Protective Effect of Hyperprolactinemia on Oxidative Stress in Patients with Psychotic Disorder on Atypical Antipsychotics Risperidone and Paliperidone: A Cross-Sectional Study.

Several studies indicate the impact of antipsychotics like risperidone and paliperidone on oxidative stress parameters, yet data remain inconsistent. We investigated the link between these medications, hyperprolactinemia (HPRL), and oxidative stress. This study was conducted at the Psychiatry Clinic, University Clinical Center, Kragujevac, between November 2022 and August 2023. Inclusion criteria comprised diagnosed psychotic disorders from the ICD-10-based F20-F29 spectrum and clinical stability on risperidone/paliperidone for ≥12 weeks with no recent dose adjustments. Exclusion criteria included pregnancy, breastfeeding, relevant medical conditions, or co-therapy with prolactin-secreting drugs. Data encompassed drug choice, administration method, therapy duration, and daily dose. Prolactin (PRL) levels, oxidative stress parameters (TBARS, H2O2, O2-, NO2-), and antioxidant system (CAT, GSH, SOD) were assessed. Of 155 subjects, women exhibited significantly higher PRL levels (p < 0.001) and symptomatic HPRL (p < 0.001). Drug choice and regimen significantly influenced TBARS (p < 0.001), NO2- (p < 0.001), O2- (p = 0.002), CAT (p = 0.04), and GSH (p < 0.001) levels. NO2- levels were affected by drug dose (p = 0.038). TBARS (p < 0.001), O2- (p < 0.001), and SOD (p = 0.022) inversely correlated with PRL levels, suggesting PRL's protective role against oxidative stress. The female sex association with higher PRL levels implies additional factors influencing PRL's antioxidant role. Antipsychotic choice and dosage impact PRL and oxidative stress markers, necessitating further exploration.

Its all about IFN-λ4: Protective role of IFNL4 polymorphism against COVID-19-related pneumonia in females.

Despite the pivotal role of IFN-λs in the innate immune response, the data on its genetic polymorphism in relation to COVID-19 severity are scarce and contradictory. In the present study, we aimed to determine if the presence of the most frequent functional single nucleotide polymorphisms (SNPs) of the two most important IFN-λs coding genes, namely IFNL3 and IFNL4, alters the likelihood of SARS-CoV-2-infected patients to develop more severe form of the disease. This observational cohort study involved 178 COVID-19 patients hospitalized at the University Clinical Centre Kragujevac, Serbia. Patients' demographics, clinical characteristics, and laboratory parameters were collected at admission. COVID-19 signs and symptoms were assessed during the hospital stay, with the worst condition determining the disease severity. Genotyping for IFNL3 (rs12980275 and rs8099917) and IFNL4 (rs12979860 and rs368234815) SNPs was conducted using TaqMan assays. Our study revealed carriers of IFNL3 and IFNL4 minor alleles to be less likely to progress from mild to moderate COVID-19, that is, to develop COVID-19-related pneumonia. After adjustment for other factors of influence, such as age, sex, and comorbidities, the likelihood of pneumonia development remained significantly associated with IFNL4 polymorphism (odds ratios [ORs] [95% confidence interval (95% CI)]: 0.233 [0.071; 0.761]). When the patients were stratified according to sex, the protective role of IFNL4 minor alleles, controlled for the effect of comorbidities, remained significant only in females (OR [95% CI]: 0.035 [0.003; 0.408]). Our results strongly suggest that IFNL4 rs12979860 and rs368234815 polymorphisms independently predict the risk of COVID-19-related pneumonia development in females.

IFNL3/4 polymorphisms as a two-edged sword: An association with COVID-19 outcome.

