Polymorphic variants of SCN1A and EPHX1 influence plasma carbamazepine concentration, metabolism and pharmacoresistance in a population of Kosovar Albanian epileptic patients

Aim The present study aimed to evaluate the effects of gene variants in key genes influencing pharmacokinetic and pharmacodynamic of carbamazepine (CBZ) on the response in patients with epilepsy. Materials & Methods Five SNPs in two candidate genes influencing CBZ transport and metabolism, namely ABCB1 or EPHX1, and CBZ response SCN1A (sodium channel) were genotyped in 145 epileptic patients treated with CBZ as monotherapy and 100 age and sex matched healthy controls. Plasma concentrations of CBZ, carbamazepine-10,11-epoxide (CBZE) and carbamazepine-10,11-trans dihydrodiol (CBZD) were determined by HPLC-UV-DAD and adjusted for CBZ dosage/kg of body weight. Results The presence of the SCN1A IVS5-91G>A variant allele is associated with increased epilepsy susceptibility. Furthermore, carriers of the SCN1A IVS5-91G>A variant or of EPHX1 c.337T>C variant presented significantly lower levels of plasma CBZ compared to carriers of the common alleles (0.71±0.28 vs 1.11±0.69 μg/mL per mg/Kg for SCN1A IVS5-91 AA vs GG and 0.76±0.16 vs 0.94±0.49 μg/mL per mg/Kg for EPHX1 c.337 CC vs TT; PG showed a reduced microsomal epoxide hydrolase activity as reflected by a significantly decreased ratio of CBZD to CBZ (0.13±0.08 to 0.26±0.17, pT SNP and SCN1A 3148A>G variants were not associated with significant changes in CBZ pharmacokinetic. Patients resistant to CBZ treatment showed increased dosage of CBZ (657±285 vs 489±231 mg/day; P<0.001) but also increased plasma levels of CBZ (9.84±4.37 vs 7.41±3.43 μg/mL; P<0.001) compared to patients responsive to CBZ treatment. CBZ resistance was not related to any of the SNPs investigated. Conclusions The SCN1A IVS5-91G>A SNP is associated with susceptibility to epilepsy. SNPs in EPHX1 gene are influencing CBZ metabolism and disposition. CBZ plasma levels are not an indicator of resistance to the therapy

Lack of Association of SULT1A1 R213H Polymorphism with Colorectal Cancer: A Meta-Analysis

BACKGROUND: A number of case-control studies were conducted to investigate the association of SULT1A1 R213H polymorphisms with colorectal cancer (CRC) in humans. But the results were not always consistent. We performed a meta-analysis to examine the association between the SULT1A1 R213H polymorphism and CRC. METHODS AND FINDINGS: Data were collected from the following electronic databases: PubMed, Elsevier Science Direct, Excerpta Medica Database, and Chinese Biomedical Literature Database, with the last report up to September 2010. A total of 12 studies including 3,549 cases and 5,610 controls based on the search criteria were involved in this meta-analysis. Overall, no significant association of this polymorphism with CRC was found (H versus R: OR = 1.04, 95%CI = 0.94-1.16, P = 0.46; HR+HH versus RR: OR = 1.01, 95%CI = 0.92-1.11, P = 0.81; HH versus RR+HR: OR = 1.01, 95%CI = 0.74-1.38, P = 0.95; HH versus RR: OR = 1.00, 95%CI = 0.77-1.31, P = 0.98; HR versus RR: OR = 1.01, 95%CI = 0.92-1.11, P = 0.86). In subgroup analysis, we also did not find any significant association in Cauasians (H versus R: OR = 1.02, 95%CI = 0.92-1.15, P = 0.68; HR+HH versus RR: OR = 0.99, 95%CI = 0.91-1.09, P = 0.90; HH versus RR+HR: OR = 1.01, 95%CI = 0.73-1.39, P = 0.97; HH versus RR: OR = 0.99, 95%CI = 0.75-1.31, P = 0.94; HR versus RR: OR = 0.99, 95%CI = 0.90-1.09, P = 0.85). The results were not materially altered after the studies which did not fulfill Hardy-Weinberg equilibrium were excluded (H versus R: OR = 1.06, 95%CI = 0.95-1.19, P = 0.31; HR+HH versus RR: OR = 1.03, 95%CI = 0.93-1.13, P = 0.56; HH versus RR+HR: OR = 1.10, 95%CI = 0.78-1.56, P = 0.57; HH versus RR: OR = 1.09, 95%CI = 0.83-1.44, P = 0.53; HR versus RR: OR = 1.02, 95%CI = 0.92-1.13, P = 0.75). CONCLUSION: This meta-analysis demonstrates that there is no association between the SULT1A1 R213H polymorphism and CRC

