Preclinical Pharmacology of CW002: A Nondepolarizing Neuromuscular Blocking Drug of Intermediate Duration, Degraded and Antagonized by l-cysteine—Additional Studies of Safety and Efficacy in the Anesthetized Rhesus Monkey and Cat

• Published in: Anesthesiology (Philadelphia) 2016-10, Vol.125 (4), p.732-743
• Main Authors: Sunaga, Hiroshi, Savarese, John J, McGilvra, Jeff D, Heerdt, Paul M, Belmont, Matthew R, Van Ornum, Scott G, Murrell, Matthew T, Malhotra, Jaideep K, Savard, Peter M, Jeannotte, Erin, Petty, Bryce J, Allen, Erica, Carnathan, Gilbert W
• Format: Article
• Language: English
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0000000000001254

BACKGROUND:CW002, a novel nondepolarizing neuromuscular blocking agent of intermediate duration, is degraded in vitro by L-cysteine; CW002-induced neuromuscular blockade (NMB) is antagonized in vivo by exogenous L-cysteine. Further, Institutional Animal Care and Use Committee–approved studies of safety and efficacy in eight anesthetized monkeys and six cats are described. METHODS:Mean arterial pressure, heart rate, twitch, and train-of-four were recorded; estimated dose producing 95% twitch inhibition (ED95) for NMB and twitch recovery intervals from 5 to 95% of baseline were derived. Antagonism of 99 to 100% block in monkeys by L-cysteine (50 mg/kg) was tested after bolus doses of approximately 3.75 to 20 × ED95 and after infusions. Vagal and sympathetic autonomic responses were recorded in cats. Dose ratios for [circulatory (ED20) or autonomic (ED50) changes/ED95 (NMB)] were calculated. RESULTS:ED95s of CW002 in monkeys and cats were 0.040 and 0.035 mg/kg; L-cysteine readily antagonized block in monkeys5 to 95% twitch recovery intervals were shortened to 1.8 to 3.6 min after 3.75 to 10 × ED95 or infusions versus 11.5 to 13.5 min during spontaneous recovery. ED for 20% decrease of mean arterial pressure (n = 27) was 1.06 mg/kg in monkeys; ED for 20% increase of HR (n = 27) was 2.16 mg/kg. ED50s for vagal and sympathetic inhibition in cats were 0.59 and >>0.80 mg/kg (n = 14 and 15). Dose ratios for [circulatory or autonomic changes/ED95 (NMB)] were all more than 15 × ED95. CONCLUSIONS:The data further verify the neuromuscular blocking properties of CW002, including rapid reversal by L-cysteine of 100% NMB under several circumstances. A notable lack of autonomic or circulatory effects provided added proof of safety and efficacy.