Yuan C S, Foss J F, Osinski J, Toledano A, Roizen M F, Moss J
Department of Anesthesia and Critical Care, University of Chicago, IL 60637, USA.
Clin Pharmacol Ther. 1997 Apr;61(4):467-75. doi: 10.1016/S0009-9236(97)90197-1.
Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood-brain barrier that has the potential to antagonize the peripherally mediated gastrointestinal effects of opioids. In recent trials in human volunteers, we demonstrated that intravenous methylnaltrexone prevented morphine-induced changes in gastrointestinal motility and transit, without affecting analgesia. In this study, 14 healthy volunteers were first given three ascending oral doses of methylnaltrexone to obtain safety and tolerance data (phase A study). In phase B, these subjects were then given single-blind oral placebo and intravenous placebo, followed by randomized, double-blind oral placebo and intravenous morphine (0.05 mg/kg) or oral methylnaltrexone (19.2 mg/kg, an established highest and safe dose based on previous administrations of two smaller doses of 0.64 mg/kg and 6.4 mg/kg in phase A) and intravenous morphine (0.05 mg/kg). Oral-cecal transit time was assessed by the pulmonary hydrogen measurement technique after lactulose ingestion. Morphine significantly increased oral-cecal transit time from 114.6 +/- 37.0 minutes (mean +/- SD) to 158.6 +/- 50.2 minutes (p < 0.001). Oral methylnaltrexone (19.2 mg/kg) completely prevented morphine-induced increase in oral-cecal transit time (110.4 +/- 45.0 minutes; not significant compared with baseline; p < 0.005 compared with morphine alone). These sessions were then followed by single-blind evaluations of descending doses of methylnaltrexone. We observed that 6.4 mg/kg oral methylnaltrexone significantly attenuated the morphine-induced delay in oral-cecal transit time (p < 0.005 compared with morphine alone), and a dose-dependent response was obtained. There was no correlation between oral methylnaltrexone effects on the transit time and the drug plasma concentration, suggesting direct preferential luminal effects of oral methylnaltrexone. Oral methylnaltrexone may have a clinical value in the prevention and treatment of constipation induced by long-term opioid use.
甲基纳曲酮是一种季铵类阿片拮抗剂，穿越血脑屏障的能力有限，具有拮抗阿片类药物外周介导的胃肠道效应的潜力。在近期针对人类志愿者的试验中，我们证明静脉注射甲基纳曲酮可预防吗啡引起的胃肠动力和转运变化，而不影响镇痛效果。在本研究中，首先给14名健康志愿者口服递增剂量的甲基纳曲酮三次，以获取安全性和耐受性数据（A期研究）。在B期，这些受试者先接受单盲口服安慰剂和静脉注射安慰剂，随后接受随机、双盲口服安慰剂和静脉注射吗啡（0.05mg/kg）或口服甲基纳曲酮（19.2mg/kg，基于A期先前给予的两剂较小剂量0.64mg/kg和6.4mg/kg确定的既定最高安全剂量）以及静脉注射吗啡（0.05mg/kg）。在摄入乳果糖后，通过肺氢测量技术评估口盲肠转运时间。吗啡显著将口盲肠转运时间从114.6±37.0分钟（平均值±标准差）增加至158.6±50.2分钟（p<0.001）。口服甲基纳曲酮（19.2mg/kg）完全预防了吗啡引起的口盲肠转运时间增加（110.4±45.0分钟；与基线相比无显著差异；与单独使用吗啡相比p<0.005）。然后对这些受试者进行甲基纳曲酮递减剂量的单盲评估。我们观察到口服6.4mg/kg甲基纳曲酮显著减轻了吗啡引起的口盲肠转运时间延迟（与单独使用吗啡相比p<0.005），并获得了剂量依赖性反应。口服甲基纳曲酮对口盲肠转运时间的影响与药物血浆浓度之间无相关性，提示口服甲基纳曲酮具有直接的肠腔优先效应。口服甲基纳曲酮在预防和治疗长期使用阿片类药物引起的便秘方面可能具有临床价值。
