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AZD-3043: a novel, metabolically labile sedative-hypnotic agent with rapid and
predictable emergence from hypnosis
#MMPMID22531340
Egan TD
; Obara S
; Jenkins TE
; Jaw-Tsai SS
; Amagasu S
; Cook DR
; Steffensen SC
; Beattie DT
Anesthesiology
2012[Jun]; 116
(6
): 1267-77
PMID22531340
show ga
BACKGROUND: Propofol can be associated with delayed awakening after prolonged
infusion. The aim of this study was to characterize the preclinical pharmacology
of AZD-3043, a positive allosteric modulator of the ?-aminobutyric acid type A
(GABA(A)) receptor containing a metabolically labile ester moiety. The authors
postulated that its metabolic pathway would result in a short-acting clinical
profile. METHODS: The effects of AZD-3043, propofol, and propanidid were studied
on GABA(A) receptor-mediated chloride currents in embryonic rat cortical neurons.
Radioligand binding studies were also performed. The in vitro stability of
AZD-3043 in whole blood and liver microsomes was evaluated. The duration of the
loss of righting reflex and effects on the electroencephalograph evoked by bolus
or infusion intravenous administration were assessed in rats. A mixed-effects
kinetic-dynamic model using minipigs permitted exploration of the clinical
pharmacology of AZD-3043. RESULTS: AZD-3043 potentiated GABA(A) receptor-mediated
chloride currents and inhibited [(35)S]tert-butylbicyclophosphorothionate binding
to GABA(A) receptors. AZD-3043 was rapidly hydrolyzed in liver microsomes from
humans and animals. AZD-3043 produced hypnosis and electroencephalograph
depression in rats. Compared with propofol, AZD-3043 was shorter acting in rats
and pigs. Computer simulation using the porcine kinetic-dynamic model
demonstrated that AZD-3043 has very short 50 and 80% decrement times independent
of infusion duration. CONCLUSIONS: AZD-3043 is a positive allosteric modulator of
the GABA(A) receptor in vitro and a sedative-hypnotic agent in vivo. The esterase
dependent metabolic pathway results in rapid clearance and short duration of
action even for long infusions. AZD-3043 may have clinical potential as a
sedative-hypnotic agent with rapid and predictable recovery.
|*Conscious Sedation
[MESH]
|Anesthesia Recovery Period
[MESH]
|Animals
[MESH]
|Chemistry, Pharmaceutical
[MESH]
|Computer Simulation
[MESH]
|Electroencephalography/drug effects
[MESH]
|Female
[MESH]
|Hypnotics and Sedatives/pharmacokinetics/*pharmacology
[MESH]
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