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

Anesthesiology. 2010 Apr;112(4):900-9. doi: 10.1097/ALN.0b013e3181d31f8c.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Cell Count
  • Blood Chemical Analysis
  • Blood Coagulation
  • Blood Pressure / drug effects
  • Cysteine / pharmacology*
  • Cysteine / toxicity
  • Dogs
  • Dose-Response Relationship, Drug
  • Heart Rate / drug effects
  • Hemodynamics / drug effects*
  • Indicators and Reagents
  • Isoquinolines / antagonists & inhibitors*
  • Isoquinolines / pharmacology*
  • Isoquinolines / toxicity
  • Neuromuscular Blocking Agents / antagonists & inhibitors*
  • Neuromuscular Blocking Agents / pharmacology*
  • Neuromuscular Blocking Agents / toxicity
  • Stroke Volume / drug effects

Substances

  • CW 002
  • Indicators and Reagents
  • Isoquinolines
  • Neuromuscular Blocking Agents
  • Cysteine