Wilder-Smith C, Halter F, Ernst T, Gennoni M, Zeyen B, Varga L, Roehmel J J, Merki H S
Department of Medicine, Inselspital, University of Berne, Switzerland.
Aliment Pharmacol Ther. 1990;4 Suppl 1:15-27.
The suppression of intragastric acidity with H2-receptor antagonists may diminish with repeated administration. To assess the degree and dose-dependence of this tolerance after short-term dosing, two doses of the H2-receptor antagonists, ranitidine (300 mg nocte or q.d.s.) and sufotidine (300 mg or 600 mg b.d.), were given to healthy volunteers for 1 and 2 weeks, respectively. After 1 and 7 days of dosing with ranitidine 300 mg q.d.s. the median 24-h and night-time pH, measured by continuous 24-h pH-metry, dropped from 3.7 to 2.2 and 5.8 to 3.2, respectively (P less than 0.0001 for both). The decline in median pH with ranitidine 300 mg nocte was only significant during the night (from 4.1 to 2.9) (P less than 0.04). There was little change in plasma gastrin concentrations between days 1 and 7 with either dosage. With sufotidine 300 mg b.d. and 600 mg b.d. for 1 and 14 days, the median 24-h pH fell from 3.7 to 2.1 and from 4.6 to 2.6, respectively (P less than 0.0001). The equivalent medians for the night decreased from 6.3 to 2.3 and from 6.6 to 3.1 (P less than 0.0001). Gastrin concentrations did not change after 14 days of dosing with sufotidine 300 mg b.d., but increased significantly during dosing with sufotidine 600 mg b.d. (P less than 0.001). Significant tolerance developed in 7-14 days and it seemed to show some dose relationship. The mechanisms behind tolerance and the role of gastrin are discussed, but remain unclear.
H2受体拮抗剂对胃内酸度的抑制作用可能会随着反复给药而减弱。为了评估短期给药后这种耐受性的程度和剂量依赖性，分别给予健康志愿者两种剂量的H2受体拮抗剂，雷尼替丁（300mg每晚或每日四次）和法莫替丁（300mg或600mg每日两次），持续1周和2周。在每日四次给予300mg雷尼替丁给药1天和7天后，通过连续24小时pH测量法测得的24小时和夜间pH中位数分别从3.7降至2.2和从5.8降至3.2（两者P均小于0.0001）。每晚给予300mg雷尼替丁时，pH中位数的下降仅在夜间显著（从4.1降至2.9）（P小于0.04）。两种剂量下第1天和第7天血浆胃泌素浓度几乎没有变化。给予每日两次300mg和600mg法莫替丁1天和14天后，24小时pH中位数分别从3.7降至2.1和从4.6降至2.6（P小于0.0001）。夜间的等效中位数从6.3降至2.3和从6.6降至3.1（P小于0.0001）。每日两次给予300mg法莫替丁给药14天后胃泌素浓度没有变化，但在每日两次给予600mg法莫替丁给药期间显著升高（P小于0.001）。7 - 14天内出现了显著的耐受性，并且似乎呈现出一定的剂量关系。文中讨论了耐受性背后的机制以及胃泌素的作用，但仍不清楚。