Coronavirus Disease 2019 (COVID-19) has been ranked among the most fatal infectious diseases worldwide, with host's immune response significantly affecting the prognosis. With an aim to timely predict the most likely outcome of SARS-CoV-2 infection, we investigated the association of IFNL3 and IFNL4 polymorphisms, as well as other potentially relevant factors, with the COVID-19 mortality. This prospective observational case-control study involved 178 COVID-19 patients, hospitalized at Corona Center or Clinic for Infectious Diseases of University Clinical Centre Kragujevac, Serbia, followed up until hospital discharge or in-hospital death. Demographic and clinical data on all participants were retrieved from the electronic medical records, and TaqMan assays were employed in genotyping for IFNL3 and IFNL4 single nucleotide polymorphisms (SNPs), namely rs12980275, rs8099917, rs12979860, and rs368234815. 21.9% and 65.0% of hospitalized and critically ill COVID-19 patients, respectively, died in-hospital. Multivariable logistic regression analysis revealed increased Charlson Comorbidity Index (CCI), N/L, and lactate dehydrogenase (LDH) level to be associated with an increased likelihood of a lethal outcome. Similarly, females and the carriers of at least one variant allele of IFNL3 rs8099917 were almost 36-fold more likely not to survive SARS-CoV-2 infection. On the other hand, the presence of at least one ancestral allele of IFNL4 rs368234815 decreased more than 15-fold the likelihood of mortality from COVID-19. Our results suggest that, in addition to LDH level, N/L ratio, and CCI, IFNL4 rs368234815 and IFNL3 rs8099917 polymorphisms, but also patients' gender, significantly affect the outcome of COVID-19.

Anxiety in patients treated in a temporary hospital in Belgrade, Serbia, during the first epidemic wave of COVID-19.

Background: It has been reported that COVID-19 patients in general often experience anxiety, depression and stress, but those problems in patients of temporary COVID-19 hospitals seem to have attracted less attention. Methods: The study included 87 SARS-Cov-2 infected subjects accommodated and treated in a temporary hospital in Belgrade, Serbia, during the first epidemic wave of COVID-19. The patients' level of anxiety was assessed on two occasions (at admission to the temporary hospital, and 2 weeks after discharge) using the Hamilton Anxiety Rating Scale (HAM-A). Demographic and clinical data were obtained through questionnairesor retrieved from patients' medical records. Results: A multiple linear regression model revealed that sex, age, the severity of COVID-19 symptoms (COVID-19_SS) and the family history of psychiatric disorder (FHPD) remain significant predictors of the level of anxiety at hospital admission (F (4, 82) = 14.916, p < 0.0001), wih an R2 of 0.421. Participants' predicted level of anxiety at admission to the temporary COVID-19 hospital can be calculated as 0.931-0.708 × SEX +0.029 × AGE +0.674 × COVID-19_SS + 1.491 × FHPD, where SEX is coded as 1 for male and 0 for female, AGE is measured in years, COVID-19_SS is coded as 0 for asymptomatic, 1 for mild, 2 for moderate and 3 for severe, and FHPD as 0 for negative and 1 for positive. Comparison between individual HAM-A score at admission to the temporary hospital (median (IQR): 7.00 (2.00-11.75)) and 2 weeks after discharge (median (IQR): 0.00 (0.00-1.00)) revealed significant reduction in the level of anxiety among study participants (Z = -7.53, p < 0.001). Conclusion: These data indicate that psychological changes exist in those hospitalized in temporary hospitals, but that they regress soon after they leave.

Risk factors for adverse drug reactions associated with clopidogrel therapy.

This study aimed to investigate the possible influence of genetic and non-genetic factors on the incidence of clopidogrel adverse drug reactions (ADRs) in cardiology patients, including the most important CYP2C19 alleles, namely *2 and *17, as well as compliance, dose, drug interactions, and clinical factors. A total of 102 clopidogrel-treated adult Caucasian patients hospitalized at the Cardiology Department of the Clinical Center of Montenegro were enrolled in the study. Data on clinical outcomes of interest were obtained by intensive monitoring ADRs during hospitalization and one year after hospital discharge. Genotyping for CYP2C19*2 and *17 was conducted using the real-time polymerase chain reaction method. ADRs were characterized using the Rawlins and Thompson classification and the World Health Organization criteria. Causality was assessed using the Naranjo probability scale. ADRs to clopidogrel were observed in 9 of 102 patients (8.8%). The observed frequencies of CYP2C19*2 and *17 were 13.2 and 25.5%, respectively. Our study, which is the first to report the frequency of CYP2C19 polymorphism in the Montenegrin population, as well as to link the pharmacovigilance of clopidogrel with CYP2C19 gene variability, shows that the incidence of ADRs of clopidogrel in cardiac patients is high and depends on CYP2C19 polymorphisms, comedication/drug interactions, and gastrointestinal comorbidity.

