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Clinical Trial 2013; 34(6): 549-552 PubMed PMID: 24378442 Citation  Keywords:  Adult, Female, Fenoterol:administration & dosage, Fetus:blood supply, Heart Rate:drug effects, Heart Rate, Fetal:drug effects, Humans, Infusions, Intravenous, Obstetric Labor, Premature:diagnostic imaging, Pregnancy, Tocolytic Agents:administration & dosa.   

OBJECTIVE: to investigate whether any changes in the preload index (PLI) occur within the first 48 hours of fenoterol intravenous tocolysis.

MATERIAL AND METHODS: Doppler evaluation of placental and fetal circulation was performed in 36 pregnant women prior to fenoterol administration and after 24/48 hours. Measurements were obtained from a longitudinal section of the inferior vena cava (IVC) and preload index was calculated. To determine changes over time, an all study variable analysis of variance (ANOVA) for repeated measurements, followed by Tukey-Kramer's multiple comparison test was used. The effects of additional clinical covariates were checked.

RESULTS: The maternal heart rate values were significantly increased after 24 hours and 48 hours in comparison to pre-treatment values. No significant changes in fetal heart rate were observed during treatment. The fetal IVC PLI values were significantly reduced after 24 hours and 48 hours of treatment. The increase in PLI values when comparing 24 and 48 hours results were not statistically significant. These observations were consistent with ANOVA post-hoc analysis.

CONCLUSIONS: 48 hours intravenous administration of fenoterol appears not to alter inferior vena cava blood flow by itself. The reduction in PLI values may reflect lower fetal preload conditions during the course of successful tocolytic treatment. Therefore, Doppler IVC PLI measurement should be considered as a possible additional assessment method of effectiveness of treatment. However, other Doppler venous blood flow parameters should be assessed to confirm the results and clarify whether maternal corticosteroids administration may be interfering with the results....

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Journal Article 2013; 34(Suppl 2): 123-129 PubMed PMID: 24362104 Citation  Keywords:  Animals, Cell Proliferation:drug effects, Estradiol:metabolism, Gene Expression Regulation:drug effects, Humans, Male, Protein Binding:drug effects, Receptors, Estrogen:metabolism, Response Elements:drug effects,.   

: Group of estrogen pollutants, where the highest estrogen activity is reported at estradiol, is characterized by the fact that even at very low concentrations have potential to cause xenoestrogenic effects. During exposure of excessive amounts of estradiols may be produced undesirable effects resulting in the feminization of males of water organisms. The presence of estradiols in drinking water implies also a risk for the human population in the form of cancers of endocrine systems, abnormalities in reproduction or dysfunctions of neuronal and immune system. Currently, the research is focused mainly to uncover the relationship between the estrogen receptors binding affinity with an estrogen response element and estradiol. In this review we summarized facts about molecular biological principles of β estradiol-estrogen receptor complex binding with estrogen response element and its successive effect on cancer genes expression....

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Journal Article 2013; 34(Suppl 2): 102-108 PubMed PMID: 24362101 Citation  Keywords:  Animals, Anti-Inflammatory Agents, Non-Steroidal:toxicity, Biomarkers:metabolism, Catalase:metabolism, Dose-Response Relationship, Drug, Glutathione Peroxidase:metabolism, Glutathione Reductase:metabolism, Glutathione Transferase:metabolism, Ibuprofen:tox.   

OBJECTIVES: The aim of the study was to investigate the effects of subchronic exposure of zebrafish to ibuprofen, using selected oxidative stress parameters as a target.

DESIGN: Toxicity tests were performed on Danio rerio according to OECD No. 203 and No. 215. In the growth test, fish were exposed to subletal concentrations of ibuprofen (0.0001, 0.05, 1, 8, and 25 mg.L-1) for 28 days. For the assessment of free radical defense in fish, the catalytic activities of glutathione reductase (GR), glutathione S-transferase (GST), glutathione peroxidase (GPx), and catalase (CAT), as well as the concentration of malondialdehyde (MDA) were measured.

RESULTS: Ibuprofen did not affect the activity of glutathione reductase and catalase. A significant (p<0.01) increase in the activity of glutathione peroxidase was found, which was proved dose-dependent (10.58 nmol NADPH per min per mg protein in the control and 20.53, 26.36, 26.89, and 45.87 nmol NADPH per min per mg protein in the ibuprofen concentrations of 0.5, 1, 8, and 25 mg.L-1. An increased (p<0.05) activity of glutathione S-transferase in the highest concentration was found compared to control. Malondialdehyde levels were found significantly (p<0.01) decreased from control in the concentrations of 0.0001 and 8 mg.L-1, but no dose-dependence was found.

CONCLUSION: The results suggest that ibuprofen causes the increase in the activity of some antioxidative and biotransformation enzymes in zebrafish (GPx and GST). We also found a significant decrease in lipid peroxidation in the concentrations of 0.0001 and 8 mg.L-1 compared to control....

