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


CONCLUSIONS
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.
Sunaga
Hiroshi
H
Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York, USA.
Malhotra
Jaideep K
JK
Yoon
Edward
E
Savarese
John J
JJ
Heerdt
Paul M
PM
D000818:Animals; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D001777:Blood Coagulation; D001794:Blood Pressure / Q000187:drug effects; D003545:Cysteine / Q000494:pharmacology* / Q000633:toxicity; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007202:Indicators and Reagents; D007546:Isoquinolines / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000633:toxicity; D009466:Neuromuscular Blocking Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000633:toxicity; D013318:Stroke Volume / Q000187:drug effects
C542547:CW 002; D007202:Indicators and Reagents; D007546:Isoquinolines; D009466:Neuromuscular Blocking Agents; D003545:Cysteine