Effect of a stable prostacyclin analogue on platelet function and experimentally-induced thrombosis in the microcirculation.
Sodium dl-4-[1R,2R,3aS,8bS)-1,2,3a,8b-tetrahydro- 2-hydroxy-1-[(3S,4RS)-3-hydroxy-4-methyl-oct-6- yne-(E)-1-enyl]-5-cyclopenta[b]benzofuranyl]butyrate (TRK-100) is a stable analogue of prostacyclin (epoprostenol, PGI2). The drug was shown to be a potent inhibitor of platelet aggregation in vitro, induced by adenosine diphosphate (ADP), using platelet-rich plasma (PRP) from human and several animal species. The inhibitory activity of TRK-100 using human platelets was half that of PGI2 and eight times that of PGE1. There was a marked tendency for platelet clumps to disaggregate following secondary aggregation in the presence of TRK-100 at final concentrations higher than 1 ng/ml. This activity was similar to PGI2 and more than 30 times that of PGE1. TRK-100 was shown to induce the disaggregation of a pre-existing thrombus in the microcirculation of the hamster cheek pouch. A dose-dependent response was obtained following oral administration of the drug at levels of 50-200 micrograms/kg. Optimal activity was observed 30-60 min after dosing and activity was sustained throughout the experimental period. TRK-100 was more active than PGE1 in the test system and appeared to be of a similar potency to PGI2. Since this drug is stable, orally active and without the hypotensive activity of PGI2, it is considered to be a potentially useful agent for antithrombotic therapy.
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D006224:Cricetinae; D004285:Dogs; D011464:Epoprostenol / Q000494:pharmacology* / Q000031:analogs & derivatives; D005343:Fibrinolytic Agents; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013997:Time Factors
D005343:Fibrinolytic Agents; C048081:beraprost; D000244:Adenosine Diphosphate; D011464:Epoprostenol; D000527:Alprostadil