Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-30
2003-09-30
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S509000
Reexamination Certificate
active
06627632
ABSTRACT:
REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER
PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK.
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 (for example, the internal anal canal) of a subject 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 which mimic 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. 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.
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 spasm 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.
Hemorrhoids are the most prevalent anorectal disorder and are the most common cause of hematochezia (i.e., passage of bloody stools). Hemorrhoidal disease is the consequence of distal displacement of the anal cushions, which normally play an important role in continence. The causes of hemorrhoids are not known. The most consistently demonstrated physiological abnormality is increased resting anal pressure (Hancock B. D.,
Br J Surg
64(2):92-5 (1975); Loder, P. B.,
Br J Surg
81(7):946-54 (1994)). Patients with non-prolapsing hemorrhoids appear to have higher anal pressures than those with prolapsing hemorrhoids (Arabi, Y. et al.,
Am J Surg
134(5):608-10 (1977); Sun, W. M. et al.,
Br J Surg
77(4): 458-62, (1990)), although the therapeutic implications of this observation remain unclear. Treatment is dependent on the degree of hemorrhoid prolapse and symptoms. Most cases (first- and second-degree hemorrhoids) generally respond to conservative medical treatment (e.g., dietary changes, sitz baths) or non-surgical procedures (e.g., rubber band ligation). Acutely thrombosed external hemorrhoids are usually characterized by severe anal pain, and internal anal sphincter hypertonia may play a role in the etiology of this pain (Gorfine, S. R.,
Dis Colon Rectum
38(5): 453-7 (1995)). Surgical excision of symptomatic thrombosed external hemorrhoids is indicated within 48 to 72 hours of the onset of 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. Anal dilatation and lateral internal sphincterotomy as treatments to reduce anal sphincter pressure in hemorrhoids have been used successfully, both as stand alone procedures and in conjunction with hemorrhoidectomy (Keighley, M. R. et al.,
Br Med J
J2(6196):967-9 (1979); Schouten W. R. et al.,
Dis Colon Rectum
28(12), 869-72 (1986); Galizia et al.,
Eur J Surg
166(3):223-8 (2000)).
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.
83(3):380-2 (1996)).
Anal fissure is one of the most common causes of anorectal pain. Anal fissures are tears in the mucosa of the distal anal canal, usually along the posterior midline. The exact causes of anal fissures remain unknown. They are often associated with trauma, e.g., passage of a hard stool, but can also occur during bouts of diarrhea, childbirth, or ulceration of a hemorrhoid (Lund, J. N. et al.,
Br J Surg.
83(10): 1335-44 (1996)). The most common symptom is pain at defecation, which can be quite severe and last for a variable time afterwards. The pain is chiefly due to an intense spasm of the internal anal sphincter muscle. Most anal fissures are adequately treated with sitz baths, stool softeners, and analgesics. Approximately 60% of acute anal fissures will heal within three weeks using this treatment regimen. Acute anal fissures, which do not heal, become chronic anal fissures or anal ulcers. Hypertonicity of the internal anal sphincter muscle and mucosal ischemia are thought to play an important role in the pathogenesis of chronic anal fissures (Schouten W. R. et al.,
Dis Colon Rectum
37(7):664-9 (1994); Lund, J. N. et al.,
Br J Surg
83(10): 1335-44 (1996)). Anodermal blood flow at the posterior midline is less than other regions of the anal canal, and perfusion of the posterior mucosa is inversely related to anal pressure. Chronic anal fissures are typically not responsive to conservative medical therapy. Current treatments are therefore directed at relieving sphincter spasm, and include anal dilatation (under anesthesia), or more commonly, lateral sphincterotomy of the internal anal sphincter. Healing occurs following surgical sphincterotomy in 95% of cases. Successful sphincterotomy (or anal dilatation) is associated with a significant decrease in intra-anal pressure and increase in anodermal blood flow (Lund, J. N. et al.,
Br J Surg
83(10): 1335-44, (1996); Schouten W. R. et al.,
Scan J Gastroenterol. Suppl
218: 78-81 (1996)). However, up to 35% of patients may experience some form of incontinence following the surgical procedure (Sharp, F. R.,
Am J Surg
171(5):512-5 (1996)). Incontinence of stool and flatulence is a humiliating disability with numerous social, medical, and financial implications. There is clearly a large unmet medical need to develop effective, non-surgical treatments for anal fissure and other colorectal conditions, including acute hemorrhoidal disease, hemorrhoidectomy pain, proctalgia fugax, and severe constipation. Considerable recent progress has been made in the understanding of anorectal physiology and pharmacology. These new insights provide important implications and opportunities for the pharmacological management of colorectal disorders.
Sphincters are circular groups of smooth muscle that control the orifices of hollow organs. They are present throughout the gastrointestinal tract and control the passage of materials through this system of the body. When constricted, sphincters close orifices leading to or from the hollow orga
Lee Charles
Lee Jung-Chung
Mak Vivien
Parks Thomas P.
Cellegy Pharmaceuticals Inc.
Henley III Raymond
Kim Vickie
LandOfFree
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