Download Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide

new england
journal of medicine
The
established in 1812
November 3, 2016
vol. 375 no. 18
Acute Neurologic Disorder from an Inhibitor of Fatty Acid
Amide Hydrolase
Anne Kerbrat, M.D., Jean‑Christophe Ferré, M.D., Ph.D., Pierre Fillatre, M.D., Thomas Ronzière, M.D.,
Stéphane Vannier, M.D., Béatrice Carsin‑Nicol, M.D., Sylvain Lavoué, M.D., Marc Vérin, M.D., Ph.D.,
Jean‑Yves Gauvrit, M.D., Ph.D., Yves Le Tulzo, M.D., Ph.D., and Gilles Edan, M.D., Ph.D.​​
a bs t r ac t
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.
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. Address reprint
requests to Dr. Edan at CHU Hôpital
Pontchaillou, 2 rue Henri Le Guilloux,
35033 Rennes CEDEX 9, France, or at
­gilles​.­edan@​­chu-rennes​.­fr.
N Engl J Med 2016;375:1717-25.
DOI: 10.1056/NEJMoa1604221
Copyright © 2016 Massachusetts Medical Society.
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.
n engl j med 375;18 nejm.org November 3, 2016
1717
The
n e w e ng l a n d j o u r na l
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-imidazol4-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 had an acute
and rapidly progressive neurologic syndrome.4
Me thods
Trial Conduct
BIA 10-2474 was developed by Bial, a Portuguese
pharmaceutical company. The research trial was
conducted by Biotrial, a contract research organization that has been approved by the French
Health Ministry. This was the first randomized,
double-blind, placebo-controlled study of BIA
10-2474 involving humans. Sequential cohorts of
8 participants (6 assigned to the active agent and
2 assigned to placebo) were enrolled. A single
ascending dose of BIA 10-2474 (0.25 mg, 1.25 mg,
2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg, and 100 mg)
had been administered to 48 healthy volunteers.
A multiple ascending dose of BIA 10-2474 (2.5 mg
for 10 days, 5 mg for 10 days, 10 mg for 10 days,
and 20 mg for 10 days) had been administrated
to 24 healthy volunteers. A total of 12 other participants, who were enrolled in an additional
cohort to study food interaction, received 40 mg
of BIA 10-2474. Therefore, BIA 10-2474 had been
administered to 84 healthy volunteers between
July 2015 and December 2015, and no serious adverse events had been reported. In January 2016,
the fifth multiple-dose cohort of 8 participants
was studied; 2 received placebo and 6 received
50 mg per day of BIA 10-2474. This report focuses on the adverse events in the patients in
this final cohort.
of
m e dic i n e
obtained from all the volunteers by Biotrial. Of
the six participants who received active treatment
in the final study cohort, three participants and
the family of the deceased participant provided
written informed consent for their inclusion in
this report. Two participants who received active
treatment in the final cohort of eight volunteers
declined to be included in this report. This article
thus reports on the clinical and radiologic findings of four of the six participants. They were
transferred from the Biotrial clinical research
facility to Centre Hospitalier Universitaire Hôpital Pontchaillou (Rennes University Hospital) after the occurrence of neurologic disorders (three
participants) or for systematic monitoring (one
participant).
During the past 5 years, in its capacity as a
contract research organization, Biotrial had conducted research at Rennes University Hospital
that involved the Departments of Neurology and
Radiology (studies of mitoxantrone–interferon
beta-1a and of biotin). Biotrial also provides
financial support to Institut des Neurosciences
Cliniques de Rennes, which funds academic research projects on brain diseases in Rennes. The
authors of this report are employed by Rennes
University Hospital but were not involved in the
conduct of the phase 1 study of BIA 10-2474.
R e sult s
Patients
The four patients who were transferred to Rennes
University Hospital were previously healthy men,
27 to 49 years of age. No major clinical or surgical history and no history of drug abuse were
reported at screening. They were taking no
medication other than the study drug. At the
time of the patients’ admission to the hospital,
analyses for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates
were negative. Two of the four patients had previously participated in phase 1 studies testing
molecules that were not related to the endocannabinoid system.
