New Hypnotic Drug Development and Pharmacologic Considerations for Clinical Anesthesia

Tanious, Mariah K.; Beutler, Sascha S.; Kaye, Alan D.; Urman, Richard D.

doi:10.1016/j.anclin.2017.01.017

Cited by 19 publications

(13 citation statements)

References 64 publications

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“…Remimazolam is an ultra–short‐acting novel benzodiazepine, similar to midazolam and remifentanil's complementary advantages 14 . It mainly acts on the GABA‐A receptor and has the advantages of rapid induction, rapid recovery, stable hemodynamics, and mild respiratory inhibition 5,6 .…”

Section: Discussionmentioning

confidence: 99%

“…13 Remimazolam is an ultra-short-acting novel benzodiazepine, similar to midazolam and remifentanil's complementary advantages. 14 It mainly acts on the GABA-A receptor and has the advantages of rapid induction, rapid recovery, stable hemodynamics, and mild respiratory inhibition. 5,6 A study has shown that the pharmacokinetic half-time of remimazolam is about one-fifth of midazolam after three hours of constant rate infusion.…”

Section: Discussionmentioning

confidence: 99%

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Effect of remimazolam induction on hemodynamics in patients undergoing valve replacement surgery: A randomized, double‐blind, controlled trial

Liu

Lai

Chen

et al. 2021

Pharmacology Res & Perspec

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Background The stability of hemodynamics during anesthesia induction in patients undergoing valve replacement surgery is particularly important. Remimazolam is a new type of benzodiazepine drug, with supposed advantages of rapid induction, rapid recovery, stable hemodynamics, and mild respiratory inhibition. Aim To evaluate the effect of remimazolam anesthesia induction on hemodynamics in patients undergoing valve replacement surgery. Methods This randomized, double‐blind, controlled trial enrolled consecutive patients undergoing mitral valve replacement (MVR)/aortic valve replacement (AVR)/double‐valve replacement (DVR) surgery on cardiopulmonary bypass (CPB). The study was conducted according to the Consolidated Standards of Reporting Trials statement. Participants were randomly assigned to receive either remimazolam or propofol induction of 30 patients each. All patients, data collectors, and data analyzers were blinded to the group allocation. The primary outcomes were the fluctuations in hemodynamic parameters (the difference of maximum or minimum heart rate to baseline, ▲HR, the difference of maximum or minimum mean arterial pressure to baseline, ▲MAP), the occurrence of cardiovascular events (hypotension, severe bradycardia), and the cumulative norepinephrine doses used per patient, averaged per group during induction. The secondary outcomes were hemodynamic parameters (heart rate, HR, mean arterial pressure, MAP, bispectral index, BIS, plasma lactic acid, Lac, and blood glucose, Glu values). Results A total of 60 patients with heart valve replacement were included in the final analysis, with 30 patients in each group. The ▲MAP was significantly lower in the remimazolam group than in the propofol group during induction ( p < .05). The incidences of hypotension and the cumulative norepinephrine doses used per patient, averaged per group during induction were significantly lower in the remimazolam group than in the propofol group ( p < .05). Conclusion Remimazolam may be safe and effective for induction and may as an alternative to propofol during anesthesia induction in patients undergoing valve replacement surgery.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effect of remimazolam induction on hemodynamics in patients undergoing valve replacement surgery: A randomized, double‐blind, controlled trial

Liu

Lai

Chen

et al. 2021

Pharmacology Res & Perspec

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“…As a novel benzodiazepine, remimazolam is created from the approach of "soft" drug development, which refers to formation of compounds by fusing a known sedative-hypnotic with a metabolically labile moiety, most commonly an ester, with the hopes of facilitating predictable, rapid enzymatic metabolism, increasing hemodynamic stability, and decreasing adverse effects related to the parent compound. 22,23 With such structural modifications, remimazolam is extensively metabolized by plasma and tissue esterases, thereby resulting in an ultraeshort-acting sedative effect profile. 2 These properties make remimazolam a potential candidate to replace propofol and midazolam in procedural anesthesia.…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Sang

Song

et al. 2020

Clinical Therapeutics

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“…General anesthesia is an essential tool in modern medicine and there is growing interest in developing new sedative-hypnotics with improved clinical utility 1,2 . Current and past clinical sedative-hypnotics represent a variety of anesthetic chemotypes (volatile ethers, barbiturates, phenylacetates, alkyl phenols, arylcyclohexylamines, imidazoles, and steroids), many identified by empiric observation, before 1980.…”

Section: Introductionmentioning

confidence: 99%

“…Current and past clinical sedative-hypnotics represent a variety of anesthetic chemotypes (volatile ethers, barbiturates, phenylacetates, alkyl phenols, arylcyclohexylamines, imidazoles, and steroids), many identified by empiric observation, before 1980. Most new hypnotics in clinical development are modifications or reformulations of these drugs 1 .…”

Section: Introductionmentioning

confidence: 99%

High-throughput Screening in Larval Zebrafish Identifies Novel Potent Sedative-hypnotics

et al. 2018

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What We Already Know about This Topic What This Article Tells Us That Is New Background Many general anesthetics were discovered empirically, but primary screens to find new sedative-hypnotics in drug libraries have not used animals, limiting the types of drugs discovered. The authors hypothesized that a sedative-hypnotic screening approach using zebrafish larvae responses to sensory stimuli would perform comparably to standard assays, and efficiently identify new active compounds. Methods The authors developed a binary outcome photomotor response assay for zebrafish larvae using a computerized system that tracked individual motions of up to 96 animals simultaneously. The assay was validated against tadpole loss of righting reflexes, using sedative-hypnotics of widely varying potencies that affect various molecular targets. A total of 374 representative compounds from a larger library were screened in zebrafish larvae for hypnotic activity at 10 µM. Molecular mechanisms of hits were explored in anesthetic-sensitive ion channels using electrophysiology, or in zebrafish using a specific reversal agent. Results Zebrafish larvae assays required far less drug, time, and effort than tadpoles. In validation experiments, zebrafish and tadpole screening for hypnotic activity agreed 100% (n = 11; P = 0.002), and potencies were very similar (Pearson correlation, r > 0.999). Two reversible and potent sedative-hypnotics were discovered in the library subset. CMLD003237 (EC50, ~11 µM) weakly modulated γ-aminobutyric acid type A receptors and inhibited neuronal nicotinic receptors. CMLD006025 (EC50, ~13 µM) inhibited both N-methyl-d-aspartate and neuronal nicotinic receptors. Conclusions Photomotor response assays in zebrafish larvae are a mechanism-independent platform for high-throughput screening to identify novel sedative-hypnotics. The variety of chemotypes producing hypnosis is likely much larger than currently known.

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New Hypnotic Drug Development and Pharmacologic Considerations for Clinical Anesthesia

Cited by 19 publications

References 64 publications

Effect of remimazolam induction on hemodynamics in patients undergoing valve replacement surgery: A randomized, double‐blind, controlled trial

Effect of remimazolam induction on hemodynamics in patients undergoing valve replacement surgery: A randomized, double‐blind, controlled trial

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

High-throughput Screening in Larval Zebrafish Identifies Novel Potent Sedative-hypnotics

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