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Journal Article 2013; 34(Suppl 2): 79-83 PubMed PMID: 24362097 Citation  Keywords:  Animals, Cholinesterase Reactivators:administration & dosage, Electromyography, Female, Heart Rate:drug effects, Injections, Intramuscular, Models, Animal, Oximes:administration & dosage, Paraoxon:administration & dosage, Pyridinium Compounds:administrati.   

OBJECTIVES: Organophosphorus compounds represent nerve agents, pesticides and several industrial compounds. Treatment after exposure to organophosphates involves the use of parasympatolytics, acetylcholinesterase (AChE) reactivators/modulators and anticonvulsive drugs. Wider clinical use of several AChE reactivators/modulators might be limited because of possible side effects, including gastrointestinal toxicity. In this study we evaluated the effect of paraoxon and an AChE reactivator (HI-6) on the gastric myoelectric activity in experimental pigs.

METHODS: Six female experimental pigs (mean weight 33 kg) entered the study. Intramuscular paraoxon (1.5 g) was administrated after the baseline gastric electrogastrography (EGG) recording, followed by HI-6 dimethansulphonate (1.5 g i.m.) 10 min. later. A further ten 15-minute-interval EGG recordings were performed. Running spectral analysis was used for the elemental evaluation of the EGG. The results were expressed as dominant frequency of slow waves at all intervals of EGG recordings. EGG power analysis was performed in all animals.

RESULTS: Paraoxon induced a non-significant decrease of dominant frequency (2.8±0.6 vs. 2.6±0.5 cycles per min.; p=0.092). Subsequent administration of HI-6 normalised dominant frequency to basal values and increased it significantly within the subsequent 30 minutes (3.0±0.4; p<0.001). Paraoxon administration did not influence the power (within a 10-minute exposure). However, the amplitudes increased significantly 90 minutes after administration of HI-6 (819±109 vs. 5054±732 μV2; p<0.001).

CONCLUSIONS: AChE reactivator HI-6 blocked the gastric effect of paraoxon significantly. Subsequent myoelectric changes in the dominant frequency and power were executed by HI-6. The effect of paraoxon was non-significant....

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Comparative Study 2013; 34(Suppl 2): 74-78 PubMed PMID: 24362096 Citation  Keywords:  Absorption, Animals, Biological Availability, Chlorides:administration & dosage, Cholinesterase Reactivators:administration & dosage, Female, Injections, Intramuscular, Injections, Intravenous, Oximes:administration & dosage, Pyridinium Compounds:administ.   

OBJECTIVES: Oxime HI-6 is an acetylcholinesterase reactivator therapeutically efficient against nerve agents. Because of their physico-chemical properties, oximes are typically applied intramuscularly (i.m.). This route of administration has also some disadvantages, and alternative strategies ought to be examined. We evaluated the pharmacokinetic profiles of two HI-6 salts after their intravenous (i.v.) administration, and compare the results with the known pharmacokinetics after i.m. administration.

METHODS: Pigs were administered with HI-6 salts (i.v), either HI-6 dichloride (10.71 mg/kg) or molar equivalent HI-6 dimethansulphonate (13.59 mg/kg). Doses of the HI-6 salts corresponded with a standard HI-6 dichloride dose in one autoinjector (500 mg) and were recalculated for one kilogram of body weight.

RESULTS: The main pharmacokinetic parameters are comparable after i.v. and i.m. HI-6 administration. The compared pharmacokinetic parameters were half-life, terminal rate constant, mean residence time of the molecule in the body, clearance, and the apparent volume in the terminal phase. The bioavailability after i.m. administration was comparable with that of i.v.; these results suggest that the oxime is well released from the muscle depot. Significant differences were found in parameters Cmax and Tmax which are important in cases of emergency when rapidity and bioavailability are paramount for the success of treatment.

CONCLUSIONS: I.v. administration should solve the problem of rapid clearance. Infusion or bolus administration may be considered as a logical subsequent step in oxime treatment strategy. The main advantage is in maintenance of an effective therapeutic plasma concentration, a more easily achievable effective therapeutic concentration, and fewer local adverse reactions....

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Journal Article 2013; 34(Suppl 2): 64-70 PubMed PMID: 24362094 Citation  Keywords:  Adult, Blood Flow Velocity, Case-Control Studies, Diastole, Echocardiography, Doppler, Female, Humans, Liver Cirrhosis, Alcoholic:diagnostic imaging, Male, Middle Aged, Risk Factors, Ventricular Dysfunction, Left:diagnostic imaging,.   

OBJECTIVES: The aim of this study was to prove that the incidence of the more unusual and largely under-researched cardiac dysfunction, i.e. diastolic, is more frequent in patients with alcoholic cirrhosis. Comparison of the incidence of left ventricular diastolic dysfunction in medical-ward patients with no prior history of cardiovascular disease to that of the patients with hepatic cirrhosis caused by alcohol abuse was carried out. The study is original from the point of view of examination of patients with cirrhosis of solely alcoholic aetiology in one Central-European university hospital.

