Drug – bio-affecting and body treating compositions – Dentifrices – Oxygen or chlorine releasing compound containing
Reissue Patent
1999-08-12
2003-11-25
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Dentifrices
Oxygen or chlorine releasing compound containing
C424S051000, C424S052000, C424S054000, C424S056000, C514S365000, C514S367000, C548S152000, C548S161000, C548S164000, C548S179000, C548S180000, C548S205000, C548S190000, C548S193000, C548S194000, C548S202000, C544S140000, C544S296000, C546S256000, C546S199000, C546S211000
Reissue Patent
active
RE038330
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to the aging of proteins resulting from their reaction with glucose and other reducing sugars and more particularly to the inhibition of the reaction of nonenzymatically glycosylated proteins and the reversal of the often resultant formation of advanced glycosylation (glycation) endproducts and cross-links.
The reaction between glucose and proteins has been known for some time. Its earlier manifestation was in the appearance of brown pigments during the cooking of food, which was identified by Maillard in 1912, who observed that glucose or other reducing sugars react with amino acids to form adducts that undergo a series of dehydrations and rearrangements to form stable brown pigments. Further studies have suggested that stored and heat treated foods undergo nonenzymatic browning as a result of the reaction between glucose and the polypeptide chain, and that the proteins are resultingly cross-linked and correspondingly exhibit decreased bioavailability.
This reaction between reducing sugars and food proteins was found to have its parallel in vivo. Thus, the nonenzymatic reaction between glucose and the free amino groups on proteins to form a stable, 1-deoxyketosyl adduct, known as the Amadori product, has been shown to occur with hemoglobin, wherein a rearrangement of the amino terminal of the beta-chain of hemoglobin by reaction with glucose, forms the adduct known as hemoglobin Alc. The reaction has also been found to occur with a variety of other body proteins, such as lens crystallins, collagen and nerve proteins. See Bucala et al., “Advanced Glycosylation; Chemistry, Biology, and Implications for Diabetes and Aging” in Advances in Pharmacology, Vol. 23. pp. 1-34, Academic Press (1992).
Moreover, brown pigments with spectral and fluorescent properties similar to those of late-stage Maillard products have also been observed in vivo in association with several long-lived proteins, such as lens proteins and collagen from aged individuals. An age-related linear increase in pigment was observed in human dura collagen between the ages of 20 to 90 years. Interestingly, the aging of collagen can be mimicked in vitro by the cross-linking induced by glucose; and the capture of other proteins and the formation of adducts by collagen, also noted, is theorized to occur by a cross-linking reaction, and is believed to account for the observed accumulation of albumin and antibodies in kidney basement membrane.
In U.S. Pat No. 4,758,583, a method and associated agents were disclosed that served to inhibit the formation of advanced glycosylation endproducts by reacting with an early glycosylation product that results from the original reaction between the target protein and glucose. Accordingly, inhibition was postulated to take place as the reaction between the inhibitor and the early glycosylation product appeared to interrupt the subsequent reaction of the glycosylated protein with additional protein material to form the cross-linked late-stage product. One of the agents identified as an inhibitor was aminoguanidine, and the results of further testing have borne out its efficacy in this regard.
While the success that has been achieved with aminoguanidine and similar compounds is promising, a need continues to exist to identify and develop additional inhibitors that broaden the availability and perhaps the scope of this potential activity and its diagnostic and therapeutic utility. A further need exists to find agents which not only inhibit this reaction and its consequences, but agents capable of reversing the already formed advanced glycosylation endproducts, thereby reversing the resultant effects thereof.
SUMMARY OF THE INVENTION
In accordance with the present invention, a method and compositions are disclosed for the inhibition and reversal of the advanced glycosylation of proteins (protein aging). In particular, the compositions comprise agents for inhibiting the formation of and reversing the pre-formed advanced glycosylation (glycation) endproducts and cross-linking. The agents are members of the class of compounds known as thiazoliums. Advanced glycation endproducts and cross-linking caused by other reactive sugars present in vivo or in foodstuffs, including ribose, galactose and fructose would also be prevented and reversed by the methods and compositions of the present invention.
The agents comprise thiazolium compounds having the following structural formula:
wherein R
1
and R
2
are independently selected from the group consisting of hydrogen, hydroxy(lower) alkyl, lower alkyl, or R
1
and R
2
together with their ring carbons may be an aromatic fused, ring;
Z is hydrogen or an amino group;
Y is amino, a group of the formula
wherein R is a lower alkyl, alkoxy, hydroxy, amino or aryl group;
or a group of the formula —CH
2
R′
wherein R′ is hydrogen, or a lower alkyl, lower alkynyl, or aryl group;
X is a halide, tosylate, methanesulfonate or mesitylenesulfonate ion;
and mixtures thereof, and a carrier therefor.
The compounds, and their compositions, utilized in this invention appear to react with an early glycosylation product thereby preventing the same from later forming the advanced glycosylation end products which lead to protein cross-links, and thereby, to protein aging, and further, react with already formed advanced glycosylation end products to reduce the amount of such products.
The present invention also relates to a method for inhibiting protein aging by contacting the initially glycosylated protein at the stage of the early glycosylation product with a quantity of one or more of the agents of the present invention, or a composition containing the same, and to a method for breaking the already formed advanced glycosylation end products to reduce the amount of such products. In the instance where the present method has industrial application, one or more of the agents may be applied to the proteins in question, either by introduction into a mixture of the same in the instance of a protein extract, or by application or introduction into foodstuffs containing the protein or proteins, all to prevent premature aging and spoilage of the particular foodstuffs, and to reverse the effects of already formed advanced glycosylation end products.
The ability to inhibit the formation of advanced glycosylation endproducts, and to reverse the already formed advanced glycosylation products in the body carries with it significant implications in all applications where protein aging is a serious detriment. Thus, in the area of food technology, the retardation of food spoilage would confer an obvious economic and social benefit by making certain foods of marginal stability less perishable and therefore more available for consumers. Spoilage would be reduced as would the expense of inspection, removal, and replacement, and the extended availability of the foods could aid in stabilizing their price in the marketplace. Similarly, in other industrial applications where the perishability of proteins is a problem, the admixture of the agents of the present invention in compositions containing such proteins would facilitate the extended useful life of the same. Presently used food preservatives and discoloration preventatives such as sulfur dioxide, known to cause toxicity including allergy and asthma in animals, can be replaced with compounds such as those described herein.
The present method has particular therapeutic application as the Maillard process acutely affects several of the significant protein masses in the body, among them collagen, elastin, lens proteins, and the kidney glomerular basement membranes. These proteins deteriorate both with age (hence the application of the term “protein aging”) and as a consequence of diabetes. Accordingly, the ability to either retard or substantially inhibit the formation of advanced glycosylation endproducts, and to reduce the amount of already formed advanced glycosylation endproducts in the body carries the promise of treatment for diabetes and, of course, impro
Cerami Anthony
Egan John J.
Hwang San-Bao
Ulrich Peter C.
Vasan Sara
Alteon Inc.
Elrifi, Ph.D. Ivor R.
Golden Matthew J.
McKane Joseph K.
Mintz Levin Cohn Ferris Glovsky & Popeo P.C.
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