SHORT-TERM HEMODYNAMIC, ANTIISCHEMIC, AND ANTIANGINAL EFFECTS OF PIRSIDOMINE, A NEW SYDNONIMINE

Pirsidomine is a new sydnonimine compound in clinical development. As a prodrug, it is transformed into a nitric oxide-releasing metabolite in vivo. In animal tests there were no signs of tolerance with repeate d administration. The short-term effects of 10, 20, and 40 mg of the d rug on pulmonary hemodynamics and ischemic parameters were examined at rest and during exercise in a double-blind, randomized, placebo-contr olled study. The study included 48 patients with documented coronary a rtery disease and exercise-induced ST-segment depression. Compared wit h the baseline test, there was a reduction of diastolic pulmonary arte ry pressure with pirsidomine at rest (placebo: -0.4 +/- 0.5 mm Hg; 10 mg: -1.5 +/- 2.4 mm Hg; 20 mg: -1.4 +/- 1.1 mm Hg; 40 mg: -2.3 +/- 1.3 mm Hg [p < 0.05]) and at the highest comparable workload (placebo: -2 .8 +/- 1.9 mm Hg; 10 mg: -7.3 +/- 6.8 mm Hg; 20 mg: -8.4 +/- 7.9 mm Hg [p < 0.05]; 40 mg: -13.8 +/- 7.1 mm Hg [p < 0.05]). ST-segment depres sion decreased at the highest comparable workload (placebo: -0.33 +/- 0.49 mm; 10 mg: -1.33 +/- 1.37 mm [p < 0.05]; 20 mg: -1.33 +/- 0.83 mm [p < 0.05]; 40 mg: -1.96 +/- 0.86 mm [p < 0.05]) and total exercise t ime increased (placebo: 15 +/- 48 s; 10 mg: 98 +/- 126 s; 20 mg: 165 /- 251 s [p < 0.05]; 40 mg: 155 +/- 174 s [p < 0.05]). Of 40 patients who complained of angina pectoris symptoms in the baseline test, 15 be came free of angina pectoris with pirsidomine. Compared with placebo, blood pressure, heart rate during exercise, and cardiac output during exercise showed no significant change, Plasma concentration response r elations of the metabolite revealed concentrations that caused a half- maximum effect of 6 ng/ml, 13 ng/ml, 20 ng/ml, and 28 ng/ml in reducti on of ST-segment depression, reduction of diastolic pulmonary artery p ressure, relief of angina pectoris symptoms, and an increase in exerci se duration, respectively. Thus, pirsidomine is an effective anti-isch emic and antianginal agent. A significant preload reduction was obtain ed with plasma metabolite concentrations lower than those necessary to achieve a satisfactory antianginal effect.