PMID- 33274491
OWN - NLM
STAT- MEDLINE
DCOM- 20210920
LR  - 20210920
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Linking)
VI  - 87
IP  - 7
DP  - 2021 Jul
TI  - Disproportionality analysis in VigiBase as a drug repositioning method for the 
      discovery of potentially useful drugs in Alzheimer's disease.
PG  - 2830-2837
LID - 10.1111/bcp.14690 [doi]
AB  - 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 muM. 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.
CI  - (c) 2020 British Pharmacological Society.
FAU - Chretien, Basile
AU  - Chretien B
AUID- ORCID: 0000-0002-7483-2489
AD  - Department of Pharmacology, Caen University Hospital, Caen, F-14000, France.
AD  - Pharmacovigilance Regional Center, Caen University Hospital, Caen, F-14000, 
      France.
FAU - Jourdan, Jean-Pierre
AU  - Jourdan JP
AUID- ORCID: 0000-0002-0553-9705
AD  - Department of Pharmacy, Caen University Hospital, Caen, F-14000, France.
AD  - Centre d'Etudes et de Recherche sur le Medicament de Normandie (CERMN), Normandie 
      Univ, UNICAEN, Caen, F-14000, France.
FAU - Davis, Audrey
AU  - Davis A
AD  - Centre d'Etudes et de Recherche sur le Medicament de Normandie (CERMN), Normandie 
      Univ, UNICAEN, Caen, F-14000, France.
FAU - Fedrizzi, Sophie
AU  - Fedrizzi S
AD  - Department of Pharmacology, Caen University Hospital, Caen, F-14000, France.
AD  - Pharmacovigilance Regional Center, Caen University Hospital, Caen, F-14000, 
      France.
FAU - Bureau, Ronan
AU  - Bureau R
AD  - Centre d'Etudes et de Recherche sur le Medicament de Normandie (CERMN), Normandie 
      Univ, UNICAEN, Caen, F-14000, France.
FAU - Sassier, Marion
AU  - Sassier M
AD  - Department of Pharmacology, Caen University Hospital, Caen, F-14000, France.
AD  - Pharmacovigilance Regional Center, Caen University Hospital, Caen, F-14000, 
      France.
FAU - Rochais, Christophe
AU  - Rochais C
AUID- ORCID: 0000-0001-7996-2082
AD  - Centre d'Etudes et de Recherche sur le Medicament de Normandie (CERMN), Normandie 
      Univ, UNICAEN, Caen, F-14000, France.
FAU - Alexandre, Joachim
AU  - Alexandre J
AD  - Department of Pharmacology, Caen University Hospital, Caen, F-14000, France.
AD  - Pharmacovigilance Regional Center, Caen University Hospital, Caen, F-14000, 
      France.
AD  - EA4650, Signalisation, electrophysiologie et imagerie des lesions 
      d'ischemie-reperfusion myocardique, Normandie Univ, UNICAEN, Caen, 14000, France.
FAU - Lelong-Boulouard, Veronique
AU  - Lelong-Boulouard V
AD  - Department of Pharmacology, Caen University Hospital, Caen, F-14000, France.
AD  - INSERM UMR 1075, COMETE-MOBILITES "Vieillissement, Pathologie, Sante", Normandie 
      Univ, UNICAEN, Caen, 14000, France.
FAU - Dolladille, Charles
AU  - Dolladille C
AD  - Department of Pharmacology, Caen University Hospital, Caen, F-14000, France.
AD  - EA4650, Signalisation, electrophysiologie et imagerie des lesions 
      d'ischemie-reperfusion myocardique, Normandie Univ, UNICAEN, Caen, 14000, France.
FAU - Dallemagne, Patrick
AU  - Dallemagne P
AD  - Centre d'Etudes et de Recherche sur le Medicament de Normandie (CERMN), Normandie 
      Univ, UNICAEN, Caen, F-14000, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201223
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Pharmaceutical Preparations)
SB  - IM
MH  - Adverse Drug Reaction Reporting Systems
MH  - *Alzheimer Disease/drug therapy
MH  - Databases, Factual
MH  - Drug Repositioning
MH  - Humans
MH  - *Pharmaceutical Preparations
MH  - Pharmacovigilance
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - anticholinesterase drugs
OT  - data mining
OT  - drug repositioning
OT  - drug repurposing
OT  - pharmacovigilance
EDAT- 2020/12/05 06:00
MHDA- 2021/09/21 06:00
CRDT- 2020/12/04 05:50
PHST- 2020/11/09 00:00 [revised]
PHST- 2020/07/11 00:00 [received]
PHST- 2020/11/28 00:00 [accepted]
PHST- 2020/12/05 06:00 [pubmed]
PHST- 2021/09/21 06:00 [medline]
PHST- 2020/12/04 05:50 [entrez]
AID - 10.1111/bcp.14690 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2021 Jul;87(7):2830-2837. doi: 10.1111/bcp.14690. Epub 2020 
      Dec 23.