Stanley William C
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4970, USA.
Expert Rev Cardiovasc Ther. 2005 Sep;3(5):821-9. doi: 10.1586/14779072.3.5.821.
Myocardial ischemia is a metabolic problem involving reduced delivery of oxygen to cardiac mitochondria, resulting in less ATP formation, acceleration of glycolysis and production of lactate and H+ by the cell. Traditional therapies for ischemia aim at restoring the balance between mitochondrial ATP production and breakdown by reducing the need for ATP via suppression of heart rate, blood pressure and cardiac contractility, or by increasing oxygen delivery via increased myocardial blood flow. Despite optimal treatment with traditional hemodynamically oriented drugs (beta-adrenergic receptor antagonist, Ca2+ channel antagonist and nitrates), many patients continue to suffer from angina. Thus, there is a need for anti-anginal drugs that act directly on cardiomyocytes to lessen the metabolic abnormalities induced by ischemia and reduce the symptoms (chest pain and exercise intolerance). Ranolazine has been demonstrated to improve exercise time to angina or 1 mm of ST-segment depression in a manner similar to currently approved drugs, but without any significant effects on heart rate or blood pressure at rest or during exercise. In two Phase III trials, ranolazine improved exercise tolerance and reduced the frequency of angina attacks in chronic severe angina patients when administered either as monotherapy or on a background of atenolol, amlodinine or diltiazem. At present, ranolazine is under review for US Food and Drug Administration approval and, if approved, it will represent the first drug of its class in the USA.
心肌缺血是一个代谢问题，涉及心脏线粒体的氧输送减少，导致三磷酸腺苷（ATP）生成减少，糖酵解加速，细胞产生乳酸和氢离子。传统的缺血治疗方法旨在通过抑制心率、血压和心脏收缩力来减少ATP需求，或通过增加心肌血流量来增加氧输送，从而恢复线粒体ATP生成与分解之间的平衡。尽管使用传统的以血流动力学为导向的药物（β-肾上腺素能受体拮抗剂、钙离子通道拮抗剂和硝酸盐）进行了最佳治疗，但许多患者仍患有心绞痛。因此，需要直接作用于心肌细胞的抗心绞痛药物，以减轻缺血诱导的代谢异常并减轻症状（胸痛和运动不耐受）。雷诺嗪已被证明能以类似于目前已批准药物的方式延长运动至心绞痛发作或ST段压低1毫米的时间，但对静息或运动时的心率或血压无任何显著影响。在两项III期试验中，雷诺嗪作为单一疗法或与阿替洛尔、氨氯地平或地尔硫䓬联合使用时，可提高慢性重度心绞痛患者的运动耐量并减少心绞痛发作频率。目前，雷诺嗪正在接受美国食品药品监督管理局的审批，若获批，它将成为美国此类药物中的首个药物。
