Pharmacodynamics and cardiopulmonary side effects of CW002, a cysteine-reversible neuromuscular blocking drug in dogs.
BACKGROUND
CW002 is a novel neuromuscular blocking drug with a duration dependent on the rate of cysteine adduction to the molecule. The current study characterized the pharmacodynamics and cardiopulmonary side effects of CW002 in dogs.


METHODS
In eight beagles, the dose required to produce 95% neuromuscular blockade (ED95) for CW002 was first determined and cysteine reversibility was confirmed. Five to 7 days later, incrementally larger doses were injected starting with 6.25 x ED95 and doubling the dose every 15 min. Before and after injection, blood was obtained for histamine analysis. Systemic and pulmonary arterial pressures, cardiac output, and left ventricular pressure and volume were recorded along with inspiratory pressure and pulmonary compliance. Ventricular contractility and lusitropy were indexed from pressure and volume data.


RESULTS
The ED95 for CW002 from pooled data was 0.009 mg/kg. At 3 x ED95, onset time was 2.6 +/- 0.9 min and duration was 47 +/- 9 min. The duration was shortened to 3.7 +/- 0.6 min by 50 mg/kg L-cysteine injected 1 min after CW002. At 25 x ED95, CW002 reduced mean arterial pressure with concomitant decreases in systemic vascular resistance, mean pulmonary artery pressure, cardiac output, contractility, and lusitropy, beginning at 50 x ED95. However, even at a dose of 100 x ED95, the average change in any variable was less than 20%. There were no changes in pulmonary vascular resistance or ventilation mechanics at any dose, and histamine release occurred in only two of eight animals.


CONCLUSIONS
CW002 is a potent neuromuscular blocking drug that at doses up to 100 x ED95 produces modest hemodynamic effects that are not associated with bronchoconstriction or consistent histamine release.
Departments of Anesthesiology of Pharmacology, Weill Medical College of Cornell University, New York, New York, USA. pmheerd@mail.med.cornell.edu
Paul M
PM
Heerdt
Jaideep K
JK
Malhotra
Brian Y
BY
Pan
Hiroshi
H
Sunaga
John J
JJ
Savarese
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003545:Cysteine / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006636:Histamine Release / Q000187:drug effects; D007546:Isoquinolines / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000633:toxicity; D008168:Lung / Q000187:drug effects*; D008170:Lung Compliance / Q000187:drug effects; D009466:Neuromuscular Blocking Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology* / Q000633:toxicity; D012129:Respiratory Function Tests; D015656:Respiratory Mechanics / Q000187:drug effects
C542547:CW 002; D007546:Isoquinolines; D009466:Neuromuscular Blocking Agents; D003545:Cysteine