Genotyping genetic variants of CYP2C19 for precision antiplatelet dosing: state of the art and future perspectives.

INTRODUCTION: Clopidogrel is the only antiplatelet agent whose activity is significantly affected by CYP2C19 polymorphism. AREAS COVERED: This review has summarized the available evidence on the clinically significant association between CYP2C19 polymorphism and clopidogrel-based therapy; reviewed the current recommendations for clinical use of CYP2C19 genotype test results in patients on clopidogrel treatment; and discussed possible pitfalls of routine application, and future perspectives of antiplatelets pharmacogenetics. EXPERT OPINION: The available body of evidence, reflected in several meta-analyses and high-quality clinical practice guidelines, shows that the presence of CYP2C19 LOF alleles, especially CYP2C19*2, correlates with impaired activation of clopidogrel and variable platelet inhibition, followed by minimal or no antiplatelet effect, and higher risk of treatment failure. In combination with other known risk factors, CYP2C19 genetic testing could be very valuable in predicting low clopidogrel efficacy. At the same time, it could be very successful in selecting patients who will most probably benefit from the clopidogrel-based therapy, thus decreasing the pool of those who might need more expensive and otherwise riskier antiplatelet alternatives.

ABCB1 polymorphism in clopidogrel-treated Montenegrin patients.

Clopidogrel is an antiplatelet drug that displays significant interindividual variability in treatment response. Its bioavailability depends on the function of P-glycoprotein (P-gp), which is coded by a highly polymorphic ABCB1 gene. Thus, the aim of this study was to investigate the effect of ABCB1 genetic polymorphism on clopidogrel efficacy and safety and to determine the frequency distribution of its most common single nucleotide polymorphisms (SNPs) in 106 Montenegrin cardiology patients. Clopidogrel efficacy and safety were followed up during 1 year after hospitalization, with the lack of efficacy and adverse drug reactions observed in 11 (10.4%) and 8 patients (7.5%), respectively. Genotyping for ABCB1 SNPs rs1128503 (1236C > T), rs2032582 (2677G > A/T), and rs1045642 (3435C > T) was performed by the real-time PCR method, and the variant alleles were detected with the frequencies of 42.9, 44.8, and 52.8%, respectively. No significant association was observed between any of the examined genotypes and clopidogrel efficacy (p = 0.253) or safety (p = 0.424). Due to small sample size, co-treatment with other drugs, and other genetic factors not taken into account, we believe the absence of correlation between ABCB1 genotypes and indicators of clopidogrel efficacy and safety in this study should be apprehended conditionally, and that larger and better-controlled studies are warranted.

SARS-CoV-2 infection induces mixed M1/M2 phenotype in circulating monocytes and alterations in both dendritic cell and monocyte subsets.

Clinical manifestations of SARS-CoV-2 infection range from mild to critically severe. The aim of the study was to highlight the immunological events associated with the severity of SARS-CoV-2 infection, with an emphasis on cells of innate immunity. Thirty COVID-19 patients with mild/moderate symptoms and 27 patients with severe/critically severe symptoms were recruited from the Clinical Center of Kragujevac during April 2020. Flow cytometric analysis was performed to reveal phenotypic and functional alterations of peripheral blood cells and to correlate them with the severity of the disease. In severe cases, the number of T and B lymphocytes, dendritic cells, NK cells, and HLA-DR-expressing cells was drastically decreased. In the monocyte population proportion between certain subsets was disturbed and cells coexpressing markers of M1 and M2 monocytes were found in intermediate and non-classical subsets. In mild cases decline in lymphocyte number was less pronounced and innate immunity was preserved as indicated by an increased number of myeloid and activated dendritic cells, NK cells that expressed activation marker at the same level as in control and by low expression of M2 marker in monocyte population. In patients with severe disease, both innate and adoptive immunity are devastated, while in patients with mild symptoms decline in lymphocyte number is lesser, and the innate immunity is preserved.

