugax.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides compositions for the treatment of anorectal disorders comprising a nitric oxide donor in combination with a second agent (typically one which modulates levels of cAMP or cGMP). The second agent can be a phosphodiesterase type V (PDE V) inhibitor. a phosphodiesterase type II (PDE II) inhibitor, a phosphodiesterase type IV (PDE IV) inhibitor, a nonspecific PDE inhibitor, a &bgr;-adrenergic agonist, a cAMP-dependent protein kinase activator, an estrogen or estogen-like compound, or an &agr;
1
-adrenergic antagonist. The agent can also be a superoxide anion (O
2
−
) scavenger, an ATP-sensitive K
+
channel activator, or a smooth muscle relaxant, although these agents do not directly modulate either cAMP or cGMP levels. The present invention further provides methods of using these compositions.
In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising a
Lee Charles
Lee Jung-Chung
Mak Vivien
Parks Thomas P.
Cellegy Pharmaceuticals Inc.
Jarvis William R. A.
Kim Vickie
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