Androgenic Effects on Ventricular Repolarization: A Translational Study From the International Pharmacovigilance Database to iPSC-Cardiomyocytes.
Androgens
/ metabolism
Antineoplastic Agents
/ adverse effects
Benzamides
Cell Differentiation
Cells, Cultured
Databases, Factual
Humans
Hypogonadism
/ drug therapy
Induced Pluripotent Stem Cells
/ physiology
International Cooperation
Long QT Syndrome
/ drug therapy
Male
Myocytes, Cardiac
/ physiology
Nitriles
Pharmacovigilance
Phenylthiohydantoin
/ adverse effects
Risk
Torsades de Pointes
/ drug therapy
Translational Research, Biomedical
androgen antagonists
hypogonadism
long QT syndrome
testosterone
torsades de pointes
Journal
Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763
Informations de publication
Date de publication:
24 09 2019
24 09 2019
Historique:
pubmed:
6
8
2019
medline:
18
6
2020
entrez:
6
8
2019
Statut:
ppublish
Résumé
Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. We searched the international pharmacovigilance database VigiBase for men (n=6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone. Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n=168) and/or TdP (n=68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio=1.4-4.7; QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.
Sections du résumé
BACKGROUND
Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking.
METHODS
We searched the international pharmacovigilance database VigiBase for men (n=6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone.
RESULTS
Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n=168) and/or TdP (n=68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio=1.4-4.7;
CONCLUSIONS
QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs.
CLINICAL TRIAL REGISTRATION
URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.
Identifiants
pubmed: 31378084
doi: 10.1161/CIRCULATIONAHA.119.040162
pmc: PMC6756939
mid: NIHMS1532205
doi:
Substances chimiques
Androgens
0
Antineoplastic Agents
0
Benzamides
0
Nitriles
0
Phenylthiohydantoin
2010-15-3
enzalutamide
93T0T9GKNU
Banques de données
ClinicalTrials.gov
['NCT03193138']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1070-1080Subventions
Organisme : NIGMS NIH HHS
ID : P50 GM115305
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL144980
Pays : United States
Organisme : NHLBI NIH HHS
ID : R56 HL141466
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
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