METHODS: Three methods of echocardiographic examination were used: (i) pulse Doppler echocardiography to assess blood flow through the mitral valve and in the pulmonary veins, (ii) tissue Doppler imaging (TDI) to assess mitral annular motion, and (iii) colour M-mode Doppler echocardiography to assess blood flow from the left atrium into the left ventricle.

RESULTS: The results found confirmed that the incidence of left ventricular diastolic dysfunction in patients with alcohol-related liver cirrhosis, classified as Child-Pugh grade A and B, was significantly higher than in the controls without any prior liver disease. Furthermore, our research team has newly noticed how the severity of diastolic dysfunction affects the morbidity and mortality of patients undergoing such treatments as the transjugular intrahepatic portosystemic shunt (TIPS), liver transplantation and other surgical interventions resulting from different indications.

CONCLUSION: The high incidence of diastolic dysfunction in cirrhotic alcoholics should not be underestimated. Examination of diastolic dysfunction should be a standard procedure for making clinical decisions about these patients....

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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): 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): 436-445 PubMed PMID: 23922050 Citation  Keywords:  Adult, Aged, Depressive Disorder:complications, Diabetes Mellitus, Type 1:complications, Diabetes Mellitus, Type 2:complications, Female, Humans, Hypertension:complications, Male, Memory Disorders:complications, Memory, Short-Term, Middle Aged, Neuropsych.   

OBJECTIVES: Deterioration of the working memory is regarded as one of the most important deficits in a number of somatic diseases. The purpose of the present study was to compare the effectiveness of working memory in 4 groups of patients: 1) diagnosed with recurrent depressive disorder (rDD), 2) with diabetes type 1 (DM1), 3) with diabetes type 2 (DM2), 4) with arterial hypertension (HA) and in healthy controls (HC).

METHODS: The study comprised 300 subjects: rDD (n=99), DM1 (n=31), DM2 (n=31), HA (n=30) and HC (n=109).Cognitive function assessment was based on Trail Making Test (TMT) and the Stroop test.

RESULTS: Analysis of variance (ANOVA) indicated statistically significant differences of the mean values among particular groups for each of the analysed results of the Stroop Test and TMT (p<0.0001). Patients with DM1 performed better in both TMT and Stroop tests, when compared to those diagnosed with HA. Patients with HA obtained better results than patients with DM2. Patients with rDD performed significantly worse than those with DM1 in both parts of TMT (A/time: p=0.022, B/time: p<0.001) and in the Stroop test (RCNb/time: p<0.001; NCWd/time: p=0.001; NCWd/errors: p=0.443). They also obtained worse results than patients with DM2 and HA, however, the differences were not statistically significant.

CONCLUSIONS: 1) Our study has confirmed previous results showing association between depressive disorder and cognitive impairment. 2) Patients with rDD had worse performance on working memory tasks than the patients with DM type 1, DM type 2 and HA. 3) Further investigation is needed to clarify the role of inflammatory and oxidative and nitrosative stress (O&NS) processes in neurocognitive dysfunctions occurring in recurrent depression and somatic disease....

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Journal Article 2013; 34(5): 409-417 PubMed PMID: 23922049 Citation  Keywords:  Adrenocorticotropic Hormone:blood, Adult, Aged, Aged, 80 and over, Corticotropin-Releasing Hormone, Depressive Disorder:blood, Dexamethasone, Female, Humans, Hypothalamo-Hypophyseal System:physiopathology, Male, Middle Aged, Pituitary-Adrenal Function Tes.   

OBJECTIVES: The underlying pathogenic mechanisms and predictors of recurrence in major depressive disorder are still largely unknown. Hypothalamic-pituitary-thyroid (HPT) axis and hypothalamus-pituitary-adrenocortical (HPA) axis dysregulation are thought to be related to the development and course of depression.

DESIGN AND SETTING: Over a ten-year period, we investigated whether the results of thyrotropin-releasing hormone (TRH) testing and combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) testing could be correlated with the recurrence of depression in 25 outpatients with clinically remitted major depression for at least 10 years.

MATERIALS AND METHODS: Twenty-five patients (16 women and 9 men, 48.1 years of age, SD=11.4, range 22-84) with major depressive disorder were available for evaluation during hospitalization. TRH and DEX/CRH tests were administered at admission.

RESULTS: Patients who recurred within ten years after remission exhibited significantly higher thyroid stimulating hormone (TSH) responses to TRH at the time of admission compared to those who did not recur. There was no significant correlation between recurrence and DEX/CRH levels after controlling for age, sex, and body mass index.

CONCLUSION: The findings of this study suggest that the TRH test may predict future recurrence in patients with depression....

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