In vivo studies with the stabilized epoprostenol analogue taprostene. Effects on platelet functions and blood clotting.
Like the native epoprostenol (prostacyclin, PGI2), the oxacyclic epoprostenol analogue taprostene affects platelet functions. In the rat taprostene inhibited in vivo induced ADP aggregation after i.v. bolus injection, i.v. infusion, s.c. and p.o. application with ED50 values of 4.6 micrograms/kg, 0.36 microgram/kg/min, 190 micrograms/kg and approximately 760 micrograms/kg, respectively. In vivo induced collagen aggregation was inhibited with an ED50 value of 17.1 micrograms/kg i.v. Referring to both bolus injection and i.v. infusion, taprostene was about 3 times less active than the native prostacyclin, but the antiaggregatory effect of taprostene was longer lasting. 5,6-Dihydroepoprostenol inhibited ADP-induced aggregation with an ED50 value of 3 micrograms/kg/min, being 10 fold less active than taprostene. Whereas epoprostenol induced a rebound effect by increasing in vivo aggregation after the end of infusion, no such effect could be seen after taprostene. In the mouse s.c. and p.o. application of taprostene inhibited aggregation with the same efficacy as in the rat. Intra-arterial infusion of taprostene into the rabbit inhibited ADP-induced aggregation ex vivo with an ED50 value of 0.49 micrograms/kg/min. An increased bleeding time was observed in rats in doses of 2.15 micrograms/kg i.v. and higher, corresponding to the antiaggregatory dose range of taprostene. Administered alone, taprostene did not prolong the clotting time in rats. However, in heparinized rats, the heparin-induced prolongation of clotting time was further increased by taprostene with a threshold dose of 21.5 micrograms/kg (= heparin sparing effect).
Michel
G
G
Department of Pharmacology, Grünenthal GmbH, Aachen, Fed. Rep. of Germany.
Seipp
U
U
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010979:Platelet Function Tests; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D002317:Cardiovascular Agents; D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; C039188:taprostene; D011464:Epoprostenol