Graphic Mining of High-Order Drug Interactions and Their Directional Effects on Myopathy Using Electronic Medical Records.

We propose to study a novel pharmacovigilance problem for mining directional effects of high-order drug interactions on an adverse drug event (ADE). Our goal is to estimate each individual risk of adding a new drug to an existing drug combination. In this proof-of-concept study, we analyzed a large electronic medical records database and extracted myopathy-relevant case control drug co-occurrence data. We applied frequent itemset mining to discover frequent drug combinations within the extracted data, evaluated directional drug interactions related to these combinations, and identified directional drug interactions with large effect sizes. Furthermore, we developed a novel visualization method to organize multiple directional drug interaction effects depicted as a tree, to generate an intuitive graphical and visual representation of our data-mining results. This translational bioinformatics approach yields promising results, adds valuable and complementary information to the existing pharmacovigilance literature, and has the potential to impact clinical practice.

A Mixture Dose-Response Model for Identifying High-Dimensional Drug Interaction Effects on Myopathy Using Electronic Medical Record Databases.

Interactions between multiple drugs may yield excessive risk of adverse effects. This increased risk is not uniform for all combinations, although some combinations may have constant adverse effect risks. We developed a statistical model using medical record data to identify drug combinations that induce myopathy risk. Such combinations are revealed using a novel mixture model, comprised of a constant risk model and a dose-response risk model. The dose represents the number of drug combinations. Using an empirical Bayes estimation method, we successfully identified high-dimensional (two to six) drug combinations that are associated with excessive myopathy risk at significantly low local false-discovery rates. From the curve of a dose-response model and high-dimensional drug interaction data, we observed that myopathy risk increases as the drug interaction dimension increases. This is the first time that such a dose-response relationship for high-dimensional drug interactions was observed and extracted from the medical record database.

Identification and Mechanistic Investigation of Drug-Drug Interactions Associated With Myopathy: A Translational Approach.

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.

Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins.

AIMS: To examine whether initiation of fibrates or statins in sulfonylurea users is associated with hypoglycaemia, and examine in vitro inhibition of cytochrome P450 (CYP) enzymes by statins, fenofibrate and glipizide. METHODS: We used healthcare data to conduct nested case-control studies of serious hypoglycaemia (i.e. resulting in hospital admission or emergency department treatment) in persons taking glipizide or glyburide, and calculated adjusted overall and time-stratified odds ratios (ORs) and 95% confidence intervals (CIs). We also characterized the in vitro inhibition of CYP enzymes by statins, fenofibrate and glipizide using fluorometric CYP450 inhibition assays, and estimated area under the concentration-time curve ratios (AUCRs) for the drug pairs. RESULTS: We found elevated adjusted overall ORs for glyburide-fenofibrate (OR 1.84, 95% CI 1.37, 2.47) and glyburide-gemfibrozil (OR 1.57, 95% CI 1.25, 1.96). The apparent risk did decline over time as might be expected from a pharmacokinetic mechanism. Fenofibrate was a potent in vitro inhibitor of CYP2C19 (IC50 = 0.2 µm) and CYP2B6 (IC50 = 0.7 µm) and a moderate inhibitor of CYP2C9 (IC50 = 9.7 µm). The predicted CYP-based AUCRs for fenofibrate-glyburide and gemfibrozil-glyburide interactions were only 1.09 and 1.04, suggesting that CYP inhibition is unlikely to explain such an interaction. CONCLUSIONS: Use of fenofibrate or gemfibrozil together with glyburide was associated with elevated overall risks of serious hypoglycaemia. CYP inhibition seems unlikely to explain this observation. We speculate that a pharmacodynamic effect of fibrates (e.g. activate peroxisome proliferator-activator receptor alpha) may contribute to these apparent interactions.

A Semi-Mechanistic Metabolism Model of CYP3A Substrates in Pregnancy: Predicting Changes in Midazolam and Nifedipine Pharmacokinetics.

Physiological changes in pregnancy, including changes in body composition and metabolic enzyme activity, can alter drug pharmacokinetics. A semi-mechanistic metabolism model was developed to describe the pharmacokinetics of two cytochrome P450 3A (CYP3A) substrates, midazolam and nifedipine, in obstetrics patients. The model parameters were optimized to fit the data of oral midazolam pharmacokinetics in pregnant women, by increasing CYP3A-induced hepatic metabolism 1.6-fold in the model with no change in gut wall metabolism. Fetal metabolism had a negligible effect on maternal plasma drug concentrations. Validation of the model was performed by applying changes in volume of distribution and metabolism, consistent with those observed for midazolam, to the pharmacokinetics parameters of immediate-release nifedipine in healthy volunteers. The predicted steady-state areas under the concentration-time curve (AUCs) for nifedipine were within 15% of the data observed in pregnant women undergoing treatment for preterm labor. This model predicts the pharmacokinetics of two CYP3A substrates in pregnancy, and may be applicable to other CYP3A substrates as well.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e2; doi:10.1038/psp.2012.5; advance online publication 26 September 2012.

