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Remimazolam: An Updated Review of a New Sedative and Anaesthetic.

ABSTRACT: Remimazolam (CNS7056) is a novel benzodiazepine for intravenous sedation; it has an ultra-short duration of action and was recently approved for use in procedural sedation and general anaesthesia. It acts on γ-aminobutyric acid type A receptors and is rapidly converted into an inactive metabolite by tissue esterase enzymes. Remimazolam has been successfully used in endoscopic inspection or surgery and general anaesthesia induction and maintenance with fast and predictable onset and recovery times, high procedure success rates, and minor respiratory and hemodynamic fluctuations and without serious drug-related adverse reactions. If needed, the effects of remimazolam can be reversed by flumazenil, which allows prompt termination of sedation. Although remimazolam has great potential for sedation in patients admitted to intensive care units, future studies are needed to evaluate its efficacy and safety in patients requiring sedation for a long period, and numerous studies are warranted to explore the optimal dose in different application scenarios. The review aimed to provide an introduction to the process of remimazolam synthesis and its current clinical uses and future clinical developments.

SUBMITTER: Hu Q

PROVIDER: S-EPMC9675580 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Remimazolam: An Updated Review of a New Sedative and Anaesthetic.

Hu Qinxue Q Liu Xing X Wen Chengli C Li Duo D Lei Xianying X

Drug design, development and therapy 20221115

Remimazolam (CNS7056) is a novel benzodiazepine for intravenous sedation; it has an ultra-short duration of action and was recently approved for use in procedural sedation and general anaesthesia. It acts on γ-aminobutyric acid type A receptors and is rapidly converted into an inactive metabolite by tissue esterase enzymes. Remimazolam has been successfully used in endoscopic inspection or surgery and general anaesthesia induction and maintenance with fast and predictable onset and recovery time ...[more]

PMID: 36411859

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Project description: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.

Project description:BackgroundElectrical cardioversion is an effective procedure for restoring normal sinus rhythm in the hearts of patients with irregular heart rhythms. It is important that the patient is not fully conscious during the procedure, as it can be painful and distressing. The drug used to make patients unaware of the procedure should rapidly achieve the desired level of sedation, should wear off quickly and should not cause cardiovascular or respiratory side effects.ObjectivesWe aimed to compare the safety, effectiveness and adverse events associated with various anaesthetic or sedative agents used in direct current cardioversion for cardiac arrhythmia in both elective and emergency settings.We sought answers to the following specific questions.• Which drugs deliver the best outcomes for patients undergoing electrical cardioversion?• Does using a particular agent confer advantages or disadvantages?• Is additional analgesic necessary to prevent pain?Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) on 27 March 2014. Our search terms were relevant to the review question and were not limited by outcomes. We also carried out searches of clinical trials registers and forward and backward citation tracking.Selection criteriaWe considered all randomized controlled trials and quasi-randomized and cluster-randomized studies with adult participants undergoing electrical cardioversion procedures in the elective or emergency setting.Data collection and analysisTwo review authors independently assessed trial quality and extracted data, consulting with a third review author for disagreements. We used standard Cochrane methodological procedures, including assessment of risk of bias for all studies.Main resultsWe included 23 studies with 1250 participants that compared one drug with one or more other drugs. Of these comparisons, 19 studies compared propofol with another drug. Seven of these compared propofol with etomidate (four of which combined the drugs with remifentanil or fentanyl), five midazolam, six thiopentone and two sevoflurane. Three studies compared etomidate with thiopentone, and three etomidate with midazolam. Two studies compared thiopentone with midazolam, one thiopentone with diazepam and one midazolam with diazepam. Drug doses and the time over which the drugs were given varied between studies. Although all studies were described as randomized, limited information was provided about the methods used for selection and group allocation. A high level of performance bias was observed across studies, as study authors had not attempted to blind the anaesthetist to group allocation. Similarly, study authors had rarely provided sufficient information on whether outcome assessors had been blinded.Included studies presented outcome data for hypotension, apnoea, participant recall, success of cardioversion, minor adverse events of nausea and vomiting, pain at injection site and myoclonus, additional analgesia and participant satisfaction. We did not pool the data from different studies in view of the multiple drug comparisons, differences in definitions and reporting of outcomes, variability of endpoints and high or unclear risk of bias across studies.Authors' conclusionsFew studies reported statistically significant results for our relevant outcomes, and most study authors concluded that both, or all, agents compared in individual studies were adequate for cardioversion procedures. It is our opinion that at present, there is no evidence to suggest that current anaesthetic practice for cardioversion should change.

Project description:BackgroundRemimazolam is a newer benzodiazepine with properties of rapid onset, short duration of action, and fast recovery. Our study was to evaluate the effects of different doses of remimazolam combined with alfentanil in colonoscopic polypectomy.MethodsOne hundred twenty patients were randomly divided into four groups: alfentanil and propofol (AP) group, alfentanil and remimazolam 0.1 mg/kg (AR1 group), 0.15 mg/kg (AR2 group), or 0.2 mg/kg (AR3 group). Patients in the four groups received alfentanil 10 μg/kg, followed by propofol 2 mg/kg and three dosages of remimazolam. Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale, heart rate (HR), oxygen saturation (SpO2), respiratory rate (RR), bispectral index (BIS) values and mean arterial pressure (MAP) were collected at intervals of 5 min and analyzed at different time points: before anesthesia (T0), 5 min (T1), 10 min (T2), 15 min after anesthesia (T3) and at the end of surgery (T4). The average MAP was calculated utilizing the average of all MAP values. The primary outcome was the success rate of sedation. Secondary outcomes included time to full alert and adverse events.ResultsThe success rate of sedation was 100% among the four groups. The incidence of hypotension was significantly decreased (all P < 0.05) and the average MAP was higher in AR1-AR3 groups than AP group (all P < 0.001). None of the patients developed bradycardia or hypertension during surgery in all study groups. BIS values were higher (all P < 0.001) and the time to full alert was statistically shorter in AR1-AR3 groups (all P < 0.05) compared with the AP group. The MOAA/S score in AR1 was higher than AR2 (P < 0.05) and the AR3 group (P < 0.05) at T1 and BIS values in the AR1 group were significantly higher than AR3 group (P < 0.05) at T4.ConclusionsRemimazolam combined with alfentanil have a non-inferior sedative effect than propofol during the colonoscopic polypectomy. Moreover, this combination of two short-acting drugs might be a safer alternative.Trial registrationThe clinical trial was registered on (16/05/2021, ChiCTR2100046492).

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Remimazolam: An Updated Review of a New Sedative and Anaesthetic.

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Remimazolam: An Updated Review of a New Sedative and Anaesthetic.

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