Silber S, Vogler A C, Krause K H, Vogel M, Theisen K
Medizinische Klinik Innenstadt der Universität München, West-Germany.
Am J Med. 1987 Nov;83(5):860-70. doi: 10.1016/0002-9343(87)90643-7.
There is increasing evidence that constant nitrate plasma levels, as induced by at least three-times-daily ingestions of isosorbide dinitrate in sustained-release form, lead to an attenuation or even complete loss of the anti-ischemic effects (nitrate tolerance). Therefore, the dependence of tolerance development on dosage intervals according to once-daily and twice-daily ingestions was assessed. Tablets of isosorbide dinitrate (80 mg) in sustained-release form were administered once-daily at 8 A.M. (dosage interval 24 hours) or twice-daily at 8 A.M. and 8 P.M. (dosage interval 12 hours), as well as at 8 A.M. and 2 P.M., respectively (maximal dosage interval 18 hours). A total of 34 patients with angiographically proven coronary artery disease, a history of stable, exercise-dependent angina pectoris, and a reproducible, exercise-induced ST-segment depression of at least 0.15 mV (1.5 mm), who initially showed a response to 80 mg of isosorbide dinitrate, were enrolled. The anti-ischemic effects of isosorbide dinitrate on exercise-induced ischemia were objectively determined by the measurement of exercise-induced ST-segment depression before as well as two, six, and 12 hours after the ingestion at the first and the 15th day of the studies. Since the dosage interval of 12 hours resulted in constant plasma levels, the initially beneficial anti-ischemic effects of isosorbide dinitrate were considerably attenuated after two weeks of treatment. In contrast, the once-daily regimen with its intermittent peaks and valleys of nitrate plasma levels showed identical anti-ischemic effects at the 15th day as compared with the first day. Ingestions at 8 A.M. and 2 P.M. also circumvented the development of nitrate tolerance, however, combined with an even more pronounced anti-ischemic effect after 12 hours as compared with the once-daily regimen. Thus, the circumvention of nitrate tolerance requires a daily "nitrate-poor" interval. The best compromise between a maximal possible anti-ischemic effect and the circumvention of tolerance development was found for the "eccentric" dosage regimen in which the tablets were ingested in the morning and early afternoon.
越来越多的证据表明，至少每日三次摄入缓释型硝酸异山梨酯所诱导的恒定血浆硝酸盐水平会导致抗缺血作用减弱甚至完全丧失（硝酸盐耐受性）。因此，评估了耐受性发展对每日一次和每日两次摄入时给药间隔的依赖性。以缓释形式的硝酸异山梨酯（80毫克）片剂在上午8点每日一次给药（给药间隔24小时），或在上午8点和晚上8点每日两次给药（给药间隔12小时），以及分别在上午8点和下午2点给药（最大给药间隔18小时）。总共34例经血管造影证实患有冠状动脉疾病、有稳定的运动诱发型心绞痛病史且运动诱发的ST段压低至少0.15毫伏（1.5毫米）且可重复，最初对80毫克硝酸异山梨酯有反应的患者被纳入研究。在研究的第1天和第15天，通过测量摄入硝酸异山梨酯前以及摄入后2小时、6小时和12小时运动诱发的ST段压低，客观地确定了硝酸异山梨酯对运动诱发缺血的抗缺血作用。由于12小时的给药间隔导致血浆水平恒定，硝酸异山梨酯最初有益的抗缺血作用在治疗两周后明显减弱。相比之下，每日一次给药方案其硝酸盐血浆水平有间歇性的峰值和谷值，在第15天时与第一天相比显示出相同的抗缺血作用。在上午8点和下午2点给药也避免了硝酸盐耐受性的发展，然而，与每日一次给药方案相比，12小时后具有更明显的抗缺血作用。因此，避免硝酸盐耐受性需要每日有一个“低硝酸盐”间隔。对于在早晨和下午早些时候摄入片剂的“偏心”给药方案，在最大可能的抗缺血作用和避免耐受性发展之间找到了最佳折衷方案。
