Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-07-27
1996-10-01
Nucker, Christine M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 4, 514 14, A61K 3816
Patent
active
055611109
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a method of treating the complications and pathology of diabetes.
The di-peptide carnosine, was discovered about 90 years ago (Gulewitsch and Amiradzibi, 1900) as a heat-stable extract derived from meat; since these early origins, considerable data has accumulated on the distribution and metabolism of the di-peptide. Carnosine (.beta.-alanyl-L-histidine) and its related compounds such as anserine (.beta.-alanyl-1-methyl-L-histidine) and homocarnosine (.gamma.-amino-butyryl-L-histidine) are present in millimolar concentrations in numerous mammalian tissues, including skeletal muscle (2-20 mM) and brain (0.3-5 mM). Although no unified hypothesis exists to account for physiological function of this group of di-peptides, their antioxidant properties, ability to protect DNA from radiation damage, ability to chelate divalent cations, and remarkable buffer capacity at physiological pH-values has led to the proposal that their primary function in vivo is to furnish protection to proteins, lipids and other macromolecules.
In addition to its role as free radical scavenger carnosine has been claimed to act as an "immunoregulator" (Nagai, Patent: GB 2143732A) with useful properties in the treatment of certain cancers (Nagai, Patent DE 3424781 A1). Camosine has also been suggested to be useful in the treatment of lipid peroxide induced cataracts (Babizhayev, 1989). There is also evidence that carnosine can accelerate the process of wound healing.
Non-enzymatic Glycosylation
Free-radical damage is not the only process to affect the structure of proteins and nucleic acids. Non-enzymatic glycosylation (glycation), the Maillard reaction in food chemistry (Maillard, 1912, or browning reaction, involves reaction of amino groups with sugar aldehyde or keto groups to produce modified amino groups and eventually forming advanced-glycosylation-end-products (AGE-products). Although glycation is slow in vivo, it is of fundamental importance in ageing and in pathological conditions where sugar levels are elevated, e.g. diabetes.
It is possible to demonstrate glycation of proteins in the test tube. Several studies have shown that most proteins and DNA are potential targets for non-enzymic glycosylation in which sugars become attached to amino groups in the molecule via a Schiff's base. Subsequently a rearrangement occurs to give the coloured product (called the Amadori product). Further slow and uncharacterised reactions of the Amadori products occur.
Analysis of the preferred glycation sites in proteins shows the epsilon amino groups of lysine residues are primary targets, particularly when in proximity to histidine residues (Shilton & Walton, 1991). In a search for stable peptides with long half-lives in vivo we found that the amino acid sequence of carnosine is similar to Lys-His, thus having the potential to react with sugars and react as scavenger for aldehyde groups. In addition carnosine is virtually non-toxic; well documented toxicity studies have indicated that the material can be administered to mammals to a level of 5-10 g/kg body weight and therefore no toxic side effects are expected over long-term treatment.
So far only one other compound has been shown to slow down glycation by reacting with sugars and blocking the Amadori re-arrangement. Aminoguanidine can reduce both in vitro and in vivo glucose-derived advanced glycation end products. Unfortunately aminoguanidine, a nucleophilic hydrazine compound, is nonphysiological and is of unknown long-term toxicity.
Diabetes
Diabetes is a metabolic disorder caused by an acute or chronic deficiency of insulin. It is diagnosed by an increased blood glucose level. The acute condition is characterised by a reduced glucose uptake of the insulin-dependent tissues. The body counteracts the resulting energy deficiency by increasing lipolysis and reducing glycogen synthesis. When the diabetic condition is severe, calories are lost from two major sources; glucose is lost in the urine, and body protein is also depleted. This is because insufficienc
REFERENCES:
patent: 4508728 (1985-04-01), Nagai et al.
patent: 4717716 (1988-01-01), Nagai et al.
Merck Manual Fifteenth Edition, Merck & Co., Rahway, NJ (1987). see pp. 1120-1121.
Hipkiss Alan R.
Michaelis Jurgen
Panagiotopoulos Sianna
King's College London
Nucker Christine M.
Peptide Technology Limited
Stucker Jeffrey
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