Merki H S, Halter F, Wilder-Smith C H
Department of Medicine, Inselspital, University of Berne, Switzerland.
Gastroenterology. 1993 Sep;105(3):748-54. doi: 10.1016/0016-5085(93)90892-g.
Gastric acid secretion in humans shows chronobiological patterns that modify the efficacy of antisecretory agents. The ability of individually titrated ranitidine infusions to overcome circadian patterns of gastric acidity and tolerance during prolonged dosing was assessed.
Eleven healthy subjects were randomized to receive ranitidine infusions of up to 600 mg/24 hours by a pH feedback-regulated pump before and after 9 days of oral dosing with ranitidine, 300 mg four times daily, beginning either in the evening or in the morning in a cross-over, third party-blinded and placebo-controlled study design.
Mean 24-hour intravenous ranitidine doses given to attain the target pH of 4 were greater after 9 days of treatment with oral ranitidine than before in the morning and evening studies (P < 0.01). The median 24-hour pH decreased from 5.1 before to 3.6 after oral dosing in the morning study (P < 0.001) and from 4.4 to 2.8 in the evening study (P < 0.001). Before oral dosing of ranitidine, the time of pH > 4 in the evening and morning fasting periods was 71% and 84%, respectively (P < 0.05). After 9 days oral ranitidine, the respective results were 20% and 53% (P < 0.05).
The reduced responsiveness to ranitidine in the evening and the tolerance to ranitidine with repeated dosing were not overcome by individually titrated, high intravenous doses of ranitidine.
人类胃酸分泌呈现时间生物学模式，这会改变抗分泌药物的疗效。评估了在长期给药期间，个体化滴定的雷尼替丁输注克服胃酸昼夜模式和耐受性的能力。
在一项交叉、第三方盲法和安慰剂对照的研究设计中，11名健康受试者被随机分配，在口服雷尼替丁（每日4次，每次300mg）9天前后，通过pH反馈调节泵接受高达600mg/24小时的雷尼替丁输注，给药起始时间分别为晚上或早上。
在早上和晚上的研究中，口服雷尼替丁治疗9天后，为达到目标pH值4而给予的平均24小时静脉雷尼替丁剂量比治疗前更大（P<0.01）。在早上的研究中，口服给药后24小时pH值中位数从之前的5.1降至3.6（P<0.001），在晚上的研究中从4.4降至2.8（P<0.001）。在口服雷尼替丁之前，晚上和早上空腹期pH>4的时间分别为71%和84%（P<0.05）。口服雷尼替丁9天后，相应结果分别为20%和53%（P<0.05）。
晚上对雷尼替丁反应性降低以及重复给药后对雷尼替丁的耐受性，并未被个体化滴定的高剂量静脉雷尼替丁所克服。
