Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-15
2002-10-01
Henley, Ray (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S316000, C514S646000, C514S663000, C514S667000, C514S668000
Reexamination Certificate
active
06458795
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to pharmaceutical compositions and methods for the treatment of irritable bowel disease (IBD) [also termed: irritable bowel syndrome (IBS)]; more particularly for the treatment of diarrhea-predominant IBD.
2. Description of the Prior Art
Irritable bowel syndrome (IBS), a chronic or recurring gastrointestinal disorder, afflicts as many as 24% of women and 19% of men in the U.S., Europe, Japan, and China. IBS produces abdominal pain or discomfort in its victims and accounts for about one-eighth of primary care and more than one-fourth of gastroenterology practice. IBS has tremendous societal and economic impact since persons with IBS symptoms miss three times as many work days as those without and incur 70% higher health care costs. The American Gastroenterological Association has recently underscored the importance of IBS by issuing both a position statement (American Gastroenterological Association (AGA) Medical Position Statement: Irritable Bowel Syndrome. Gastroenterology 112:2118-2119 (1997)) and a technical review (Drossman D A, Whitehead W E, Camilleri M., “Irritable bowel syndrome: a technical review for practice guideline development”, Gastroenterology 112:2120-2137 (1997)) on IBS. The description herein of IBS is based chiefly on these documents and on other current literature (such as that reviewed in Snape W J Jr., “Irritable bowel syndrome”, In: Bockus Gastroenterology, 5th edition (W. S. Haubrich, F. Schoffner, ed.) Philadelphia: W. B. Saunders, pp. 1619-1636 (1995)).
IBS presents itself as abdominal pain accompanied by altered bowel habits. There is no established biological marker for IBS, which appears to result from faulty regulation in both the gastrointestinal and nervous systems. Once clinicians rule out other possible causes of IBS symptoms, they must devise a treatment plan based upon the severity and nature of the symptoms as well as other factors such as the degree of impairment the individual is experiencing in the activities of daily living. At present, treatment options range from education and dietary modification to drug therapy to psychological therapy. Drug and/or psychological therapy is called for in those 30% of IBS patients with moderate or severe symptoms. Given an IBS prevalence of 19% to 24%, IBS sufferers requiring such therapy represent 6-7% of the population at large, or well over 100 million individuals in continual need of such therapy in the U.S., Europe, Japan, and China.
While the symptoms of IBS have a physiological basis, no physiological mechanism unique to IBS has been identified. Rather, the same mechanisms that cause occasional abdominal discomfort in healthy individuals operate to produce the symptoms of IBS. The symptoms of IBS are therefore a product of quantitative differences in the motor reactivity of the intestinal tract, and increased sensitivity to stimuli or spontaneous contractions.
Due to a lack of readily identifiable structural or biochemical abnormalities in this syndrome, the medical community has developed a consensus definition and criteria, known as the Rome criteria, to aid in diagnosis of IBS. According. to the Rome criteria, IBS is indicated by abdominal pain or discomfort which is (1) relieved by defecation and/or (2) associated with a change in frequency or consistency of stools, plus two or more of the following: altered stool frequency, altered stool form, altered stool passage, passage of mucus, and bloating or feeling of abdominal distention (Dalton, C. and Drossman, D. A., Am Fam Physician 1997 55(3):875-880). Thus, a hallmark of IBS is abdominal pain that is relieved by defecation, and which is associated with a change in the consistency or frequency of stools. IBS may be diarrhea-predominant, constipation-predominant, or an alternating combination of both.
Persons with IBS exhibit hypersensitivity, particularly hyperalgesia, in response to painful distensions in the small bowel and colon and to normal intestinal function. Furthermore, there are also increased or unusual areas of visceral pain. The abdominal pain is often poorly localized, and may be migratory and/or variable in nature. The pain may be worsened by meals and reduced upon defecation. Furthermore, IBS symptoms, including hyperalgesia, are commonly initiated or exacerbated by stress (Dalton, C. and Drossman, D. A., Am Fam Physician 1997 55(3):875-880).
Women apparently are more often affected than men, and the prevalence of irritable bowel syndrome is lower among the elderly (Camilleri, M. and Choi, M.-G., Aliment Pharmacol Ther 1997 11(1):3-15). It also seems clear that psychological factors, either stress or overt psychological disease, modulate and exacerbate the physiological mechanisms that operate in IBS (Drossman, D. A. et al., Gastroenterology 1988 95:701-708; Gaynes B N, Drossman D A: The role of psychosocial factors in irritable bowel syndrome. Baillieres Best Prac Res Clin Gastroenterol 13:437-452, 1999; Jones J, Boorman J, Cann P, Forbes A, Gomborone J, Heaton K, Hungin P, Kumar D, Libby G, Spiller R, Read N, Silk D, Whorwell P: British society of gastroenterology guidelines for the management of the irritable bowel syndrome. Gut 47:ii 1-ii 19, 2000). Some studies suggest that only about 10% to 50% of those afflicted with IBS actually seek medical attention. Nonetheless, IBS still accounts for up to about 3.5 million physician visits per year, and is the most common diagnosis in gastroenterologists' practice, accounting for about 25% of all patients (Camilleri and Choi, 1997). In a study published in 1993, persons afflicted with IBS were found to have more frequent doctor visits, a lower quality of life, and to miss three times as many days from work as those with no bowel symptoms (Drossman, D. A., Dig Dis Sci 1993 38:1569-1580). As a consequence, persons with IBS incur higher health care costs than those without IBS (Talley, N. J. et al., Gastroenterology 1995 109:1736-1741).
The AGA position statement recommends antispasmodic (anticholinergic) medication for IBS pain and bloating, or a tricyclic antidepressant or serotonin-selective reuptake inhibitor if the pain is severe. Dietary fiber is recommended (cisapride is also mentioned) for IBS constipation, whereas loperamide is recommended for diarrhea. For treatment of IBS patients presented with predominant diarrhea, the bile acid sequestrant “cholestyramine may be considered for a subgroup of patients with cholecystectomy or who may have idiopathic bile acid malabsorption.” Clearly, there is no single pharmacologic treatment appropriate to all IBS sufferers. However, it is equally clear that it is acceptable clinical practice to employ a bile acid sequestrant to treat diarrhea associated with IBS.
The technical review issued by the AGA states that treatment with the bile acid sequestrant “cholestyramine should be considered in patients with IBS who have predominant diarrhea.” Cholestyramine, a copolymer of styrene and divinylbenzene possessing trimethylbenzylammonium groups, has a somewhat limited capacity to bind bile acids, so very large quantities (as much as 20 grams per day) must be ingested in order to alleviate symptoms.
There is presently no effective treatment for irritable bowel syndrome (K. B. Klein, Controlled treatment trials in the irritable bowel syndrome: a critique, Gastroenterology 95: 232-241, 1988). Although largely ineffective, current treatment is multifactorial and consists of stress management, diet, and drugs, in that order. The patient is reassured that the disease is not life threatening and is advised to reduce or eliminate any controllable stress in his or her life. Relaxation exercises and biofeedback may be attempted to alter the psychogenic components of the illness. With respect to diet, the patient is advised to avoid any food to which he or she possesses a known sensitivity with respect to exacerbating the problem. A high fiber diet, either insoluble wheat bran or soluble psyllium, is almost routinely recommended, but with little if any
Clarke Dennis P.
Henley Ray
Miles & Stockbridge
University of Florida
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