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A prostacyclin analog impairs the response to tissue-type plasminogen activator during coronary thrombolysis: evidence for a pharmacokinetic interaction.
Kerins, D M; Shuh, M; Kunitada, S; Fitzgerald, G A; Fitzgerald, D J.
Afiliação
  • Kerins DM; Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee.
J Pharmacol Exp Ther ; 257(1): 487-92, 1991 Apr.
Article em En | MEDLINE | ID: mdl-1708425
Inhibition of thromboxane (TX) A2 with aspirin enhances the response to coronary thrombolysis. However, experimental evidence suggests that platelet activation during coronary thrombolysis is mediated by a number of agonists, in addition to TXA2. As a consequence, greater benefit would be expected with antiplatelet agents that have a broader spectrum of activity. However, a recent clinical trial, combining tissue plasminogen activator (t-PA) with the prostacyclin analog, iloprost, did not detect such a benefit. To address the mechanism of this response, we compared the effect of iloprost, a stable analog of prostacyclin, with GR32191, a TXA2/prostaglandin endoperoxide receptor antagonist, on the response to i.v. t-PA in a closed chest, canine model of coronary thrombosis. GR32191 reduced the time to reperfusion by 47% (n = 6, P less than .05), consistent with a role for TXA2-mediated platelet activation in impairing thrombolysis. In contrast, iloprost increased the time to reperfusion by 50% (n = 5, P = NS) and in four of nine animals reperfusion failed to occur despite inhibition of platelet aggregation. In a separate series of experiments, steady-state plasma t-PA clearance increased by 38% (407 +/- 49 vs. 294 +/- 42 ml/min; n = 8, P less than .02) during infusion of iloprost and recovered after its withdrawal. This appeared to be a specific effect, as infusion of nitroglycerin at a dose which induced a similar fall in blood pressure altered neither the time to reperfusion nor plasma t-PA. Iloprost impairs the thrombolytic response to t-PA via an increase in the clearance of this agent.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trombose Coronária / Terapia Trombolítica / Iloprosta / Ativador de Plasminogênio Tecidual Limite: Animals Idioma: En Revista: J Pharmacol Exp Ther Ano de publicação: 1991 Tipo de documento: Article
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Trombose Coronária / Terapia Trombolítica / Iloprosta / Ativador de Plasminogênio Tecidual Limite: Animals Idioma: En Revista: J Pharmacol Exp Ther Ano de publicação: 1991 Tipo de documento: Article