The first day of drug administration (day 1)
was January 6, 2016; clinical follow-up extended
to 55 days. A 50-mg dose of BIA 10-2474 was
Participants and Study Oversight
administered orally to each patient between 8 a.m.
The trial was approved by the institutional review and 8:45 a.m. each day; Patient 1 received the
board of Brest on June 23, 2015. Written in- drug for 5 consecutive days, and Patients 2, 3, and
formed consent for participation in the trial was 4 for 6 consecutive days. The first serious adverse
1718
n engl j med 375;18 nejm.org November 3, 2016
Acute Neurologic Disorder from an FA AH Inhibitor
Table 1. Clinical Data for the Four Patients.*
Variable
Patient 1
Patient 2
Patient 3
Patient 4†
Age (yr)
49
38
42
27
Cumulative dose of BIA 10-2474 (mg)
250
300
300
300
First symptoms
5
7
5
—
Admission to the hospital
5
7
8
—
Peak of symptoms
9
9
10
—
Blurred vision,
headache
Anterograde amnesia, headache
Dizziness,
headache
None
Sequence of neurologic symptoms
(days after treatment initiation)
Description of neurologic symptoms
First neurologic symptoms
Subsequent neurologic symptoms
Headache
Severe
Mild
Moderate
—
Gait disturbance
Severe
Mild
Severe
—
Slurred speech
Severe
Mild
Severe
—
Dizziness
Severe
—
Severe
—
Blurred vision
Severe
—
Severe
—
Description of neurologic signs
Altered consciousness
Somnolence
—
Mild
Moderate
—
Severe
—
—
—
Anterograde amnesia
NA
Severe
—
—
Retrograde amnesia
NA
Mild
—
—
Coma
Amnesia
Cerebellar syndrome
Limb ataxia
Severe
Mild
Severe
—
Gait ataxia
Severe
Mild
Severe
—
Postural ataxia
Severe
Mild
Severe
—
Dysarthria
Severe
Mild
Severe
—
Nystagmus
Severe
—
Moderate
—
No
1 g/day
for 5 days
1 g/day
for 3 days
No
Glucocorticoid treatment at admission
*NA denotes not available owing to severely altered consciousness.
†Patient 4 had no neurologic symptoms or signs.
event was reported on day 5. Clinical and radio- University Hospital at 8:50 p.m. The physician in
logic data are summarized in Tables 1 and 2.
the emergency department described moderate
limb ataxia, which was worse on the left side, inPatient 1
volving the arm and leg equally; moderate cerebelAt 11 a.m. on day 5, Patient 1 reported moderate lar dysarthria; and gaze-evoked and directionblurred vision and floating specks. At 3:30 p.m., changing nystagmus. The patient was awake and
he reported moderate headache. When gait dis- had no sensory loss, weakness, oculomotor paralyturbance and slurred speech developed, he was sis, Babinski sign, reflex alteration, or memory
transferred from the Biotrial clinical research defect. The temperature was 36.4°C, heart rate 62
facility to the emergency department of Rennes beats per minute, blood pressure 149/89 mm Hg,
n engl j med 375;18 nejm.org November 3, 2016
1719
The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Table 2. Description of Magnetic Resonance Imaging Abnormalities in the Four Patients.*
Variable
Patient 1
Day 6
Patient 2
Day 8
Day 7
Day 8
Patient 3
Day 9
Day 8
Patient 4
Day 9
Hyperintense lesions on diffusion-weighted images
Pons
Hippocampus
Amygdala
Mammillary bodies
No
Severe
Severe
Moderate
Severe
Severe
Mild
Mild
Mild
Severe
Mild
Moderate
Moderate
Moderate
Moderate
—
Severe
Mild
Moderate
Moderate
—
Mild
Moderate
Severe
—
Moderate
Moderate
—
—
Cortex
—
Severe
—
—
—
—
—
Thalamus
—
Severe
—
—
—
—
—
External capsule
—
Severe
—
—
—
—
—
Pathologic hypersignal on FLAIR
images
Pons
Hippocampus
NA
No
Severe
Severe
Severe
Severe
Severe
Severe
Moderate
Severe
Severe
Severe
Moderate
Moderate
Amygdala
Moderate
Severe
Moderate
Moderate
—
—
Mammillary bodies
Moderate
Severe
Moderate
Moderate
—
—
Medulla oblongata
Mild
Severe
—
—
Mild
Mild
