Psychomotor Recovery Following Remimazolam-induced Sedation and the Effectiveness of Flumazenil as an Antidote

被引：116

作者：

Chen, Xia ^{[1
,2
]}

Sang, Nuoer ^{[3
]}

Song, Kaicheng ^{[3
]}

Zhong, Wen ^{[1
]}

Wang, Hongyun ^{[1
]}

Jiang, Ji ^{[1
]}

Huang, Yuguang ^{[3
]}

Hu, Pei ^{[1
]}

机构：

[1] Peking Union Med Coll Hosp, Chn Pharmacol Res Ctr, Beijing, Peoples R China

[2] Capital Med Univ, Beijing Tiantan Hosp, Clin Trial Ctr, China Natl Clin Res Ctr Neurol Dis, Beijing, Peoples R China

[3] Peking Union Med Coll Hosp, Dept Anesthesiol, Beijing, Peoples R China

来源：

CLINICAL THERAPEUTICS | 2020年 / 42卷 / 04期

关键词：

Remimazolam; Psychomotor function; Post-procedure recovery; Clinical pharmacology; CENTRAL-NERVOUS-SYSTEM; CNS; 7056; PHARMACOLOGICAL CONSIDERATIONS; RECEPTOR MODULATOR; MIDAZOLAM; PHARMACOKINETICS; LORAZEPAM; PLACEBO; AGONIST; SAFETY;

D O I：

10.1016/j.clinthera.2020.02.006

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Purpose: Remimazolam tosylate (HR-7056) is a novel ester-type benzodiazepine with ultrafast onset of effect. The compound is being developed for sedation induction and maintenance during anesthesia. It was approved for procedural anesthesia in December 2019 by the National Medical Products Administration of China. Previous studies have reported on remimazolam's effects on consciousness and cognition. Although the time to full psychomotor recovery after remimazolam-mediated sedation is critical for decisions regarding hospital discharge, relevant clinical evidence is still lacking. This study investigated the residual psychomotor effects of remimazolam and their recovery from sedating treatment in 2 simulated clinical settings: (1) single-dose administration for sedation initiation; and (2) constant rate infusion for sedation maintenance. Methods: A single-ascending-dose, parallel-group, midazolam-controlled study and a 2-way crossover study evaluating the reversal effect of flumazenil versus placebo after a 2-h constant rate infusion were conducted with HR-7056 in 87 Chinese healthy volunteers; the studies used a double-blind, randomized trial design. A battery of psychomotor tests was administered before dosing and several times postdose over 4-6 h. Pharmacokinetic, sedation, and safety assessments were performed throughout the studies. Findings: After bolus infusion, the Bispectral Index score decreased in a concentration-dependent manner with HR-7056, accompanied by a sharp drop of Modified Observer's Assessment of Alertness/Sedation score. The recovery of consciousness was much faster with HR-7056 than with midazolam. During the constant rate infusion, the Bispectral Index score was maintained between 40 and 60 with an average plasma remimazolam concentration of similar to 1000 ng/mL. Subjects' performance in saccadic and smooth pursuit eye movement, body sway, test of choice reaction time, and word recall was significantly impaired after single-dose midazolam and after constant rate infusion of remimazolam. The end-of-infusion injection of flumazenil shortened the median time to full alertness to 3.5 min and effectively reversed psychomotor and cardiovascular dysfunction. (C) 2020 The Authors. Published by Elsevier Inc.

引用

页码：614 / 624

页数：11

共 24 条

[1] A Placebo- and Midazolam-Controlled Phase I Single Ascending-Dose Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of Remimazolam (CNS 7056): Part I. Safety, Efficacy, and Basic Pharmacokinetics[J]. Antonik, Laurie J.;Goldwater, D. Ronald;Kilpatrick, Gavin J.;Tilbrook, Gary S.;Borkett, Keith M. ANESTHESIA AND ANALGESIA, 2012(02)
[2] Drug selection for ambulatory procedural sedation[J]. Barends, Clemens R. M.;Absalom, Anthony R.;Struys, Michel M. R. F. CURRENT OPINION IN ANESTHESIOLOGY, 2018(06)
[3] A Phase IIa, Randomized, Double-Blind Study of Remimazolam (CNS 7056) Versus Midazolam for Sedation in Upper Gastrointestinal Endoscopy[J]. Borkett, Keith M.;Riff, Dennis S.;Schwartz, Howard I.;Winkle, Peter J.;Pambianco, Daniel J.;Lees, James P.;Wilhelm-Ogunbiyi, Karin. ANESTHESIA AND ANALGESIA, 2015(04)
[4] Bispectral index monitoring of sedation during endoscopy[J]. Bower, AL;Ripepi, A;Dilger, J;Boparai, N;Brody, FJ;Ponsky, JL. GASTROINTESTINAL ENDOSCOPY, 2000(02)
[5] Human pharmacology of positive GABA-A subtype-selective receptor modulators for the treatment of anxiety[J]. Chen, Xia;van Gerven, Joop;Cohen, Adam;Jacobs, Gabriel. ACTA PHARMACOLOGICA SINICA, 2019(05)
[6] Pharmacodynamic response profiles of anxiolytic and sedative drugs[J]. Chen, Xia;Broeyer, Freerk;de Kam, Marieke;Baas, Joke;Cohen, Adam;van Gerven, Joop. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2017(05)
[7] AZD6280, a Novel Partial γ-Aminobutyric Acid A Receptor Modulator, Demonstrates a Pharmacodynamically Selective Effect Profile in Healthy Male Volunteers[J]. Chen, Xia;Jacobs, Gabriel;de Kam, Marieke L.;Jaeger, Judith;Lappalainen, Jaakko;Maruff, Paul;Smith, Mark A.;Cross, Alan J.;Cohen, Adam;van Gerven, Joop. JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, 2015(01)
[8] An Overview of the CNS-Pharmacodynamic Profiles Nonselective and Selective GABA Agonists[J]. Chen, Xia;de Haas, Sanne;de Kam, Marieke;van Gerven, Joop. ADVANCES IN PHARMACOLOGICAL SCIENCES, 2012
[9] The central nervous system effects of the partial GABA-Aα2,3-selective receptor modulator AZD7325 in comparison with lorazepam in healthy males[J]. Chen, Xia;Jacobs, Gabriel;de Kam, Marieke;Jaeger, Judith;Lappalainen, Jaakko;Maruff, Paul;Smith, Mark A.;Cross, Alan J.;Cohen, Adam;van Gerven, Joop. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2014(06)
[10] The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABA-A α2,3 selective agonist, in comparison with lorazepam in healthy volunteers[J]. de Haas, S. L.;Franson, K. L.;Schmitt, J. A. J.;Cohen, A. F.;Fau, J. B.;Dubruc, C.;van Gerven, J. M. A. JOURNAL OF PSYCHOPHARMACOLOGY, 2009(06)

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