Recombinant single-chain urokinase-type plasminogen activator (rscu-PA) induces thrombolysis and systemic fibrinolysis in a canine model of coronary artery thrombosis

The thrombolytic efficacy of recombinant single-chain urokinase-type plasminogen activator (rscu-PA) was studied in an open-chest canine model of coronary artery thrombosis. Dogs (n = 16) were anesthetized, a left thoracotomy performed, and a two cm segment of the left circumflex coronary artery was isolated and instrumented with an electromagnetic flow probe, an intracoronary stimulation electrode, and an adjustable mechanical occluder. Anodal direct current (100 microA) was applied to the stimulation electrode until thrombosis occurred (n = 14). After 30 min of thrombotic occlusion, rscu-PA was administered intravenously. Dogs were sacrificed either 6 h after thrombolysis or 6.5 h after initiation of rscu-PA when thrombolysis did not occur. In group A (30-50 micrograms/kg bolus rscu-PA + 20-40 micrograms/kg/min infusion rscu-PA for 30 min, n = 5) thrombolysis occurred in one case (20%) and this artery reoccluded. In group B (250 micrograms/kg bolus rscu-PA + 25 micrograms/kg/min infusion rscu-PA for 30 min, n = 6) all reperfused and only one reoccluded (16.6%). In group C (200 micrograms/kg bolus rscu-PA + 100 micrograms/kg/min rscu-PA infusion for 30 min, n = 2) both reperfused and neither reoccluded. Infarct size, determined as a percentage of left ventricle, was smaller when thrombolysis was followed by persistent reperfusion (n = 7), than when reperfusion did not occur (n = 4): 16.9 +/- 3.7% vs 31.3 +/- 2.2%, respectively (mean +/- SEM, p less than 0.02). If thrombolysis was followed by reocclusion, infarct size was 27.0 +/- 10.0%. In this study thrombolysis occurred when changes in prothrombin time, partial thromboplastin time, fibrinogen and fibrin split products were suggestive of systemic finbrinogenolysis. In conclusion, effective thrombolysis with rscu-PA appears to limit infarct size and to be accompanied by evidence of systemic fibrinolysis.     

Disopyramide-induced ventricular tachycardia

A patient with ischemic cardiomyopathy and congestive heart failure was treated with disopyramide phosphate for ventricular arrhythmias. The development of ventricular tachycardia was associated with elevated plasma disopyramide levels and prolongation of the QRS and QT intervals, suggesting a disopyramide-induced depression of ventricular conduction and a prolongation of recovery. Thus, in patients with congestive heart failure, as well as in patients with renal and/or hepatic dysfunction, special care must be exercised with respect to the use of disopyramide.     

The nitroglycerin polymer gel matrix system: a new method for administering nitroglycerin evaluated with plasma nitroglycerin levels

A new topical dosage form of nitroglycerin has been developed in which nitroglycerin and its vehicle are incorporated in a polymer gel matrix of fixed dimension. Venous plasma nitroglycerin concentrations were measured for 24 h after application of nitroglycerin polymer gel systems measuring 10 cm and containing 2% nitroglycerin (wt/wt) to 10 normal male volunteers. Five of these subjects were subsequently tested with 20-cm2 gel systems of similar composition. With the 10-cm2 nitroglycerin polymer gel system, venous plasma nitroglycerin concentrations were 0.83 +/- 0.26 ng/ml ast 4 h and 0.89 +/- 0.23 ng/ml at 24 h. For the 20-cm2 system, venous plasma nitroglycerin concentrations were 1.83 +/- 0.55 ng/ml at 8 h and 1.81 +/- 0.13 ng/ml at 24 h. The only adverse effect noted was headache, which affected all the subjects tested with the 20-cm2 appliance. The plasma nitroglycerin concentrations obtained with the polymer gel system appear to be in a clinically useful range; thus this new form of topical nitroglycerin should be of benefit to patients in whom sustained plasma nitroglycerin concentrations are desirable, e.g., those patients with chronic congestive heart failure and angina on awakening.