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Journal Article 2014; 35(Suppl 2): 180-185 PubMed PMID: 25638384 Citation  Keywords:  Acetaminophen:administration & dosage, Adolescent, Adult, Aged, Aged, 80 and over, Analgesics, Non-Narcotic:administration & dosage, Child, Child, Preschool, Czech Republic:epidemiology, Drug Overdose:epidemiology, Drug-Related Side Effects and Adverse Re.   

<strong>OBJECTIVES:strong> Paracetamol overdose belongs to frequent calls to Toxicological Information Centre (TIC) in the Czech Republic and to the National Toxicological Information Centre (NTIC) in Slovakia. The aim of the study was to evaluate outcomes and side effects of paracetamol overdose in both countries.

<strong>METHODS:strong> Data concerning paracetamol poisoning extracted from TIC and NTIC databases 2000-2013 and discharge reports were analysed. Numbers and outcomes in patients presenting within 24 hours of a single paracetamol overdose were compared in relation to 3 paracetamol concentration bands (≤ 100 mg/l, 100-149 mg/l, and 150 mg/l).

<strong>RESULTS:strong> 5397 inquiries concerning paracetamol were recorded in TIS and NTIC. Data from 196 discharge reports with plasma level were studied. Median age of the patients was 18 (0.2-86) years. Eight/196 (4.1%) patients developed side effects after N-acetylcysteine (NAC) administration. 120 cases fulfilled time criteria of the study and were divided into 3 groups, where 55.7%, 73.1% and 96.9% patients have been treated with NAC. Among these 120 patients, favourable outcome was seen in 100%, 100%, and 92.8%, respectively. One death due to suicidal attempt with plasma level 407 mg/l presenting at 20 hours has been recorded among 120 patients. No patient without NAC treatment died due to acute overdose and plasma concentration ≤ 150 mg/I at 4 hours.

<strong>CONCLUSIONS:strong> These data support the opinion that NAC should not be used in patients with < 149 mg/l levels in absence of higher risk factors because of very low risk of hepatotoxicity on one side, and side effects on the other side.

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Journal Article 2014; 35(Suppl 2): 175-179 PubMed PMID: 25638383 Citation  Keywords:  Animals, Antioxidants:pharmacology, Antipsychotic Agents:pharmacology, Cells, Cultured, Clozapine:pharmacology, Inflammation:drug therapy, Interleukin-6:metabolism, Macrophages:drug effects, Mice,.   

<strong>OBJECTIVES:strong> Clozapine is an atypical antipsychotic drug known for its impact on production of pro-inflammatory cytokines. The aim of our work was to examine the impact of clozapine on the production of interleukin 6 (IL-6) by the LPS (lipopolysaccharide) stimulated macrophage cells and to confirm or exclude that it regulates the inflammation due to its interaction with alpha 7 nicotinic receptor (nAChR). Secondly, we focused on a verification of the antioxidant effect of clozapine.

<strong>METHODS:strong> The levels of IL-6 in cell culture media were determined by ELISA method. Antioxidant properties of clozapine were estimated based on the reduction of 2,2-diphenyl-1-picrylhydrazyl radical.

<strong>RESULTS:strong> The IL-6 level produced by cells treated clozapine decreased significantly from IL-6 level created by clozapine-untreated cells. However, the production of IL-6 in the cells treated with clozapine and simultaneously with selective alpha 7 nAChR antagonist methyllycaconitine did not alter significantly from the IL-6 production in the cells treated just with clozapine. The free radical scavenging activity of clozapine in concentration 1.00 mM was found equivalent to 0.13 mM of standard antioxidant N-acetyl-L-cystein.

<strong>CONCLUSION:strong> Our study confirmed, that clozapine reduces production of IL-6 in LPS-activated macrophage cells nevertheless we denied that it would be mediated through alpha 7 nAChR. Moreover antioxidant potential of clozapine was observed.

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Journal Article 2014; 35(Suppl 2): 169-174 PubMed PMID: 25638382 Citation  Keywords:  Depressive Disorder:complications, Female, Humans, Hypothalamo-Hypophyseal System:growth & development, Neurotransmitter Uptake Inhibitors:adverse effects, Pituitary-Adrenal System:growth & development, Postpartum Period:psychology, Pregnancy, Pregnancy C.   

<strong>:strong> Depression during pregnancy and in the post partum period is a significant health issue in modern society. The estimated prevalence of depression in pregnancy ranges from 13-20%. The major dilemma for gynecologists is to treat or not to treat depression during gestation and lactation. Consequences of untreated depression can be so serious that the benefit of antidepressant therapy may overweigh the possible risk for injury of fetal/neonatal development. Currently, selective serotonin re-uptake inhibitors (SSRIs) and serotonin and noradrenaline re-uptake inhibitors (SNRIs) are commonly used for treatment of maternal depression. The review article brings up-to-date knowledge on effects of maternal adversity (depression) and/or antidepressants on the development of the hypothalamus-pituitary-adrenal axis of the offspring in relation to postnatal behavior and reactivity to stressful stimuli. Treated as well as untreated maternal depression presents a risk for the developing fetus and neonate. The authors stress the need to evaluate the relative safety of SNRIs/SNRIs by means of relevant experimental models to assess if these drugs can be assigned to treat pregnant and lactating depressive women.

