Use of radical-scavenging compounds for treatment and prevention of NO-dependent microcirculation disorders

Abstract

A method of treatment of the human or non-human animal body for treating NO-dependent microcirculation disorders is disclosed, for example microcirculation disorders caused by metabolic diseases, such as elevated levels of homocystin-homocystein inflammatory reactions or autoimmune diseases, furthermore peripheral microcirculation disorders or microcirculation disorders associated with increased cell fragmentation, which method comprises administering to a human or non-human animal body in need of such treatment an effective amount of a pharmaceutical composition containing a substance which scavenges free radicals, e.g. a pyrimido-pyrimidine selected from Dipyridamole, Mopidamol and the pharmaceutically acceptable salts thereof, and the use such substance for the manufacture of a corresponding pharmaceutical composition, optionally in combination with an agent capable of increasing NO procution.

Description

RELATED APPLICATIONS [0001] Benefit of U.S. Provisional Application Ser. No. 60 / 288,605, filed on May 4, 2001, is hereby claimed.FIELD OF THE INVENTION [0002] This invention relates to a method of treatment of disorders of the microcirculation, particularly those where insufficient generation of NO seems to be the cause of the problem, using substances to scavange free radicals such as Dipyridamole or Mopidamol in doses lower than those needed to directly inhibit platelet aggregation alone or in combination with substance to increase cellular Nitric oxide (NO) production such as HMG CoA reductase inhibitors at doses below the typical dose to lower serum lipids but sufficient to still enhance eNOS in cells of the vasculature. BACKGROUND OF THE INVENTION [0003] By laboratory models reflecting the complex physiology of the blood vessel it could be shown that the vasculature is not a passive conduit, but interacts profoundly with the blood through an intricate system of checks and balan...

AI Technical Summary

Benefits of technology

[0016] NO-dependent disorders of the microcirculation can be approached by either increasing the local production of NO or, preferably, by combining the increase of NO with reducing the local destruction of NO.

[0019] It is found that a substance which scavenges free radicals increases the local production of NO. Accordingly, NO-dependent microcirculation disorders can be treated according to the present invention by a method of treatment comprising a substance which scavenges free radicals.

[0024] Preferred is the combination of Mopidamol or even more preferred Dipyridamole with an agent selected from the class of HMG CoA reductase inhibitors. The combination of sub- / or therapeutical doses of HMG CoA reductase inhibitors known to upregulate expression of eNOS (endothelial nitric oxide synthetase), which have clinical benefit at lipid lowering doses, with doses of Dipyridamole or Mopidamol, which inhibits destruction of NO.

Problems solved by technology

Again here the major problem remaining is the acute rethrombosis of the reopened segment of the blood vessel, where strong inhibitors of platelet aggregation or the combination of platelet inhibition with inhibitors of fibrin formation have shown to be effective.

Using more potent platelet inhibitors such as various orally available inhibitors of the platelet fibrinogen receptor however have shown no improvement over the effect achieved by ASA.

All studies have been negative, in fact the treatment arm showed a higher risk for bleeding and increased mortality.