Extremely low-frequency electromagnetic field induces a change in proliferative capacity and redox homeostasis of human lung fibroblast cell line MRC-5.

Numerous studies have shown that extremely low-frequency electromagnetic field (ELF-EMF) by modulating oxidative-antioxidative balance in the cells achieved beneficial and harmful effects on living organisms. The aim of this study was to research changes of both proliferative capacity and redox homeostasis of human lung fibroblast cell line MRC-5 during exposure to ELF-EMF (50 Hz). The human lung fibroblast cell line MRC-5 were exposed to ELF-EMF once a day in duration of 1 h during 24 h (1 treatment 1 h/day), 48 h (2 treatments 1 h/day), 72 h (3 treatments 1 h/day), and 7 days (7 treatments 1 h/day). After 24 h of the last treatment, the proliferative capacity of the cells and the concentrations and activities of the components of the oxidative/antioxidative system were determined: superoxide anion (O2.-), hydrogen peroxide (H2O2), nitric oxide (NO), peroxynitrite (ONOO-), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR), and glutathione-S-transferase (GST). The results of this study show that ELF-EMF may affect a cell cycle regulation of human lung fibroblast cell line MRC-5 through modulation of oxidative/antioxidative defense system. The effects of ELF-EMF on proliferation and redox balance of human lung fibroblast cell line MRC-5 depend on exposure time.

EGFR Polymorphism and Survival of NSCLC Patients Treated with TKIs: A Systematic Review and Meta-Analysis.

Tyrosine kinase inhibitor- (TKI-) based therapy revolutionized the overall survival and the quality of life in non-small-cell lung cancer (NSCLC) patients that have epidermal growth factor receptor (EGFR) mutations. However, EGFR is a highly polymorphic and mutation-prone gene, with over 1200 single nucleotide polymorphisms (SNPs). Since the role of EFGR polymorphism on the treatment outcome is still a matter of debate, this research analyzed the available literature data, according to the PRISMA guidelines for meta-analyses. Research includes PubMed, Scopus, ISI Web of Science, and 14 of genome-wide association studies (GWAS) electronic databases in order to provide quantitative assessment of the association between ten investigated EGFR SNPs and the survival of NSCLC patients. The pooled HR and their 95% CI for OS and PFS for different EGFR polymorphisms using a random or fixed effect model based on the calculated heterogeneity between the studies was applied. The longest and the shortest median OSs were reported for the homozygous wild genotype and a variant allele carriers for rs712829 (-216G>T), respectively. Quantitative synthesis in our study shows that out of ten investigated EGFR SNPs (rs11543848, rs11568315, rs11977388, rs2075102, rs2227983, rs2293347, rs4947492, rs712829, rs712830, and rs7809028), only four, namely, rs712829 (-216G>T), rs11568315 (CA repeat), rs2293347 (D994D), and rs4947492, have been reported to affect the outcome of TKI-based NSCLC treatment. Of these, only -216G>T and variable CA repeat polymorphisms have been confirmed by meta-analysis of available data to significantly affect OS and PFS in gefitinib- or erlotinib-treated NSCLC patients.

Cigarette smoking and heavy coffee consumption affecting response to olanzapine: The role of genetic polymorphism.

