Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase

Abstract : BACKGROUND A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, and some have been tested in phase 1 and 2 studies. In a phase 1 study, BIA 10-2474, an orally administered reversible FAAH inhibitor, was given to healthy volunteers to assess safety. METHODS Single doses (0.25 to 100 mg) and repeated oral doses (2.5 to 20 mg for 10 days) of BIA 10-2474 had been administered to 84 healthy volunteers in sequential cohorts; no severe adverse events had been reported. Another cohort of participants was then assigned to placebo (2 participants) or 50 mg of BIA 10-2474 per day (6 participants). This report focuses on neurologic adverse events in participants in this final cohort. A total of 4 of the 6 participants who received active treatment consented to have their clinical and radiologic data included in this report. RESULTS An acute and rapidly progressive neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration. The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness. Magnetic resonance imaging showed bilateral and symmetric cerebral lesions, including microhemorrhages and hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging sequences predominantly involving the pons and hippocampi. One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment, and the other patient had a residual cerebellar syndrome. One patient remained asymptomatic. CONCLUSIONS An unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial. The underlying mechanism of this toxic cerebral syndrome remains unknown.
Keywords : pain
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-01412967
Contributor : Laurent Jonchère <>
Submitted on : Friday, December 9, 2016 - 10:40:08 AM
Last modification on : Wednesday, March 27, 2019 - 4:38:14 PM

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Anne Kerbrat, Jean-Christophe Ferré, Pierre Fillâtre, Thomas Ronzière, Stephane Vannier, et al.. Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase. New England Journal of Medicine, Massachusetts Medical Society, 2016, 375 (18), pp.1717--1725. ⟨10.1056/NEJMoa1604221⟩. ⟨hal-01412967⟩

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