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

Abstract

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. ED 95 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× 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) given 1 min after approximately 4-5× ED95 doses of all the three compounds abolished block within 2-3 min. Conclusions: l-Cysteine adduction occurs at different rates by design in olefinic isoquinolinium diester neuromuscular blockers, yielding corresponding durations of action. Antagonism by exogenous l-cysteine is superior to anticholinesterases, inducing inactivation of the active molecules to restore function rapidly at any time. Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins.