Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-12-18
2001-05-08
Moezie, M. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S021800
Reexamination Certificate
active
06228839
ABSTRACT:
BACKGROUND OF THE INVENTION
Growth of the gastrointestinal mucosa is markedly influenced by nutritional status and enteral nutrient availability. This is evidenced by the disproportionate loss of gut mucosal mass relative to body weight during starvation and other states of malnutrition [Steiner et al. (1968)
Am. J. Physiol.
215:75-77; Ziegler et al. (1995)
Endocrinology
136:5148-5154]. Fasting or severe protein-calorie restriction result in mucosal cell atrophy, decreased digestive enzyme activity and absorptive capacity, and impaired intestinal barrier function [Ziegler, T. R. (1996) Springer-Verlag, New York, pp. 25-52; Hagemann and Stragand (1977)
Cell Tiss. Kinet.
10:3-14]. Malnutrition is also associated with reduced antioxidant capacity in the intestinal mucosa [Ogasawara et al. (1989)
Res. Exp. Med.
189:195-204]. Enteral refeeding after a period of malnutrition rapidly regenerates intestinal cellularity and mucosal mass [Ziegler, T. R. (1996) Springer-Verlag, New York, pp. 25-52; Hagemann and Stragand (1977)
Cell Tiss. Kinet.
10:3-14; Ogasawara et al. (1989)
Res. Exp. Med.
189:195-204].
The tripeptide glutathione (L-glutamyl-L-cysteinyl-glycine, GSH) is the most abundant low molecular weight thiol in mammalian cells and plays a key role in the detoxification of cellular free radicals, chemical toxins, and carcinogens [Robinson et al. (1997)
J. Surg. Res.
69:325-330]. GSH deactivates potentially harmful oxidants by serving as a hydrogen donor to reduce reactive molecules with concomitant conversion to its oxidized disulfide form, GSSG [Meister, A. (1991)
Pharmacol. Ther.
51:155-194]. GSH is synthesized endogenously in mucosal cells utilizing specific amino acid substrates, can be derived exogenously from dietary sources, or may enter the gut lumen via bile and by direct secretion from mucosal cells [Hagen et al. (1990)
Am J. Physiol.
259:G530-G535; Dahm and Jones (1994)
Am. J. Physiol.
267:G292-G300]. GSH present in the gut lumen and within enterocytes appears to be required for normal intestinal function, in part, by protecting intestinal epithelial cells from damage by dietary electrophiles and fatty acid hydroperoxides [Lash et al. (1986)
Proc. Natl. Acad Sci.
83:4641-4645; Martensson et al. (1989)
Proc. Natl. Acad. Sci.
87:1715-1719; Aw et al. (1992)
Am. J. Physiol.
262:G99-G106]. GSH also appears to play a role in maintaining the proper sulfhydryl/disulfide balance of gut luminal proteins, potentially modulating activity of thiol-containing enzymes on the brush border [Gilbert, H. F. (1989) Academic, San Diego, pp. 73-87; Ziegler, D. M. (1985)
Annu. Rev. Biochem.
54:305-329].
Previous studies demonstrate that malnutrition reduces tissue GSH content [Ogasawara et al. (1989)
Res. Exp. Med.
189:195-204; Cho et al. (1981)
J. Nutr.
111:914-922; Robinson et al. (1997)
J. Surg. Res.
69:325-330]. In animal models, fasting or an insufficient dietary supply of amino acids that may serve as GSH substrates (e.g., glutamine and cysteine) depletes GSH levels in both small intestine and colon [Ogasawara et al. (1989) Res. Exp. Med. 189:195-204; Robinson et al. (1997)
J. Surg. Res.
69:325-330; Kelly, F. J. (1993)
Br. J. Nutr.
69:589-596]. Therefore, malnutrition-associated depletion of cellular GSH in gut epithelial cells may increase their susceptibility to oxidative injury and exacerbate the degeneration of the intestinal mucosa [Kelly, F. J. (1993)
Br. J. Nutr.
