Platelet-activating factor antagonism and streptokinase-induced hypotension in clinical acute myocardial infarction

Abstract

Continuing efforts are being made to improve thrombolytic therapy for acute myocardial infarction (AMI). The rate of streptokinase (SK) infusion is commonly limited by the hypotension that is induced. If this could be avoided, an accelerated regimen of SK could be given, analagous to that used for other thrombolytic agents such as alteplase. The mechanism of the SK-induced hypotension is unknown, but there is some evidence that platelet-activating factor (PAF) plays a role. The potent PAF receptor antagonist lexipafant (10 mg) (n=35), or matching placebo (n=36), was administered intravenously over 5 min, in a randomized double-blinded protocol, to consecutive patients about to receive SK for AMI; all but three had inferior MI, because of the preference for strategies other than SK therapy in patients with anterior MI. The rate of infusion of SK was set to give 1.5x10(6) units over 30 min, anticipating significant hypotension. Blood pressure fell sharply over the first 10 min of SK administration. The maximum fall in systolic blood pressure occurred between 8 and 12 min, and averaged 43+/-28 mmHg (mean+/-S.D.) and 40+/-26 mmHg in patients given placebo and lexipafant respectively. Systolic pressure having fallen to <90 mmHg, according to protocol the SK administration rate was reduced in 21 of 36 (58%) of patients given placebo and in 19 of 35 (54%) of patients given lexipafant. The total SK dose was given to all subjects over 40.3+/-17.5 and 40.2+/-13.4 min for the placebo and lexipafant groups respectively. Peak and time integrals of creatine kinase were not different in the two groups. There were no adverse effects attributable to lexipafant. It is concluded that the PAF receptor antagonist lexipafant has no significant effect on SK-induced hypotension and does not facilitate an accelerated regimen of administration.

Pathophysiology of streptokinase-induced hypotension in acute myocardial infarction: a systematic review of clinical evidence

“…Streptokinase has been proposed to directly stimulate intravascular synthesis of platelet-activating factor (PAF) in patients with acute myocardial infarction, that is known to cause vasodilation. However, administration of Lexipafant, a potent PAF-receptor antagonist did not sufficiently prevent the occurrence of hypotension in patients with acute myocardial infarction receiving streptokinase [ 9 ].…”

“…Platelet activation is known to trigger the release of serotonin, which in turn stimulates the release of endothelial nitric oxide, a potent vasodilator. However, Taylor et al in a randomised clinical trial involving 71 patients with acute myocardial infarction found that the use of Lexipafant, a potent platelet-activating factor antagonist did not evade the hypotensive effect of streptokinase therapy [ 9 ]. The use of oral medication as the investigational product in this study has an arguable drug pharmacokinetic profile due to the wide age gaps among patients and the potential confounding effect of different gender bias.…”

“…Figure 2 presents the summary of cumulative evidence from clinical studies on the pathophys- Neuhof, 1975Neuhof, 1975Koren, 1986Koren, 1986 Pachai, 1997 Frangi, 1993Gemmill, 1993 Hydrocortisone inhibit phospholipase A2 Pernat, 1997Gemmill, 1993Gemmill, 1993Taylor, 2001 e92…”

“…A plethora of research conducted in laboratory and animal studies do provide the basis for understanding, however the results of which were not immediately transferrable to humans. Studies with specific interest in the clinical outcomes of streptokinase therapy in patients with acute myocardial infarction were conducted with variable study designs that span from observational cohort study [ 4 – 6 ] to double-blind randomised controlled trial [ 7 – 9 ]. However, the studies were conducted with different treatment regimens of streptokinase therapy and needed to be interpreted with caution.…”