Moderate
Severe
—
—
—
—
Anterior temporal lobe
—
Severe
Mild
Mild
—
—
Cortex
—
Severe
—
—
—
—
Thalamus
—
Severe
—
—
—
—
Midbrain
Microhemorrhages on susceptibility-weighted images
Pons
Hippocampus
Amygdala
Medulla oblongata
Day 8
NA
No
Severe
Severe
Mild
Moderate
Mild
Moderate
Moderate
Severe
Mild
Moderate
—
Mild
—
Severe
Mild
Moderate
Mild
Mild
Mild
Moderate
—
—
—
—
Midbrain
—
Moderate
—
—
—
—
Cortex
—
Severe
—
—
—
—
External capsule
—
Severe
—
—
—
—
Basal ganglia
—
Severe
—
—
—
—
*FLAIR denotes fluid-attenuated inversion recovery, and NA not available.
and oxygen saturation 95% while the patient was
breathing ambient air. A cranial computed tomographic (CT) scan and a CT angiogram were
initially interpreted as normal. A subtle hypodensity in the pons could be seen, retrospectively.
The complete blood count and blood levels of
electrolytes, urea, creatinine, and C-reactive protein (CRP) were normal, as were the results of
coagulation and liver-function tests. The patient
received 160 mg of aspirin. At 7:45 a.m. on day 6,
he suddenly became confused and agitated, and
1720
he had worse limb and postural ataxia with severe dysmetria, limb and truncal kinetic tremor,
and an inability to sit up in bed.
Magnetic resonance imaging (MRI) (Fig. 1)
showed hyperintensities in the pons and hippocampi on fluid-attenuated inversion recovery
(FLAIR) and diffusion-weighted sequences, with
multiple microhemorrhages in the pons. As the
patient’s condition deteriorated further, he became
unconscious (Glasgow Coma Scale score of 9, on
a scale from 3 to 15, with lower scores indicat-
n engl j med 375;18 nejm.org November 3, 2016
Acute Neurologic Disorder from an FA AH Inhibitor
A
B
C
E
F
G
I
J
D
H
K
Figure 1. Magnetic Resonance Imaging (MRI) Studies in Patient 1.
Panels A through F depict MRI studies from day 6, and Panels G through K depict studies from day 8. On day 6, MRI showed hyperintense
lesions (thin arrows) on diffusion-weighted images in the pons (diffuse lesion; Panel A) and right hippocampus (punctate lesion; Panel D),
microhemorrhages (thick arrows) on susceptibility-weighted images in the pons (Panel B) and hippocampi (Panel E), and pathologic
hypersignal (arrowhead) on fluid-attenuated inversion recovery (FLAIR) images in the pons (Panel C) and midbrain (Panel F). On day 8,
MRI showed worsening of lesions: hyperintense lesions on diffusion-weighted images involving mainly the cortex, external capsula, thalami
(Panel J) and the pons, hippocampi, amygdala, and mammillary bodies (not shown); microhemorrhages on susceptibility-weighted images
in the hippocampi, amygdala, external capsula, all the basal ganglia, and the cortex (Panels G, H, and I); and pathologic hypersignal on
FLAIR images in the cortex, thalami (Panel K), and the brain stem, hippocampi, and amygdala (not shown).
ing a reduced level of consciousness; the pupils
were symmetric and reactive to light), and he
required tracheal intubation and mechanical
ventilation with sedation. The temperature became elevated to 38.2°C. The cerebrospinal fluid
had 173 white cells per cubic millimeter (87% of
which were neutrophils), a protein level of 353 mg
n engl j med 375;18
per deciliter, and a glucose level of 4.58 mmol
per liter; the serum glucose level was 8 mmol per
liter (144 mg per deciliter). He received acyclovir,
cefotaxime, and amoxicillin until cerebrospinal
fluid studies for herpes simplex virus, varicella
virus, and Listeria monocytogenes were determined
to be negative. Levels of antinuclear antibodies,
nejm.org
November 3, 2016
1721
The
B
A
D
n e w e ng l a n d j o u r na l
of
m e dic i n e
C
E
F
G
Figure 2. MRI Studies in Patient 2.
