title: 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.
abstract: 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 monkeys: 5 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.
authors.affiliation: From the Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York (H.S., J.J.S., P.M.H., M.R.B., M.T.M., J.K.M., P.M.S., B.J.P.); Cedarburg Pharmaceuticals, A Division of Albany Molecular Research, Inc., Grafton, Wisconsin (J.D.M.); Department of Chemistry, Concordia University, Mequon, Wisconsin (S.G.V.O.); Animal Resources Facility, Albany Medical Center, Albany, New York (E.J.); and Impact Pharmaceutical Services, Inc., Research Triangle Park, North Carolina (E.A., G.W.C.). Current affiliation: Department of Anesthesiology, Jikei University School of Medicine, Nishishimbashi, Minatoku, Tokyo, Japan (H.S.).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sunaga
authors.forename: John J
authors.initials: JJ
authors.lastname: Savarese
authors.forename: Jeff D
authors.initials: JD
authors.lastname: McGilvra
authors.forename: Paul M
authors.initials: PM
authors.lastname: Heerdt
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Belmont
authors.forename: Scott G
authors.initials: SG
authors.lastname: Van Ornum
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Murrell
authors.forename: Jaideep K
authors.initials: JK
authors.lastname: Malhotra
authors.forename: Peter M
authors.initials: PM
authors.lastname: Savard
authors.forename: Erin
authors.initials: E
authors.lastname: Jeannotte
authors.forename: Bryce J
authors.initials: BJ
authors.lastname: Petty
authors.forename: Erica
authors.initials: E
authors.lastname: Allen
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Carnathan