Abstract
Editor's PerspectiveWhat We Already Know about This Topic The investigational etomidate analog ABP-700 causes involuntary muscle movements in humans at anesthetic doses and seizures in dogs at 10-fold higher toxicologic doses The mechanism of seizures in dogs, and their relationship to involuntary muscle movements in humans, is unknown What This Article Tells Us That Is New Toxicologic studies in dogs using supratherapeutic ABP-700 doses caused involuntary muscle movements and seizures, but these were temporally and electroencephalographically distinct, suggesting different underlying mechanisms Events occurred at ABP-700 and metabolite concentrations one and two orders of magnitude higher, respectively, than those found in humans Electrophysiologic studies of the principal metabolite of ABP-700 in oocyte-expressed gamma-aminobutyric acid type A receptors showed inhibition at the high supratherapeutic concentrations achieved in the dogs, and such inhibition may explain seizure activity Proepileptiform effects of ABP-700 in dogs may not be relevant to humans at therapeutic doses Background: The etomidate analog ABP-700 produces involuntary muscle movements that could be manifestations of seizures. To define the relationship (if any) between involuntary muscle movements and seizures, electroencephalographic studies were performed in Beagle dogs receiving supra-therapeutic (similar to 10x clinical) ABP-700 doses. gamma-aminobutyric acid type A (GABA(A)) and glycine receptor studies were undertaken to test receptor inhibition as the potential mechanism for ABP-700 seizures. Methods: ABP-700 was administered to 14 dogs (6 mg/kg bolus followed by a 2-h infusion at 1 mg center dot kg(-1) center dot min(-1), 1.5 mg center dot kg(-1) center dot min(-1), or 2.3 mg center dot kg(-1) center dot min(-1)). Involuntary muscle movements were documented, electroencephalograph was recorded, and plasma ABP-700 and CPM-acid concentrations were measured during and after ABP-700 administration. The concentration-dependent modulatory actions of ABP-700 and CPM-acid were defined in oocyte-expressed alpha(1)beta(3)gamma(2L) GABA(A) and alpha(1)beta glycine receptors (n = 5 oocytes/concentration) using electrophysiologic techniques. Results: ABP-700 produced both involuntary muscle movements (14 of 14 dogs) and seizures (5 of 14 dogs). However, these phenomena were temporally and electroencephalographically distinct. Mean peak plasma concentrations were (from lowest to highest dosed groups) 35 mu M, 45 mu M, and 102 mu M (ABP-700) and 282 mu M, 478 mu M, and 1,110 mu M (CPM-acid). ABP-700 and CPM-acid concentration-GABA(A) receptor response curves defined using 6 mu M gamma-aminobutyric acid exhibited potentiation at low and/or intermediate concentrations and inhibition at high ones. The half-maximal inhibitory concentrations of ABP-700 and CPM-acid defined using 1 mM gamma-aminobutyric acid were 770 mu M (95% CI, 590 to 1,010 mu M) and 1,450 mu M (95% CI, 1,340 to 1,560 mu M), respectively. CPM-acid similarly inhibited glycine receptors activated by 1 mM glycine with a half-maximal inhibitory concentration of 1,290 mu M (95% CI, 1,240 to 1,330 mu M). Conclusions: High dose ABP-700 infusions produce involuntary muscle movements and seizures in Beagle dogs via distinct mechanisms.
CPM-acid inhibits both GABA(A) and glycine receptors at the high (similar to 100x clinical) plasma concentrations achieved during the dog studies, providing a plausible mechanism for the seizures.
Original language | English |
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Pages (from-to) | 287-304 |
Number of pages | 18 |
Journal | Anesthesiology |
Volume | 131 |
Issue number | 2 |
DOIs | |
Publication status | Published - Aug-2019 |
Keywords
- CYCLOPROPYL-METHOXYCARBONYL METOMIDATE
- PRETREATMENT REDUCES MYOCLONUS
- GENERAL ANESTHETIC ETOMIDATE
- GABA(A) RECEPTORS
- IN-VITRO
- EPILEPTIFORM DISCHARGES
- HYPNOTIC RECOVERIES
- RECOMBINANT GABA(A)
- A RECEPTOR
- SEIZURES