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Cyclopropyl methoxycarbonyl metomidate

Raymond J Malapero, Michael P Zaccagnino, Ethan Y Brovman, Alan David Kaye, Richard D Urman
Etomidate is an imidazole derivative that possesses important sedative properties employed in anesthesia practice, however, etomidate has a number of well-know side effects which limit its use in certain subpopulations and over long periods of time, mostly related to dose-dependent adrenal suppression. This review focuses on novel etomidate derivatives with an emphasis on pharmacological properties which afford improved safety profile and potentially desirable clinical effects. The pharmacology and clinical investigation of some of these etomidate derivatives, e...
October 2017: Journal of Anaesthesiology, Clinical Pharmacology
Narjeet Khurmi, Perene Patel, Molly Kraus, Terrence Trentman
Understanding the pharmacologic options for pediatric sedation outside the operating room will allow practitioners to formulate an ideal anesthetic plan, allaying anxiety and achieving optimal immobilization while ensuring rapid and efficient recovery. The authors identified relevant medical literature by searching PubMed, MEDLINE, Embase, Scopus, Web of Science, and Google Scholar databases for English language publications covering a period from 1984 to 2017. Search terms included pediatric anesthesia, pediatric sedation, non-operating room sedation, sedation safety, and pharmacology...
October 2017: Paediatric Drugs
Ervin Pejo, Xiaojuan Zhou, S Shaukat Husain, Douglas E Raines
BACKGROUND: Etomidate potently suppresses adrenocortical steroid synthesis with potentially deleterious consequences by binding to 11β-hydroxylase and inhibiting its function. The authors hypothesized that other sedative-hypnotics currently in clinical use or under development (or their metabolites) might bind to the same site at clinically relevant concentrations. The authors tested this hypothesis by defining etomidate's affinity for this site and the potencies with which other sedative-hypnotics (and their metabolites) inhibit etomidate binding...
November 2016: Anesthesiology
Ervin Pejo, Jifeng Liu, Xiangjie Lin, Douglas E Raines
BACKGROUND: Methoxycarbonyl etomidate (MOC-etomidate) and cyclopropyl methoxycarbonyl metomidate (CPMM) are rapidly metabolized "soft" etomidate analogs. CPMM's duration of hypnotic effect is context insensitive, whereas MOC-etomidate's is not. In this study, we tested the hypothesis that CPMM's effect is context insensitive because, unlike MOC-etomidate, its metabolite fails to reach physiologically important concentrations in vivo even with prolonged continuous infusion. METHODS: We compared the potencies with which MOC-etomidate and CPMM activate α1(L264T)β3γ2 γ-aminobutyric acid type A receptors and induce loss-of-righting reflexes (i...
April 2016: Anesthesia and Analgesia
Peter Santer, Ervin Pejo, Yan Feng, Wei Chao, Douglas E Raines
BACKGROUND: Cyclopropyl-methoxycarbonyl metomidate (CPMM) is a rapidly metabolized etomidate analog that is currently in clinical trials. The goal of this study is to assess CPMM's potential value as an anesthetic agent for use in patients with sepsis by defining its actions in an acute inflammatory model of sepsis. METHODS: Escherichia coli lipopolysaccharide (1 mg/kg) was injected intravenously into Sprague-Dawley rats. Thirty minutes later, CPMM, etomidate, or vehicle (n = 8 per group) was infused for 1 h...
August 2015: Anesthesiology
Jason A Campagna, Kevin Pojasek, David Grayzel, John Randle, Douglas E Raines
BACKGROUND: Cyclopropyl-methoxycarbonyl metomidate (CPMM, also known as ABP-700) is a second-generation "soft" (i.e., metabolically labile) etomidate analogue. The purpose of this study was to characterize CPMM's pharmacology in beagle dogs in preparation for potential first in human phase 1 clinical trials. METHODS: CPMM's and etomidate's hypnotic activity and duration of action were assessed using loss of righting reflex and anesthesia score assays in three or four dogs...
December 2014: Anesthesiology
Rile Ge, Ervin Pejo, Hilary Gallin, Spencer Jeffrey, Joseph F Cotten, Douglas E Raines
BACKGROUND: Cyclopropyl-methoxycarbonyl metomidate (CPMM) is a "soft" etomidate analogue currently being developed as a propofol alternative for anesthetic induction and maintenance. METHODS: We compared the potencies of CPMM and propofol by assessing their abilities to directly activate α1(L264T)β3γ2 gamma-aminobutyric acid type A (GABAA) receptors and induce loss of righting reflexes in tadpoles. We also measured the rates of encephalographic recovery in rats after CPMM and propofol infusions ranging in duration from 5 to 120 minutes...
March 2014: Anesthesia and Analgesia
Rile Ge, Ervin Pejo, Joseph F Cotten, Douglas E Raines
INTRODUCTION: Etomidate 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...
2013: Critical Care: the Official Journal of the Critical Care Forum
S Shaukat Husain, Ervin Pejo, Rile Ge, Douglas E Raines
BACKGROUND: Methoxycarbonyl etomidate is the prototypical very rapidly metabolized etomidate analog. Initial studies suggest that it may be too short acting for many clinical uses. We hypothesized that its duration of action could be lengthened and clinical utility broadened by incorporating specific aliphatic groups into the molecule to sterically protect its ester moiety from esterase-catalyzed hydrolysis. To test this hypothesis, we developed a series of methoxycarbonyl etomidate analogs (spacer-linked etomidate esters) containing various aliphatic-protecting groups and spacer lengths...
November 2012: Anesthesiology
Rile Ge, Ervin Pejo, S Shaukat Husain, Joseph F Cotten, Douglas E Raines
BACKGROUND: Methoxycarbonyl etomidate is the prototypical soft etomidate analog. Because it has relatively low potency and is extremely rapidly metabolized, large quantities must be infused to maintain hypnosis. Consequently with prolonged infusion, metabolite reaches sufficient concentrations to delay recovery. Dimethyl-methoxycarbonyl metomidate (DMMM) and cyclopropyl-methoxycarbonyl metomidate (CPMM) are methoxycarbonyl etomidate analogs with higher potencies and slower clearance. Because of these properties, we hypothesized that dosing would be lower and electroencephalographic and hypnotic recoveries would be faster - and less context-sensitive - with DMMM or CPMM versus methoxycarbonyl etomidate or etomidate...
November 2012: Anesthesiology
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