69:589-596]. Also, there is evidence to suggest that GSH is involved in regulation of cell growth [Hwang and Sinskey (1991) Butterworth-Heinemann Ltd., Jordan Hill, Oxford, pp. 548-569].
In studies using a variety of cultured mammalian cells, a more reduced state of the extracellular GSH pool was associated with increased cell proliferation, while a more oxidized GSH pool was associated with slower cell growth [Hwang and Sinskey (1991) Butterworth-Heinemann Ltd., Jordan Hill, Oxford, pp. 548-569]. Intracellular and extracellular antioxidant status also appears to influence cell proliferation mediated by specific growth factor peptides, including platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) [Sundaresan et al. (1995)
Science
270:296-299; Burdon et al. (1994)
Free Radical Res.
21:121-123; Burdon, R. (1995)
Free Radical Biol. Med.
18:775-794; Kawamura et al. (1994)
Dig. Dis. Sci.
39:2191-2196]. It is therefore possible that the reducing environment regulated by GSH in gut mucosa may be important not only for detoxification reactions allowing normal tissue growth and function, but also for regulating cell proliferation in response to nutrients and growth factors.
Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, is a mesenchymally-derived peptide which appears to be an important endogenous mediator of epithelial growth, regeneration and repair [Finch et al. (1989)
Science
245:752-755]. Exogenous administration of recombinant human KGF in cell culture systems or in in vivo animal models stimulates proliferation and differentiation of specific epithelial cell types, including hepatocytes and enterocytes, and also appears to have cytoprotective functions [Aukerman et al. (1997) Springer-Verlag, New York, pp. 293-303]. In healthy rats fed ad libitum diets, administration of KGF induced epithelial cell proliferation in the stomach, duodenum, colon, liver and pancreas [Housley et al. (1994)
J. Clin. Invest.
94:1764-1777].
We recently found that the administration of KGF enhances small intestinal and colonic mucosal growth during enteral refeeding after a 3-day period of fasting. The mechanisms by which KGF acts as a potent gut mitogen during enteral nutrition are unclear. The current study was designed to investigate mucosal GSH status associated with gut growth stimulated by enteral nutrition and by KGF in a fasting/refeeding rat model. The major aims of this study were: 1) to determine whether different levels of enteral refeeding changes small intestinal and colonic mucosal levels of GSH and GSSG and the GSH redox potential; and 2) to assess the effects of the gut-trophic hormone KGF on mucosal GSH antioxidant capacity in models of altered enteral nutrition. A further aim was to determine whether changes in mucosal GSH status are associated with changes in indices of mucosal growth.
There is a strong need for methods for treating patients and animals suffering from malnutrition, starvation and/or malabsorption, especially during refeeding after a period of insufficient nutrition, and there is also a longfelt need in the art for methods of treatment which result in an improvement in local and/or systemic improvement in the oxidation state, particularly as measured by the glutathione/reduced glutathione ratio, due to age, disease, catabolic stress, sequelae to certain medical treatment regimens, trauma, inflammation, among other conditions. The present invention meets that need.
SUMMARY OF THE INVENTION
The present invention provides a method for the improvement of systemic oxidation-reduction state, as measured in the study described hereinbelow by the GSH and GSSG concentrations and the GSH reducing potential, as well as an improvement of the oxidation-reduction state of the gastrointestinal epithelial cells, for example, during refeeding after fasting, malnutrition or other stress. Administration of KGF to a human or animal during fasting, malnutrition, a course of chemotherapy or irradiation therapy, or other stress improves systemic antioxidant strains and serves to reduce or prevent oxidative stress or damage in the gastrointestinal tract. The present method includes the step of administering an amount of keratinocyte growth factor effective to improve antioxidant status by a suitable means. Desirably, the keratinocyte growth factor corresponds in amino acid sequence to that of the animal or human to whom it is administered. Suitab
Jones Dean P.
Ziegler Thomas R.
Emory University
Greenlee Winner and Sullivan P.C.
Moezie M.
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