Hurlimann S, Abbühl B, Inauen W, Halter F
Gastrointestinal Unit, University Hospital, Inselspital Bern, Switzerland.
Aliment Pharmacol Ther. 1994 Apr;8(2):193-201. doi: 10.1111/j.1365-2036.1994.tb00278.x.
High-dose once daily oral omeprazole dosing can inhibit acid secretion almost completely but several days elapse before maximum efficacy is established. The acid inhibitory effect obtained with high doses of a histamine H2-receptor antagonist is built up rapidly but has the tendency to fade--the term 'tolerance' has been applied to characterize this phenomenon.
To obtain more information on the dynamics of acid inhibition during prolonged dosing, we compared the acid suppressory effects of oral high-dose omeprazole with high-dose ranitidine. Twenty-eight healthy volunteers were randomly assigned to a 2-week dosing with omeprazole or ranitidine in a double-blind, double-dummy, parallel-group study design. Omeprazole was given as 1 capsule of 40 mg mane and ranitidine as 2 tabs of 150 mg q.d.s. The median 24-h pH, daytime pH and night-time pH were measured by ambulatory continuous 24-h pH metry on days -8, -6, 1, 2, 7 and 14.
High reproducibility was observed for the two baseline acidity measurements. Ranitidine exerted its peak acid suppressant effect on day 1 of dosing; the degree of acid inhibition faded from day 2 to 7, with no significant change thereafter. The decline in antisecretory activity was more pronounced during the day than the night. In contrast, acid inhibition by omeprazole increased throughout the first week, and antisecretory activity was stable thereafter. Despite the considerable differences in median intragastric pH values at the end of the 14-day study, plasma gastrin levels were elevated to a similar degree with both medications.
This study confirms the 'tolerance' phenomenon previously observed with high-dose histamine H2-receptor antagonist dosing. The dynamics with which it occurs exclude a typical exaggerated first-dose response. Prolonged high-dose histamine H2-receptor dosing compromises the feedback mechanism regulating gastrin release, whilst this is maintained during dosing with omeprazole.
每日一次大剂量口服奥美拉唑可几乎完全抑制胃酸分泌，但需数天时间才能达到最大疗效。高剂量组胺H2受体拮抗剂所产生的胃酸抑制作用起效迅速，但有逐渐减弱的趋势——“耐受性”这一术语已被用于描述这一现象。
为获取更多关于长期给药期间胃酸抑制动态变化的信息，我们比较了口服高剂量奥美拉唑与高剂量雷尼替丁的胃酸抑制效果。在一项双盲、双模拟、平行组研究设计中，28名健康志愿者被随机分配接受为期2周的奥美拉唑或雷尼替丁给药。奥美拉唑给予40mg胶囊，每日早晨1粒，雷尼替丁给予150mg片剂，每日4次，每次2片。在第-8、-6、1、2、7和14天，通过动态连续24小时pH监测法测量24小时pH中位数、日间pH和夜间pH。
两次基线酸度测量具有高度可重复性。雷尼替丁在给药第1天发挥其最大胃酸抑制作用；从第2天到第7天，胃酸抑制程度逐渐减弱，此后无显著变化。白天抗分泌活性的下降比夜间更明显。相比之下，奥美拉唑的胃酸抑制作用在第一周内持续增强，此后抗分泌活性保持稳定。尽管在14天研究结束时胃内pH中位数存在显著差异，但两种药物使血浆胃泌素水平升高的程度相似。
本研究证实了先前在高剂量组胺H2受体拮抗剂给药时观察到的“耐受性”现象。其发生的动态变化排除了典型的首剂反应过度现象。长期高剂量组胺H2受体给药会损害调节胃泌素释放的反馈机制，而在奥美拉唑给药期间该机制得以维持。
