Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat: a comparison with mivacurium.
BACKGROUND
No replacement for succinylcholine is yet available. GW280430A (AV430A) is a representative of a new class of nondepolarizing neuromuscular blocking drugs called asymmetric mixed-onium chlorofumarates. It undergoes rapid degradation in plasma by chemical hydrolysis and inactivation by cysteine adduction, resulting in a very short duration of effect. The neuromuscular, cardiovascular, and autonomic pharmacology of GW280430A is compared herein with that of mivacurium.


METHODS
Adult male rhesus monkeys and adult male cats were anesthetized with nitrous oxide-oxygen-halothane and chloralose-pentobarbital, respectively. The neuromuscular blocking properties of GW280430A and mivacurium were compared at a stimulation rate of 0.15 Hz in the extensor digitorum of the foot (monkey) and the tibialis anterior (cat). Sympathetic responses were assayed in the cat in the nictitating membrane preparation, and vagal effects were evaluated in the cat via observation of bradycardic responses after stimulation of the cervical right vagus nerve.


RESULTS
GW280430A and mivacurium were equipotent in the monkey (ED95 was 0.06 mg/kg in each case). GW280430A was half as potent as mivacurium in the cat. The total duration of action of GW280430A was less than half that of mivacurium in the monkey; recovery slopes were more than twice as rapid. The 25-75% recovery index of GW280430A did not vary significantly after various bolus doses or infusions, averaging 1.4-1.8 min in the monkey, significantly shorter than the same time interval (4.8-5.7 min) for mivacurium. Dose ratios for autonomic versus neuromuscular blocking properties in the cat were greater than 25 for both GW280430A and mivacurium. The ratio ED Hist:ED95 Neuromuscular Block in the monkey was significantly greater (approximately 53 vs. 13) for GW280430A, indicating approximately four times less relative prominence of the side effects of skin flushing and decrease of blood pressure, which are associated with release of histamine.


CONCLUSIONS
These experiments show a much shorter neuromuscular blocking effect and much-reduced side effects in the case of GW280430A vis-à-vis mivacurium. These results, together with the novel chemical degradation of GW280430A, suggest further evaluation in human subjects.
Savarese
John J
JJ
Department of Anesthesiology, Weill Medical College of Cornell University and New York-Presbyterian Hospital, New York, New York 10021, USA. jjsavare@med.cornell.edu
Belmont
Matthew R
MR
Hashim
Mir A
MA
Mook
Robert A
RA
Boros
Eric E
EE
Samano
Vicente
V
Patel
Sanjay S
SS
Feldman
Paul L
PL
Schultz
Jan-Ake I
JA
McNulty
Michael
M
Spitzer
Timothy
T
Cohn
Douglas L
DL
Morgan
Philip
P
Wastila
William B
WB
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002415:Cats; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D000077590:Mivacurium; D009469:Neuromuscular Junction / Q000187:drug effects; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D009626:Terminology as Topic; D013997:Time Factors
D007546:Isoquinolines; D003473:Neuromuscular Nondepolarizing Agents; D000077590:Mivacurium; C451919:gantacurium