Evaluation of the Efficacy and Safety of Antiplatelet Therapeutics in Rabbits.

Hemostasis is a multifactorial process that involves vasoconstriction of blood vessels, activation of the coagulation cascade, and platelet aggregation. Inappropriate activation of hemostatic processes can result in thrombosis and tissue ischemia. In patients at risk for thrombotic events, antiplatelet therapeutic agents inhibit platelet activation, thereby reducing the incidence of pathologic clot formation.

Pleiotropic effects of clopidogrel.

Clopidogrel is a widely prescribed prodrug with anti-thrombotic activity through irreversible inhibition of the P2Y receptor on platelets. It is FDA-approved for the clinical management of thrombotic diseases like unstable angina, myocardial infarction, stroke, and during percutaneous coronary interventions. Hepatic clopidogrel metabolism generates several distinct metabolites.

Clopidogrel treatment inhibits P2Y-Mediated constriction in the rabbit middle cerebral artery.

Clopidogrel is an effective purinergic 2Y receptor (P2Y) antagonist used to prevent arterial thrombosis, but its use is associated with adverse bleeding. Clinical studies have demonstrated that clopidogrel users have an increased risk of cerebral microbleeds and intracerebral hemorrhage. Our previous studies suggest that non-platelet mechanisms mediate these adverse bleeding events; we hypothesize that clopidogrel or one of its metabolites interacts with blood vessels directly to cause bleeding.

DT-678 inhibits platelet activation with lower tendency for bleeding compared to existing P2Y antagonists.

The novel clopidogrel conjugate, DT-678, is an effective inhibitor of platelets and thrombosis in preclinical studies. However, a comparison of the bleeding risk with DT-678 and currently approved P2Y antagonists has yet to be determined. The objective of this study was to evaluate the bleeding tendency of animals treated with clopidogrel, ticagrelor, and DT-678.