Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-09-08
2003-08-26
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000, C514S181000
Reexamination Certificate
active
06610674
ABSTRACT:
TECHNICAL FIELD
This invention provides methods for treating inflammatory conditions, including but not limited to, inflammatory bowel disease (ulcerative colitis, Crohn's disease, and proctitis), other noninfectious, inflammatory conditions of the GI tract (microscopic colitis, allergic eosinophilic gastroenteritis, food allergies, pill induced esophagitis, celiac disease, recurrent polyps, and hemorrhoids), and psoriasis using progesterone and progesterone analogs.
BACKGROUND OF THE INVENTION
Inflammatory Bowel Disease
“Inflammatory bowel disease” (IBD) encompasses the idiopathic, chronic inflammatory bowel diseases ulcerative colitis (UC), Crohn's disease (CD), and proctitis. Researchers do not know the cause of these diseases, but believe that they involve genetic and immunologic influences on the gastrointestinal tract's ability to distinguish foreign from self-antigens and/or to alter the mucosal immune response. They share many overlapping epidemiological, clinical, and therapeutic features. IBD affects up to 1,000,000 Americans and disease symptoms can be so severe as to prevent the patient from carrying on a normal life. The total cost of the disease, including lost productivity, in the US is two billion dollars per year. Ward et al., Clinical economics review: medical management of inflammatory bowel disease,
Ailment Pharmacol Ther
13:15-25 (1999). Drug therapies that allow patients to avoid surgical intervention could reduce the cost significantly.
IBD (UC, CD, and proctitis) is different from spastic colon or irritable bowel syndrome, which is a motility disorder of the gastrointestinal tract. UC is characterized by a diffuse, continuous, superficial, ulcerative inflammation of the colon, not due to any known single cause. The inflammation often begins within the rectum and extends proximally into the bowel. UC affects the inner mucosal layer of the colon (lamina propria) in a continuous manner, with no portions of healthy tissues between the diseased areas. Additionally, it affects only the colon, not other areas of the gastrointestinal (GI) tract, except in rare instances. UC may be accompanied by bloody diarrhea, constipation, very frequent bowel movements (often 15 to 20 per day), explosive diarrhea, rectal incontinence, pus, mucus, gas, fever, tachycardia, weakness, and anemia. UC creates striking changes in the mucosa and submucosa of the colon and rectum. The disease causes diffuse severe ulceration, inflammation, and congestion of the lining of the colon and rectum. More severe disease states include thinning of the bowel, susceptibility to ulcers, fibrosis, contraction, and narrowing of the intestinal lumen.
CD is characterized by focal, asymmetric, transmural inflammation affecting any portion of the gastrointestinal tract from the mouth to the anus. The ileum and right colon are, however, most often involved. CD affects all layers of the intestine, but there can be patches of normal bowel in between the diseased regions. Depending on where in the bowel the disease manifests itself, CD can cause nausea vomiting, epigastric pain, diarrhea, cramping abdominal pain, rectal bleeding, loss of appetite, fever, night sweats, malaise, arthralgias, and weight loss.
Proctitis, inflammation of the rectum, is invariably present in UC and is sometimes present in CD. It may also occur independently from these diseases. Proctitis is another manifestation of IBD with pathology similar to UC. A patient presenting with proctitis may later develop full-blown UC or CD.
Physicians and medical researchers have not been successful in identifying a cause for these diseases, although several theories have been postulated. The diseases may be caused by a pathogen or other antigen that initiates the inflammatory response in the bowel, accompanied by a defect in the ability to down-regulate the immune response. Once initiated, many of the pathophysiological events in IBD are related to amplification of the inflammatory process. In response to antigens, cytokines and other inflammatory mediators are released. Some cytokines promote T cell activity. The inflammatory cascade continues with IL-2, helper T cells, B-cell proliferation, and antibody synthesis. Stimulated neutrophils and macrophages accumulate and further damage the tissue by releasing reactive oxygen species and other biologically active products. Additional acute inflammatory cells respond to the tissue damage, whether or not the primary initiating stimulus has ceased.
Other research on IBD suggests that abnormalities in the immune system, nonimmune cells in the intestinal mucosa, genetic risk determinants, and random environmental factors may all be necessary to induce IBD. Papadakis et al., Current Theories on the Causes of Inflammatory Bowel Disease,
Gastroenterol Clin North Am
28:283-296 (1999). Researchers have also postulated that tumor necrosis factor-&agr; (TNF-&agr;), a proinflammatory cytokine, may play an important role in the pathogenesis of inflammatory bowel disease. Sanborn et al, Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety,
Inflamm Bowel Dis
5:119-33 (1999). The uncertainty about the cause of IBD has lead to confusion about the appropriate treatment strategy.
Currently, no treatment exists that will cure or effectively manage both forms of inflammatory bowel disease. Present treatments include aminosalicylates (sulfasalazine, mesalamine), glucocorticoids (hydrocortisone, prednisone), antibiotics (to reduce secondary infection), immunosuppressants (6-mercaptopurine, cyclosporine), belladonna, atropine, and phenobarbital. Immunosuppressants (6-mercaptopurine, azathioprine, FK-506/tacrolimus) and neuroimmunomodulation agents (somatostatin, substance P, local anesthetics) have also been used as therapy for IBD. Prevention of adhesion and recruitment has been suggested by using antisense oligonucleotides to ICAM-1. Other miscellaneous therapies that have been suggested include arachidonic acid metabolites, anti-free radicals, short-chain fatty acids, nicotine, bismuth, ketotifen, heparin, interferon-&agr;, chloroquinone/hydroxychloroquine, hyperbaric oxygen, IV immunoglobulin, and leukapheresis. Sands, Novel Therapies for Inflammatory Bowel Disease,
Inflammatory Bowel Disease
28:323-351 (1999).
Infliximab, an anti-TNF-&agr; antibody, has recently been developed as a treatment for Crohn's disease, because overproduction of TNF-&agr; leads to inflammation. Biological activities attributed to TNF-&agr; include induction of pro-inflammatory cytokines such as IL-1 and IL-6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, and activation of neutrophil and eosinophil functional activity. REMICADE™ (Infliximab) Prescribing Information.
Additional medical management strategies include psychotherapy, diet control, fluid and electrolytes. A significant number of patients must resort to surgical removal of the affected portion of the bowel. None of the known therapies provide successful long term treatment for all patients, and many of the therapies have serious side effects. For example, patients treated with steroid drugs, such as glucocorticoids, can develop diabetes, hypertension, psychological changes, Cushings syndrome, changes in protein metabolism, osteoporosis, cataracts, avascular hip necrosis, and infection. Patients taking immunosuppressants run serious risk of infection and may have an increased incidence of cancer.
Other Noninfectious, Inflammatory Conditions of the GI Tract
Improved treatments are also needed for other noninfectious, inflammatory conditions of the GI tract, including but not limited to microscopic colitis, allergic eosinophilic gastroenteritis, food allergies, pill induced esophagitis, celiac disease, recurrent polyps, and hemorrhoids.
Microscopic colitis is another form of colitis, where only microscopic changes are seen in the GI tract tissue. No gross clinical manifestation
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Jiang S.
Padmanabhan Sreeni
University of Pennsylvania
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