pirsidomine and Myocardial-Ischemia

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.

Topics: Aged; Angina Pectoris; Coronary Disease; Double-Blind Method; Exercise Test; Female; Heart; Hemodynamics; Humans; Male; Middle Aged; Myocardial Ischemia; Prodrugs; Sydnones; Time Factors; Vasodilator Agents

The antiischemic effect of pirsidomine (CAS 936 (3-(cis-2,6-dimethylpiperidino)-N-(4-methoxybenzoyl))-sydnon imine), a new nitric oxide donor, was investigated in a model of myocardial infarction in the dog. Dogs were anaesthetised, thoracotomized, and the left descending coronary artery was occluded for 6 h. Pirsidomine was given intraduodenally (i.d.) at the dose of 1.0 mg/kg to 11 dogs 30 min prior to coronary occlusion. Eleven dogs received the solvent i.d. and served as controls. Pirsidomine administration completely prevented the increase in left ventricular end-diastolic pressure and pulmonary artery pressure induced by the coronary occlusion and resulted in a marked decrease in systolic and diastolic blood pressure, cardiac output, left ventricular contractility, left ventricular work and left ventricular oxygen consumption. Additionally, pirsidomine completely prevented the occlusion-induced increase in flow in the non-occluded circumflex coronary artery. Regional blood flow measurements (with radioactive microspheres) revealed that pirsidomine induced a significant reduction in blood flow in the non-ischemic areas (both epi- and endocardial) but in the course of the ischemia, significantly increased flow in the ischemic epicardial areas. Infarct-size (triphenyltetrazolium chloride technique) in control dogs was 45% of the area at risk, but only 26% (P < 0.05) in pirsidomine-treated dogs. Thus, pirsidomine had a marked antiischemic effect in this model. This was probably due to the hemodynamic unloading of the heart as well as to redistribution of blood from the non-ischemic to the ischemic areas of the myocardium.

Topics: Animals; Blood Pressure; Cardiac Output; Coronary Circulation; Dogs; Female; Male; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Myocardium; Oxygen Consumption; Sydnones; Vasodilator Agents; Ventricular Function, Left

The hemodynamic profile and antiarrhythmic properties of pirsidomine, a nitric oxide donor, were examined in pigs. Intravenous administration of pirsidomine (1 mg/kg) to chloralose-anesthetized open-chest pigs resulted in a decreased afterload, and a reduced myocardial contractility and myocardial oxygen consumption (assessed by rate-pressure product), with no alterations in heart rate. After induction of regional myocardial ischemia by occlusion of the left anterior descending coronary artery, pigs given pirsidomine experienced fewer ventricular ectopic beats (119 +/- 29) than control animals did (217 +/- 53; p < 0.05), seen primarily as a reduction in the number of couplets and triplets. Although the incidence of ventricular fibrillation was unaffected by pirsidomine, the time to onset of this arrhythmia was significantly prolonged by this intervention (21.3 +/- 0.9 min versus 16.1 +/- 2.5 min in controls; p < 0.05). Furthermore, the ST-segment depression seen throughout the 30-min occlusion period in controls was not sustained beyond 5 min postocclusion in pirsidomine-treated pigs. Taken together, and in the absence of an ex vivo antiplatelet effect with this dose of pirsidomine, these results suggest that the antiarrhythmic effect of pirsidomine lies in its hemodynamic effects, resulting in a reduction of ischemia. The ex vivo effect of pirsidomine on free radical generation from isolated leukocytes was also investigated. Luminol-enhanced chemiluminescence produced by leukocytes in response to phorbol myristate acetate was markedly depressed in cells isolated from blood withdrawn after administration of pirsidomine, compared with cells tested before drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arrhythmias, Cardiac; Electrocardiography; Free Radicals; Hemodynamics; Injections, Intravenous; Myocardial Ischemia; Myocardial Reperfusion; Platelet Aggregation; Swine; Sydnones; Vasodilator Agents