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.
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 approximately 4-5x 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 3x 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 approximately 70x less potent than CW 002. L-cysteine (10-50 mg/kg intravenously) given 1 min after approximately 4-5x 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.
Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York 10065, USA. jjsavare@med.cornell.edu
John J
JJ
Savarese
Jeff D
JD
McGilvra
Hiroshi
H
Sunaga
Matthew R
MR
Belmont
Scott G
SG
Van Ornum
Peter M
PM
Savard
Paul M
PM
Heerdt
D000475:Alkenes / Q000037:antagonists & inhibitors; D000818:Animals; D001279:Atracurium / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D055598:Chemical Phenomena; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003545:Cysteine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004491:Edrophonium / Q000008:administration & dosage; D000882:Haplorhini; D007546:Isoquinolines / Q000037:antagonists & inhibitors*; D008253:Macaca mulatta; D008297:Male; D008298:Maleates / Q000037:antagonists & inhibitors*; D009388:Neostigmine / Q000008:administration & dosage; D019148:Neuromuscular Blockade; D009466:Neuromuscular Blocking Agents / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000475:Alkenes; C542547:CW 002; C550913:CW 011; D002800:Cholinesterase Inhibitors; D007546:Isoquinolines; D008298:Maleates; D009466:Neuromuscular Blocking Agents; D001279:Atracurium; D009388:Neostigmine; D004491:Edrophonium; D003545:Cysteine; C451919:gantacurium; C101584:cisatracurium