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Journal Article 2014; 35(Suppl 2): 158-168 PubMed PMID: 25638381 Citation  Keywords:  Animals, Benzo(a)pyrene:administration & dosage, Carcinogens:administration & dosage, DNA Adducts:administration & dosage, Flavonols:administration & dosage, Male, Rats, Rats, Wistar,.   

<strong>OBJECTIVES:strong> Flavanol dihydromyricetin (DHM) has been shown to counteract acute ethanol (EtOH) intoxication and reduce excessive EtOH consumption. Since this flavonoid is being considered for human use, the in vivo study of DHM interactions with the cytochrome P450 (CYP) multienzyme system in the respect of metabolic activation of a model food-born carcinogen, benzo[a]pyrene (BaP), is of high importance. Flavonoids of known properties, alpha-naphthoflavone (ANF) and beta-naphthoflavone (BNF) were included into the study to compare their and DHM effects on BaP-DNA adduct formation. METH0 DS: The flavonoids were administered by oral gavage either 72 hrs prior or simultaneously with a single dose of BaP to experimental rats. The expression of CYP1A1/2 enzymes was examined based on the enzymatic activity with a marker substrate, 7-ethoxyresorufin, and on Western blots. The nuclease P1 version of the 32P-postlabeling assay was used to detect and quantify covalent DNA adducts formed by BaP.

<strong>RESULTS:strong> Treatment of rats with a single dose of DHM or ANF prior to or simultaneously with BaP did not produce an increase in levels of CYP1A1 and in formation of BaP-DNA adducts in liver. BNF, a known inducer of CYP1A1, showed a synergistic effect on BaP-mediated CYP1A1 induction and BaP activation in liver. Contrary to that, in small intestine the stimulatory effect of BNF on both parameters was not detected. Animal pre-treatment with DHM or ANF before BaP administration resulted in a significant elevation of BaP-DNA adducts, namely in the distal part of small intestine, while the CYP1A1 mediated 7-ethoxyresorufin-O-deethylation (EROD) was decreased markedly. It is important to note that under all regimens of animal treatment, DHM or ANF produced the higher inhibitory effect on the BaP-DNA adduct formation and BaP-induced EROD activity of CYP1A1 when administered simultaneously than sequentially with BaP. Our data show that DHM or ANF did not enhance the BaP-activation leading to BaP-mediated genotoxicity (the formation of BaP-DNA adducts) in rat liver, however, in small intestine the pretreatment of rats with these flavonoids may enhance BaP genotoxicity.

<strong>CONCLUSIONS:strong> The data indicate that the intake of DHM prior to or simultaneously with the administration of BaP may increase the risk of a BaP-induced tumorigenesis in small intestine.

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Journal Article 2014; 35(Suppl 2): 155-157 PubMed PMID: 25638380 Citation  Keywords:  Adjuvants, Immunologic:pharmacology, Animals, Cytokines:metabolism, Female, Hemocyanin:pharmacology, Mice, Mice, Inbred BALB C, Models, Animal, Oximes:pharmacology, Pyridinium Compounds:pharmacology,.   

<strong>OBJECTIVES:strong> HI-6 or asoxime in some sources is an antidotum for nerve agents. In recent experiments, implication of HI-6 in immunity response was proved; however, the issue was not studied in details. In this experiment, role of cytokines in HI-6 impact on immunity was searched. DESIG N: BALB/c mice were exposed to saline, HI-6 in a dose 1-100 mg/kg and/or 1 keyhole limpet hemocyanin (KLH) 1 mg/kg. Mice were sacrificed 21 days after experiment beginning and interleukins (IL) 1, 2, 4, 6 were determined by Enzyme Linked Immunosorbent Assay (ELISA).

<strong>RESULTS:strong> The animals had no pathological manifestation. From the tested cytokines, no significant alteration was found for the IL-1, IL-4 and IL-6. IL-2 was significantly increased in a dose response manner.

<strong>CONCLUSIONS:strong> The experimental data well correlates with the previous work where HI-6 caused increase of antibodies production. HI-6 is suitable to be used as an adjuvant whenever immunity should be pharmacologically altered.

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Journal Article 2014; 35(Suppl 2): 149-154 PubMed PMID: 25638379 Citation  Keywords:  Antioxidants:pharmacology, DNA Damage:drug effects, Emodin:pharmacology, Humans, Mutagenicity Tests, Mutagens:pharmacology, Mutation:drug effects,.   

<strong>OBJECTIVES:strong> Emodin is a bioactive anthraquinone that has diverse biological effects. It is also known as a biosynthetic precursor of hypericin. The purpose of this study was to assess mechanisms of potential genotoxic and antioxidant effects of emodin. We also investigated the potential genotoxic effect of photoactivated emodin.

