The evaluation of tirofiban hydrochloride in a high shear rate arterial thrombosis model in baboons

[摘要] English: Background: Acute coronary syndrome (ACS) is a major cause of mortality and morbidityworld-wide, and is responsible for roughly 2.5 million hospital admissions world-wide annually.ACS is commonly associated with platelet thrombus formation on disrupted atheroscleroticplaques, therefore effective and safe anti-platelet drugs are needed to help treat and preventACS. The current most popular anti-platelet drugs are associated with increased bleeding riskand reduced efficacy, thus drugs with a wider therapeutic window (more efficacy with lessbleeding) need to be developed. Tirofiban hydrochloride is a small, short half-life molecule thatinhibits platelet aggregation by antagonising the glycoprotein IIb/IIIa receptor on plateletspreventing fibrinogen and von Willebrand factor to cross-link platelets, thereby inhibiting thefinal pathway of platelet aggregation. Tirofiban hydrochloride was believed to be a verypromising drug due to its short half-life, as an antidote strategy is not needed to reverseadverse bleeding events, but it soon fell out of favour when it was found not to be as effectiveas for example abciximab in preventing ischaemic events. This was possibly due to therecommended dose being suboptimal.Methods and Results: We studied the efficacy of tirofiban hydrochloride to inhibit plateletthrombus formation on an injured and partially occluded artery by evaluating the effect ofescalating doses on cyclic flow reduction (CFR) formation in a high shear arterial thrombosismodel in baboons, and also evaluated its safety in two different bleeding models. We thencompared our results to results found in the same model using clopidogrel. A significant effecton the number of CFRs was only observed after injection of three times (30 μg/kg bolus plus0.45 μg/kg/min infusion) the therapeutic dose tirofiban, but it was a weak inhibitor at this dose.Only after injection of nine times (90 μg/kg bolus plus 1.35 μg/kg/min infusion) therecommended therapeutic dose, a strong complete inhibition was observed. A further dose of 27 times (270 μg/kg bolus plus 4.05 μg/kg/min infusion) the recommended therapeutic dosewas given to evaluate the effect of an overdose on the bleeding tendency. A significantprolongation in bleeding time (3.05 minutes to 11.90 minutes) was observed after injection ofnine times the therapeutic dose, an average 2.7 ± 2.44 fold increase in blood loss was alsoobserved at this dose. A maximum increase in blood loss of an average of 3.4 ± 1.77 fold wasseen after injection of 27 times the therapeutic dose. The efficacy of tirofiban hydrochloridewas comparable to that of clopidogrel found in earlier studies, but the blood loss was muchless when compared to the average 4.3 ± 2.6 fold increase with clopidogrel at 2.5 mg/kg and8.0 ± 5.0 fold increase at 5 mg/kg.Conclusion: Tirofiban hydrochloride is an effective anti-platelet drug, but only offers adequateprotection against arterial thrombosis at a dose between three and nine times therecommended therapeutic dose. However, it still remains safer in terms of bleeding than themost common anti-platelet drugs used today. We recommend that further in vivo studies bedone to determine the optimal dose for tirofiban hydrochloride treatment, and that new clinicaltrials be done with higher dose tirofiban hydrochloride.

[发布机构] University of the Free State