Other Potential Uses

Bivalirudin has also been studied in animal models for its potential role in both surgical and interventional fields. Its antithrombotic effects were first studied in a baboon carotid endarterectomy model (Kelly et al., 1992). In later studies using endarterectomized rats, significant decreases in platelet deposition with bivalirudin were shown using mIndium-labeled platelets (Hamelink et al., 1995) and scanning electron microscopy (Jackson et al., 1996).

Bivalirudin has also been studied for prevention of vascular restenosis in a rat carotid artery injury model. Xue and associates (2000, 2001) found that bivalirudin reduced platelet deposition on denuded intima. Platelet-derived growth factor levels were also decreased following bivalirudin infusion. The authors suggested that balloon catheter injury-induced neointima formation might be suppressed by bivalirudin.

Bivalirudin has been administered to rabbits following balloon injury and reduces vascular restenosis in the femoral artery of angioplasty-injured, diet-induced atherosclerotic rabbits (Sarembock et al., 1996). These studies support the possible role of thrombin in restenosis.

In contrast to the above study, Kranzhofer et al. (1999) administered bivalirudin to rabbits over 3 days immediately after balloon injury to the abdominal aorta and right iliac artery. Markers of inflammation, including intercellular adhesion molecule-1, macrophage colony-stimulating factor, tumor necrosis factor, and inter-leukin-lp, were examined by immunohistochemistry. These workers found that bivalirudin did not acutely reduce vascular smooth muscle cell proliferation or inflammation postangioplasty. They did not rule out other mechanisms by which thrombin inhibition could prevent restenosis.

Bivalirudin has also been shown to reduce thrombin-generated increase in levels of plasminogen activator inhibitor-1 (PAI-1) in cultured baboon aortic smooth muscle cells (Ren et al., 1997). Elevated levels of PAI-1 have been found in patients with coronary artery disease (Hamsten et al., 1985; Francis et al., 1988; Sakata et al., 1990), and numerous authors have suggested their role in the development of atherosclerosis and thrombosis (Ren et al., 1997). Bivalirudin may potentially prevent intravascular thrombogenesis through inhibition of thrombin-induced PAI-1 production (Ren et al., 1997; Shen et al., 1998).

Bivalirudin has also been studied in a rat model of endotoxemia and found to increase survival rate in one (but not the other) study (Cicala et al., 1995; Itoh et al., 1996). Bivalirudin reduced endotoxin-induced thrombocytopenia, leukope-nia, and fibrinogen consumption, suggesting a possible future therapeutic role in sepsis (Cicala et al., 1995).

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