r-59274 and sulotroban

To clarify whether activated platelets play an important role in the occurrence and exacerbation of disseminated intravascular coagulation (DIC), we investigated the effects of 4 anti-platelet drugs, a PGI2 analog (CS-570), a thromboxane synthetase inhibitor (dazoxiben), a thromboxane receptor antagonist (BM-13177), and ticlopidine, in an experimental DIC model in rats. Experimental DIC was induced by a continuous infusion of lipopolysaccharide (LPS derived from E. coli, 055 B5, 25 mg/kg/hr) for 4 hrs. In the time-course determination of the coagulation parameters and prostanoids, an abrupt increase in TxB2 (a stable metabolite of TxA2) and 6-keto-PGF1 alpha (a stable metabolite of PGI2) was followed by a decrease in platelet count, a prolongation of blood coagulation time, and an increase in fibrinogen/fibrin degradation products (FDP). Four hours after the start of LPS infusion, the rats were considered to be in the state of DIC. The effects of the anti-platelet drugs were investigated 4 hrs after the start of LPS infusion. CS-570 and ticlopidine ameliorated DIC in a dose-dependent manner. CS-570 (10 micrograms/kg/min) improved DIC in the platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fbg), and FDP, without affecting TxB2 and 6-keto-PGF1 alpha formation. Ticlopidine (200 mg/kg, i.p.) prevented the exacerbation of DIC in such item parameters as platelet count, APTT, and FDP. Both dazoxiben and BM-13177 (30 mg/kg, i.p.) ameliorated DIC in following parameters as platelet count, APTT and FDP. Dazoxiben, but not BM-13177, significantly inhibited the increase in TxB2 concentration at 4 hr. These observations suggest that drugs which inhibit platelet activation by a TxA2-dependent route are effective in improving DIC induced by LPS, and that drugs which inhibit multiple platelet-activating routes improve DIC in more item parameters than drugs which inhibit only the TxA2-dependent activating route. Consequently, it is concluded that activated platelets might play an important role in the occurrence and exacerbation of DIC induced by LPS, and that one of the roles of TxA2 in DIC is to activate platelets.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Coagulation; Disseminated Intravascular Coagulation; Endotoxins; Epoprostenol; Fibrin; Humans; Imidazoles; Kidney Glomerulus; Male; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Count; Prostaglandins, Synthetic; Rats; Rats, Inbred Strains; Sulfonamides; Thromboxane B2; Thromboxane-A Synthase; Ticlopidine