Evaluation of reliability and validity of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30, Albanian version) among breast cancer patients from Kosovo

Selvete Shuleta-Qehaja,1 Zoran Sterjev,2 Ljubica Shuturkova2 1Kosovo Medicines Agency, Rrethi i spitalit (QKUK), Pristina, Kosovo; 2University &lsquo;Ss Cyril and Methodius&rsquo;, Faculty of Pharmacy, Skopje, Macedonia Patients and methods: A sample of breast cancer patients (n=62 women) were interviewed for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) in Albanian. Reliability of the questionnaire was considered acceptable if Cronbach&rsquo;s alpha was &ge;0.70. Item convergent-discriminant validity was tested through multitrait scaling analysis. Construct validity was tested under the hypotheses that QLQ-C30 interscale correlations would have an acceptable value of &ge;0.40 and as well as by known group comparisons assessing differences of patient subgroups with reference to disease stage and education level.Results: The mean age of the patients was 50 years (standard deviation: 10.9 years). Cronbach&rsquo;s alpha ranged from 0.54 for the cognitive functioning scale to 0.96 for the global health quality of life (GH/QoL) scale. In multitrait scaling analysis, the strength of Spearman&rsquo;s correlations between an item and its own subscale was &ge;0.40, with the exception of item 5 (р=0.22); results for item discriminant validity were satisfactory, with the exception of item 5, which showed higher correlation with other subscales than with its own physical functioning. The Spearman&rsquo;s interscale coefficients generally were correlated with each other. Results of known group comparisons did not show significant differences in terms of disease stage. Regarding education level, patients with high school/university education had better functional scales scores only in certain subscales compared to other subgroups; furthermore, patients with secondary school education had better GH/QoL compared to other subgroups of patients.Conclusion: The EORTC QLQ-C30 (v3.0) in Albanian was found to be valid and reliable for women with breast cancer and could be considered as a starting point for further evaluation study.&nbsp;Keyword: women, oncology, internal consistency, functional scale, symptom scale, HRQo

Evaluation of statin utilization in the Republic of Macedonia during 2013&ndash;2016

Zorica Naumovska,1 Aleksandra K Nestorovska,1 Aleksandra Grozdanova,1 Kristina Hristova,2 Aleksandar Dimovski,1 Ljubica Suturkova,1 Zoran Sterjev1 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, SS &ldquo;Cyril and Methodius&rdquo;, Skopje, Republic of Macedonia; 2Department of Health Insurance Fund of R. Macedonia, Skopje, Republic of Macedonia Purpose: A rational use of statins has a major and increasing importance in public health and allocation of financial resources by the health insurance funds (HIFs). The aim of this study was to evaluate the market share and utilization trends of statins in the Republic of Macedonia (R. Macedonia) from 2013 to 2016. Materials and methods: A retrospective analysis and data comparison for the utilization of HMG-CoA inhibitors (C10AA) in R. Macedonia from 2013 to 2016 were conducted. The data obtained from HIF, IMS Health, pharmaceutical industry and marketing authorization holders (MAHs) were evaluated through defined daily doses per 1000 insurers per day (DDD/TID). Results: Cardiovascular drugs are the most commonly prescribed and utilized drugs in R. Macedonia. The HIF cost for cardiovascular disease (CVD) increased to &euro;2,243,777.00 in the period from 2013 to 2016. Since 2012, the reimbursement shows that atorvastatin accounts for the highest expenditure reaching &euro;2,162,958.00 while rosuvastatin reached &euro;1,645,860.00 in 2016. The increased consumption of statins is confirmed from the records obtained from IMS Health databases in the evaluated period in R. Macedonia suggesting increased expenditures with total growth of 35.65% reaching &euro;4,421,280.24 in 2016. Evident growth of statin consumption is confirmed from the data obtained from the pharmaceutical industry and MAH. The statin use increased from 42.347 DDD/TID in 2013 to 71.697 DDD/TID in 2016, although it is lower in comparison to other European Union (EU) countries (1.1&ndash;2.5-fold). Conclusion: The rapid increase in the consumption of statins can be attributed mostly to an increase in the consumption volume. It is inevitable to widen the price reduction concept with initiatives that may control statin consumption amounts with measures such as educational programs for rational drug utilization and targeting eligible population. Keywords: statins, cardiovascular prevention, expenditures for statin utilization prescription drug expenditur

