Thadani U, Fung H L, Darke A C, Parker J O
Am J Cardiol. 1982 Feb 1;49(2):411-9. doi: 10.1016/0002-9149(82)90518-5.
The effects of different oral doses of isosorbide dinitrate administered acutely and four times daily during sustained therapy were studied in 12 patients with angina pectoris. After administration of 30, 60 and 120 mg of isosorbide dinitrate, the average plasma concentrations were higher and the area under the plasma concentration time curve was greater during sustained than during acute therapy (p less than 0.01). Reduction in standing systolic blood pressure was greater during acute than during sustained therapy (p less than 0.001). This reduction in systolic blood pressure was dose-related and persisted for 8 hours during acute therapy, but was not dose-related and was demonstrable for only 4 hours during sustained therapy. Compared with placebo therapy, exercise duration to the onset of angina and to the development of moderate angina increased significantly after each dose of isosorbide dinitrate for 8 hours during acute therapy but for only 2 hours during sustained therapy. During acute therapy, administration of a single dose of 15 or 30 mg of isosorbide dinitrate produced similar improvement in exercise tolerance as did a dose of 60 or 120 mg. During sustained therapy (15 mg four times daily), exercise tolerance increased to the same magnitude as with doses of 30, 60 or 120 mg four times daily. In most patients, near maximal improvement in exercise tolerance occurred after a dose of 15 or 30 mg four times daily. It is concluded that during sustained therapy with isosorbide dinitrate, partial tolerance to the antianginal and circulatory effects develops rapidly.
对12例心绞痛患者研究了急性给予不同口服剂量的硝酸异山梨酯并在维持治疗期间每日4次给药的效果。给予30、60和120mg硝酸异山梨酯后，维持治疗期间的平均血浆浓度较高，血浆浓度-时间曲线下面积也大于急性治疗期间（p<0.01）。急性治疗期间站立收缩压的降低幅度大于维持治疗期间（p<0.001）。这种收缩压的降低与剂量相关，在急性治疗期间持续8小时，但与剂量无关，在维持治疗期间仅持续4小时。与安慰剂治疗相比，急性治疗期间每次给予硝酸异山梨酯后，心绞痛发作和中度心绞痛发生时的运动持续时间在8小时内显著增加，但在维持治疗期间仅增加2小时。在急性治疗期间，给予单剂量15或30mg硝酸异山梨酯产生的运动耐量改善与60或120mg剂量相似。在维持治疗期间（每日4次，每次15mg）,运动耐量增加到与每日4次给予30、60或120mg剂量时相同的幅度。在大多数患者中，每日4次给予15或30mg剂量后运动耐量接近最大改善。结论是，在硝酸异山梨酯维持治疗期间，对抗心绞痛和循环系统作用的部分耐受性迅速产生。
