Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1998-11-12
2001-05-15
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S489000, C424S468000, C424S497000, C424S486000, C424S450000, C424S463000, C424S473000
Reexamination Certificate
active
06231888
ABSTRACT:
FIELD OF THE INVENTION
The invention is in the field of polyp and colon cancer chemoprevention and chemotherapy.
BACKGROUND OF THE INVENTION
Colorectal Polyps: The Disease, Diagnosis and Treatment
A colorectal polyp is a circumscribed mass of tissue that projects above the surface of the bowel mucosa. It is classified as pedunculated or sessile, depending on whether it contains a discrete stalk. While most small polyps are asymptomatic lesions detected only by screening or diagnostic studies, larger polyps, greater than 10 mm, may ulcerate and cause intestinal bleeding, as well as have malignant potential.
Colorectal polyps are extremely common in adults in Western countries, they are found in more than 30% of autopsies conducted on people greater than 60 years of age (Correa P.,
Gastroenterology
77:1245-1251 (1979)). The colonic polyp has been implicated as a precursor in the development of colorectal cancer (Morson B. C.,
Cancer
34:845-850 (1974)). Current data suggest a polyp to cancer sequence, with colorectal neoplasmic changes as a continuous process from normal mucosa, to adenoma, and then to carcinoma (Schottenfeld, D. & Winawer, S. J.,
Cancer: Epidemiology and Prevention
, Philadelphia, W. B. Saunders, 703-727 (1982)).
Histologically, polyps are classified as neoplastic, i.e., adenomas, with malignant potential or as non-neoplastic, known as benign adenomas (Fenoglio, C. M. & Pascal, R. R.,
Cancer
50:2601-2608 (1982)). Approximately 70% of polyps removed at colonoscopy are adenomas, (Konishi, F. & Morson, B. C.,
J. Clin. Pathol
. 35:830-841 (1982)) with the potential to become larger than 10 mm, and therefore, having the probability of becoming tumorigenic. It is, therefore, of great importance to identify colonic polyps and to treat them before they can become malignant.
Most commonly, polyps are described as sporadic, arising spontaneously in about a quarter of the population by age 50, with the prevalence increasing with age, and which may or may not result in colorectal cancer (Winawer, S. J., et al.,
Gatstroenterology
112:594-642 (1997)). Familial adenomatous polyposis (FAP), on the other hand, is an autosomal dominant, inherited disorder, characterized by the presence of hundreds of adenomatous polyps in young adults and in the eventual development of colorectal cancer (Schussheim, A., et al.,
Gastroenterol. Nutr
. 17:445-448 (1993)).
Colonoscopy is considered the best method for detecting polyps accurately, especially those measuring less than 10 mm in diameter (Rex, D. K., et al.,
Gastroenterology
112:17-23 (1997)). Most polyps found during colonoscopy can be completely and safely removed by electrocautery (fulguration) (Knutson, C. D. & Max, M. H.,
Arch Surg
114:30-435 (1979)). Some complications, however, may develop during colonoscopy, most commonly perforation and bleeding, occurring in 0.1 to 0.2% of patients (Rankin, G. B.,
Gastrointestinal Endoscopy
, Philadelphia, W. B. Saunders, 875-878 (1987)). In addition, it is not always possible to detect all polyps using colonoscopy because of the anatomy of the colon. In fact, in a recent study, it was shown that a carefully performed complete colonoscopy by an experienced examiner will miss an average of about 24% of polyps that are less than 10 mm in diameter (Rex, D. K., et al.,
Gastroenterology
112:24-28 (1997)).
Non-Steroidal Anti-Inflammatory Drugs and Colorectal Polyps
To overcome the current technical limitations of colonoscopy, and to avoid the need for surgical procedures, extensive research has been focused during the past decade on finding pharmacologic agents that might be used to treat or prevent colorectal polyps. Especially, the effect of non-steroidal inflammatory drugs (NSAIDs) on colorectal polyps has become of interest.
