PMID- 19932726
OWN - NLM
STAT- MEDLINE
DCOM- 20100603
LR  - 20131121
IS  - 1096-0295 (Electronic)
IS  - 0273-2300 (Linking)
VI  - 56
IP  - 3
DP  - 2010 Apr
TI  - Prediction of drug-related cardiac adverse effects in humans--A: creation of a 
      database of effects and identification of factors affecting their occurrence.
PG  - 247-75
LID - 10.1016/j.yrtph.2009.11.006 [doi]
AB  - This is the first of two reports that describes the compilation of a database of 
      drug-related cardiac adverse effects (AEs) that was used to construct 
      quantitative structure-activity relationship (QSAR) models to predict these AEs, 
      to identify properties of pharmaceuticals correlated with the AEs, and to 
      identify plausible mechanisms of action (MOAs) causing the AEs. This database of 
      396,985 cardiac AE reports was linked to 1632 approved drugs and their chemical 
      structures, 1851 clinical indications (CIs), 997 therapeutic targets (TTs), 432 
      pharmacological MOAs, and 21,180 affinity coefficients (ACs) for the MOA 
      receptors. AEs were obtained from the Food and Drug Administration's (FDA's) 
      Spontaneous Reporting System (SRS) and Adverse Event Reporting System (AERS) and 
      publicly available medical literature. Drug TTs were obtained from Integrity; 
      drug MOAs and ACs were predicted by BioEpisteme. Significant cardiac AEs and 
      patient exposures were estimated based on the proportional reporting ratios 
      (PRRs) for each drug and each AE endpoint as a percentage of the total AEs. 
      Cardiac AE endpoints were bundled based on toxicological mechanism and 
      concordance of drug-related findings. Results revealed that significant cardiac 
      AEs formed 9 clusters affecting Purkinje nerve fibers (arrhythmia, bradycardia, 
      conduction disorder, electrocardiogram, palpitations, QT prolongation, rate 
      rhythm composite, tachycardia, and Torsades de pointes), and 5 clusters affecting 
      the heart muscle (coronary artery disorders, heart failure, myocardial disorders, 
      myocardial infarction, and valve disorders). Based on the observation that each 
      drug had one TT and up to 9 off-target MOAs, cardiac AEs were highly correlated 
      with drugs affecting cardiovascular and cardioneurological functions and certain 
      MOAs (e.g., alpha- and beta-adeno, dopamine, and hydroxytryptomine receptors).
CI  - Copyright 2010. Published by Elsevier Inc.
FAU - Matthews, Edwin J
AU  - Matthews EJ
AD  - U.S. Food and Drug Administration, Center for Food Safety and Applied Nutrition, 
      Office of Food Additive Safety (OFAS), 5100 Paint Branch Parkway, College Park, 
      MD 20740, USA. Edwin.Matthews@fda.hhs.gov
FAU - Frid, Anna A
AU  - Frid AA
LA  - eng
PT  - Journal Article
DEP - 20091122
PL  - Netherlands
TA  - Regul Toxicol Pharmacol
JT  - Regulatory toxicology and pharmacology : RTP
JID - 8214983
RN  - 0 (Pharmaceutical Preparations)
SB  - IM
MH  - *Adverse Drug Reaction Reporting Systems
MH  - Cardiovascular Diseases/chemically induced/*epidemiology
MH  - Cluster Analysis
MH  - *Databases, Factual
MH  - Drug Labeling
MH  - *Drug-Related Side Effects and Adverse Reactions/*epidemiology
MH  - Forecasting
MH  - Heart/*drug effects
MH  - Humans
MH  - Pharmaceutical Preparations/classification
MH  - Product Surveillance, Postmarketing
MH  - Purkinje Fibers/drug effects
MH  - Quantitative Structure-Activity Relationship
MH  - Software
MH  - United States/epidemiology
MH  - United States Food and Drug Administration
EDAT- 2009/11/26 06:00
MHDA- 2010/06/04 06:00
CRDT- 2009/11/26 06:00
PHST- 2009/06/08 00:00 [received]
PHST- 2009/09/29 00:00 [revised]
PHST- 2009/11/06 00:00 [accepted]
PHST- 2009/11/26 06:00 [entrez]
PHST- 2009/11/26 06:00 [pubmed]
PHST- 2010/06/04 06:00 [medline]
AID - S0273-2300(09)00228-1 [pii]
AID - 10.1016/j.yrtph.2009.11.006 [doi]
PST - ppublish
SO  - Regul Toxicol Pharmacol. 2010 Apr;56(3):247-75. doi: 10.1016/j.yrtph.2009.11.006. 
      Epub 2009 Nov 22.