Recent progress in the clinical development of thromboxane A₂ receptor antagonists

Abstract

A summary of the current clinical status and results from clinical trials employing TP receptor antagonists published from the period mid-1989 through 1993 is presented. This class of agent was found to be safe, well-tolerated and have potent antiplatelet activity, although clear evidence of efficacy in large studies remains to be established. As antithrombotic agents TP receptor antagonists thus far have been found to have little or no benefit in PCTA versus placebo in preventing restenosis or affecting clinical course. In thrombolytic therapy smaller studies have demonstrated a significant reduction in the ‘time to lysis’ but failed to show benefit when compared to placebo in recanalisation or reocclusion rates. In contrast, pilot trials in coronary artery bypass surgery showed significant reduction in early occlusion rate versus placebo while efficacy was also demonstrated in reducing platelet deposition on mature aortic Dacron grafts compared to placebo. As antiasthmatic agents TP receptor antagonists were shown to be effective in moderating PGD₂- and/or allergen-induced bronchoconstriction, although significant clinical benefit has, as yet, not been observed in patients with allergic rhinitis or in asthmatic patients employing a number of pulmonary measurements and/or clinical criteria. In hypertensive patients with RAS and in kidney transplant patients with CyA-induced nephrotoxicity TP receptor antagonists also failed to show benefit. The reasons for the lack of efficacy of early clinical candidates are unclear but may be associated with deficiencies in their pharmacokinetic and/or pharmacodynamic profiles. The emergence of second generation agents, such as ifetroban, with clearly superior overall pharmacokinetics and pharmacodynamics should allow unequivocal evaluation of TP receptor antagonists as therapeutic agents in human disease.