<strong>METHODS:strong> Potential genotoxicity was determined by the alkaline comet assay and the Ames test. The potential DNA protectivity of emodin was determined by the DNA-topology assay. On purpose to clarify molecular mechanism of its DNA protectivity against Fe(2+)-induced DNA breaks, three different assays were used (Reducing power-, DPPH- and Fe(2+)-chelating assay).

<strong>RESULTS:strong> Using the alkaline comet assay and the Ames test we confirmed the genotoxic effect of both non-photoactivated and photoactivated emodin in a dose-dependent manner. Genotoxicity of photoactivated emodin did not differ from that obtained with non-photoactivated one. The DNA-topology assay revealed a DNA-protective activity of emodin. In the reducing power and DPPH assays emodin exhibited weak antioxidant activities. We did not observe any chelating activity of emodin in the Fe(2+)-chelating assay.

<strong>CONCLUSIONS:strong> We found out that emodin exhibited dual activities. On one side it was genotoxic inducing primary DNA lessions (determined by the comet assay) as well as gene mutations (determined by the Ames test). On the other side it exhibited DNA-protective activity (determined by the DNA-topology assay). Molecular mechanism underlying this DNA protective effect can be attributed to its free radicals scavenging and reducing activities.

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Journal Article 2014; 35(Suppl 2): 141-148 PubMed PMID: 25638378 Citation  Keywords:  Animals, Electron Transport Complex II:drug effects, Formazans:metabolism, Interferon-gamma:pharmacology, Mice, Mice, Inbred C57BL, Peritoneum:cytology, Pyrimidines:pharmacology, Spleen:cytology,.   

<strong>OBJECTIVES:strong> Formation of formazan is a commonly used measure of cytotoxicity of compounds. It is a product of reduction of tetrazolium salts such as 4-[3- (4-iodophenyl)-2- (4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1) and 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyltetrazolium chloride. The extent of substrates reduction reflects the activity of enzymes succinate dehydrogenase (SDH; respiratory complex II) and lactate dehydrogenase (LDH), respectively. The aim of present study was a) to investigate formazan formation under the conditions of in vitro stimulation of cells with interferon-γ (IFN-γ) and lipopolysaccharide (LPS), and b) to analyse possible interference of pyrimidine analogues with formazan production.

<strong>METHODS:strong> Peritoneal cells and splenocytes were obtained from C57BL/6 mice. They were cultured at 37 degrees C, 5% CO2 in humidified incubator. Levels of formazan were determined at the interval of 24 h of culture using the WST-1 and LDH assays. Nitric oxide (NO) was activated by IFN-γ plus LPS and assayed by Griess reagent 24 h afterwards. Pyrimidines were applied concomitantly with immunostimulatory agents.

<strong>RESULTS:strong> IFN-γ enhanced concentration of SDH-produced formazan by macrophages (not by splenocytes) by approximately 50%. The activity of LDH remained unaffected. LPS was ineffective in both cases. While pyrimidines with NO-inhibitory properties suppressed the IFN-γ-enhanced levels of SDH-produced formazan, they did not change the LDH-dependent formazan production.

<strong>CONCLUSION:strong> IFN-γ augments the SDH-produced formazan by macrophages. It does not change the LDH-dependent formazan formation. The enhancing effect may have a significant impact upon the appropriate interpretation of cytotoxic properties of drugs investigated under the conditions of immune stimulation of cells.

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Journal Article 2014; 35(Suppl 2): 133-140 PubMed PMID: 25638377 Citation  Keywords:  Animals, Cosmetics:toxicity, Eye Diseases:chemically induced, Humans, In Vitro Techniques, Irritants:toxicity, Skin Diseases:chemically induced,.   

<strong>BACKGROUND:strong> The aim of this study was to compare human and animal skin irritation data with results of selected in vitro methods, including HET-CAM test, Neutral Red Release Assay, Neutral Red Uptake Assay and EpiOcular eye irritation test and with already existing data of eye irritation obtained from animal experiments.

<strong>METHODS:strong> Chemicals employed in previous skin irritation validation studies and commercially available cosmetic formulations were subjected to further testing using in vitro methods Neutral Red Release (NRR) assay, Neutral Red Uptake (NRU) assay, HET-CAM test and EpiOcular assay.

<strong>RESULTS:strong> The study revealed that skin irritants are not necessarily eye irritants; specifically volatile or solid materials may be misclassified. NRR assay provided false negative results in case of substances with fixative effect or not removable under standard washing procedure, emphasizing the role of microscopical evaluation as a crucial additional endpoint. Although overpredictive, HET-CAM test provided the lowest false negative rate. The most aggressive cosmetic formulation was correctly identified by EpiOcular assay, in accordance with NRU and NRR assays results, while HET-CAM test correctly identified the mildest formulation.

<strong>CONCLUSIONS:strong> Each of the in vitro methods is related to a specific endpoint of ocular irritation and provides only partial information on the mode of action of the tested material. Despite good reproducibility of individual in vitro assays, only the weight-of-evidence approach and results of multiple selected in vitro tests can allow for estimation of eye irritation hazard in vivo.

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