The massive hypercoagulation response caused by the interaction of blood with the extracorporeal device during cardiopulmonary bypass (CPB) surgery requires high-dose unfractionated Heparin Sodium (UFH) to achieve circulation. Intimatan is in preclinical development as the preferred anticoagulant for cardiac surgery and is intended to replace UFH for this indication. Although UFH is the standard of anticoagulant care for cardiac surgery, its inability to inhibit thrombin activity bound to the extracorporeal circuit and its required neutralization by protamine to control bleeding post surgery promote systemic inflammation and perpetuate the prothrombotic state. Thus, UFH poses serious liabilities to the recovering patient. Whereas UFH may protect the ischemic myocardium from inflammation injury due to both global reperfusion at removal of the aortic cross clamp and to local reperfusion of the myocardium and endothelium at revascularization of the occluded coronary artery, its anti-inflammatory/cardioprotective effects are severely limited by the bleeding dose. Intimatan is a heparin cofactor II agonist that provides a durable and sustained inhibition of bound thrombin activity and generation after cardiac surgery in the pig; protamine is not required due to its improved hemorrhagic profile. Intimatan is also a potent inhibitor of complement activation. Presently, however, its synthesis at the manufacturing scale has not been established and the scope of its potential antiinflammatory efficacy during CPB is unknown.
The Specific Aims of this proposal are: (1) to manufacture experimental consistency batches of Intimatan at the 500 g scale towards the goal of producing GMP quantities in Phase II SBIR required for toxicology and early clinical studies, and; (2) to compare the safety and efficacy of Intimatan as an anticoagulant, antiinflammatory and cardioprotectant agent relative to UFH during CPB in a surgical revascularization model of ischemic reperfusion injury subsequent to antecedent evolving myocardial infarction in the pig. These studies will further clarify the potential relevance of Intimatan's drug profile for the management of surgical-related hemorrhage, inflammation, thrombosis and myocardial infarction during and after cardiac surgery in the recovering patient.
|Tanaka, Kenichi A; Szlam, Fania; Vinten-Johansen, Jakob et al. (2005) Effects of antithrombin and heparin cofactor II levels on anticoagulation with Intimatan. Thromb Haemost 94:808-13|