title: Dose-response and Cardiopulmonary Side Effects of the Novel Neuromuscular-blocking Drug CW002 in Man.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: From the Department of Anesthesiology, Yale Medical School, New Haven, Connecticut (P.M.H.); Department of Anesthesiology, Weill Cornell Medical College, New York, New York (H.S., M.T.M., J.K.M., D.G., M.S., P.S., J.J.S., C.A.L.); and School of Pharmacy, Union University, Jackson, Tennessee (J.S.O.).
authors.forename: Paul M
authors.initials: PM
authors.lastname: Heerdt
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sunaga
authors.forename: Joel S
authors.initials: JS
authors.lastname: Owen
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Murrell
authors.forename: Jaideep K
authors.initials: JK
authors.lastname: Malhotra
authors.forename: Deena
authors.initials: D
authors.lastname: Godfrey
authors.forename: Michelle
authors.initials: M
authors.lastname: Steinkamp
authors.forename: Peter
authors.initials: P
authors.lastname: Savard
authors.forename: John J
authors.initials: JJ
authors.lastname: Savarese
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Lien
mesh_terms: D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D019148:Neuromuscular Blockade / Q000379:methods*; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D012119:Respiration / Q000187:drug effects*; D055815:Young Adult
chemical_list: C542547:CW 002; D007546:Isoquinolines; D003473:Neuromuscular Nondepolarizing Agents