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 × 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.