A novel class of ion displacement ligands as antagonists of the αIIbß3 receptor that limit conformational reorganization of the receptor.

A collection of αIIbß3 integrin receptor antagonists possessing a unique MIDAS metal ion displacement mechanism of action is presented. Insight into these agents' structure-activity relationships, binding modality, and pharmacokinetic and pharmacodynamic profiles highlight the potential of these small molecule ion displacement ligands as attractive candidates for clinical development.

Clot lysis in a primate model of peripheral arterial occlusive disease with use of systemic or intraarterial reteplase: addition of abciximab results in improved vessel reperfusion.

PURPOSE: This study was designed to compare the ability of reteplase (a fibrinolytic agent) alone or in combination with abciximab (a monoclonal antibody antagonist of platelet glycoprotein IIb/IIIa) to achieve and sustain vessel patency in an acute model of peripheral arterial occlusive disease in cynomolgus monkeys. MATERIALS AND METHODS: Total arterial occlusion was induced in the femoral arteries of 32 cynomolgus monkeys (eight groups of four) by endothelial injury and injection of thrombin-treated autologous blood. Reteplase was administered by intravenous bolus dose or by intraarterial infusion at the site of the clot. Abciximab was administered as a single weight-adjusted intravenous bolus dose. Platelet activity was measured by ex vivo platelet aggregation before and after abciximab treatment. Different groups of animals received sequential partial doses of reteplase with or without increasing doses of abciximab until either the weight-adjusted human dose equivalent of reteplase was reached or vessel recanalization was achieved. RESULTS: Animals receiving reteplase-only regimens demonstrated variability in the times required for reperfusion and the permanence of the effect. The coadministration of abciximab at doses of the antibody that achieved near or full inhibition of platelet function generally decreased the time to reperfusion and resulted in more consistent and sustained vessel patency. In the case of systemic intravenous reteplase, the coadministration of abciximab resulted in effective reperfusion of thrombosed vessels at decreased doses of the lytic agent. CONCLUSIONS: Reteplase administered systemically or at the site of thrombotic occlusion restored blood flow for periods of varying duration in monkeys with acute femoral artery thrombosis. The coadministration of systemic intravenous abciximab to intravenous or intraarterial reteplase allowed the use of lower doses of fibrinolytic agent with more accelerated and sustained reperfusion.

Effects of abciximab on the acute pathology of blood vessels after arterial stenting in nonhuman primates.

OBJECTIVES: This study was designed to assess the effect of abciximab on platelet and leukocyte deposition 60 min after stent insertion in nonhuman primates. BACKGROUND: Although it is well established that abciximab improves both short- and long-term clinical outcomes after stent placement, there have been no studies assessing its effect on early platelet and leukocyte deposition. METHODS: Cynomolgus monkeys were pretreated with aspirin and either saline or a 0.4 mg/kg bolus of abciximab, and then subjected to angioplasty and Palmaz-Schatz stent placement in the common iliac artery or abdominal aorta. After 60 min, animals were euthanized and the stented artery was evaluated by immunohistochemistry and morphometry. RESULTS: Complete occlusion of the stented vessel with a thin fibrin(ogen) meshwork and trapped blood occurred in two saline-treated and two abciximab-treated animals. In the four remaining saline-treated animals, a layer of erythrocytes trapped in a network of fibrin(ogen) was noted close to the vessel wall, and this was covered by a layer of large, irregular platelet thrombi. Leukocytes formed a monolayer on top of the platelets and near stent struts. In the four remaining abciximab-treated animals, the mean erythrocyte area was 65% smaller (p = 0.070), the platelet aggregate area was 89% smaller (p = 0.049) and the luminal area was 59% larger (p = 0.004). A monolayer of leukocytes also formed on top of the platelets and near stent struts. CONCLUSIONS: In control stented blood vessels in this study, platelet thrombi formed not at the vessel wall, but on top of an erythrocyte-rich layer, and platelets recruited leukocytes. Abciximab decreased the size of platelet thrombi, but did not prevent leukocyte recruitment.

Abciximab pharmacodynamics are unaffected by antecedent therapy with other GPIIb/IIIa antagonists in non-human primates.

BACKGROUND: Tirofiban and eptifibatide are currently approved for the medical stabilization of non-ST segment elevation acute coronary syndromes. In patients undergoing percutaneous coronary intervention (PCI) during infusion of these drugs, conversion to abciximab, which has long term proven clinical efficacy and cost-effectiveness, following PCI may be desirable. The purpose of this study was to determine if the binding or pharmacodynamics of abciximab is affected by a prior infusion of either tirofiban or eptifibatide. METHODS: In vitro binding experiments were performed to determine if prior exposure to tirofiban or eptifibatide altered the affinity and extent of binding of abciximab to GPIIb/IIIa. For in vivo experiments, cynomolgus monkeys were pretreated with a bolus and 18 hour infusion of saline, tirofiban, or eptifibatide. At the end of the initial treatment, a bolus and 12 hr infusion of abciximab was started without delay. Inhibition of platelet aggregation, GPIIb/IIIa receptor blockade and abciximab pharmacokinetics were measured during and after both infusions. RESULTS: Equilibrium binding of abciximab in vitro was unaffected by tirofiban or eptifibatide. The extent and duration of abciximab inhibition of ex vivo platelet aggregation, receptor blockade, and abciximab pharmacokinetics in monkeys during and after the abciximab infusion were not affected by prior infusion of the animals with tirofiban or eptifibatide. CONCLUSIONS: In vitro and in vivo studies revealed that the molecular interaction of abciximab with the platelet GPIIb/IIIa receptor is not altered by immediate prior exposure of platelets to small molecule GPIIb/IIIa antagonists. These preclinical studies suggest that the efficacy of abciximab should not be impaired if it is initiated following termination of therapy with small molecule GPIIb/IIIa antagonists.