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 ∼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.

[1]  C. Lien,et al.  Pharmacology of Muscle Relaxants and Their Antagonists , 2010 .

[2]  J. Hunter,et al.  Reversal of neuromuscular block. , 2009, British journal of anaesthesia.

[3]  M. Eikermann,et al.  Impaired Upper Airway Integrity by Residual Neuromuscular Blockade: Increased Airway Collapsibility and Blunted Genioglossus Muscle Activity in Response to Negative Pharyngeal Pressure , 2009, Anesthesiology.

[4]  C. Lien,et al.  Fumarates: unique nondepolarizing neuromuscular blocking agents that are antagonized by cysteine. , 2009, Journal of critical care.

[5]  J. Vender,et al.  Intraoperative Acceleromyographic Monitoring Reduces the Risk of Residual Neuromuscular Blockade and Adverse Respiratory Events in the Postanesthesia Care Unit , 2008, Anesthesiology.

[6]  M. Eikermann,et al.  Reversal of Profound, High-dose Rocuronium–induced Neuromuscular Blockade by Sugammadex at Two Different Time Points: An International, Multicenter, Randomized, Dose-finding, Safety Assessor–blinded, Phase II Trial , 2008, Anesthesiology.

[7]  J. Vender,et al.  Residual Neuromuscular Blockade and Critical Respiratory Events in the Postanesthesia Care Unit , 2008, Anesthesia and analgesia.

[8]  P. Cheeseman,et al.  Safety and efficacy of N‐acetylcysteine in children with non‐acetaminophen‐induced acute liver failure , 2008, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[9]  M. Naguib.  Sugammadex: another milestone in clinical neuromuscular pharmacology. , 2007, Anesthesia and analgesia.

[10]  L. Brion,et al.  Cysteine, cystine or N-acetylcysteine supplementation in parenterally fed neonates. , 2006, The Cochrane database of systematic reviews.

[11]  S. Lorenzini,et al.  Age-related influence on thiol, disulfide, and protein-mixed disulfide levels in human plasma. , 2006, The journals of gerontology. Series A, Biological sciences and medical sciences.

[12]  Sanjay S. Patel,et al.  Preclinical Pharmacology of GW280430A (AV430A) in the Rhesus Monkey and in the Cat: A Comparison with Mivacurium , 2004, Anesthesiology.

[13]  Sanjay S. Patel,et al.  Clinical Pharmacology of GW280430A in Humans , 2004, Anesthesiology.

[14]  S. Oja,et al.  Mechanisms of L-Cysteine Neurotoxicity , 2000, Neurochemical Research.

[15]  Abraham Weizman,et al.  Cysteine-induced hypoglycemic brain damage: an alternative mechanism to excitotoxicity , 2004, Amino Acids.

[16]  Sanjay S. Patel,et al.  Neuromuscular blocking activity and therapeutic potential of mixed-tetrahydroisoquinolinium halofumarates and halosuccinates in rhesus monkeys. , 2003, Journal of medicinal chemistry.

[17]  B. Plaud,et al.  Residual Paralysis in the PACU after a Single Intubating Dose of Nondepolarizing Muscle Relaxant with an Intermediate Duration of Action , 2003, Anesthesiology.

[18]  L. Eriksson.  Evidence-based practice and neuromuscular monitoring: it's time for routine quantitative assessment. , 2003, Anesthesiology.

[19]  T. Heier,et al.  Efficacy of Tactile-guided Reversal from Cisatracurium-induced Neuromuscular Block , 1998, Anesthesiology.

[20]  C. Meistelman.  Update on neuromuscular pharmacology , 2001, Current opinion in anaesthesiology.

[21]  J. Viby-Mogensen.  Postoperative residual curarization and evidence-based anaesthesia. , 2000, British journal of anaesthesia.

[22]  Aaron F. Koppman.  Surrogate endpoints and neuromuscular recovery. , 1997 .

[23]  O. Ekberg,et al.  Functional Assessment of the Pharynx at Rest and during Swallowing in Partially Paralyzed Humans: Simultaneous Videomanometry and Mechanomyography of Awake Human Volunteers , 1997, Anesthesiology.

[24]  L. Skovgaard,et al.  Residual neuromuscular block is a risk factor for postoperative pulmonary complications A prospective, randomised, and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium , 1997, Acta anaesthesiologica Scandinavica.

[25]  A. Kopman.  Surrogate endpoints and neuromuscular recovery. , 1997, Anesthesiology.

[26]  A. Bjorksten,et al.  The Maximum Depth of an Atracurium Neuromuscular Block Antagonized by Edrophonium to Effect Adequate Recovery , 1995, Anesthesiology.

[27]  F. Donati,et al.  Reversal of Neuromuscular Blockade , 1992, Anesthesiology.

[28]  R. Shulman,et al.  Cysteine usage increases the need for acetate in neonates who receive total parenteral nutrition. , 1991, American Journal of Clinical Nutrition.

[29]  A. Bjorksten,et al.  Determinants of the reversal time of competitive neuromuscular block by anticholinesterases. , 1991, British journal of anaesthesia.

[30]  C. Federiuk.  Efficacy of N-acetylcysteine in the treatment of acetaminophen overdose: Smilkstein MJ, Knapp GI, Kulig KW, et al N Engl J Med 319: 1557–1562 Dec 1988 , 1989 .

[31]  G. Knapp,et al.  Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985) , 1988, The New England journal of medicine.

[32]  F. Donati,et al.  Postoperative neuromuscular blockade: a comparison between atracurium, vecuronium, and pancuronium. , 1988, Anesthesiology.

[33]  F. Donati,et al.  Dose‐response Curves for Edrophonium, Neostigmine, and Pyridostigmine after Pancuronium and D‐tubocurarine , 1987, Anesthesiology.

[34]  J. Critchley,et al.  Intravenous N-acetylcysteine: still the treatment of choice for paracetamol poisoning. , 1979, British medical journal.

[35]  P. Crome,et al.  Intravenous N-acetylcysteine: the treatment of choice in paracetamol poisoning? , 1979, British medical journal.

[36]  J. Viby-Mogensen,et al.  Residual curarization in the recovery room. , 1979, Anesthesiology.