A time series of diffusion-weighted images on day 7 (Panel A), day 8 (Panel B), and day 9 (Panel C) shows progressive
worsening of hyperintense lesions in the hippocampi and amygdala. MRI on day 9 (Panels C through G) showed
several moderate microhemorrhages (thick arrows) on susceptibility-weighted images in the median part of the
pons (Panel D) and in the hippocampi and amygdala (Panel E) as well as pathologic hypersignal (arrowhead) on
FLAIR images in the pons and anterior temporal lobe (Panel F) and in the hippocampi and amygdala (Panel G).
complement, and ADAMTS13 (a disintegrin and
metalloproteinase with a thrombospondin type 1
motif, member 13) were normal, and there were
no signs of thrombotic microangiopathy.
On day 7, the patient’s heart rate was slower
than 40 beats per minute, and he was hypotensive. A CT scan showed edema of the brain stem,
hippocampi, and temporal lobes. On day 8, he
had bilateral dilated and light-unreactive pupils.
MRI showed diffuse hyperintense lesions on
FLAIR and diffusion-weighted sequences and
multiple microhemorrhages, mainly involving the
brain stem, hippocampi, cortex, and thalamus.
He was declared brain dead the following day.
An autopsy was performed, but the results have
not been made available to the authors.
Patient 2
On day 7, Patient 2 began asking the same questions repeatedly about recent activities. He was
transferred from the Biotrial clinical research
facility to the emergency department of Rennes
1722
n engl j med 375;18
University Hospital. A neurologic examination
was performed by the on-duty neurologist. The
patient was incapable of encoding new facts,
events, or names. Although the retrieval of information from years ago was relatively preserved,
his memory for the previous 2 to 3 months was
incomplete. He reported moderate headache.
Brain MRI showed hippocampal and anterior pontine signal hyperintensities on diffusion-weighted
sequences (Fig. 2). The complete blood count
and blood levels of electrolytes, urea, creatinine,
and CRP were normal, as were the results of
coagulation and liver-function tests.
On day 8, he had moderate dysarthria and
moderate limb and gait ataxia (he was incapable
of walking in a straight line). A second MRI scan
showed hyperintense lesions on FLAIR and diffusion-weighted sequences and several microhemorrhages involving the pons and hippocampi. The
patient received intravenous glucocorticoids from
day 8 to day 12. On day 9, his condition was
unchanged. A third MRI showed an increased
nejm.org
November 3, 2016
Acute Neurologic Disorder from an FA AH Inhibitor
A
B
C
D
E
F
G
H
Figure 3. MRI Studies in Patient 3.
MRI on day 8 showed hyperintense lesions (thin arrows) on diffusion-weighted images in the pons (Panel A), several
microhemorrhages (thick arrows) on susceptibility-weighted images in the median pons (Panel B), and pathologic
hypersignal (arrowhead) on FLAIR images in the pons (Panel C) and hippocampi (Panel D). MRI on day 9 showed
punctate hyperintense lesions (thin arrows) on diffusion-weighted images in the hippocampi and amygdala (Panel E),
worsening of existing microhemorrhages (thick arrows) on susceptibility-weighted images in the median pons (Panel F)
as well as new microhemorrhages in the hippocampi and amygdala (Panel G), and pathologic hypersignal (arrowhead)
on FLAIR images (Panel H) in the pons, anterior part of the medulla oblongata, and the hippocampi (not shown).
number of microhemorrhages. His condition
gradually improved, and at the last clinical
follow-up, on day 55, his amnesic symptoms
had lessened, but he had partial retrograde
amnesia regarding the period from 2 months
before to 1 month after administration of the
drug and minimal anterograde amnesia. Dysarthria and ataxia were no longer evident. MRI
showed that the diffusion-weighted hyperintensities had disappeared and that the FLAIR hyperintensities had partially regressed (Fig. S1 in
the Supplementary Appendix, available with the
full text of this article at NEJM.org). The hippocampi had heterogeneous signal hyperintensities, and some focal hyperintensities were still
visible in the pons on FLAIR images. No new
lesion had appeared.
