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Journal of Clinical and Experimental Toxicology | Volume: 2
December 03-04, 2018 | Dubai, UAE
International Conference on
6
th
International Conference on
Toxicology, Clinical Toxicology & Pharmacology
Recycling & Waste Management
Joint Event
&
T
he genotoxicity of 3-(1-(cyclohexyl(methyl)carbamoyl)-lH-
imidazol-4-yl)pyridine 1-oxide, BIA 10-2474, a novel fatty
acid amide hydrolase (FAAH) inhibitor developed by BIAL for
treatment of medical conditions in which there is an advantage
in enhancing the level of endogenous anandamide (AEA) and
tonically increasing the drive of the endocannabinoid system,
was evaluated for its genotoxicity. Studies included the Ames
(
Salmonella typhimurium
) reversemutation test, the
Escherichia
coli
WP2uvrA test, an in vitro chromosome damage assay in
human lymphocytes, and an in vivo micronucleus test in mice.
All results were negative. Despite standard comprehensive and
meticulous toxicological evaluation, apparent and catastrophic
neurotoxicityinthefirst-in-humanphase1studyin2016resulted
in cessation of the trial. While the mechanism underlying
the adverse events remains ill-defined, there is rationale for
expansion of routine ICH harmonized guidelines for preclinical
Geno toxicologic testing. We present both a hypothesis for the
mechanism of neurotoxicity and a propose a path forward for
a more comprehensive evaluation of promising new drugs.
e:
drpressvm2@gmail.comA proposal for expansion of current guidelines for the genotoxicity testing of new drugs: The case of
BIA 10-2474, a novel fatty acid amide hydrolase inhibitor
Peter Pressman
The Daedalus Foundation, USA
Toxicology 2018 & Recycling 2018, Volume 2
DOI: 10.4066/2630-4570-C1-003