Browsing by Subject "Drug-Related Side Effects and Adverse Reactions"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Identification and Mechanistic Investigation of Drug-Drug Interactions Associated With Myopathy: A Translational Approach
    (Wiley Blackwell (John Wiley & Sons), 2015-09) Han, X.; Quinney, S. K.; Wang, Z.; Zhang, P.; Duke, J.; Desta, Z.; Elmendorf, J. S.; Flockhart, D. A.; Li, L.; Department of Medical & Molecular Genetics, IU School of Medicine
    Myopathy is a group of muscle diseases that can be induced or exacerbated by drug-drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine-simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System.
  • Thumbnail Image
    Item
    Random control selection for conducting high-throughput adverse drug events screening using large-scale longitudinal health data
    (Wiley, 2021-09) Chiang, Chien-Wei; Zhang, Penyue; Donneyong, Macarius; Chen, You; Su, Yu; Li, Lang; Biostatistics, School of Public Health
    Case-control design based high-throughput pharmacoinformatics study using large-scale longitudinal health data is able to detect new adverse drug event (ADEs) signals. Existing control selection approaches for case-control design included the dynamic/super control selection approach. The dynamic/super control selection approach requires all individuals to be evaluated at all ADE case index dates, as the individuals' eligibilities as control depend on ADE/enrollment history. Thus, using large-scale longitudinal health data, the dynamic/super control selection approach requires extraordinarily high computational time. We proposed a random control selection approach in which ADE case index dates were matched by randomly generated control index dates. The random control selection approach does not depend on ADE/enrollment history. It is able to significantly reduce computational time to prepare case-control data sets, as it requires all individuals to be evaluated only once. We compared the performance metrics of all control selection approaches using two large-scale longitudinal health data and a drug-ADE gold standard including 399 drug-ADE pairs. The F-scores for the random control selection approach were between 0.586 and 0.600 compared to between 0.545 and 0.562 for dynamic/super control selection approaches. The random control selection approach was ~ 1000 times faster than dynamic/super control selection approach on preparing case-control data sets. With large-scale longitudinal health data, a case-control design-based pharmacoinformatics study using random control selection is able to generate comparable ADE signals than the existing control selection approaches. The random control selection approach also significantly reduces computational time to prepare the case-control data sets.
  • Thumbnail Image
    Item
    Tracheal Aspirate as an Alternative Biologic Sample for Pharmacogenomics Testing in Mechanically Ventilated Pediatric Patients
    (Wiley, 2021-03) Hargreaves, Katherine A.; Pratt, Victoria M.; Medeiros, Elizabeth B.; Lynnes, Ty C.; Granfield, Caitlin A.; Skaar, Todd C.; Iwata-Otsubo, Aiko; Tillman, Emma M.; Medical and Molecular Genetics, School of Medicine
    Patients in the pediatric intensive care unit are exposed to multiple medications and are at high risk for adverse drug reactions. Pharmacogenomic (PGx) testing could help decrease their risk of adverse reactions. Although whole blood is preferred for PGx testing, blood volume in this population is often limited. However, for patients on mechanical ventilation, tracheal secretions are abundant, frequently suctioned, and discarded. Thus, the aim of this pilot study was to determine if tracheal aspirates could be used as a source of human genomic DNA for PGx testing. We successfully extracted DNA from tracheal secretions of all 23 patients in the study. The samples were successfully genotyped for 10 clinically actionable single nucleotide variants across 3 cytochrome P450 genes (CYP2D6, CYP2C19, and CYP3A5). Using DNA from whole blood samples in 11 of the patients, we confirmed the accuracy of the genotyping with 100% concordance. Therefore, our results support the use of tracheal aspirates from mechanically ventilated children as an adequate biospecimen for clinical genetic testing.
  • Thumbnail Image
    Item
    Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity
    (Elsevier, 2015-09) Hayashi, Paul H.; Fontana, Robert J.; Chalasani, Naga; Stolz, Andrew A.; Talwalker, Jay A.; Navarro, Victor J.; Lee, William M.; Davern, Timothy J.; Kleiner, David E.; Gu, Jiezhun; Hoofnagle, Jay H.; Department of Medicine, IU School of Medicine
    IMPORTANCE: Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE: To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES: The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS: The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.