Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-09-19
2002-05-14
Carr, Deborah D. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C554S227000
Reexamination Certificate
active
06387952
ABSTRACT:
TECHNICAL FIELD
The present invention is directed to treating gastrointestinal disorders, including inflammatory bowel disease, particularly colitis, and to methods of increasing the short chain fatty acid content of the colon.
BACKGROUND ART
It is now well recognized that short chain fatty acids (SCFA), particularly those having from 1 to 4 carbon atoms are implicated in the treatment of numerous diseases and/or conditions of the gastrointestinal tract, particularly the colon. It is universally accepted that SCFA are a major energy source for the colon and other related tissues.
SCFA are liberated on the bodies of mammals predominately through the anaerobic fermentation of undigested carbohydrates in the colon. Of the SCFA, acetic acid, propionic acid, and butyric acid account for 90-95% of SCFA in the colon. Kim, Young-In, “Short-Chain Fatty Acids in Ulcerative Colitis”,
NUTRITION REVIEWS,
Vol. 56, 1, pp. 17-24. The ratio of acetic (“acetate”) to propionic (“propionate”) to butyric (“butyrate”) acids is about 1:0.31:0.15, and the proportions vary with the substrate (largely roughage), composition of anaerobic flora, and pH. However, the fermentation products are remarkably similar in the human colon, the large cecum of herbivores, and bovine rumen. Soergel, K. H., “Colonic Fermentation: Metabolic and Clinical Implications”,
CLIN INVESTIG
72, 742-48 (1994). Deficiencies in SCFA have been associated with inflamed colonic mucosa, Sheppach, W., et al., “Effects of Short-Chain Fatty Acids on the Inflamed Colonic Mucosa”,
SCAND. J. GASTROENTEROL,
Suppl. 222, pp. 53-57 (1997) and ulcerative colitis, W. Sheppach, “Short-Chain Fatty Acids Improve Epithelia in Ulcerative Colitis? Speculation or Mechanism”, Falk Symp. (1994), 73 (Short Chain Fatty Acids), pp. 206-213; diversion colitis, Soergel, op. cit.; and other disorders.
Studies have shown that increasing SCFA levels brings about therapeutically significant improvements in areas such as prevention of Colorectal Cancer, W. Sheppach, et al. “Role of Short-Chain Fatty Acids in the Prevention of Colorectal Cancer”,
EUR J. CANCER,
Vol. 31A, No. 7/8, pp. 1077-80, 1995; treatment of colitis, W. Sheppach, “Effects of Short Chain Fatty Acids on Gut Morphology and Function”,
GUT
1994, Supplement 1, pp. 35-38; ulcerative colitis, Jorgersen, J. R., et al., “Influence of Feces from Patients with Ulcerative Colitis on Butyrate Oxidation in Rat Colonocytes”,
DIGESTIVE DISEASES AND SCIENCES,
Vol. 44, 10 pp. 2099-2109 (1999), Kim, op. cit., Sheppach, Falk Symp. (1994), 73 (Short Chain Fatty Acids), op. cit. (pp. 206-213); and diversion colitis Soergel, op. cit. In addition, SCFA's are implicated in immune system response, Perez, R., et al. “Selective Targeting of Kupffer Cells with Liposomal Butyrate Augments Portal Venous Transfusion-Induced Immunosuppression”,
TRANSPLANTATION,
Vol. 65, 10, p. 1294-98, 1998; Perez, R., et al. “Sodium Butyrate Upregulates Kupffer Cell PGE
2
Production and Modulates Immune Function”,
J. SURGICAL RES.,
78 pp. 1-6 (1998); apoptosis in hepatic tumors, Watkins, S. M., et al.; “Butyric Acid and Tributyrin Induce Apoptosis in Human Hepatic Tumor Cells”, J. Dairy Res., 66, pp. 559-67 (1999); and in inhibiting fluid loss in chloera-infected mammals, Rabboni, G. H., et al., “Short-Chain Fatty Acids Inhibit Fluid and Electrolyte Loss Inducted by Cholera Toxin in Proximal Colon of Rabbit In Vitro”,
DIGESTIVE DISEASES AND SCI.,
Vol. 44, 8, pp. 1547-53 (1999).
