Daniel Kurnik

Common Genetic Variants of Microsomal Epoxide Hydrolase Affect Warfarin Dose Requirements Beyond the Effect of Cytochrome P450 2C9

Warfarin dose response is partially explained by the polymorphisms in the cytochrome P450 (CYP) 2C9 gene, affecting S‐warfarin clearance, as well as by age and body weight. We examined the influence on warfarin dose requirements of candidate genes encoding microsomal epoxide hydrolase (mEH), as well as glutathione S‐transferase A1 (GSTA1) components of vitamin K epoxide reductase and the γ‐glutamylcarboxylase (GGCX) gene.

Bioavailability of oral vs. subcutaneous low-dose methotrexate in patients with Crohn's disease.

Background : Oral methotrexate and folic acid are partly absorbed by a common intestinal transporter.

Increased warfarin doses and decreased international normalized ratio response after nationwide generic switching

Our objective was to examine possible changes in the effectiveness of warfarin after a nationwide generic substitution of formulations in 1998.

Muscle pain and serum creatine kinase are not associated with low serum 25(OH) vitamin D levels in patients receiving statins

Objective  Vitamin D deficiency has been associated in some studies with nonspecific musculoskeletal pain and, more specifically, with statin‐induced myalgia, which was ameliorated by high‐dose vitamin D supplements. Our objective was to explore the association between vitamin D status and statin‐induced myalgia and elevation of serum creatine kinase (CK).

Hyperkalemia and renal function during monotherapy and dual renin-angiotensin blockade in the community setting.

BACKGROUND In controlled trials, dual therapy with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) is associated with hyperkalemia and decreased renal function, but there is no information about these adverse effects in clinical practice. OBJECTIVE The aim of this study was to assess the incidence of hyperkalemia and decreased renal function during dual therapy (ACE-I plus ARB) in a community-based setting. METHODS In a retrospective cohort database study, we identified patients who received ARBs added to ongoing ACE-I therapy and who had at least 1 measurement of serum creatinine and potassium during each treatment period. We compared rates of hyperkalemia (>5.5 mmol/L) during equal periods of monotherapy and dual therapy and the rate of a significant rise in serum creatinine (≥0.5 mg/dL) between study periods. We assessed the impact of potential confounders on outcomes by logistic regression analysis. RESULTS Among 425 patients (median follow-up 19 months for each treatment period), hyperkalemia was 2-fold more common during dual therapy than monotherapy (11.1% and 5.6% of patients, respectively) (relative risk = 1.96; 95% CI, 1.22-3.14; P < 0.001). In 77 patients with reduced renal function on monotherapy (serum creatinine ≥1.5 mg/dL), the rate of hyperkalemia was 20.8/100 patient-years, resulting in a number needed to harm of 10.1 patients, compared with 52.6 patients among those with preserved renal function. Mean serum creatinine between treatment periods increased >0.5 mg/dL in 7.5% of patients, more commonly in patients with decreased (18.2%) than with preserved (5.2%) baseline renal function (P < 0.001). CONCLUSION In the community setting, dual therapy was associated with hyperkalemia and a decrease in renal function. The absolute risks were especially high among patients with reduced baseline renal function.

Estimated glomerular filtration rate in a population with normal to mildly reduced renal function as predictor of cardiovascular disease

Background While moderate and severe chronic kidney disease is an established independent risk factor for cardiovascular disease (CVD), the association of estimated glomerular filtration rate (eGFR) differences within the normal to mildly reduced range (from 60 to >90 ml/min/1.73 m2) and CVD is less clear. Our aim was to examine the association of eGFR with incident CVD in a cohort of predominantly healthy subjects with normal to mildly reduced renal function. Design Retrospective cohort study. Methods We collected demographic, clinical, and laboratory parameters of subjects free of diabetes mellitus or CVD who attended annual medical screening examinations between 2001 and 2009. Main outcome measures were a new diagnosis of coronary artery disease (CAD) or cerebrovascular events (CVE). Results During a median follow up of 4.3 years, among 10,909 subjects (mean eGFR 78.5 ± 12.2 ml/min/1.73 m2), 10.3% were diagnosed with CAD (n = 1025) or CVE (n = 94). Compared with subjects in the highest eGFR quintile (≥88.8 ml/min/1.73 m2), subjects in the lowest quintile (≤68.2 ml/min/1.73 m2) had a hazard ratio (HR) of 1.64 (95% CI 1.35–2.00; p < 0.001) for a CAD outcome, but this association was no longer significant after adjustment for age and other confounders (adjusted HR 1.08; p = 0.55). Similar findings were obtained for the association of eGFR with CVE. Conclusions In a predominantly healthy population with normal to mildly reduced renal function, lower eGFR is associated with higher risk for CVD; however, this association is not independent but merely reflects the association of age and other cardiovascular risk factors with reduced eGFR.

Potential drug interactions in travelers with chronic illnesses: a large retrospective cohort study.

BACKGROUND Data regarding the prevalence of potential interactions between travel-related medications (TRM) and chronic medications in use, or medical conditions of travelers to developing countries are limited. METHODS A retrospective cohort study of travelers to low income countries. We extracted data on demographics, travel destinations, use of chronic medications, drug allergies, and relevant medical conditions. The following TRM were evaluated: mefloquine, primaquine, doxycycline, atovaquone/proguanil, fluoroquinolone antibiotics, rifaximin, azithromycin, and acetazolamide. RESULTS A total of 16,263 travelers were included in the analysis, of whom 3299(20%) suffered from chronic illnesses and 2316(14%) reported chronic medication use. A potential drug-drug interaction with TRM was identified in 1047(45%) of travelers using chronic medication. Fluoroquinolones and azithromycin were the most commonly implicated TRMs. A potential medical condition interaction with TRM was identified in 717(22%) of travelers having chronic illnesses. acetazolamide, primaquine and mefloquine, were the most commonly TRMs implicated. Drug allergies, which can pose a relative contraindication for use of acetazolamide, were reported by 1323(8.1%) of all travelers. CONCLUSIONS Potential drug-drug and drug-disease interactions involving TRM might occur in a significant proportion of travelers with chronic medical conditions. Education of health practitioners regarding such potential drug interactions and caution when in prescribing travel-related medications is warranted.

The effect of genetic polymorphisms on warfarin pharmacodynamics

The warfarin sensitivity index (WSId)= INR/warfarin dose, is mainly determined by pharmacokinetic factors (CYP 2C9 genotype and age). WSIc (INR/plasma warfarin concentration) should reflect the influence of pharmacodynamic factors. We examined the effect on WSIc of polymorphisms in genes coding the enzymes of the vitamin K dependent γ‐carboxylation system, together with oxidative stress markers (given the putative antioxidant activity of the vitamin K cycle).