Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase.
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.



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.



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.



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.
From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d'Investigation Clinique-Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) - all in Rennes, France.
Anne
A
Kerbrat
From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d'Investigation Clinique-Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) - all in Rennes, France.
Jean-Christophe
JC
Ferré
From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d'Investigation Clinique-Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) - all in Rennes, France.
Pierre
P
Fillatre
From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d'Investigation Clinique-Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) - all in Rennes, France.
Thomas
T
Ronzière
From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d'Investigation Clinique-Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) - all in Rennes, France.
Stéphane
S
Vannier
From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d'Investigation Clinique-Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) - all in Rennes, France.
Béatrice
B
Carsin-Nicol
From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d'Investigation Clinique-Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) - all in Rennes, France.
Sylvain
S
Lavoué
From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d'Investigation Clinique-Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) - all in Rennes, France.
Marc
M
Vérin
From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d'Investigation Clinique-Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) - all in Rennes, France.
Jean-Yves
JY
Gauvrit
From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d'Investigation Clinique-Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) - all in Rennes, France.
Yves
Y
Le Tulzo
From the Departments of Neurology (A.K., T.R., S.V., M.V., G.E.), Radiology (J.-C.F., B.C.-N., J.-Y.G.), and Infectious Diseases and Medical Intensive Care (P.F., S.L., Y.L.T.), Centre d'Investigation Clinique-Plurithématique, INSERM 1414 (P.F., Y.L.T., G.E.), and EA 4712 Comportement et Noyaux Gris Centraux Laboratory (M.V.), Rennes University Hospital, and the Vision, Action, and Information Management System in Health team, Institut National de Recherche en Informatique et en Automatique (A.K., J.-C.F., J.-Y.G.) - all in Rennes, France.
Gilles
G
Edan
D000208:Acute Disease; D000284:Administration, Oral; D000328:Adult; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D001926:Brain Death; D002526:Cerebellar Diseases / Q000139:chemically induced*; D002531:Cerebellum / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000175:diagnosis; D003244:Consciousness Disorders / Q000139:chemically induced*; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000009:adverse effects*; D004311:Double-Blind Method; D020234:Gait Ataxia / Q000139:chemically induced; D006261:Headache / Q000139:chemically induced; D064368:Healthy Volunteers; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced*; D008875:Middle Aged; D011149:Pons / Q000473:pathology*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D003497:Cyclic N-Oxides; D011725:Pyridines; D000099252:Fatty Acid Amide Hydrolases; C000612073:BIA 10-2474