Premium
Disproportionality analysis in VigiBase as a drug repositioning method for the discovery of potentially useful drugs in Alzheimer's disease
Author(s) -
Chrétien Basile,
Jourdan JeanPierre,
Davis Audrey,
Fedrizzi Sophie,
Bureau Ronan,
Sassier Marion,
Rochais Christophe,
Alexandre Joachim,
LelongBoulouard Véronique,
Dolladille Charles,
Dallemagne Patrick
Publication year - 2021
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14690
Subject(s) - pharmacovigilance , duloxetine , pharmacology , medicine , drug , drug repositioning , adverse effect , alternative medicine , pathology
Aims Drug repositioning aims to propose new indications for marketed drugs. Although several methods exist, the utility of pharmacovigilance databases for this purpose is unclear. We conducted a disproportionality analysis in the World Health Organization pharmacovigilance database VigiBase to identify potential anticholinesterase drug candidates for repositioning in Alzheimer's disease (AD). Methods Disproportionality analysis is a validated method for detecting significant associations between drugs and adverse events (AEs) in pharmacovigilance databases. We applied this approach in VigiBase to establish the safety profile displayed by the anticholinesterase drugs used in AD and searched the database for drugs with similar safety profiles. The detected drugs with potential activity against acetylcholinesterase and butyrylcholinesterases (BuChEs) were then evaluated to confirm their anticholinesterase potential. Results We identified 22 drugs with safety profiles similar to AD medicines. Among these drugs, 4 (clozapine, aripiprazole, sertraline and S ‐duloxetine) showed a human BuChE inhibition rate of over 70% at 10 −5 M. Their human BuChE half maximal inhibitory concentration values were compatible with clinical anticholinesterase action in humans at their normal doses. The most active human BuChE inhibitor in our study was S ‐duloxetine, with a half maximal inhibitory concentration of 1.2 μM. Combined with its ability to inhibit serotonin (5‐HT) reuptake, the use of this drug could represent a novel multitarget directed ligand therapeutic strategy for AD. Conclusion We identified 4 drugs with repositioning potential in AD using drug safety profiles derived from a pharmacovigilance database. This method could be useful for future drug repositioning efforts.