Objectives: To evaluate the effect of cigarette smoking and heavy coffee consumption on efficacy and safety of olanzapine treatment in schizophrenia patients, in relation to genetic polymorphism.Methods: The study involved 120 patients with schizophrenia, treated with olanzapine for 30 days. Therapy efficacy was determined using three different psychiatric scales, and safety by assessing metabolic adverse effects and extrapyramidal symptoms. Genotyping included CYP1A2*1C, CYP1A2*1F and CYP1A1/1A2 intergenic polymorphism, as well as CYP2D6*3, CYP2D6*4 and CYP2D6*6.Results: Cigarette smoking and heavy coffee consumption decreased the efficacy and increased the safety of olanzapine treatment (P < 0.001). Although the effect was detected only in carriers of CYP1A2*1F allele, covariate analysis revealed that it is independent of CYP1A2 genotype. Olanzapine dose was inversely correlated with the drug efficacy (P ≤ 0.002) and LDL level (P = 0.004). Women and older subjects responded better to therapy (P < 0.026), but had more certain adverse effects (P ≤ 0.049). When controlling for other relevant factors, CYP2D6 metabolizer status affects olanzapine efficacy (P = 0.032).Conclusions: We confirm the effect of cigarette smoking and heavy coffee consumption on olanzapine efficacy and safety. The relevance of CYP1A2 genotype for the described effect needs further investigation. Olanzapine treatment outcome is also affected by dose, sex, age and CYP2D6 metabolizer status.

Oxidative stress biomarkers in amniotic fluid of pregnant women with hypothyroidism.

Purpose: Hypothyroidism in pregnancy is the serious state that may lead to fetal morbidity and mortality. Oxidative stress biomarkers in the amniotic fluid can provide important information on the health, development and maturation of the fetus during pregnancy. In this study, we examined whether maternal hypothyroidism contributes to increased oxidative stress biomarkers in the amniotic fluid during the first trimester of pregnancy. Materials and methods: The study was conducted on healthy pregnant women and pregnant women with hypothyroidism (gestational age: 16-18 weeks). Oxidative stress biomarkers, such as superoxide anion (O2•-), hydrogen peroxide (H2O2), nitric oxide (NO), peroxynitrite (ONOO-), lipid peroxide (LPO), reduced glutathione (GSH) and oxidized glutathione (GSSG) were assayed in the amniotic fluid. Results: The results of this study indicated that concentrations of O2•- and NO are significantly higher, while the concentration of H2O2 is significantly lower in the amniotic fluid of pregnant women with hypothyroidism in comparison to healthy pregnant women. There were no differences in concentrations of LPO, GSH and GSSG among tested groups. Also, we found that amniotic fluid concentration of O2•- is negatively correlated with the body weight and Apgar score values of the newborns. Conclusion: These results suggest that pregnancy hypothyroidism is characterized by the amniotic fluid oxidative stress. Incorporation of the oxidative stress biomarkers measurement in the amniotic fluid may be of clinical importance in the management of pregnancy hypothyroidism.

CFTR IVS8 Poly-T Variation Affects Severity of Acute Pancreatitis in Women.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) is important for normal pancreatic function. Its coding gene is polymorphic, and the variations have been associated with the increased risk for acute pancreatitis. However, their impact on the disease severity is still unknown. Therefore, the aim of our study was to determine the functional importance of common cystic fibrosis transmembrane conductance regulator variations IVS8-poly T, R117H, and M470V for the severity of acute pancreatitis. METHOD: The study involved 98 acute pancreatitis patients. The severity of the disease was determined based on the Atlanta Classification system. IVS8-poly T, R117H, and M470V genotyping was performed using PCR-RFLP method. RESULTS: IVS8-5T, IVS8-7T, IVS8-9T, and M470V alleles were found at the frequencies of 5.7, 75.5, 18.9, and 55.7%, respectively, while R117H was not observed. Among women, the severe form of the disease was more frequent in carriers of at least one IVS8 9T allele (RR for 9T/9T + 9T/non-9T vs. non-9T/non-9T: 2.115; 95% CI: 1.241-3.605). This association was not detected in men and was not affected by M470V. In addition, co-morbidities increased the severity of acute pancreatitis (p = 0.022). CONCLUSION: Our study reveals that IVS8 poly-T variation affects severity of acute pancreatitis in women and that existent co-morbidities worsen the clinical course of the disease.

