Is Anesthesiology Going Soft?

Egan, Talmage D.

doi:10.1097/aln.0b013e3181ae8460

Cited by 45 publications

(16 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The development of soft etomidate analogues follows a trend in drug development toward agents that are ultra-short-acting and is in response to the need in the operating room and intensive care unit for more precise temporal control of drug effects [30]. Esmolol and remifentanil are commonly used examples of soft drugs that serve this need and use the same labile ester strategy employed in our etomidate analogues [31].…”

Section: Discussionmentioning

confidence: 99%

Adrenocortical suppression and recovery after continuous hypnotic infusion: etomidate versus its soft analogue cyclopropyl-methoxycarbonyl metomidate

Pejo

Cotten

et al. 2013

Crit Care

View full text Add to dashboard Cite

IntroductionEtomidate is no longer administered as a continuous infusion for anesthetic maintenance or sedation, because it results in profound and persistent suppression of adrenocortical steroid synthesis with potentially lethal consequences in critically ill patients. We hypothesized that rapidly metabolized soft analogues of etomidate could be developed that do not produce persistent adrenocortical dysfunction even after prolonged continuous infusion. We hope that such agents might also provide more rapid and predictable anesthetic emergence. We have developed the soft etomidate analogue cyclopropyl-methoxycarbonyl etomidate (CPMM). Upon termination of 120-minute continuous infusions, hypnotic and encephalographic recoveries occur in four minutes. The aims of this study were to assess adrenocortical function during and following 120-minute continuous infusion of CPMM and to compare the results with those obtained using etomidate.MethodsDexamethasone-suppressed rats were randomized into an etomidate group, CPMM group, or control group. Rats in the etomidate and CPMM groups received 120-minute continuous infusions of etomidate and CPMM, respectively. Rats in the control group received neither hypnotic. In the first study, adrenocortical function during hypnotic infusion was assessed by administering adrenocorticotropic hormone (ACTH) 90 minutes after the start of the hypnotic infusion and measuring plasma corticosterone concentrations at the end of the infusion 30 minutes later. In the second study, adrenocortical recovery following hypnotic infusion was assessed by administering ACTH every 30 minutes after infusion termination and measuring plasma corticosterone concentrations 30 minutes after each ACTH dose.ResultsDuring hypnotic infusion, ACTH-stimulated serum corticosterone concentrations were significantly lower in the CPMM and etomidate groups than in the control group (100 ± 64 ng/ml and 33 ± 32 ng/ml versus 615 ± 265 ng/ml, respectively). After hypnotic infusion, ACTH-stimulated serum corticosterone concentrations recovered to control values within 30 minutes in the CPMM group but remained suppressed relative to those in the control group for more than 3 hours in the etomidate group.ConclusionsBoth CPMM and etomidate suppress adrenocortical function during continuous infusion. However, recovery occurs significantly more rapidly following infusion of CPMM.

show abstract

Section: Discussionmentioning

confidence: 99%

Adrenocortical suppression and recovery after continuous hypnotic infusion: etomidate versus its soft analogue cyclopropyl-methoxycarbonyl metomidate

Pejo

Cotten

et al. 2013

Crit Care

View full text Add to dashboard Cite

show abstract

“…18 In anesthesia, the soft drug concept is useful because it enables precise titration to effect and rapid recovery. The short acting opioid remifentanil and beta-blocker esmolol are familiar applications of this pharmaceutic approach in perioperative practice.…”

Section: Discussionmentioning

confidence: 99%

Azd-3043

et al. 2012

Self Cite

View full text Add to dashboard Cite

Background Propofol can be associated with delayed awakening after prolonged infusion. The aim of this study was to characterize the preclinical pharmacology of AZD-3043, a positive allosteric modulator of the γ-aminobutyric acidA (GABAA) receptor containing a metabolically-labile ester moiety. We postulated that its metabolic pathway would result in a short acting clinical profile. Methods The effects of AZD-3043, propofol and propanidid were studied on GABAA receptor-mediated chloride currents in embryonic rat cortical neurons. Radioligand binding studies were also performed. The in vitro stability of AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the loss of righting reflex and effects on the electroencephalograph evoked by bolus or infusion intravenous (IV) administration were assessed in rats. A mixed-effects kinetic-dynamic model using minipigs permitted exploration of the clinical pharmacology of AZD-3043. Results AZD-3043 potentiated GABAA receptor-mediated chloride currents and inhibited [35S]tert-butylbicyclophosphorothionate binding to GABAA receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from humans and animals. AZD-3043 produced hypnosis and electroencephalograph depression in rats. Compared to propofol, AZD-3043 was shorter acting in rats and pigs. Computer simulation using the porcine kinetic-dynamic model demonstrated that AZD-3043 has very short 50 and 80% decrement times independent of infusion duration. Conclusions AZD-3043 is a positive allosteric modulator of the GABAA receptor in vitro and a sedative/hypnotic agent in vivo. The esterase dependent metabolic pathway results in rapid clearance and short duration of action even for long infusions. AZD-3043 may have clinical potential as a sedative/hypnotic agent with rapid and predictable recovery.

show abstract

“…"Soft" drugs are those molecules that are purposefully designed to be rapidly metabolized (metabolically labile) [1]. In anesthesia, a soft drug is useful because it enables precise titration to effect and rapid recovery, which may allow swift and clear-headed recovery of consciousness and early home readiness [2].…”

Section: Introductionmentioning

confidence: 99%

“…Yield: 83%; mp: 103e105 C 1. H NMR (DMSO-d 6 ) d 3.78 (s, 3H), 4.91 (s, 1H), 6.77e6.84 (m, 2H), 12.18 (s, 1H).…”

mentioning

confidence: 99%

Phenyl acetate derivatives, fluorine-substituted on the phenyl group, as rapid recovery hypnotic agents with reflex depression

Zhang

Chen

et al. 2015

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

Is Anesthesiology Going Soft?

Cited by 45 publications

References 16 publications

Adrenocortical suppression and recovery after continuous hypnotic infusion: etomidate versus its soft analogue cyclopropyl-methoxycarbonyl metomidate

Adrenocortical suppression and recovery after continuous hypnotic infusion: etomidate versus its soft analogue cyclopropyl-methoxycarbonyl metomidate

Azd-3043

Phenyl acetate derivatives, fluorine-substituted on the phenyl group, as rapid recovery hypnotic agents with reflex depression

Contact Info

Product

Resources

About