Research Department, Ono Pharmaceutical Co., Ltd, Mishima, Osaka, 618-8585, Japan.
Biomed Contextm, Bergisch Gladbach, Germany.
Eur J Pharmacol. 2021 Apr 5;896:173886. doi: 10.1016/j.ejphar.2021.173886. Epub 2021 Jan 23.
As a new and ultra fast-acting IV benzodiazepine, pharmacological tolerance may be anticipated during long-term treatment with remimazolam e.g. in intensive care. In this context, tolerance is particularly relevant for withdrawal syndrome. However, apart from primates, existing models of sedative tolerance are unsuitable for remimazolam due to its excessive metabolic clearance (i.e. in rodents) or paradoxical responses (in dogs). Pigs are a well-established model species, especially for in-vivo drug safety studies, and appear a well suited as model for evaluation of remimazolam. In a series of experiments from dose-range-finding bolus and infusion studies through to 28-day continuous level sedation, we established a viable model of intravenous benzodiazepine sedation in NIBS micropigs to compare tolerance development during 28 days sedation with either midazolam or remimazolam. Dose increases after 28 days were lower for remimazolam (0 to 3-fold) than for midazolam (2 to 4-fold) and recovery times were approximately 40% faster for remimazolam vs midazolam. Tolerance to remimazolam is therefore likely in long-term human sedation and may be less than that seen for midazolam.
作为一种新型超快速起效的 IV 苯二氮䓬类药物，在重症监护中长期使用瑞马唑仑（例如）时可能会出现药物耐受性。在这种情况下，耐受性对于戒断综合征特别重要。然而，除灵长类动物外，由于其代谢清除率过高（即啮齿动物）或反常反应（犬），现有的镇静耐受性模型不适合瑞马唑仑。猪是一种成熟的模式物种，特别是用于体内药物安全性研究，并且似乎非常适合作为评估瑞马唑仑的模型。在一系列从剂量范围发现的推注和输注研究到 28 天连续镇静水平的实验中，我们建立了一种可行的尼布斯微型猪静脉注射苯二氮䓬类镇静模型，以比较在 28 天镇静期间咪达唑仑或瑞马唑仑的耐受性发展。与咪达唑仑（2 至 4 倍）相比，28 天后瑞马唑仑的剂量增加（0 至 3 倍）较低，恢复时间比咪达唑仑快约 40%。因此，瑞马唑仑在长期人类镇静中可能会产生耐受性，并且可能比咪达唑仑的耐受性低。
