Background Etomidate is a rapidly-acting sedative-hypnotic that provides hemodynamic stability. However because it causes prolonged suppression of adrenocortical steroid synthesis, its clinical utility and safety are limited. We describe the results of studies to define the pharmacology of (R)-3-methoxy-3-oxopropyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-etomidate), the first etomidate analogue designed to be susceptible to ultra-rapid metabolism. Methods The γ-aminobutyric acid type A receptor activities of MOC-etomidate and etomidate were compared using electrophysiological techniques in human α1β2γ2L receptors. MOC-etomidate’s hypnotic concentration was determined in tadpoles using a loss of righting reflex assay. Its in-vitro metabolic half-life was measured in human liver S9 fraction and the resulting metabolite provisionally identified using high performance liquid chromatography/mass spectrometry techniques. The hypnotic and hemodynamic actions of MOC-etomidate, etomidate, and propofol were defined in rats. The abilities of MOC-etomidate and etomidate to inhibit corticosterone production were assessed in rats. Results MOC-etomidate potently enhanced γ-aminobutyric acid type A receptor function and produced loss of righting reflex in tadpoles. Metabolism in human liver S9 fraction was first-order with an in-vitro half-life of 4.4 min versus > 40 min for etomidate. MOC-etomidate’s only detectable metabolite was a carboxylic acid. In rats, MOC-etomidate produced rapid loss of righting reflex that was extremely brief and caused minimal hemodynamic changes. Unlike etomidate, MOC-etomidate produced no adrenocortical suppression 30 minutes after administration. Conclusions MOC-etomidate is an etomidate analogue that retains etomidate’s important favorable pharmacological properties. However, it is rapidly metabolized, ultra-short acting, and does not produce prolonged adrenocortical suppression following bolus administration.
Our estimates suggest the prominent relative roles of children aged ≤10 years (particularly among those aged 3-6 years) in propagating RSV epidemics. These results, combined with further modeling work, should help inform RSV vaccination policies.
; for the FAST Research Group IMPORTANCE Methotrexate and mycophenolate mofetil are commonly used immunomodulatory therapies for achieving corticosteroid-sparing control of noninfectious uveitis, but there is uncertainty about which drug is more effective. OBJECTIVE To compare the effect of methotrexate and mycophenolate for achieving corticosteroid-sparing control of noninfectious intermediate uveitis, posterior uveitis, and panuveitis. DESIGN, SETTING, AND PARTICIPANTS The First-line Antimetabolites as Steroid-sparing Treatment (FAST) uveitis trial screened 265 adults with noninfectious uveitis requiring corticosteroid-sparing immunosuppressive therapy from 9 referral eye centers in India, the
Background Etomidate is a sedative-hypnotic that is often used in critically ill patients because it provides superior hemodynamic stability. However it also binds with high affinity to 11β-hydroxylase, potently suppressing synthesis of steroids by the adrenal gland that are necessary for survival. We report the results of studies to define the pharmacology of (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), a pyrrole analogue of etomidate specifically designed not to bind with high affinity to 11β-hydroxylase. Methods The hypnotic potency of carboetomidate was defined in tadpoles and rats using loss of righting reflex assays. Its ability to enhance wild-type α1β2γ2L and etomidate-insensitive mutant α1β2(M286W)γ2L human γ-aminobutyric acid type A receptor activities was assessed using electrophysiological techniques. Its potency for inhibiting in vitro cortisol synthesis was defined using a human adrenocortical cell assay. Its effects on in vivo hemodynamic and adrenocortical function were defined in rats. Results Carboetomidate was a potent hypnotic in tadpoles and rats. It increased currents mediated by wild-type, but not etomidate-insensitive mutant γ-aminobutyric acid type A receptors. Carboetomidate was three orders of magnitude less potent an inhibitor of in vitro cortisol synthesis by adrenocortical cells than was etomidate. In rats, carboetomidate caused minimal hemodynamic changes and did not suppress adrenocortical function at hypnotic doses. Conclusions Carboetomidate is an etomidate analogue that retains many of etomidate’s beneficial properties, but is dramatically less potent as an inhibitor of adrenocortical steroid synthesis. Carboetomidate is a promising new sedative-hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable.
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