Epidemiological studies have shown that chronic aspirin use is associated with a 50-70 percent reduction in the incidence of colorectal cancer (Logan, R. F. A., et al.,
Br. Med. J
. 307:285-289 (1993); Rosenberg, L., et al.,
J. Natl. Cancer Inst
. 83:355-358 (1991); Thun, M. J., et al.,
New Engl. J. Med
. 325:1593-1596 (1991); Suh, O., et al.,
Cancer
72:11171-1177(1993); Peleg II et al.,
Arch. Intern. Med
. 154:394-399 (1994)). In addition, multiple animal studies have documented a chemoprotective effect of selected NSAIDs as judged by a reduction in the frequency and number of premalignant and malignant lesions (Reddy, B. S., et al.,
Cancer Res
. 50:2562-2568 (1990); Reddy, B. S., et al.,
Carcinogenesis
14:1493-1497 (1993); Rao, C. V., et al.,
Cancer Res
. 51:4528-4534 (1991); Craven, P. A., & DeRuberis, F. R.,
Carcinogenesis
14:541-546 (1992); Northway, M. G., et al.,
Cancer
66:2300-2305 (1990); Moorghen, M., et al.,
J. Pathol
156:341-347 (1988); Reddy, B. S., et al.,
Cancer Res
. 47:5340-5346 (1987); Reddy, B. S., et al.,
Carcinogenesis
13:1019-1023 (1992); Skinner, S. A., et al.,
Arch. Surg
. 126:1094-1096 (1991)). In a recent case study of a patient with villous adenomas of the cecum, who refused surgical resection, a course of NSAID therapy, using piroxicam, 30 mg weekly, showed dramatic and sustained regression of the premalignant adenomas for up to 20 months (Gowen, G. F.,
Dis. Colon Rectum
39:101-102 (1996)). In clinical studies of familial adenomatous polyposis, using the NSAID, sulindac, at a daily dose of 300 mg, taken systemically, it was shown that the number and size of colonic polyps was significantly decreased (Giardelio, F. M., et al.,
New Engl. J. Med
. 328:1313-1316 (1993); Labaylle, D., et al.,
Gastroenterology
101:635-639 (1991); Waddell, W. R., et al.,
Am. J. Surg
. 157:175-179 (1989)). In a small pilot study, in which sulindac or piroxicam was used against sporadic colonic polyps, however, there was no similar regression of adenomatous polyps (Ladenheim, J., et al.,
Gastroenterology
108:1083-1087 (1995); Hixson, L. J., et al.,
Am. J. Gastroenterol
88:1652-1656 (1993)). These results, however, were disputed in a more recent multicenter study of nearly 100 patients, with sporadic polyps of 4-12 mm. When sulindac, 300 mg daily, or sulindac, 150 mg daily, or placebo, were given for one year, it was demonstrated that sulindac, regardless of dose, induced regressions and prevented the progression of sporadic colorectal adenomas (DiSario, J. A., et al.,
Gastroenterology
112 (Suppl):555A (1997)).
NSAIDs and Apoptosis
The precise mechanism responsible for the anti-neoplastic effect of NSAIDs is unknown. A number of recent publications have suggested that NSAIDs may be accomplishing these chemoprotective effects by induction of apoptosis, the “programmed cell death” phenomenon (Savill, J.,
Eur. J. Clin. Invest
. 24:715-723 (1994); Thompson, C. B.,
Science
267:1456-1462 (1995); Bright, J. and Khar, A.,
Biosci Rep
. 14:67-81 (1994)). In 1965, Lockshin and colleagues introduced the concept of “programmed cell death” to describe the phenomenon that had long been observed in embryogenesis where certain predetermined cells in the embryo would die at a particular stage during development (Lockshin, R. A. and Williams, C. M.
J. Insect Physiol
. 11:123-133 (1965)). In 1972, Kerr et al., linked this concept with a mode of cell death, defined on strict morphological criteria such as the detachment of a cell from its substratum, coupled by the fragmentation of the nucleus and cytoplasm, in a process which, they termed “apoptosis.” (Kerr, J. F. R., et al.,
Br. J Cancer
26:239-257 (1972)). This active cell death, under tight genetic control, is found in all tissues, and is responsible both for regulating cell number and type, as well as for disposing cells with damaged or mutant DNA. Defects in apoptosis, however, can lead to cancer, autoimmune disease and neurodegeneration (Pritchard, D. and Watson, A. J. M.,
Pharmacol Ther
. 72:149-169 (1996)).
Defective apoptosis has been implicated in the pathogenesis of colorectal cancer. In 1995, Bedi et al. quantified the amount of apoptosis in frozen sections of biopsies of colorectal epithelium from normal mucosa, adenomas from patients with familial adenomatous polyposis, sp
Flashner Moshe
Lerner E. Itzhak
Penhasi Adel
Fubara Blessing
Graeser D 'Vorah
Page Thurman K.
Perio Products Ltd.
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