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Department of Anesthesiology

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Cysteine reversal of the novel neuromuscular blocking drug CW002 in dogs: pharmacodynamics, acute cardiovascular effects, and preliminary toxicology.

TitleCysteine reversal of the novel neuromuscular blocking drug CW002 in dogs: pharmacodynamics, acute cardiovascular effects, and preliminary toxicology.
Publication TypeJournal Article
Year of Publication2010
AuthorsSunaga H, Malhotra JK, Yoon E, Savarese JJ, Heerdt PM
JournalAnesthesiology
Volume112
Issue4
Pagination900-9
Date Published2010 Apr
ISSN1528-1175
KeywordsAnimals, Blood Cell Count, Blood Chemical Analysis, Blood Coagulation, Blood Pressure, Cysteine, Dogs, Dose-Response Relationship, Drug, Heart Rate, Hemodynamics, Indicators and Reagents, Isoquinolines, Neuromuscular Blocking Agents, Stroke Volume
Abstract

BACKGROUND: CW002 is a neuromuscular blocking drug that is inactivated by endogenous L-cysteine. This study determined the exogenous L-cysteine dose-response relationship for CW002 reversal along with acute cardiovascular effects and organ toxicity in dogs.

METHODS: Six dogs were each studied four times during isoflurane-nitrous oxide anesthesia and recording of muscle twitch, arterial pressure, and heart rate. CW002 (0.08 mg/kg or 9 x ED95) was injected, and the time to spontaneous muscle recovery was determined. CW002 was then administered again followed 1 min later by 10, 20, 50, or 100 mg/kg L-cysteine (1 dose/experiment). After twitch recovery, CW002 was given a third time to determine whether residual L-cysteine influenced duration. Preliminary toxicology was performed in an additional group of dogs that received CW002 followed by vehicle (n = 8) or 200 mg/kg L-cysteine (n = 8). Animals were awakened and observed for 2 or 14 days before sacrificing and anatomic, biochemical, and histopathologic analyses.

RESULTS: L-cysteine at all doses accelerated recovery from CW002, with both 50 and 100 mg/kg decreasing median duration from more than 70 min to less than 5 min. After reversal, duration of a subsequent CW002 dose was also decreased in a dose-dependent manner. Over the studied dose range, L-cysteine had less than 10% effect on blood pressure and heart rate. Animals receiving a single 200-mg/kg dose of L-cysteine showed no clinical, anatomic, biochemical, or histologic evidence of organ toxicity.

CONCLUSION: The optimal L-cysteine dose for rapidly reversing the neuromuscular blockade produced by a large dose of CW002 in dogs is approximately 50 mg/kg, which has no concomitant hemodynamic effect. A dose of 200 mg/kg had no evident organ toxicity.

DOI10.1097/ALN.0b013e3181d31f8c
Alternate JournalAnesthesiology
PubMed ID20234310