Patient 3
On day 5, Patient 3 reported mild asthenia, headache, and dizziness, but repeated neurologic
examinations performed by the physician at the
Biotrial clinical research facility were normal. At
n engl j med 375;18
7:38 a.m. on day 8, he presented with a subacute
gait disturbance, slurred speech, and a syncope.
He was transferred from the Biotrial facility to
the emergency department of Rennes University
Hospital. A neurologic examination was performed by the on-duty neurologist. The patient
was somnolent and had severe limb, gait, and
postural ataxia (he was unable to walk or sit up
in bed without assistance) and moderate dysarthria. No sensory or motor disturbances (including oculomotor paralysis) and no memory defects
were found. Nystagmus (gaze-evoked and direction-changing) subsequently appeared. The headache ceased. The results of blood tests were
normal. MRI showed hyperintensities on diffusion-weighted and FLAIR sequences in the brain
stem (pons and medulla oblongata) and hippocampi and a focal microhemorrhage in the pons
(Fig. 3). The cerebrospinal fluid had a protein
level of 1.13 g per liter but no white or red cells.
He received intravenous glucocorticoids from
day 8 to day 10. On day 9, the cerebellar syndrome was unchanged. On day 10, he had severe
nejm.org
November 3, 2016
1723
The
n e w e ng l a n d j o u r na l
dysarthria and somnolence. He was given 1 g of
intravenous cyclophosphamide.
His condition gradually improved beginning
on day 11, and he could walk without assistance
on day 13. At the last clinical follow-up on day
55, he was able to walk without assistance but
had difficulty with tandem gait and had nystagmus on left lateral gaze. MRI showed that the
diffusion-weighted and FLAIR hyperintensities
in the medulla oblongata and hippocampi had
disappeared (Fig. S2 in the Supplementary Appendix). Focal hyperintensities were still visible
in the pons on FLAIR images, as were micro­
hemorrhages.
Patient 4
Patient 4 had moderate diarrhea on days 6 and 7.
MRI scans on days 8 and 10 were normal, except
for an asymptomatic cavernous malformation
located in the brain stem. On day 55, he remained
asymptomatic.
Discussion
The healthy volunteers described in this article
participated in a phase 1 study of BIA 10-2474, a
new FAAH inhibitor. They had received the highest cumulative dose (250 to 300 mg) administered to humans. A total of 84 healthy volunteers
had previously received cumulative doses of up
to 200 mg of BIA 10-2474. No clinical severe
adverse event had been reported. The product
contained in the capsules administered to all the
volunteers was the same as that used for the
toxicology studies, and assays confirmed that it
was of high purity.4 These data suggest that the
toxic effects we observed were related to drug
accumulation. This hypothesis is supported by
the nonlinear pharmacokinetics of BIA 10-2474
for doses higher than 40 to 100 mg.4
The clinical syndrome in these patients was
an acute and rapidly progressive central nervous
system disorder with limb, gait, and postural
ataxia as well as dysarthria and nystagmus, all
of which are compatible with a cerebellar syndrome; amnesia compatible with medial temporal
amnesia; headache; and altered consciousness.
Consistent with these clinical signs and symptoms, the lesions on MRI involved mainly the
pons and hippocampi, bilaterally and symmetrically. The cerebellar syndrome can be explained
by lesions in the cerebellar peduncles of the
crossing cerebellar fibers at the pontine and
1724
of
m e dic i n e
mesencephalic levels, because the cerebellum
was not directly affected on MRI. Thalamic and
cortical lesions were seen in Patient 1 and had
radiologic characteristics that were similar to
those of the pontine and hippocampal lesions;
these findings suggest that a similar pathophysiological process took place that was restricted
mostly to gray matter in many regions of the
brain. The MRI findings included microhemorrhages on susceptibility-weighted images and hyperintensities on FLAIR and diffusion-weighted
images. The diffusion hyperintensities may have
been related to vasogenic or cytotoxic edema.
