Perioperative Medicine  |   November 2018
Preclinical Pharmacology in the Rhesus Monkey of CW 1759-50, a New Ultra-short Acting Nondepolarizing Neuromuscular Blocking Agent, Degraded and Antagonized by L-Cysteine
Author Notes
  • From the Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York (J.J.S., H.S., M.R.B., M.T.M., F.E.C.); Cedarburg Pharmaceuticals, Albany Molecular Research, Inc., Grafton, Wisconsin (J.D.M.); Animal Resources Facility, Albany Medical Center, Albany, New York (E.J.); the Department of Cardiovascular Pharmacology, Burroughs Wellcome Co., Research Triangle Park, North Carolina (W.B.W.); and the Department of Anesthesiology, Yale School of Medicine, New Haven, Connecticut (P.M.H.). Current position: Jikei University School of Medicine, Tokyo, Japan (H.S.).
  • Submitted for publication July 27, 2017. Accepted for publication July 19, 2018.
    Submitted for publication July 27, 2017. Accepted for publication July 19, 2018.×
  • Deceased.
    Deceased.×
  • Address correspondence to Dr. Savarese: Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065. jjsavare@med.cornell.edu or jjsavarese@icloud.com. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Basic Science / Neuromuscular Diseases and Drugs / Neurosurgical Anesthesia
Perioperative Medicine   |   November 2018
Preclinical Pharmacology in the Rhesus Monkey of CW 1759-50, a New Ultra-short Acting Nondepolarizing Neuromuscular Blocking Agent, Degraded and Antagonized by L-Cysteine
Anesthesiology 11 2018, Vol.129, 970-988. doi:10.1097/ALN.0000000000002408
Anesthesiology 11 2018, Vol.129, 970-988. doi:10.1097/ALN.0000000000002408
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Gantacurium is an ultra-short acting nondepolarizing neuromuscular blocking agent in the monkey and in man that is degraded nonenzymatically by adduction of l-cysteine under physiologic conditions

  • Administration of gantacurium results in decreased mean arterial pressure and increased heart rate

What This Article Tells Us That Is New:

  • CW 1759-50 is a new nondepolarizing neuromuscular blocking agent that may have a clinical profile that is superior to that of gantacurium

  • Studies in rhesus monkeys comparing CW 1759-50 with gantacurium found both of them to be ultra-short acting because of their rapid degradation by l-cysteine adduction

  • The effects of CW 1759-50 on mean arterial pressure and heart rate were substantially less than those of gantacurium

Background: Structure–activity studies were performed to identify a new neuromuscular blocking agent retaining the ultra-short acting characteristics of gantacurium, including degradation and reversal by l-cysteine, but lacking its histaminoid properties in man. CW 1759-50 has emerged from this program.

Methods: Adduction of CW 1759-50 with l-cysteine was studied by high-performance liquid chromatography and mass spectrometry. Institutional Animal Care and Use Committee–approved comparisons of CW 1759-50 to gantacurium were performed in rhesus monkeys. ED95 for neuromuscular blockade was established. Spontaneous recovery was compared to reversal by l-cysteine in paired studies of boluses or infusions. In addition, changes in mean arterial pressure and heart rate after very large doses of 15 to 60 × ED95 were compared.

Results: The half-time of adduction of l-cysteine to CW 1759-50 in vitro was 2.3 min. The ED95 of CW 1759-50 was 0.069 ± 0.02 mg/kg; ED95 of gantacurium was 0.081 ± 0.05 mg/kg (P = 0.006). Duration of action (recovery to 95% twitch height after 98 to 99% blockade) was as follows: CW 1759-50, 8.2 ± 1.5 min; and gantacurium, 7.4 ± 1.9 min; (n = 8 and 9, P = 0.355). Administration of l-cysteine (30 mg/kg) shortened recovery (i.e., induced reversal) from CW 1759-50 after boluses or infusions (P always less than 0.0001). Recovery intervals (5 to 95% twitch) ranged from 6.1 to 6.7 min (and did not differ significantly) after boluses of 0.10 to 0.50 mg/kg, as well as control infusions (P = 0.426 by analysis of variance). Dose ratios comparing changes of 30% in mean arterial pressure or heart rate to ED95 for neuromuscular blockade (ED 30% Δ [mean arterial pressure or heart rate]/ED95) were higher for CW 1759-50 than for gantacurium.

Conclusions: CW 1759-50, similar to gantacurium, is an ultra-short acting neuromuscular blocking agent, antagonized by l-cysteine, in the monkey. The circulatory effects, however, are much reduced in comparison with gantacurium, suggesting a trial in humans.