Prevalence of a host-adapted group B Salmonella enterica in harbour porpoises (Phocoena phocoena) from the south-west coast of England.

A monophasic group B Salmonella enterica 4,12:a:- was first isolated in harbour porpoises (Phocoena phocoena) in Scotland in 1991. This paper reports the isolation of the same group B S enterica from harbour porpoise carcases found stranded along the Cornwall and Devon coastlines. Between 1991 and 2002, 80 harbour porpoises were submitted for postmortem examination and subjected to bacteriological examination under the UK Cetacean Strandings Investigation Programme. A total of 28 Salmonella isolates were recovered and subjected to several tests, including biochemical, molecular and serological analysis.

Association of genotypes of the CYP3A cluster with midazolam disposition in vivo.

The genes that encode for CYP3A4 and CYP3A5 are located in the same region (CYP3A cluster) on chromosome 7. Midazolam (MDZ) is a substrate for both CYP3A4 and CYP3A5. We hypothesize that MDZ disposition in vivo is associated with genotypes of the CYP3A cluster. A meta-analysis of the pharmacokinetic (PK) parameters from seven clinical trials was carried out, in which MDZ was administered both intravenously and orally. DNA samples were available from 116 patients. There were significant ethnic differences in the allelic frequencies of these four common single-nucleotide polymorphisms (SNPs) in the CYP3A cluster. Significant linkage disequilibrium was found between CYP3A5(*)3 and CYP3A4(*)1A in Caucasians, and between CYP3A5(*)1 and CYP3A4(*)1B in African Americans. There were no differences in MDZ disposition in vivo between different genotypes, haplotypes and diplotypes in the CYP3A cluster (P>0.05). No significant differences in MDZ PK parameters were observed between Caucasians and African Americans. Women had higher weight-corrected systemic and oral clearance than men, but dose-adjusted AUC and bioavailability differences were not observed between sexes. The clinical importance of elevated CYP3A activity in women remains to be determined. The r(GC)'s of MDZ PK parameters were between 0.3 and 13.6%. In conclusion, the meta-analysis of seven studies suggests that environmental factors explain the majority of CYP3A activity variation. Further studies are necessary to define the functional significance of SNPs in the CYP3A cluster and the effects of CYP3A genotypes on MDZ disposition in vivo.

Isolation and characterization of Brucella from the lungworms of a harbor porpoise (Phocoena phocoena).

Adult female nematodes identified as Pseudalius inflexus were collected from the lungs of a juvenile male harbor porpoise (Phocoena phocoena) found dead on a beach in Cornwall, UK. Classic and molecular typing methods, immunologic and electron microscopy immunolabeling techniques, provided evidence of Brucella sp. infection within the uterine tissue of nematodes of this marine mammal. This finding presents further evidence to suggest parasites should be considered as a potential means of transfer of bacterial infection in marine mammals and highlights the zoonotic implications for humans exposed to marine mammals through occupation or leisure.

Hydrolysis of capecitabine to 5'-deoxy-5-fluorocytidine by human carboxylesterases and inhibition by loperamide.

Capecitabine is an oral prodrug of 5-fluorouracil that is indicated for the treatment of breast and colorectal cancers. A three-step in vivo-targeted activation process requiring carboxylesterases, cytidine deaminase, and thymidine phosphorylase converts capecitabine to 5-fluorouracil. Carboxylesterases hydrolyze capecitabine's carbamate side chain to form 5'-deoxy-5-fluorocytidine (5'-DFCR). This study examines the steady-state kinetics of recombinant human carboxylesterase isozymes carboxylesterase (CES) 1A1, CES2, and CES3 for hydrolysis of capecitabine with a liquid chromatography/mass spectroscopy assay. Additionally, a spectrophotometric screening assay was utilized to identify drugs that may inhibit carboxylesterase activation of capecitabine. CES1A1 and CES2 hydrolyze capecitabine to a similar extent, with catalytic efficiencies of 14.7 and 12.9 min(-1) mM(-1), respectively. Little catalytic activity is detected for CES3 with capecitabine. Northern blot analysis indicates that relative expression in intestinal tissue is CES2 > CES1A1 > CES3. Hence, intestinal activation of capecitabine may contribute to its efficacy in colon cancer and toxic diarrhea associated with the agent. Loperamide is a strong inhibitor of CES2, with a K(i) of 1.5 muM, but it only weakly inhibits CES1A1 (IC(50) = 0.44 mM). Inhibition of CES2 in the gastrointestinal tract by loperamide may reduce local formation of 5'-DFCR. Both CES1A1 and CES2 are responsible for the activation of capecitabine, whereas CES3 plays little role in 5'-DFCR formation.