Clinical pharmacology of GW280430A in humans.
BACKGROUND
An ultrashort-acting nondepolarizing neuromuscular blocking agent that could be an alternative to succinylcholine has been the focus of a concerted effort in the field of muscle relaxants. GW280430A showed a promising pharmacodynamic profile in preclinical work and a wide margin of safety and so was selected for study in humans.


METHODS
Thirty-one volunteers participated in this study, which determined the dose producing 95% block (ED95) and the safety and pharmacodynamics of increasing ED95 multiples. Anesthesia was induced and maintained with propofol, midazolam, and fentanyl. Neuromuscular transmission was measured at the adductor pollicis using ulnar nerve stimulation, and responses were recorded continuously by standard mechanomyographic monitoring.


RESULTS
The ED95 for GW280430A is 0.19 mg/kg. The time to onset of 90% block ranged from 1.3 to 2.1 min, depending on the dose. Clinical durations ranged from 4.7 to 10.1 min and increased with increasing dose. Five to 95% and 25-75% recovery rates were approximately 7 and 3 min, respectively, and were independent of the dose administered. Transient cardiovascular side effects were observed at doses beginning at 3 x ED95 and above and were suggestive of histamine release. Most volunteers receiving 4 x ED95 exhibited plasma histamine concentrations indicative of significant histamine release.


CONCLUSIONS
GW280430A has a rapid onset and ultrashort duration of action. The recovery rate is rapid, predictable, and independent of dose. Doses at least up to 2.5 x ED95 seem to be free of side effects and seem to be able to provide relaxation within 60-90 s.
Belmont
Matthew R
MR
Department of Anesthesiology, New York Presbyterian-Weill Medical Cornell Medical Center, New York, New York 10021, USA. mab2012@med.cornell.edu
Lien
Cynthia A
CA
Tjan
Joseph
J
Bradley
Eleanor
E
Stein
Brenna
B
Patel
Sanjay S
SS
Savarese
John J
JJ
D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000097:blood; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D013390:Succinylcholine / Q000494:pharmacology
D007546:Isoquinolines; D003473:Neuromuscular Nondepolarizing Agents; D006632:Histamine; D013390:Succinylcholine; C451919:gantacurium