Epidermal Growth Factor Receptor Gene in Non-Small-Cell Lung Cancer: The Importance of Promoter Polymorphism Investigation.

Recently, epidermal growth factor receptor (EGFR) was a key molecule in investigation of lung cancer, and it was a target for a new therapeutic strategy, based on molecular analyses. In this review, we have summarized some issues considering the role of EGFR in lung cancer, its coding gene, and its promoter gene polymorphisms (SNPs) -216G/T and -191C/A in non-small-cell lung cancer (NSCLC). The position of the SNPs indicates their significant role in EGFR regulation. The accumulation of knowledge regarding SNPs lately suggests their significant and important role in the onset of carcinogenesis, the prediction of the onset of metastases, the response to therapy with TKI inhibitors, and the onset of toxic effects of the applied therapy. Based on this, we suggest further studies of the relationship of clinical significance to SNPs in patients with lung tumors.

Effects of maternal subclinical hypothyroidism on amniotic fluid cells oxidative status.

In this study, we researched the effects of maternal subclinical hypothyroidism on the amniotic fluid cells oxidative metabolism during the first trimester of pregnancy. Oxidative stress and damage biomarkers were assayed in the amniotic fluid cells of healthy and pregnant women with subclinical hypothyroidism. Obtained results show that amniotic fluid cells of pregnant women with subclinical hypothyroidism have significantly higher concentrations of oxidative stress biomarkers (superoxide anion, nitric oxide, peroxynitrite) and oxidative damage (lipid peroxide and micronuclei frequency), but lower concentrations of hydrogen peroxide and oxidized glutathione in comparison to healthy pregnant women. We also showed that oxidative stress biomarkers were positively correlated with micronuclei frequency and lipid peroxide concentration in amniotic fluid cells of pregnant women with subclinical hypothyroidism. The present study provides the first evidence for prooxidative effects of maternal subclinical hypothyroidism on the fetus obtained by the estimating oxidative metabolism in the amniotic fluid cells.

N-Acetyltransferase-2 (NAT2) phenotype is influenced by genotype-environment interaction in Ethiopians.

BACKGROUND AND OBJECTIVES: N-acetyltransferase 2 (NAT2) metabolize several drugs including isoniazid. We investigated the effect of genotype, geographical difference, and smoking habit on NAT2 phenotype in Ethiopians. METHODS: Genotyping for NAT2 191G > A, 341 T > C, 590G > A, and 857G > A was performed in 163 unrelated healthy Ethiopians (85 living in Ethiopia and 78 living in Sweden). The NAT2 phenotype was determined using caffeine as a probe and log AFMU/(AFMU + 1X + 1 U) urinary metabolic ratio (MR) as an index. RESULTS: The frequencies of NAT2*4, *5, *6, *7, and *14 haplotypes were 14.1, 48.5, 30.1, 5.5, and 1.8%, respectively. The frequencies of rapid (NAT2*4/*4), intermediate (heterozygous *4), and slow (no *4 allele) acetylator genotypes were 1.8, 24.6, and 73.6%, respectively. The distribution NAT2 MR was bimodal with 70% being phenotypically slow acetylators. NAT2 genotype (p < 0.0001) and country of residence (p = 0.004) independently predicted NAT2 phenotype. Controlling for the effect of genotype, ethnic Ethiopians living in Ethiopia had significantly higher NAT2 MR than those living in Sweden (p = 0.006). NAT2 genotype-phenotype concordance rate was 75%. Distinct country-of-residence-based genotype-phenotype discordance was observed. The proportion of phenotypically determined rapid acetylators was significantly higher and slow acetylators was lower in Ethiopians living in Ethiopia (39% rapid, 61% slow) than in Sweden (20% rapid, 80% slow). Sex and smoking had no significant effect on NAT2 MR. CONCLUSIONS: We report a high prevalence of NAT 2 slow acetylators in Ethiopians and a conditional NAT2 genotype-phenotype discordance implicating a partial phenotype conversion and metabolic adaptation. Gene-environment interactions regulate NAT2 phenotype.

