Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1985-07-26
1989-05-09
Waddell, Frederick E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514550, 514866, A61K 31195, A61K 3122
Patent
active
048290874
DESCRIPTION:
BRIEF SUMMARY
Diabetes (sugar sickness) can appear in different forms. The so called youth diabetes (Diabetes I) is characterized by the inability of the Islets of Langerhans of the Pancreas adequately to produce and deliver sufficient insulin for the elimination of glucose from the blood, which would be their function. Insulin has to be injected. Such patients are "insulin dependent." It is different with the so called old-diabetes (Diabetes II): which is characterized by the inability of the insulin which is present in the cells of the Islets of Langerhans to be delivered to the blood. Such patients are thus not "insulin dependent." Their treatment consists of special diet and, further, of substances which activate insulin secretion. Well-known substances for this are for example the sulphonyl ureas. They activate the secretion of insulin with a special process directly and/or together with an increase in blood sugar.
It is well known that there is a connection between the thiol content of the cells in the Islets of Langerhans and glucose-induced insulin secretion. Thereby it was revealed that the tripeptide glutathion, which is naturally contained in the Islets of Langerhans, forms a Redox-system and that a correlation exists between the relationship of reduced glutathion (GSH) to oxidized glutathion (GSSG) and the concentration of glucose during the induced secretion of insulin (Ammon et al., Diabetes 29 (1980), No. 10 P. 830-834). Furthermore the Redox-pair NADP/NADPH (Nicotinamide-adenine-dinucleotide-phosphate) serves as a hydrogen conveyor.
Furthermore, it is well known that chemical agents, which oxidize NADPH and GSH, inhibit glucose-induced insulin secretion (Ammon et al., Arch. Pharmakol. 207 (1979), P. 91-96; Ammon et al., Endocrinology, Vol. 112, No. 2 (1983), 720-726).
On the other hand, an addition of GSH and Cysteine "in vitro" revealed an increase in glucose-induced insulin secretion (Ammon et al., Arch Pharmakol. 317 (1981), P. 262-267). Further research has indicated that, despite the addition of GSH and Cysteine "in vitro," without a high enough concentration of glucose to effect stimulation, no insulin secretion will be caused. From all these observations, the stylized model pictured below was postulated, which shows the effect of the already mentioned Redox-pair. It is apparent from this that the permeability of the .beta.-cell of an Islet of Langerhans, in the sense of greater or lesser insulin secretion, depends on the Redox condition of the SH-group membrane. ##STR2##
The protein of the membrane allows an increased secretion of insulin in a reduced state of the SH-groups, while in an oxidized state, only limited secretion is possible. This reduction of the Membrane-S-S-Groups through hydrogen transfer can occur through GSH formed from oxidized GSSG, which itself can once again be transferred into GSH, through the Redox-pair NADP/NADPH by means of hydrogen transfer. The NADP, formed thus by hydrogen transfer can, on the other hand, be transferred into the reduced form NADPH by hydrogen transfer out of the Glucose-PPS-(Pentosephosphateshunt) Path.
The inducement of increasing insulin secretion follows in this way: ##STR3## Glucose increases the reduced glutathion concentration of the Islets of Langerhans and also the secretion of insulin, while the external addition of insulin leads to a decrease of the intracellular SH-content and to the inhibition of insulin secretion. The external supply of GSH magnifies the insulin liberating effect of glucose, whereas GSH in the absence of glucose has no effect.
The task of the discovery at hand is to show substances which will induce insulin secretion in the presence of glucose. Taking the above mentioned working model as a basis, the substances are those that increase the reduced thiol-group content of the .beta.-cell and thereby take over the function of GSH, in that they push the Redox-condition of the membrane-like SH-groups of the .beta.-cell toward the reduced side.
This objective is achieved by cysteine derivatives or the salts thereof, of the formul
REFERENCES:
Chemical Abstracts, vol. 71 (1969) 111089w.
Chemical Abstracts, vol. 99, (1983) 206966x.
Chemical Abstracts, vol. 96 (1982) 46096w.
Hermann P. T. Ammon, Andreas Grimm, Suszanne Lutz, Doris Wagner-Teschner, Monika Handel, and Ingrid Hagenloh, Diabetes, vol. 29, pp. 830-834, Oct. 1980.
H. P. T. Ammon, M. S. Akhtar, A. Grimm, and N. Niklas, Naunyn-Schmiedeberg's Arch. Pharmacol., vol. 307, 91-96, 1979.
Hermann P. T. Ammon, Rolf, Hagele, Nabil Youssif, Roslindis Eujen, and Najiba El-Amri, Endocrinology, vol. 112, 720-726, 1983.
H. P. T. Ammon and M. Abdel-hamid, Naunyn-Schmiedeberg's Arch. Pharmacol., vol. 317, 262-267, 1981.
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