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Titre du document / Document title

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) / Author(s)

SAVARESE John J. (1) ; MCGILVRA Jeff D. (1) ; SUNAGA Hiroshi (1) ; BELMONT Matthew R. (1) ; VAN ORNUM Scott G. (1) ; SAVARD Peter M. (1) ; HEERDT Paul M. (1) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, ETATS-UNIS

Résumé / 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. 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) given 1 min after approximately 4—5 X 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.

Revue / Journal Title

Anesthesiology    ISSN  0003-3022   CODEN ANESAV 

Source / Source

2010, vol. 113, no1, pp. 58-73 [16 page(s) (article)] (35 ref.)

Langue / Language

Anglais

Editeur / Publisher

Lippincott Williams & Wilkins, Hagerstown, MD, ETATS-UNIS  (1940) (Revue)

Mots-clés anglais / English Keywords

Thiol

;

Sulfur containing aminoacid

;

Anesthesia

;

Inactivation

;

Cysteine

;

Mots-clés français / French Keywords

Thiol

;

Aminoacide soufré

;

Anesthésie

;

Inactivation

;

Cystéine

;

Mots-clés espagnols / Spanish Keywords

Tiol

;

Aminoácido azufrado

;

Anestesia

;

Inactivación

;

Cisteína

;

Localisation / Location

INIST-CNRS, Cote INIST : 3042, 35400019165373.0100

Nº notice refdoc (ud4) : 23014752



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