Estradiol decreases blood pressure in association with redox regulation in preeclampsia.

In this study, we tested a hypothesis that a short-term estradiol therapy may reduce blood pressure in preeclampsia by modulating plasma oxidative stress. The intramuscular injections of 10 mg 17-beta-estradiol were prescribed to preeclamptic pregnant women during the 3-day therapy before a labor induction. The analyses of mean arterial pressure (MAP), serum estradiol concentrations, plasma superoxide anion (O2.), hydrogen peroxide (H2O2), nitrites (NO2-), and peroxynitrite (ONOO-) were conducted before and during the therapy. We found that the plasma concentrations of oxidative stress markers, such as O2- and H2O2, are higher in preeclampsia and positively correlated with the MAP value. Moreover, it was shown that the plasma concentration of NO2- as an indicator of NO levels is higher in preeclampsia. A short-term intramuscular application of estradiol decreases the MAP value and the plasma concentration of O.-, H2O2, NO2-, and ONOO- in preeclampsia. A positive correlation between the decrease of MAP values and the decrease of plasma concentrations of O2-, H2O2, and ONOO- was found in preeclampsia during a short-term estradiol therapy. We conclude that the short-term estradiol therapy decreases the MAP value in preeclampsia by modulating the plasma oxidative stress. We speculate that the estradiol metabolism in preeclampsia is an important mechanism that contributes to vascular dysfunction.

Anxiety-like behavioural effects of extremely low-frequency electromagnetic field in rats.

In recent years, extremely low-frequency electromagnetic field (ELF-EMF) has received considerable attention for its potential biological effects. Numerous studies have shown the role of ELF-EMF in behaviour modulation. The aim of this study was to investigate the effect of short-term ELF-EMF (50 Hz) in the development of anxiety-like behaviour in rats through change hypothalamic oxidative stress and NO. Ten adult male rats (Wistar albino) were divided in two groups: control group-without exposure to ELF-EMF and experimental group-exposed to ELF-EMF during 7 days. After the exposure, time open field test and elevated plus maze were used to evaluate the anxiety-like behaviour of rats. Upon completion of the behavioural tests, concentrations of superoxide anion (O2·-), nitrite (NO2-, as an indicator of NO) and peroxynitrite (ONOO-) were determined in the hypothalamus of the animals. Obtained results show that ELF-EMF both induces anxiety-like behaviour and increases concentrations of O2·- and NO, whereas it did not effect on ONOO- concentration in hypothalamus of rats. In conclusion, the development of anxiety-like behaviour is mediated by oxidative stress and increased NO concentration in hypothalamus of rats exposed to ELF-EMF during 7 days.

Pharmacokinetics and Pharmacogenetics of Carbamazepine in Children.

Although carbamazepine is one of the oldest anticonvulsant drugs, it is still heavily utilized for treatment of epilepsy in children. The aim of this article was to review the current knowledge about pharmacokinetics and pharmacogenetics of carbamazepine in children. The literature for this review was systematically searched for in the MEDLINE and SCINDEKS databases. Oral bioavailability of carbamazepine in children is about 75-85%, and it is approximately 75-85% bound to plasma proteins. Apparent volume of distribution is 1.2-1.9 l/kg and total clearance between 0.05 and 0.1 l/h/kg. Pharmacokinetics of carbamazepine in children is age and body weight dependent and highly variable due to influence of dosing regimen and co-medication. The current evidence on the importance of pharmacogenetics for carbamazepine efficacy and safety in children supports the association of PXR*1B, HNF4a rs2071197, CYP1A2*1F, ABCC2 1249G>A, and PRRT2 c.649dupC with either pharmacokinetics or pharmacodynamics of carbamazepine. The importance of human leukocyte antigen (HLA) typing for prediction of adverse drug reactions to carbamazepine in children is also confirmed. Both genetic and environmental factors are responsible for shaping pharmacokinetics and pharmacodynamics of carbamazepine in children. To ensure safe and effective use of carbamazepine in this population, physicians should adjust dosing regimen according to existing pattern of genetic and environmental influences.