Faculty Collaboration Database

Dose-response and Cardiopulmonary Side Effects of the Novel Neuromuscular-blocking Drug CW002 in Man. Anesthesiology 2016 Dec;125(6):1136-1143

Date

10/18/2016

Pubmed ID

27749289

DOI

10.1097/ALN.0000000000001386

Scopus ID

2-s2.0-84991489693 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

BACKGROUND: CW002 is a benzylisoquinolinium nondepolarizing neuromuscular-blocking drug found to be inactivated by cysteine in preclinical studies. The current study represents a dose escalation clinical trial designed to describe CW002 potency, duration, cardiopulmonary side effects, and histamine release.

METHODS: Healthy subjects anesthetized with sevoflurane/nitrous oxide were divided into five groups (n = 6), each receiving a fixed CW002 dose (0.02, 0.04, 0.06, 0.08, or 0.10 mg/kg), and one group (n = 4) receiving 0.14 mg/kg. Blood pressure and heart rate were continuously recorded along with airway dynamic compliance. Neuromuscular blockade was assessed with mechanomyography at the adductor pollicis. Arterial blood was obtained before and after CW002 injection for analysis of plasma histamine concentration. Potency was estimated from a baseline sigmoid Emax model.

RESULTS: ED50 was found to be 0.036 mg/kg (95% CI, 0.020 to 0.053 mg/kg) and ED95 0.077 mg/kg (95% CI, 0.044 to 0.114 mg/kg). At 0.14 mg/kg (1.8 × ED95), 80% twitch depression occurred in 94 ± 18 s with complete block in 200 ± 87 s. Clinical recovery (25% of maximum twitch) occurred in 34 ± 3.4 min, with a 5 to 95% recovery interval of 35.0 ± 2.7 min. The time to a train-of-four ratio greater than 0.9 ranged from 59 to 86 min. CW002 did not elicit histamine release or significant (greater than 10%) changes in blood pressure, heart rate, or dynamic airway compliance.

CONCLUSIONS: In healthy subjects receiving sevoflurane/nitrous oxide, CW002 at 1.8 × estimated ED95 produces a clinical duration less than 40 min, elicits no histamine release, and has minimal cardiopulmonary side effects.

Author List

Heerdt PM, Sunaga H, Owen JS, Murrell MT, Malhotra JK, Godfrey D, Steinkamp M, Savard P, Savarese JJ, Lien CA

Author

Cynthia A. Lien MD Chair, Professor in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Adult
Blood Pressure
Dose-Response Relationship, Drug
Female
Heart Rate
Histamine Release
Humans
Isoquinolines
Male
Middle Aged
Neuromuscular Blockade
Neuromuscular Nondepolarizing Agents
Respiration
Young Adult