Stengele E, Ruf G, Jähnchen E, Trenk D, Löffler K, Schulz W, Roskamm H
Department of Clinical Pharmacology, Heart-Center, Bad Krozingen, Germany.
Am J Cardiol. 1996 May 1;77(11):937-41. doi: 10.1016/s0002-9149(96)00006-9.
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.
匹昔多明是一种正处于临床开发阶段的新型西多胺类化合物。作为一种前药，它在体内转化为释放一氧化氮的代谢产物。在动物试验中，重复给药未出现耐受性迹象。在一项双盲、随机、安慰剂对照研究中，研究了10毫克、20毫克和40毫克该药物在静息和运动状态下对肺血流动力学和缺血参数的短期影响。该研究纳入了48例有冠状动脉疾病记录且运动诱发ST段压低的患者。与基线测试相比，静息时匹昔多明可降低舒张压肺动脉压（安慰剂组：-0.4±0.5毫米汞柱；10毫克组：-1.5±2.4毫米汞柱；20毫克组：-1.4±1.1毫米汞柱；40毫克组：-2.3±1.3毫米汞柱[p<0.05]）以及在最高可比工作量时（安慰剂组：-2.8±1.9毫米汞柱；10毫克组：-7.3±6.8毫米汞柱；20毫克组：-8.4±7.9毫米汞柱[p<0.05]；40毫克组：-13.8±7.1毫米汞柱[p<0.05]）。在最高可比工作量时ST段压低有所降低（安慰剂组：-0.33±0.49毫米；10毫克组：-1.33±1.37毫米[p<0.05]；20毫克组：-1.33±0.83毫米[p<0.05]；40毫克组：-1.96±0.86毫米[p<0.05]）且总运动时间增加（安慰剂组：15±48秒；10毫克组：98±126秒；20毫克组：165±251秒[p<0.05]；40毫克组：155±174秒[p<0.05]）。在基线测试中抱怨有胸痛症状的40例患者中，15例服用匹昔多明后胸痛症状消失。与安慰剂相比，血压、运动时心率和运动时心输出量无显著变化。代谢产物的血浆浓度-反应关系显示，在降低ST段压低、降低舒张压肺动脉压、缓解胸痛症状和增加运动持续时间方面，分别导致半数最大效应的浓度为6纳克/毫升、13纳克/毫升、20纳克/毫升和28纳克/毫升。因此，匹昔多明是一种有效的抗缺血和抗心绞痛药物。在血浆代谢产物浓度低于达到满意抗心绞痛效果所需浓度时，即可显著降低前负荷。
