A miniature pig model of pharmacological tolerance to long-term sedation with the intravenous benzodiazepines; midazolam and remimazolam

Io, Toshiro; Saunders, Rob; Pesic, Marija; Petersen, Karl‐Uwe; Stoehr, Thomas

doi:10.1016/j.ejphar.2021.173886

Cited by 16 publications

(9 citation statements)

References 21 publications

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“…131 Remimazolam has been used to sedate pigs for 28 days. 132 A bioreactor study using human hepatocytes showed no adverse changes in remimazolam metabolism over a 5 day period. 133 However, there remains a need for it to be assessed in proper randomised clinical trials against current standard drugs (propofol, midazolam, and dexmedetomidine).…”

Section: Intensive Care Sedationmentioning

confidence: 96%

Current status of perioperative hypnotics, role of benzodiazepines, and the case for remimazolam: a narrative review

Sneyd

Gambús

Rigby-Jones

2021

British Journal of Anaesthesia

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Anaesthesiologists and non-anaesthesiologist sedationists have a limited set of available i.v. hypnotics, further reduced by the withdrawal of thiopental in the USA and its near disappearance in Europe. Meanwhile, demand for sedation increases and new clinical groups are using what traditionally are anaesthesiologists' drugs. Improved understanding of the determinants of perioperative morbidity and mortality has spotlighted hypotension as a potent cause of patient harm, and practice must be adjusted to respect this. High-dose propofol sedation may be harmful, and a critical reappraisal of drug choices and doses is needed. The development of remimazolam, initially for procedural sedation, allows reconsideration of benzodiazepines as the hypnotic component of a general anaesthetic even if their characterisation as i.v. anaesthetics is questionable. Early data suggest that a combination of remimazolam and remifentanil can induce and maintain anaesthesia. Further work is needed to define use cases for this technique and to determine the impact on patient outcomes.

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Section: Intensive Care Sedationmentioning

confidence: 96%

Current status of perioperative hypnotics, role of benzodiazepines, and the case for remimazolam: a narrative review

Sneyd

Gambús

Rigby-Jones

2021

British Journal of Anaesthesia

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“…Bevans and colleagues ( Bevans et al, 2017 ) reported that remimazolam could induce sedation in mice via the inhalation route and that remimazolam potentiated the effects of remifentanil when both drugs were administered by that route to rats. Io et al ( Io et al, 2021 ) observed tolerance to remimazolam over a 28 days dosing period in the pig. However, the tolerance observed (assessed by the requirement to increase the dose to maintain the same sedative effect) was less than that seen with midazolam.…”

Section: Remimazolammentioning

confidence: 99%

“…Remimazolam is likely to have the same liabilities, but they are probably mitigated to an extent because of the short duration of effect and the requirement for intravenous administration. Indeed, Io et al ( Io et al, 2021 ) observed tolerance to the effects of remimazolam over a 28 days dosing period in the pig, but note that the tolerance observed (assessed by the requirement to increase the dose to maintain the same sedative effect) was less than that seen with midazolam. As might be predicted, a reduced sedative effect of remimazolam has been observed in subjects with an existing tolerance to benzodiazepines resulting from long-term use equivalent to 15–20 mg diazepam per day ( Yoshikawa et al, 2021 ).…”

Section: Remimazolammentioning

confidence: 99%

Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

Kilpatrick¹

2021

Front. Pharmacol.

143

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A program to identify novel intravenous sedatives with a short and predictable duration of action was initiated in the late 1990’s by Glaxo Wellcome. The program focussed on the identification of ester-based benzodiazepine derivatives that are rapidly broken down by esterases. Remimazolam was identified as one of the lead compounds. The project at Glaxo was shelved for strategic reasons at the late lead optimization stage. Via the GSK ventures initiative, the program was acquired by the small biotechnology company, TheraSci, and, through successive acquisitions, developed as the besylate salt at CeNeS and PAION. The development of remimazolam besylate has been slow by industry standards, primarily because of the resource limitations of these small companies. It has, however, recently been approved for anesthesia in Japan and South Korea, procedural sedation in the United States, China, and Europe, and for compassionate use in intensive care unit sedation in Belgium. A second development program of remimazolam was later initiated in China, using a slightly different salt form, remimazolam tosylate. This salt form of the compound has also recently been approved for procedural sedation in China. Remimazolam has the pharmacological profile of a classical benzodiazepine, such as midazolam, but is differentiated from other intravenous benzodiazepines by its rapid conversion to an inactive metabolite resulting in a short onset/offset profile. It is differentiated from other intravenous hypnotic agents, such as propofol, by its low liability for cardiovascular depression, respiratory depression, and injection pain. The benzodiazepine antagonist flumazenil can reverse the effects of remimazolam in case of adverse events and further shorten recovery times. The aim of this review is to provide an analysis of, and perspective on, published non-clinical and clinical information on 1) the pharmacology, metabolism, pharmacokinetics, and pharmacodynamic profile of remimazolam, 2) the profile of remimazolam compared with established agents, 3) gaps in the current understanding of remimazolam, 4) the compound’s discovery and development process and 5) likely future developments in the clinical use of remimazolam.

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“…Benzodiazepines are often included in anti-epileptic prescriptions, and patients with epilepsy receiving AEDs can require a greater dose of anesthetic drugs [15]. Yoshikawa et al [16] reported that remimazolam could be inappropriate in long-term benzodiazepine user.…”

Section: Discussionmentioning

confidence: 99%

Total intravenous anesthesia with remimazolam in a patient with epilepsy who underwent deep brain stimulation: a case report

Lee

Hong

Lim

et al. 2022

J Korean Ster Func Neurosurg

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Drugs administered for anesthesia can trigger seizure attacks in patients with epilepsy. Benzodiazepines have been consistently reported to be anticonvulsants, and a novel benzodiazepine, remimazolam, was recently introduced. We report a case of total intravenous anesthesia maintained with remimazolam in a patient with epilepsy who underwent deep brain stimulation of both anterior thalamic nuclei. Despite the administration of multiple anti-epileptic drugs, no tolerance to remimazolam was observed. Perioperative seizures were also not observed. Remimazolam can be considered the anesthetic of choice in patients with epilepsy.

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A miniature pig model of pharmacological tolerance to long-term sedation with the intravenous benzodiazepines; midazolam and remimazolam

Cited by 16 publications

References 21 publications

Current status of perioperative hypnotics, role of benzodiazepines, and the case for remimazolam: a narrative review

Current status of perioperative hypnotics, role of benzodiazepines, and the case for remimazolam: a narrative review

Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

Total intravenous anesthesia with remimazolam in a patient with epilepsy who underwent deep brain stimulation: a case report

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