Pharmacodynamics and cardiopulmonary side effects of CW002, a Cysteine-reversible neuromuscular blocking drug in dogs

Abstract

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 blokade (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 × 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 × 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 × 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 × ED 95. However, even at a dose of 100 × 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 × ED 95 produces modest hemodynamic effects that are not associated with bronchoconstriction or consistent histamine release.