The apparent diffusion coefficient usually helps
to differentiate between vasogenic and cytotoxic
edema. However, because the microhemorrhages
disrupted the signal, apparent-diffusion-coefficient maps could not be reliably used to characterize the underlying mechanism.
The meningitis reported in Patient 1 may have
been from severe brain-tissue injury, but it is
possible that there was an inflammatory component to the toxic syndrome. No meningitis was
found in the other patient who underwent a lumbar puncture and who had a milder form of the
syndrome (Patient 3). The syndrome was partially
reversible in Patients 2 and 3, and the potential
benefit of early high-dose glucocorticoid infusion
remains an open question. Long-term clinical
and MRI follow-up of the surviving patients is
planned. Because three of the four volunteers
who had received the molecule presented with
adverse events, a genetic susceptibility to these
effects is improbable.
The atypical distribution of the brain lesions;
the widespread, bilateral, and symmetric pattern
of the injury; and the drug-accumulation–dependent toxic effects suggest direct toxicity of BIA
10-2474.5 Nevertheless, the precise mechanism
of this toxic cerebral syndrome is unknown. The
distribution of the brain lesions does not exactly
match the location of the endocannabinoid system.6 Endocannabinoid receptors and FAAHs are
highly expressed in the hippocampi but not in the
pons. Moreover, severe toxic effects in the central
nervous system as a result of an increased level
of endocannabinoids have not been reported previously; this suggests the possibility of an offtarget effect of the drug, owing to the low
specificity of BIA 10-2474 for FAAH, or an effect
of a metabolite.4 These unanticipated severe adverse events were caused by the drug and reflect
the complexities of clinical drug research.
n engl j med 375;18 nejm.org November 3, 2016
Acute Neurologic Disorder from an FA AH Inhibitor
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Ms. Sara Calmanti for her help in writing the first
draft of this article and Ms. Elizabeth Portier for her help in
References
1. Cravatt BF, Demarest K, Patricelli MP,
et al. Supersensitivity to anandamide and
enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide
hydrolase. Proc Natl Acad Sci U S A 2001;​
98:​9371-6.
2. Roques BP, Fournié-Zaluski MC,
Wurm M. Inhibiting the breakdown of
endogenous opioids and cannabinoids to
alleviate pain. Nat Rev Drug Discov 2012;​
11:​292-310.
3. Huggins JP, Smart TS, Langman S,
Taylor L, Young T. An efficient randomised, placebo-controlled clinical trial
editing an earlier version of the manuscript; the family of the
patient who died and the three other patients for consenting to
the publication of their clinical and MRI data; and the staff at
Rennes University Hospital for caring for the patients.
with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which
modulates endocannabinoids but fails to
induce effective analgesia in patients with
pain due to osteoarthritis of the knee.
Pain 2012;​153:​1837-46.
4. Report by the Temporary Specialist
Scientific Committee (TSSC), “FAAH
(Fatty Acid Amide Hydrolase)”, on the
causes of the accident during a Phase 1
clinical trial in Rennes in January 2016.
Saint-Denis, France:​Agence Nationale de
Sécurité du Médicament et des Produits
de Santé (http://ansm​.sante​.fr/​var/​ansm_
site/​storage/​original/​application/​
744c7c6daf96b141bc9509e2f85c227e​
.pdf).
5. Sharma P, Eesa M, Scott JN. Toxic and
acquired metabolic encephalopathies:
MRI appearance. AJR Am J Roentgenol
2009;​193:​879-86.
6. Hu SS, Mackie K. Distribution of the
endocannabinoid system in the central
nervous system. Handb Exp Pharmacol
2015;​231:​59-93.
Copyright © 2016 Massachusetts Medical Society.
n engl j med 375;18 nejm.org November 3, 2016
1725