Clinical pharmacology of GW280430A in humans. Anesthesiology 2004 Apr;100(4):768-73
Date
04/17/2004Pubmed ID
15087609DOI
10.1097/00000542-200404000-00004Scopus ID
2-s2.0-1642392352 (requires institutional sign-in at Scopus site) 64 CitationsAbstract
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.
Author List
Belmont MR, Lien CA, Tjan J, Bradley E, Stein B, Patel SS, Savarese JJAuthor
Cynthia A. Lien MD Chair, Professor in the Anesthesiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Blood Pressure
Dose-Response Relationship, Drug
Heart Rate
Histamine
Humans
Isoquinolines
Male
Middle Aged
Neuromuscular Nondepolarizing Agents
Succinylcholine