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Hypnotics and sedatives ...New agents in the horizon..part 1


Remimazolam (CNS 7056) is a new benzodiazepine metabolized by tissue esterases so that it has a rapid, more predictable offset of action than other clinically available benzodiazepines. The first clinical studies of remimazolam (CNS 7056) were published recently.
The first phase I study was a relatively compre- hensive, placebo and active midazolam controlled single-dose escalation study in 81 subjects. Ten cohorts of subjects received remimazolam from 0.01 to 0.30 mg/kg, or midazolam 0.075 mg/kg or placebo for comparison. Frequent arterial and venous blood samples were taken for pharmaco- kinetic analysis, and Modified Observer’s Assess- ment of Alertness/Sedation (MOAA/S) scores and bispectral index (BIS) monitoring were used as the main assessments of sedation.
Remimazolam produced rapid dose-dependent sedation at doses from 0.075 mg/kg, with onset times of 1 – 3 min. Remimazolam 0.075 – 0.20 mg/kg produced similar peak sedation to midazolam 0.075mg/kg, but median recovery times at these doses ranged from 5 to 20min, compared with 40min for midazolam. There were three cases of hemoglobin desaturation at higher remimazolam doses, likely reflecting some upper airway obstruction, but no cardiovascular instability or serious adverse events.
Noncompartmental analysis confirmed rapid metabolism, with the mean (SD) clearance of remi- mazolam (70.3 (13.9) l/h) being three times that of midazolam 23.0 (4.5) l/h, the mean residence time of remimazolam (0.51h) seven times less than midazolam (3.6h) and the mean (SD) steady state volume of distribution for remimazolam (34.8 (9.4) l) less than half that of midazolam (81.8 (27.1) l 
The first phase II study of remimazolam was in patients undergoing diagnostic upper gastrointestinal endoscopy .Unfortunately, problems with the study design made it difficult to evaluate some of the results. One hundred patients were randomized in a double-blind manner at seven sites to receive a single dose of remimazolam (0.10, 0.15 or 0.20mg/kg) or midazolam (0.075 mg/kg). Success was achieved in 32%, 56%, 64% and 44% of patients respectively, but success was defined by a composite endpoint. Half of the patients required additional sedation with either midazolam or propofol, and this additional sedation was considered a failure, even though endoscopy was completed in all patients with mean procedure times of 3.3 – 4.3 min. The onset of sedation in the remimazolam groups was 1.5 – 2.5 min compared with 5 min for midazolam. Recovery in the remimazolam groups was 11.0– 13.4 min compared with 17.2 min for midazolam, but the additional sedation given made it difficult to evaluate the effect of remimazolam alone
Bodor N, Buchwald P. Soft drug design: general principles and recent applications. Med Res Rev 2000; 20:58–101. 

Sneyd JR. Remimazolam: new beginnings or just a me-too? Anesth Analg 2012; 115:217


 

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