Influence of potential gene polymorphisms on propofol dosage regimen in patients undergoing abdominal hysterectomy

Propofol (2,6-diisopropylphenol) is the most common intravenous anesthetic used in modern medicine. It is postulated that individual differences in genetic factors [polymorphism of single nucleotide polymorphisms (SNPs)] in the genes encoding metabolic enzymes, molecular targets and molecular binding sites of propofol can be responsible for susceptibility to propofol effects. The aim of our study was to investigate the influence of the cytochrome P450 2B6 isozyme CYP2B6 (rs3745274), γ-aminobutyric acid type A (GABAA) receptor α1 subunit GABRA1 (rs2279020) and ATP-binding cassette subfamily B member 1 ABCB1 (rs1045642) gene polymorphisms on propofol therapeutic outcomes in the patients undergoing abdominal hysterectomy. Ninety patients aged 29-74 years, with different ethnicities were included in this study. The presence of polymorphisms was analyzed using TaqMan SNP genotype analysis on Stratagene MxPro 3005P real-time polymerase chain reaction (qPCR). The distribution of all three genetic variants was within the Hardy-Weinberg equilibrium. There was no significant difference (p >0.05) in the allelic frequencies of polymorphic variants and genotype distributions between adult and older patients and between patients of different ethnicities. Our study did not detect a statistically significant influence of the CYP2B6 (c.516G>A), GABRA1 (c.1059+15G>A) and ABCB1 (c.3435T>C) variants on the variability of clinical parameters (doses for induction in anesthesia, additional doses, induction time and wake time after anesthesia and side effects of propofol). However, the observed trend on the possible influence of the CYP2B6 (c.516G>A) and GABRA1 (c.1059+15G>A) variants warrant an extension of these studies on a larger number of patients

Cost-effectiveness analysis of treating transplant-eligible multiple myeloma patients in Macedonia

Vjollca Qerimi,1,2 Aleksandra Kapedanovska Nestorovska,1 Zoran Sterjev,1 Sonja Genadieva-Stavric,3 Ljubica Suturkova1 1Faculty of Pharmacy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia; 2Institute of Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Health Services Research and Health Technology Assessment, UMIT &ndash; University for Health Sciences, Medical Informatics and Technology, Hall in Tirol, Austria; 3Medical Faculty, University Hematology Clinic, Skopje, Macedonia Purpose: A decision-analytic model was developed to study the impact of induction regimens vincristine, adriamycin, dexamethasone (VAD); thalidomide, dexamethasone (TD); and bortezomib, dexamethasone (BorD), followed by autologous stem cell transplantation (ASCT) for treating multiple myeloma (MM) patients in Macedonia. Additionally, a cost-effectiveness analysis (CEA) of treatment sequences to predict health effects and costs of different treatment sequences was performed.Methods: Model strategies were based on a previously published study for treating patients with MM in Macedonia. The data on disease progression and treatment effectiveness were obtained from the published reports of randomized clinical trials (GIMEMA M-B02005, IFM 2005-01). Utility parameters were extracted from the literature. To compare treatment combinations, a decision tree model was developed. Additionally, a cost analysis for one-time per-protocol costs was performed from a Macedonian national health care perspective. The incremental cost-effectiveness ratios (ICERs)/quality-adjusted life years (QALYs) gained for 1-, 10-, and 20-year time horizons were determined. Costs and health outcomes were discounted to evaluate the effects of time in the model.Results: The one-time costs of BorD (EUR 5,656) were higher compared to VAD (EUR 303) and TD (EUR 329), increasing the overall costs for BorD. Thus, the BorD combination dominated in the baseline results (1 and 10 years) and the ICER for TD vs. VAD was EUR 7,564/QALY (20 years, undiscounted model). However, in the discounted 20-year model, BorD showed an ICER of EUR 138,747/QALY gained for BorD vs. TD.Conclusion: The CEA performed indicated that considering 1-year time horizon costs, VAD may be a cost-effective alternative vs. TD or BorD. However, for the longer period (10 or 20 years) including the discounting of future costs and outcomes, the TD and BorD combinations showed higher health benefits in terms of QALYs and more cost-effective vs. VAD. These results should be considered as supportive evidence by decision-makers and providers when deciding on the most cost-effective induction treatment strategy prior to ASCT in MM patients. Keywords: decision-analytic modeling, decision tree, multiple myeloma, incremental cost-effectiveness ratio, transplant-eligibl