Argatroban During Percutaneous Transluminal Coronary Angioplasty: Results of a Dose-Verification Study.

Background. Thrombin is a key enzyme in thrombogenesis. In animals, specific antithrombotic therapy at the time of coronary angioplasty reduced the incidence of subacute occlusion and inhibited the restenosis response. Argatroban is a highly selective synthetic thrombin antagonist that binds in a competitive manner. This is a report of a dose-verification study, assessing the safety and feasibility of intravenous Argatroban administration in patients undergoing percutaneous transluminal coronary angioplasty. Methods. Before angioplasty an intravenous bolus of 30 g/kg argatroban was administered, followed by a continuous infusion of 3.5 g/kg/min for 72 hours. Bolus injection was repeated, and the infusion rate was increased in order to achieve an activated coagulation time (ACT) of over 300 seconds. Following interim analysis, the bolus and initial infusion rate for the subsequent treatment groups was determined. Study endpoints were the occurrence of adverse events, coagulation tests, and qualitative angiogram reading. Patients were monitored by continuous 12-lead electrocardiographic recording over 24 hours, and underwent control angiography 18–24 hours following angioplasty. Results. Four treatment groups, comprised of 2, 8, 9, and 11 patients, respectively, were studied. The first two patients were excluded from analysis, since the initial dose was ineffective to attain an ACT-authorizing coronary angioplasty. The group with the highest dosage received a 250 g/kg intravenous bolus of argatroban, followed by a 4 hour infusion of 15 g/kg/min. At 4 hours the infusion rate was lowered to 3.8 g/kg/min and was continued for 68 hours without adjustment for catheter removal. The adverse event profile included myocardial infarction, aortocoronary bypass graft, bailout procedures, and repeat coronary angioplasty. Thrombin-time (TT), activated partial thromboplastin time (APTT), and prothrombin time (PT) were significantly related to argatroban plasma concentration, as demonstrated by regression analyses (R-square 0.64, 0.71, and 0.84, respectively). Prothrombin fragments 1 and 2 and thrombin-antithrombin III complex did not fit into a mathematical model, but showed slightly increased levels after reduction or cessation of the infusion rate. Conclusions. This dose-verification study, including 30 patients at four dose levels, indicated that argatroban infusion in coronary angioplasty patients can be administered safely, and results in an adequate and predictable level of anticoagulation

Reduction of blood pressure, plasma cholesterol, and atherosclerosis by elevated endothelial nitric oxide.

In the vascular system, nitric oxide is generated by endothelial NO synthase (eNOS). NO has pleiotropic effects, most of which are believed to be atheroprotective. Therefore, it has been argued that patients suffering from cardiovascular disease could benefit from an increase in eNOS activity. However, increased NO production can cause oxidative damage, cell toxicity, and apoptosis and hence could be atherogenic rather than beneficial. To study the in vivo effects of increased eNOS activity, we created transgenic mice overexpressing human eNOS. Aortic blood pressure was approximately 20 mm Hg lower in the transgenic mice compared with control mice because of lower systemic vascular resistance. The effects of eNOS overexpression on diet-induced atherosclerosis were studied in apolipoprotein E-deficient mice. Elevation of eNOS activity decreased blood pressure ( approximately 20 mm Hg) and plasma levels of cholesterol (approximately 17%), resulting in a reduction in atherosclerotic lesions by 40%. We conclude that an increase in eNOS activity is beneficial and provides protection against atherosclerosis