Détail de la notice
Titre du Document
Rapid Chemical Antagonism of Neuromuscular Blockade by L-Cysteine Adduction to and Inactivation of the Olefinic (Double-bonded) Isoquinolinium Diester Compounds Gantacurium (AV430A), CW 002, and CW 011
Auteur(s)
SAVARESE John J. ; MCGILVRA Jeff D. ; SUNAGA Hiroshi ; ...
Résumé
Background: The ultra-short-acting neuromuscular blocker gantacurium is chemically degraded in vitro by rapid adduction of L-cysteine to its central olefinic double bond. Preliminary data have suggested that exogenous (intravenous) L-cysteine abolishes gantacurium blockade. Two new analogues of gantacurium (CW 002 and CW 011) have been synthesized to undergo slower L-cysteine adduction, yielding intermediate duration. L-Cysteine adduction to and antagonism of these novel agents is further defined herein. Methods: Comparative reaction half-time for L-cysteine adduction in vitro of the three compounds was determined by high-performance liquid chromatography. ED95 for twitch inhibition in monkeys under isoflurane was calculated, and duration at ~4-5× ED95 was correlated with reaction half-time for adduction. Speed of L-cysteine antagonism was contrasted with anticholinesterase reversal. Potencies of CW 002 and its adduction product were compared to provide a basis for L-cysteine antagonism. Results: Rate of L-cysteine adduction in vitro (reaction half-time) was 11.4 and 13.7 min for CW 002 and CW 011 versus 0.2 min for gantacurium, and was inversely related to duration of block (P < 0.0001). CW 002 and CW 011 were 3 X longer acting than gantacurium (28.1 and 33.3 min vs. 10.4 min), but only half the duration of cisatracurium. The adduct of CW 002 was ~70 × less potent than CW 002. L-Cysteine (10-50 mg/kg intravenously) give
Editeur
Lippincott
Identifiant
PMID : 20526187 ISSN : 0003-3022 CODEN : ANESAV
Source
Anesthesiology (Philadelphia) A. 2010, vol. 113, n° 1, pp. 58-73 [16 pages] [bibl. : 35 ref.]
Langue
Anglais
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