1. Disproportionality analysis in VigiBase as a drug repositioning method for the discovery of potentially useful drugs in Alzheimer's disease
- Author
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Patrick Dallemagne, Véronique Lelong-Boulouard, Ronan Bureau, Charles Dolladille, Basile Chrétien, Christophe Rochais, Sophie Fedrizzi, Audrey Davis, Marion Sassier, Jean-Pierre Jourdan, and Joachim Alexandre
- Subjects
Drug ,Databases, Factual ,media_common.quotation_subject ,Disease ,Pharmacology ,030226 pharmacology & pharmacy ,03 medical and health sciences ,Pharmacovigilance ,0302 clinical medicine ,Alzheimer Disease ,Medicine ,Adverse Drug Reaction Reporting Systems ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Adverse effect ,Clozapine ,media_common ,Sertraline ,business.industry ,Drug Repositioning ,Drug repositioning ,Pharmaceutical Preparations ,Aripiprazole ,business ,medicine.drug - Abstract
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.
- Published
- 2020