Short-term hemodynamic, anti-ischemic, 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 repeated administration. The short-term effects of 10, 20, and 40 mg of the drug on pulmonary hemodynamics and ischemic parameters were examined at rest and during exercise in a double-blind, randomized, placebo-controlled study. The study included 48 patients with documented coronary artery disease and exercise-induced ST-segment depression. Compared with the baseline test, there was a reduction of diastolic pulmonary artery 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 depression 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 time 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 became 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 relations 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 reduction of ST-segment depression, reduction of diastolic pulmonary artery pressure, relief of angina pectoris symptoms, and an increase in exercise duration, respectively. Thus, pirsidomine is an effective anti-ischemic and antianginal agent. A significant preload reduction was obtained with plasma metabolite concentrations lower than those necessary to achieve a satisfactory antianginal effect.
Stengele
E
E
Department of Clinical Pharmacology, Heart-Center, Bad Krozingen, Germany.
Ruf
G
G
Jähnchen
E
E
Trenk
D
D
Löffler
K
K
Schulz
W
W
Roskamm
H
H
D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy / Q000503:physiopathology; D003327:Coronary Disease / Q000188:drug therapy / Q000503:physiopathology; D004311:Double-Blind Method; D005080:Exercise Test; D005260:Female; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D013558:Sydnones / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use
D011355:Prodrugs; D013558:Sydnones; D014665:Vasodilator Agents; C073303:pirsidomine