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