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Comparative Study 2013; 34(Suppl 2): 55-63 PubMed PMID: 24362093 Citation  Keywords:  Animals, Benzo(a)pyrene:metabolism, Carcinogens:metabolism, Cytochrome P-450 CYP1A1:metabolism, Cytochromes b5:pharmacology, Humans, Inactivation, Metabolic, Male, Microsomes, Liver:drug effects, Oxidation-Reduction, Rats,.   

OBJECTIVES: Cytochrome P450 (CYP) 1A1 is the most important enzyme in both activation and detoxification of carcinogenic benzo[a]pyrene (BaP), in combination with microsomal epoxide hydrolase (mEH). To evaluate metabolism of BaP in human, identification of a suitable animal model that mimics the metabolic fate of BaP in human is of great importance. The aim of this work was to compare BaP oxidation by human CYP1A1 and CYP1A1 of one animal model, rat. Investigation of the effect of cytochrome b5 on BaP oxidation by CYP1A1 was another target of this study.

METHODS: High performance liquid chromatography (HPLC) was employed for separation of BaP metabolites formed by enzymatic systems. Their structures were identified by mass- and NMR-spectrometry.

RESULTS: Human hepatic microsomes oxidized BaP to BaP-9,10-dihydrodiol, BaP-4,5-dihydrodiol, BaP-7,8-dihydrodiol, BaP-1,6-dione, BaP-3,6-dione and BaP-3-ol. The same metabolites were generated by rat liver microsomes, but BaP-9-ol and a metabolite Mx, the structure of which has not been identified as yet, were also formed in these microsomes. Human CYP1A1 expressed with NADPH:CYP reductase (POR) in Supersomes™ oxidized BaP to the same metabolites as microsomes, but BaP-4,5-dihydrodiol has not been detected. Rat recombinant CYP1A1 in this SupersomesTM system oxidized BaP to BaP-9,10-dihydrodiol, a metabolite Mx, BaP-4,5-dihydrodiol, BaP-7,8-dihydrodiol, BaP-1,6-dione, BaP-3,6-dione, BaP-9-ol and BaP-3-ol. Addition of cytochrome b5 to rat and human recombinant CYP1A1 systems led to a more than 2-fold increase in BaP oxidation.

CONCLUSION: The results show similarities between human and rat CYP1A1 in BaP oxidation and demonstrate rats as a suitable model mimicking BaP oxidation in human....

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Journal Article 2013; 34(Suppl 2): 43-54 PubMed PMID: 24362092 Citation  Keywords:  Animals, Antineoplastic Agents:pharmacokinetics, Benzo(a)pyrene:pharmacology, Biotransformation:drug effects, Cytochrome P-450 CYP1A1:metabolism, Cytochrome P-450 CYP1A2:metabolism, Cytochrome P-450 Enzyme System:metabolism, Drug Evaluation, Preclinical, .   

OBJECTIVES: The aim of this study was to investigate a role of cytochrome P450 (CYP) and peroxidase in ellipticine oxidative activation in two mouse strains differing in expression of NADPH:CYP reductase (POR) [the HRN (Hepatic Cytochrome P450 Reductase Null) mice, in which POR is deleted in hepatocytes and its wild-type (WT) counterpart], and in levels of CYP1A1/2 and cytochrome b5 that were modulated by treatment of these mouse models with a CYP1A inducer, benzo[a]pyrene (BaP).

METHODS: Ellipticine-DNA adducts were detected by 32P-postlabeling. HPLC was employed for the separation and characterization of ellipticine metabolites.

RESULTS: Hepatic microsomes of HRN and WT mice activate ellipticine to form ellipticine-derived DNA adducts. A 2.2- and 10.4-fold increase in amounts of ellipticine-derived DNA adducts formed by liver microsomes was caused by exposure of HRN and WT mice to BaP, respectively. The results found and utilization of NADPH and arachidonic acid, cofactors of CYP- and cyclooxygenase (COX)-dependent enzyme systems, respectively, as well as inhibitors of CYP1A1/2 and 3A, demonstrate that the CYP1A and 3A enzymes play a major role in ellipticine activation in liver microsomes. In addition, the COX enzyme is important in ellipticine activation in liver of HRN mice.

CONCLUSION: The CYP1A and 3A enzymes activate ellipticine mainly in liver of WT mice, whereas peroxidase COX plays this role in liver of HRN mice. Treatment of mice with BaP increases an impact of CYP1A on ellipticine activation. A pattern of expression levels of these enzymes plays a crucial role in their impact on this process....

