Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines, XV: Antithrombotic Effect of Selected Oligoamines in Rats

Abstract

Oligoamines which exert antiplatelet and anticoagulant properties in vitro show as well antithrombotic effects in mesenteric arterioles and venoles of rats. The formation of thrombi in these vessels was induced by a laser beam and quantified by the thrombus formation index (TFI). The most potent compound RE 1492 already reduced the formation of thrombi after i.v. administration of 1 mg/kg significantly. After oral administration, however, only a minor effect even after a 200 mg/kg dose is observed. This suggests that the oligoamine was poorly absorbed from the gastrointestinal tract. The tricarbamate of RE 1492 (identical to RE 1492 C), however, was a suitable prodrug. Eight hours after a single oral dose of 10 mg/kg significant antithrombotic properties in arterioles and venules were seen. (TFI = 3.63 (A), 1.77 (V); control: 1.76 (A), 1.29 (V).) After p.o. application of 30 mg/kg RE 1492 C the onset of activity is after 2 h (TFI = 3.44/1.48). A maximum effect is reached after 4 h (TFI: 4.43/2.84) and maintained up to 24 h (TFI = 4.49/2.45). After 48 h the effect in arterioles is still significant (p less than 0.05, chi 2-test). The results obtained with five other carbamates (RE 2029 C, RE 1964 C, RE 2120 C, RE 2112 C, and RE 1981 C) 4 h after p.o. administration in general show a stronger effect in arterioles than in venules which is in the same range as in RE 1492 C.

Interaction of Viagra with the NO Donors Molsidomine and RE 2047 with Regard to Antithrombotic and Blood Pressure Lowering Activities

“…As sildenafil is also predominantly metabolized in the liver it will have a high affinity to this organ so that blood platelets can be loaded there with both compounds. The transfer of sildenafil from blood plasma to blood platelets may be poor because it is strongly bound to plasma proteins (96%) [5] . In molsidomine the N-ethoxycarbonyl group can be hydrolysed by means of ubiquitous unspecific esterases or even spontaneously.…”

“…The latter has already been recognized for Zaprinast [4] and Viagra, of which sildenafil is the active compound [5] . The combined application of sildenafil with NO donors such as organic nitrates and molsidomine is declared to be a contraindication.…”

New Oxadiazole Derivatives Showing partly Antiplatelet, Antithrombotic and Serotonin Antagonistic Properties

“…Compounds 6a, 6d, 6e, 12e and 12f were tested by the method of Hoenicka et al [15] in a heme-containing sGCassay [14] in the presence of Mg 2ϩ ions towards their ability to stimulate sGC (Institute of Cardiovascular Research, Bayer AG, Wuppertal).…”

“…In order to examine the inhibition of thrombosis of our oxadiazoles we used an in vivo thrombosis model [14]. In brief, the formation of thrombi in mesenteric vessels of rats was induced by the beam of an argon laser via a microscope (35 mW, 50 ms).…”

New antithrombotic 1‐Phthalazinamines with Serotonin Antagonistic Properties

“…The influence of selected test compounds on the formation of thrombi in vivo was assayed in a laser thrombosis model [7]. The compounds were administered orally to male Wistar rats (60 mg/kg).…”