In most studies reported above, SCFA were administered in the form of their soluble salts, i.e., alkali metal acetates, propionates, and butyrates. The “ate” salt suffix has been used rather uniformly in the medical literature to refer to both the salt and free acid forms of the SCFA, unless indicated to the contrary.
Administration of SCFA, notably butyrate, both in oral form and as an enema or suppository, has been found to affect a variety of disorders, as indicated above. However, butyric acid and its salts are notoriously odorous, so much so that patients often discontinue treatment because of the foul odors involved. In U.S. Pat. No. 5,569,680, administration of glycerine tris(butyrate ester), known as tributyrin, is said to improve patient compliance through use of a less odiferous substance. However, tributyrin is still somewhat odiferous, perhaps due to incomplete esterification, or due to partial hydrolysis liberating butyric acid. Thus, the administrative problems of butyrate, while ameliorated by tributyrin, are not completely solved by its use. Moreover, as indicated by Smith, J. G., et al. “Butyric Acid from the Diet: Actions at the Level of Gene Expression”,
CRIT. REV. IN FOOD SCI.,
Vol. 38, 4, pp. 259-97 (1998), the effects of butyrate derivatives such as arginine butyrate, butyramide, monobutyrin, and tributyrin are not the same, and thus additional butyrate-releasing compounds are desired.
DISCLOSURE OF INVENTION
The present invention pertains to a method of increasing the short chain fatty acid (SCFA) content of the gastrointestinal tract, in particular the colon. The present invention also pertains to a method for treating various gastrointestinal disorders by supplying a substantially odor-free compound which can be absorbed and/or metabolized in situ in the gastrointestinal tract to liberate SCFA, and to compounds suitable for use therein.
REFERENCES:
patent: 4861613 (1989-08-01), White et al.
patent: 4983329 (1991-01-01), Cooper
patent: 5175323 (1992-12-01), Cooper
patent: 5569680 (1996-10-01), Wu
patent: 5986117 (1999-11-01), Cooper
W. Scheppach, H.P. Bartram and F. Richter, “Role of Short-chain Fatty Acids in the Prevention of Colorectal Cancer”, Eur J. Cancer, vol. 31A, No. 7/8, pp. 1077-1080, 1995.
W. Scheppach, S.U. Christl, H.-P. Bartram, F. Richter & H. Kasper, “Effects of Short-Chain Fatty Acids on the Inflamed Colonic Mucosa”, Scand. J. Gastroenterol, Suppl. 222, pp. 53-57 (1997).
J.R. Jorgensen and P.B. Mortensen, “Influence of Feces from Patients with Ulcerative Colitis on Butyrate Oxidation in Rat Colonocytes”, Digestive Diseases and Sciences, vol. 44, 10 pp. 2099-2109 (1999).
Richard V. Perez et al., “Selective Targeting of Kupffer Cells With Liposomal Butyrate Augments Portal Venous Transfusino-Induced Immunosuppression1,2, Transplantation”, vol.. 65, 10, p. 1294-1298, 1998.
Richard Perez et al., “Sodium Butyrate Upregulates Kupffer Cell PGE2Production and Modulates Immune Function1”, J. Surgical Res., 78 pp. 1-6 (1998).
Steven M. Watkins et al., “Butyric acid and tributyrin induce apoptosis in human hepatic tumour cells”, J. Dairy Res., 66 pp. 559-567 (1999).
G.H. Rabbani et al., “Short-Chain Fatty Acids Inhibit Fluid and Electrolyte Loss Induced by Cholera Toxin in Proximal Colon of Rabbit In Vivo”, Digestive Diseases and Sci., vol. 44, 8, pp. 1547-1553 (1999).
Janet G. Smith et al., “Butyric Acid from the Diet: Actions at the Level of Gene Expression”, Crit. Rev. in Food Sci., vol. 38, 4, pp. 259-297 (1998).
Young-In Kim, “Short-Chain Fatty Acids In Ulcerative Colitis”, Nutrition Reviews, vol. 56, 1, pp. 17-24,1998.
K.H. Soergel, “Colonic fermentation: metabolic and clinical implications”, CLN Investig 72, 742-48 (1994).
W. Scheppach, “Effects of short chain fatty acids on gut morphology and function”, GUT 1994, Supplement 1, pp. 35-38.
Harkins Robert W.
Mazurek Harry
ARCO Chemical Technology L.P.
Brooks & Kushman P.C.
Carr Deborah D.
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