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Journal Article 2013; 34(Suppl 2): 25-30 PubMed PMID: 24362089 Citation  Keywords:  Adolescent, Adult, Central Nervous System Agents:poisoning, Czech Republic:epidemiology, Databases, Factual, Drug Overdose:epidemiology, Drug-Related Side Effects and Adverse Reactions:diagnosis, Female, Humans, Information Centers:statistics & numerical .   

OBJECTIVES: To analyze the number and trends in calls to the Toxicological Information Center (TIC) concerning pharmaceutical poisoning retrospectively during the past 15 years and to compare selected characteristics of the poisonings.

DESIGN: Inquiries arising from drug poisonings in the years 1997-2012 were extracted and evaluated from the Czech database recording the consultations of TIC specialists. In addition, their cause, severity and dose evaluation (data electronically collected after 2005) were compared in the years 2005-2012 using standard statistical methods.

RESULTS: During 15 years total 152,649 calls due to all types of potentially toxic agents were recorded in the TIC database. Central nervous system (CNS) affecting drugs represented 39.8% of calls due to all pharmaceutical poisonings. The proportion of adults was 72.2% and women comprised 64.4% of all patients. Whereas the number of calls caused by poisoning with tricyclic antidepressants (TCAs) and barbiturates decreased (by 366.7% and 340%, respectively), the calls due to selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines overdose increased (by 1347.4% and 359.8%). The dose of CNS affecting drugs in 2005-2012 was considered lethal in 14.6% of the inquiries due to barbiturates and 8.6% due to TCAs, but only in 1.6% calls due to SSRIs and 0.5% of benzodiazepines. The highest percentage of medications errors was found during the treatment with barbiturates (16.4%).

CONCLUSIONS: The current drugs prescription with improved safety profiles brings the beneficial effect of lowering the severity of poisonings and better prognosis of intoxications as observed in the TIC statistics....

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Journal Article 2013; 34(Suppl 2): 11-20 PubMed PMID: 24362087 Citation  Keywords:  Animals, Carcinogens:toxicity, Cyanobacteria:chemistry, Food Chain, Kidney:drug effects, Liver:drug effects, Male, Microcystins:toxicity, Rats, Rats, Wistar, Spleen:drug effects,.   

OBJECTIVES: Cyanobacteria are producers of potent and environmentally abundant microcystins, representing an emerging global health issue. In the present study, we investigated the impact of pure microcystins and cyanobacterial biomass on laboratory rats (Wistar albino rats, males, 30 days old) under different exposure scenarios.

METHODS: The rats were fed diets containing fish meat with microcystins in various concentrations and forms (cyanobacterial biomass and isolated microcystins) for 28 days.

RESULTS: Although considerable amounts of microcystins (MCs) were administered to the rats, all levels of MCs in the liver were close to the detection limit (3-5 ng/g fresh weight) using liquid chromatography - tandem mass spectrometry. Only rats exposed to cyanobacterial biomass had clearly higher hepatic and splenic somatic indexes while markers of oxidative stress (glutathione-S-transferase, glutathione reductase, lipid peroxidatio) were significantly increased in the group exposed to the high dose of MCs. Most of the analysed biochemical parameters did not show clear differences among groups. Levels of bilirubin and lipases were significantly increased only after exposure to cyanobacterial biomass and MCs, respectively. Considering microscopic findings in the liver, kidney, thymus, spleen and brain, histopathology was dominated by alterations in the hepatic parenchyma and renal cortical tubular system.

CONCLUSIONS: The present study demonstrates that oral exposure to MCs and cyanobacterial biomass may induce biochemical and detoxification responses associated with damage to liver and kidneys and in the laboratory rat....

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Journal Article 2013; 34(5): 402-408 PubMed PMID: 23922043 Citation  Keywords:  Adult, Alleles, Antigens, Differentiation, T-Lymphocyte:genetics, Asian Continental Ancestry Group:genetics, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Linkage Disequilibrium, Male, Middle Age.   

OBJECTIVE: This study was conducted to find the possible association between CD226 polymorphisms and inflammatory demyelinating diseases in Korean population.

METHODS: A total of 14 CD226 SNPs were selected based on their linkage disequilibrium, minor allele frequency, and location. Then, the SNPs were genotyped in 178 IDD patients and 237 healthy controls. Subsequently, we conducted logistic analysis to find possible associations

RESULTS: Statistical analyses revealed only a marginal signal for a common SNP rs1788229 with inflammatory demyelinating disease (p=0.05), while other SNPs failed to show associations with any diseases. However, the significance of rs1788229 disappeared after a multiple testing correction of the data (p>0.05). Interestingly, rs763361, which showed significant associations with multiple sclerosis in several previous studies, did not show any association at all.

CONCLUSIONS: While prior studies have found CD226 polymorphisms to be significantly associated with inflammatory demyelinating diseases, our results indicate the CD226 polymorphisms to be not associated with the diseases in Korean population. However, our results suggest that the causal genes for inflammatory demyelinating diseases may vary depending on the population....

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