title: A prostacyclin analog impairs the response to tissue-type plasminogen activator during coronary thrombolysis: evidence for a pharmacokinetic interaction.
abstract: 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.
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee.
authors.forename: D M
authors.initials: DM
authors.lastname: Kerins
authors.forename: M
authors.initials: M
authors.lastname: Shuh
authors.forename: S
authors.initials: S
authors.lastname: Kunitada
authors.forename: G A
authors.initials: GA
authors.lastname: Fitzgerald
authors.forename: D J
authors.initials: DJ
authors.lastname: Fitzgerald
mesh_terms: D000527:Alprostadil / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004285:Dogs; D004347:Drug Interactions; D006538:Heptanoic Acids / Q000494:pharmacology; D016285:Iloprost / Q000494:pharmacology*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D015424:Reperfusion; D015912:Thrombolytic Therapy; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D013928:Thromboxane A2; D010959:Tissue Plasminogen Activator; D000527:Alprostadil; C060013:vapiprost; D016285:Iloprost