Method for raising the blood glucose level in mammals

Inactive Publication Date: 2002-06-13
PROSIDION LIMITED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

0048] A significant advantage of the present invention is the low burden imposed on the organism, since only small doses of external hormone, if any, need to be administered: according to the invention, glucagon degradation is decelerated or completely stopped by the use of the DP OV inhibitors of the invention, so that, in the organism of an adult human, typically a quantity of administered or endogenously released glucagon of from 2 pmol to 200 pmol is maintained. Too rapid a proteolytic degradation is prevented.
0049] The effectors of DP IV and DP IV-analogous enzymes administered according to the invention may be used in pharmaceutically administrable formulation complexes as inhibitors, substrates, pseudosubstrates, inhibitors of DP IV expression, binding proteins or antibodies to those enzyme proteins or combinations of those different substances that reduce the DP IV or DP Iv-analogous protein concentration in the mammalian organism. Effectors used according to the invention are, for example, DP IV inhibitors, such as the dipeptide derivatives and dipeptide mimetics alanyl-pyrolidide, isoleucyl-thiazolidide, and the pseudosubstrate N-valyl-prolyl, O-benzoyl hydroxylamine or salts thereof, especially fumarates thereof. Such compounds are known from the literature or can be manufactured analogously to the methods described in the literature (Demuth, 1990).
0050] The method of the invention represents a novel procedure for raising

Problems solved by technology

Blood sugar concentrations that are too low may lead to pathological states in the human or animal organism.
In particular, after accidents, so-called hypoglycaemic shock may occur which may lead in patients to hyperorexia, sweating and ev

Method used

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  • Method for raising the blood glucose level in mammals
  • Method for raising the blood glucose level in mammals
  • Method for raising the blood glucose level in mammals

Examples

Experimental program
Comparison scheme
Effect test

example 2

Effect of Glucagon on Endogenous Glucose Release After Incubation in Plasma of DP IV-Positive and DP IV Negative Rats

[0058] To test whether glucagon-degrading activity is present in the plasma of DP IV-negative rats, 6.8 .mu.g of glucagon were reinsulated for three hours at 37.degree. C. in 1.0 ml of plasma of normal, DP IV-positive rats and in 1.0 ml of plasma of DPrats. From 10 to 50 .mu.l of the incubation solution were injected i.v. into normal Wistar rats and compared with a saline control. The biological response, that is to say the increase in blood glucose resulting from the glucagon-stimurelease of hepatic glucose, was monitored for 60(FIG. 3).

example 3

Effect of Glucagon on Glucose Response in Wistar Rats After i.v. Injection of Preincubated Glucagon in the Plasma of a Normal Rat, in the Presence and Absence of DP IV Inhibitor

[0059] To test whether the effect of the glucagon-degrading activin plasma can be inhibited by a specific DP IV inhibitor, 6.8 .mu.g of glucagon were induced for three hours at 37.degree. C. in 1.0 of normal rat plasma and in 1.0 ml of normal rat plasma additionally containing 0.01 mmol of isoleucyl-thiazolidide. From 10 to 50 .mu.l of the incubation solution were injected iv. into normal Wistar rats and compared with a saline control. The biological response, that is to say the increase in blood glucose resulting from the glucagon-stimulated release of hepatic glucose, was monitored for 30(FIG. 4).

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Abstract

The invention comprises the use of activity-reducing effectors of dipeptidyl peptidase (DP IV) and DP IV-analogous enzyme activity in the blood of a mammal to raise the blood sugar level in mammalian organisms.

Description

[0001] Referenced-Applications[0002] This application is a divisional application of co-pending U.S. Ser. No. 09 / 365,404 filed Aug. 2, 1999.BACKGROUND OF INVENTION[0003] The invention relates to a method in which, by reducing dipeptidyl peptidase IV (DP IV) or DP IV-analogous enzyme activity in the blood of a mammal by administration of activity-reducing effectors, the endogenous (or additionally exogenously adminisglycogenolytically active peptide glucagon or analogues thereof is / are degraded to a reduced extent by DP IV and D IV-like Penzymes, thereby reducing or delaying the decrease in concentration of that peptide hormone or analogues thereof.[0004] Owing to that increased stability of (endogenous or exogenously administered) glucagon and its analogues brought about by the action of DP IV effectors, thereby making them available in greater number for the glycogenolytic stimulation of the glucareceptors of, in particular, liver cells, the duration of activity of the body's own g...

Claims

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Application Information

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IPC IPC(8): A61K38/05A61K38/55
CPCA61K38/26A61P3/00
Inventor DEMUTH, HANS-ULRICHHOFFMANN, TORSTENKUHN-WACHE, KERSTINROSCHE, FRED
Owner PROSIDION LIMITED
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