Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1990-02-14
1991-01-15
Rollins, John W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514313, 514866, 514884, A61K 3147
Patent
active
049854399
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to glucose tolerance factor (GTF) and specifically to a glucose tolerance factor isolated from yeast which is useful in lowering blood sugar in mammals and to a quinoline derivative contained in the GTF fraction. The invention relates as well to a process for isolating GTF in substantially pure form.
BACKGROUND ART
In an article entitled "High-Chromium Yeast and Glucose Tolerance Factor", McCarthy et al., J. Prevention Medicine, Vol. 2 (1983), McCarthy discussed the history of glucose tolerance factor and its discovery in the 1950's by Schwarz and Mertz. GTF was found to be associated with trivalent chromium.
Brewer's yeast was found to be an effective source of GTF with chromium. Torula yeast is low in chromium; chromium-deficient rats fed a diet of torula yeast continued to demonstrate impaired glucose tolerance.
In almost all subsequent work, attention was concentrated on the isolation and characterization of the chromium-containing fractions from brewer's yeast or other sources and on the evaluation of the chromium status of man and metabolic effects of chromium or GTF-enriched diets.
In Szalay, U.S. Pat. No. 4,343,905, the patentee attempted to concentrate GTF-chromium complex from synthetically processed brewer's yeast by reacting it with chromium oxide and amino acids. Szalay stated that the presence of chromium as an inorganic salt in food produces an increase in glucose oxidation in a human's biological system, particularly when extracts of brewer's yeast containing chromium are added.
The relationship of chromium content in food and its effects on glucose oxidation activity are discussed, for example, in Toepfer et al., "Chromium Foods in Relation to Biological Activity," J. Agr. Food Chem. 21:69 (1973). Specifically, this article described the biological activity of various chromium-containing foods and the relationship of GTF activity (expressed as a function of increased insulin response with chromium) to chromium content.
Other workers have concurred in the existence of chromium-containing GTF based on other observations. Chromium salts in the concentration 1 ppm increased cell carbon dioxide production after a lag period of 3 hours while chromium-containing yeast fractions stimulated the process immediately. In chromium-deficient rats, mice, and squirrel monkeys, impaired glucose tolerance could be improved overnight by both chromium salts and yeast extracts, but the latter was more efficient and acted more quickly. In humans, chromium improved glucose tolerance in certain undernourished children and in one patient who became chromium deficient while receiving total parenteral nutrition. Jeejeebhoy, Am. J. Clin. Nutr 30:531-538 (1977). Intestinal absorption of chromium was much more effective from GTF than from inorganic salts. In vitro GTF increased insulin effects on glucose uptake and glucose carbon incorporation in rat epididymal fat pad (the fat pad assay) and on the incorporation of certain amino acids into proteins. Chromium salts were also effective, but only in higher concentration.
Puzzling was the fact that glucose intolerance in chromium-deficient animals could be corrected as quickly with chromium as with GTF. This observation made it unlikely that chromium, in order to be effective, had to be incorporated into GTF in vivo. At the same time, one observation seemed to be crucial as a proof of the biological role of GTF: although certain tissues of fetuses contain significant amounts of chromium, inorganic chromium does not cross the placenta while GTF does. Mertz, Nutrition Rev. 33:129-135 (1975).
Additional proof was provided by experience with genetically diabetic db/db mice. Whereas inorganic chromium was without effect, GTF from brewer's yeast or from pork kidneys, when given intraperitoneally, significantly decreased plasma glucose (but did not normalize it). Its effect was most pronounced in those animals that displayed both hyperglycemia and hyperinsulinemia. The authors concluded that such animals probably did not synthesize GTF
REFERENCES:
patent: 4242257 (1980-12-01), Silio
patent: 4343905 (1982-08-01), Szalay
Wojahn, Arznceimittel Forsch., 2:163-165 (1952).
Toepfer, E. W. et al., J. Agric. Food Chem., 25: 162-166 (1977).
Davies, D. M. et al., Biomed. Med., 33: 297-311 (1985).
Barrett, J. et al., Polyhedron, 4: 1-14 (1985).
Mirsky, N. et al., J. Inorg. Biochem., 13: 11-21 (1980).
Holdsworth, E. S. et al., J. Inorganic Biochem., 21: 31-44 (1984).
Kumpulainen, J. et al., Bioinorganic Chemistry, 8: 419-429 (1978).
Haylock, S. J. et al., J. Inorganic Biochemistry, 18: 195-211 (1983).
Mertz, W., Nutrition Reviews, 33: 129-135 (1975).
Haylock, S. J. et al., J. Inorganic Biochemistry, 19: 105-107 (1983).
Tuman, R. W. et al., Diabetes, 26: 820-825 (1977).
Barseghian, deceased Ken
Hwang David
Lev-Ran Arye
Anheuser-Busch Companies, Inc.
Rollins John W.
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