Individual short-acting opioids and the risk of opioid-related adverse events in adolescents.

PURPOSE: Hydrocodone, codeine, oxycodone, and tramadol are frequently prescribed to adolescents for moderate pain related to minor trauma or dental, surgical, or medical procedures. Pharmacokinetic and pharmacodynamic differences between these opioids could affect their relative safety. We aimed to compare occurrence of opioid-related adverse events in adolescents without cancer or other severe conditions taking hydrocodone, codeine, oxycodone, and tramadol. METHODS: Retrospective cohort study of 201 940 Tennessee Medicaid enrollees 12 to 17 years of age without cancer, other severe conditions, or evidence of substance abuse with 529 731 filled prescriptions for study opioids. Adverse events were defined as an emergency department visit, hospital admission, or death related to opioid use, confirmed by medical record review. Serious events had opioid-related escalation of care, hospitalization, or death. Propensity-score adjusted hazard ratios (HRs) were calculated with hydrocodone as the reference category. RESULTS: The incidence of opioid-related adverse events per 10 000 person-years of opioid exposure was 97.5 for hydrocodone (127 events/13 026 person-years), 91.2 for codeine (58/6,359), 229.7 for oxycodone (43/1,872), and 317.7 for tramadol (47/1479). The HRs for tramadol in comparison with hydrocodone for all and serious events were 2.98 (2.03-4.39) and 2.94 (1.81-4.75), respectively. Increased risk for tramadol was consistently present when the adverse events were restricted to those with neurologic-respiratory depression/other symptoms of possible overdose. CONCLUSION: In adolescents without cancer or other severe conditions prescribed short-acting opioids, the incidence of both all opioid-related adverse events and more serious events with opioid-related escalation of care, hospitalization, or death was consistently greater for tramadol than for hydrocodone.

The impact of age and CYP2C9 and VKORC1 variants on stable warfarin dose in the paediatric population.

The influence of genetic variation on warfarin dose requirement is limited for paediatric patients. We performed a retrospective, cross-sectional study to examine the effect of variant CYP2C9 and VKORC1 genotypes on warfarin dose in 100 children. Those with VKORC1 genotype AA required 48% of the dose of homozygous wild-type (GG, P < 0·0001). Patients with any variant CYP2C9 allele required 71% of the dose for wild-type (P = 0·001). The effect of variant VKORC1 alleles tended to vary with age, suggesting developmental ontogeny may influence warfarin sensitivity. Age, CYP2C9 genotype, VKORC1 genotype and age:VKORC1 interaction accounted for 53% of warfarin dose variability.

Propoxyphene and the risk of out-of-hospital death.

PURPOSE: The opioid analgesic propoxyphene was withdrawn from the US market in 2010, motivated by concerns regarding fatality in overdose and adverse cardiac effects, including prolongation of the QT interval. These concerns were based on case reports, summary vital statistics, and surrogate endpoint studies. METHODS: Using the linked Tennessee Medicaid database (1992-2007), we conducted a retrospective cohort study that compared risk of sudden cardiac, medication toxicity, and total out-of-hospital death for propoxyphene users with that for comparable nonusers of any prescribed opioid analgesic and users of hydrocodone, an opioid with similar indications. Cohort members had 1,873,500 propoxyphene prescriptions, 1,873,500 matched nonuser control periods, and 936,750 matched hydrocodone prescriptions. RESULTS: Current propoxyphene users had no increased risk for sudden cardiac death (versus nonusers: hazard ratio [HR] = 1.00 [0.81-1.23]; versus current hydrocodone users: HR = 0.91 [0.68-1.21]) but did have increased risk for medication toxicity deaths (versus nonusers: HR = 1.85 [1.07-3.19], p = 0.027; versus current hydrocodone users: HR = 2.10 [0.87-5.10], p = 0.100). Because toxicity deaths were a small proportion of study deaths, total out-of-hospital mortality differed by less than 10% between the study groups and was not significantly elevated for propoxyphene (versus nonusers: HR = 1.09 [0.95-1.25]; versus current hydrocodone users: HR = 1.06 [0.87-1.29] ). CONCLUSIONS: Our findings support the concern that propoxyphene has greater toxicity in overdose but do not provide evidence that it increases the risk of sudden cardiac death.

The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients.

OBJECTIVE: Tacrolimus, an immunosuppressive drug widely prescribed in kidney transplantation, requires therapeutic drug monitoring due to its marked interindividual pharmacokinetic variability and narrow therapeutic index. Previous studies have established that CYP3A5 rs776746 is associated with tacrolimus clearance, blood concentration, and dose requirement. The importance of other drug absorption, distribution, metabolism, and elimination (ADME) gene variants has not been well characterized. METHODS: We used novel DNA biobank and electronic medical record resources to identify ADME variants associated with tacrolimus dose requirement. Broad ADME genotyping was performed on 446 kidney transplant recipients, who had been dosed to a steady state with tacrolimus. The cohort was obtained from Vanderbilt's DNA biobank, BioVU, which contains linked deidentified electronic medical record data. Genotyping included Affymetrix drug-metabolizing enzymes and transporters Plus (1936 polymorphisms), custom Sequenom Massarray iPLEX Gold assay (95 polymorphisms), and ancestry-informative markers. The primary outcome was tacrolimus dose requirement defined as blood concentration to dose ratio. RESULTS: In analyses, which adjusted for race and other clinical factors, we replicated the association of tacrolimus blood concentration to dose ratio with CYP3A5 rs776746 (P=7.15×10), and identified associations with nine variants in linkage disequilibrium with rs776746, including eight CYP3A4 variants. No NR1I2 variants were significantly associated. Age, weight, and hemoglobin were also significantly associated with the outcome. In final models, rs776746 explained 39% of variability in dose requirement and 46% was explained by the model containing clinical covariates. CONCLUSION: This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.

