Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase

• Published in: The New England journal of medicine Vol. 375; no. 18; pp. 1717 - 1725
• Main Authors: Kerbrat, Anne, Ferré, Jean-Christophe, Fillatre, Pierre, Ronzière, Thomas, Vannier, Stéphane, Carsin-Nicol, Béatrice, Lavoué, Sylvain, Vérin, Marc, Gauvrit, Jean-Yves, Le Tulzo, Yves, Edan, Gilles
• Format: Journal Article
• Language: English
• Published: United States Massachusetts Medical Society 03.11.2016
• Subjects: Acute Disease; Administration, Oral; Adult; Amidohydrolases - antagonists & inhibitors; Analgesics; Animal models; Brain Death; Cannabinoids; Cerebellar Diseases - chemically induced; Cerebellum; Cerebellum - pathology; Cerebral Hemorrhage - chemically induced; Cerebral Hemorrhage - diagnosis; Consciousness Disorders - chemically induced; Cyclic N-Oxides - administration & dosage; Cyclic N-Oxides - adverse effects; Double-Blind Method; Drug dosages; Enzymes; Fatty acids; Fatty-acid amide hydrolase; Gait Ataxia - chemically induced; Headache; Headache - chemically induced; Healthy Volunteers; Hippocampus; Hippocampus - pathology; Human health and pathology; Humans; Hydrolase; Inhibitor drugs; Life Sciences; Magnetic Resonance Imaging; Male; Memory; Memory Disorders - chemically induced; Middle Aged; Neuroimaging; Neurological disorders; Neurons and Cognition; Oral administration; Patient safety; Patients; Pons; Pons - pathology; Psychiatrics and mental health; Pyridines - administration & dosage; Pyridines - adverse effects; Toxicity; pain
• ISSN: 0028-4793; 1533-4406; 1533-4406
• DOI: 10.1056/NEJMoa1604221

Three patients had severe ataxia and memory impairment in a phase 1 trial of a fatty acid amide hydrolase inhibitor designed as an analgesic and antiinflammatory drug. One patient became brain dead. MRI of the brain showed lesions in the pons and hippocampi. A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. 1 FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, 2 and some have been tested for these purposes in phase 1 and phase 2 studies. 3 Phase 3 studies were not pursued owing to a lack of efficacy. BIA 10-2474, with the chemical name 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide, is a new reversible FAAH inhibitor. A phase 1 study was conducted in healthy volunteers to explore the safety profile of BIA 10-2474. Five of the six participants who had received the highest cumulative dose . . .