Method for raising the blood glucose level in mammals

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...

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 lowered blood glucose concentration in the serum of mammals. It is simple, capable of commercial exploitation and suitable for use in human medicine in the treatment especially of diseases that result from below-average blood glucose values.

[0051] The effectors may be used in the form of pharmaceutical preparations that contain the active ingredient in combination with customary excipients known from the prior art and / or customary adjuvants. They are administered, for example, parenterally (for example i.v., in physiological saline solution) or enterally (for example orally, formulated with customary excipients such as, for example, glucose).

[0052] Depending upon their endogenous stability and bio-availability and upon the severity of the condition, single or multiple doses of the effectors may be administered to obtain the desired normalisation of the blood glucose values. For example, in the case of aminoacyl-thiazolidides-, such a dosage range may be from 0.1 mg to 10 mg of effector substance per kilogram. The effectors are preferably administered approximately 120 minutes after food intake. The effectors may also be used together with or at short intervals from glucagon or analogues thereof.

[0053] FIG. 1 shows MALDI-TOF Mass Spectra of 0.14 mmol Glucagon Solution and 40 mmol TRIS / HCL (pH=7.6) in the presence of 40 nmol DP IV (the removal of the dipeptides His-Ser and Gln-Gly occurs sequentially depending upon the incubation time);

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 even to loss of consciousness and death.

Consequently, if DP IV is present, degradation of the incretins occurs, which in turn leads to reduced glucose degradation.

As a result, insulin production falls, bringing glucose degradation to an end.

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