Intermuscular adipose tissue in patients with systemic lupus erythematosus.

OBJECTIVE: Patients with SLE frequently have debilitating fatigue and reduced physical activity. Intermuscular adipose tissue (IMAT) accumulation is associated with reduced physical exercise capacity. We hypothesised that IMAT is increased in patients with SLE and associated with increased fatigue, reduced physical activity and increased inflammation. METHODS: In a cross-sectional study, 23 patients with SLE and 28 control participants were evaluated. IMAT was measured in the calf muscles using sequential T 1-weighted MRI. Patient-reported physical activity and fatigue were measured and a multiplex proteomic assay was used to measure markers and mediators of inflammation. RESULTS: IMAT accumulation (percentage of IMAT area to muscle area) was significantly higher in SLE versus control participants (7.92%, 4.51%-13.39% vs 2.65%, 1.15%-4.61%, median, IQR, p<0.001) and remained significant after adjustment for age, sex, race and body mass index (p<0.001). In patients with SLE, IMAT accumulation did not differ significantly among corticosteroid users and non-users (p=0.48). In the study cohort (patients and controls), IMAT was positively correlated with self-reported fatigue score (rho=0.52, p<0.001) and inversely correlated with self-reported walking distance (rho=-0.60, p<0.001). Several markers of inflammation were associated with IMAT accumulation in patients with SLE, and gene ontology analysis showed significant enrichment for pathways associated with macrophage migration and activation in relation to IMAT. CONCLUSION: Patients with SLE have greater IMAT accumulation than controls in the calf muscles. Increased IMAT is associated with greater fatigue and lower physical activity. Future studies should evaluate the effectiveness of interventions that improve muscle quality to alleviate fatigue in patients with SLE.

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update.

CYP2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 genotype impacts clopidogrel active metabolite formation. CYP2C19 intermediate and poor metabolizers who receive clopidogrel experience reduced platelet inhibition and increased risk for major adverse cardiovascular and cerebrovascular events. This guideline is an update to the 2013 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of clopidogrel based on CYP2C19 genotype and includes expanded indications for CYP2C19 genotype-guided antiplatelet therapy, increased strength of recommendation for CYP2C19 intermediate metabolizers, updated CYP2C19 genotype to phenotype translation, and evidence from an expanded literature review (updates at www.cpicpgx.org).

Variation in the α2A-adrenergic receptor gene and risk of gestational diabetes.

AIM: Sympathetic activation suppresses insulin secretion via pancreatic ADRA2A.  Because sympathetic activity and insulin demand increase during pregnancy, we tested the hypothesis  that ADRA2A variants are associated with gestational diabetes (GDM). PATIENTS & METHODS: Among Caucasian pregnant women without pre-existing diabetes, we genotyped 458 who had GDM and 1537 without GDM for seven ADRA2A variants. RESULTS: rs1800038 (OR: 2.34; p = 0.020) and rs3750625 (OR: 1.56; p = 0.010) increased the risk of GDM, and rs11195418 decreased it (OR: 0.62; p = 0.025). The associations remained significant after adjustment for maternal age, maternal BMI, parity and a genetic risk score that included variants previously associated with Type 2 diabetes mellitus and GDM. CONCLUSION: ADRA2A genetic variation contributes independently to the risk of GDM in Caucasian women.

Increased oxidative stress in patients with depression and its relationship to treatment.

Oxidative stress may play a role in the pathogenesis of depression. We tested the hypothesis that urinary F2 isoprostanes, a robust marker of oxidative stress, was increased in patients with depression and associated with symptoms and response to treatment. Urinary F2 isoprostanes was compared in 18 patients with depression and 36 age and sex matched control subjects. In patients, we tested the association between oxidative stress, depression questionnaires and antidepressant treatment. Urinary F2 isoprostane excretion was significantly higher in patients with depression than in control subjects. This association remained significant after adjustment for age, sex and BMI. Depression symptom severity scores were not correlated with F2 isoprostane excretion. Nine patients were treated with sertraline or bupropion for 8 weeks. Depression severity rating scale scores decreased significantly and F2 isoprostane excretion increased. The increase in F2 isoprostane excretion was inversely correlated with the improvement in Hamilton Depression Rating 17 items. In conclusion, oxidative stress is increased in patients with depression. However, although treatment with either bupropion or sertraline reduces the symptoms of depression, it may increase F2 isoprostane excretion. These results suggest that alternative mechanisms, beyond oxidative stress, may be involved in the development of depression and subsequent responses to treatment.