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Case Reports 2011; 32(1): 1-3 PubMed PMID: 21407153 Citation  Keywords:  Abdominal Abscess:epidemiology, Antiviral Agents:administration & dosage, Drug Therapy, Combination, Female, Hepatitis C, Chronic:drug therapy, Humans, Interferon-alpha:administration & dosage, Middle Aged, Oophoritis:epidemiology, Polyethylene Glycols:ad.   

BACKGROUND: Serious infections are rare complications of standard treatment in chronic hepatitis C with pegylated interferon alpha (Peg IFN) and ribavirin.

CASE: We report two cases of life-threatening tubo-ovarian abscess (TOA) in women older than 40 year of age. No casual risk factors of TOA could be identified in them. In one case septic shock and acute renal failure occured. TOA was caused by endogenic bacteria (Porphyromonas asaccharolytica in the first case and Streptococcus intermedius in the latter). Surgical treatment and interruption of IFN therapy was necessary in both cases.

CONCLUSIONS: Serious gynecological infections may have the significant negative influence on chronic hepatitis C therapy outcome. Because of the risk of TOA developing during IFN therapy gynecological care is needed in chronic hepatitis C management....

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Journal Article 2010; 31(Suppl 2): 46-50 PubMed PMID: 21187832 Citation  Keywords:  Animals, Aryl Hydrocarbon Hydroxylases:metabolism, Colon:enzymology, Cytochrome P-450 CYP3A:metabolism, Cytochrome P-450 Enzyme System:metabolism, Duodenum:enzymology, Escherichia coli, Gastrointestinal Tract:enzymology, Male, Models, Animal, Probiotics:p.   

OBJECTIVES: The aim of the study was to find whether probiotic Escherichia coli Nissle 1917 O6:K5:H1 (EcN) influences the expression of cytochromes P450 (CYP) in the rat intestine.

DESIGN: Live bacterial suspension of EcN was administered to healthy male Wistar rats daily for 7 days. Control group of rats was stressed by oral application of the saline solution daily for 7 days as well. Sections of the duodenum, jejunum, ileum, caecum and colon have been taken from each experimental animal. With all individual samples, microsomal fraction has been prepared and expression of selected CYPs was determined by Western blotting. The levels of expression of CYPs were also evaluated by mRNA using real-time PCR.

RESULTS: It was found that there are changes in expression of CYP enzymes studied along the intestine. CYP1A1, 2B1/2 and 2E1 are present mainly in the duodenum and jejunum; on the other hand, CYP2C6 is expressed mainly in the caecum and colon. CYP3A was found all over the rat intestine. The results show that there are no prominent differences between control samples and samples with EcN, only the expression of CYP3A protein in the duodenum appears to exhibit a clear tendency to decrease. In the case of the colon, a significant increase in the expression of CYP3A (most likely CYP3A1) after treatment of rats with EcN was found.

CONCLUSION: This in vivo study revealed that the levels of colon CYP3A could be significantly increased in rats treated with probiotic EcN. On the contrary, the expression of CYP3A in the duodenum decreased. However, the changes in the expression of CYP enzymes are probably not as extensive to be clinically important in man; hence, most likely the probiotic EcN has little influence on the intestinal drug metabolism by CYP enzymes....

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Journal Article 2010; 31(Suppl 2): 105-113 PubMed PMID: 21187831 Citation  Keywords:  Animals, Carps:metabolism, Ceruloplasmin:metabolism, Cytochrome P-450 CYP1A1:metabolism, Cytochrome P-450 Enzyme System:metabolism, Dose-Response Relationship, Drug, Fungicides, Industrial:pharmacology, Gills:drug effects, Glutathione:metabolism, Glutathi.   

OBJECTIVES: The aim of the study was to investigate effects of the fungicide formulation Spartakus (prochloraz 450 g.L-1) on common carp Cyprinus carpio through biometric, biochemical, haematological and antioxidant indices, induction of xenobiotic metabolizing enzymes and histological examination of selected tissues.

DESIGN: The test was performed on juvenile fish, which was exposed to Spartakus (concentrations of prochloraz: 0.05; 0.15 and 0.38 mg.L-1) for 28 days. Haematological indices were assessed using unified methods of haematological examination in fish. Plasma biochemical indices were determined by biochemical analyzer. Concentration of total cytochrome P450 (CYP), glutathione (GSH) content and glutathione-S-transferase (GST) activity were determined spectrophotometrically in hepatopancreas. Activity of liver ethoxyresorufin-O-deethylase (EROD) activity was measured spectrofluorimetrically. Ferric reducing ability of plasma (FRAP) and ceruloplasmin activity were assessed spectrophotometrically. Histological changes in samples of hepatopancreas, skin, gills, spleen, head kidney and caudal kidney were examined by light microscopy.

RESULTS: There was a significant rise in hepatosomatic index (HSI) (p<0.01), CYP and EROD (p<0.05) of fish exposed to prochloraz of 0.15 and 0.38 mg.L-1 whereas GST was induced by all concentrations tested and GSH by 0.38 mg.L-1 (p<0.05). Red blood cell count decreased significantly (p<0.05) in prochloraz of 0.05 and 0.15 mg.L-1. Plasma potassium increased (p<0.01) in all Spartakus treated groups, a decline in total protein (p<0.05), ALT, Na+ and Ca (p<0.01) was found in fish exposed to prochloraz of 0.38 mg.L-1. Ceruloplasmin activity was elevated (p<0.05) in the highest concentration tested, FRAP declined (p<0.05) in the same group. Histopathological changes in gills were demonstrated in all pesticide treated groups, with a decreased activity of skin mucous cells in prochloraz of 0.38 mg.L-1.

CONCLUSION: The subchronic exposure to Spartakus influenced HSI, induced xenobitic metabolizing enzymes, initiated a disorder of selected plasma indices and a decline in red blood cell count, caused minor histological impairment, and affected antioxidant activities of the test fish....

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Journal Article 2010; 31(Suppl 2): 36-45 PubMed PMID: 21187827 Citation  Keywords:  Aniline Compounds:metabolism, Animals, Anisoles:metabolism, Aryl Hydrocarbon Hydroxylases:physiology, Carcinogens:metabolism, Cytochrome P-450 CYP2E1:physiology, Cytochrome P-450 Enzyme System:physiology, Environmental Pollutants:metabolism, Hydroxylamine.   

OBJECTIVES: N-(2-methoxyphenyl)hydroxylamine is a human metabolite of two industrial and environmental pollutants and bladder carcinogens 2-methoxyaniline (o-anisidine) and 2-methoxynitrobenzene (o-nitroanisole). Metabolism of N-(2-methoxyphenyl)hydroxylamine by rat hepatic microsomes and identification of the major microsomal enzymes participating in this process are aims of this study.

METHODS: HPLC with UV detection was employed for the separation of N-(2-methoxyphenyl)hydroxylamine metabolites. Inducers and inhibitors of microsomal enzymes and rat recombinant CYPs were used to characterize the enzymes participating in N-(2-methoxyphenyl)hydroxylamine metabolism.

RESULTS: N-(2-methoxyphenyl)hydroxylamine is metabolized by rat hepatic microsomes predominantly to o-anisidine, the parent carcinogen from which N-(2-methoxyphenyl)hydroxylamine is formed, while o-aminophenol and two N-(2-methoxyphenyl)hydroxylamine metabolites, whose exact structures have not been identified as yet, are minor products. Selective inhibitors of microsomal CYPs, NADPH:CYP reductase and NADH:cytochrome b5 reductase and hepatic microsomes of rats pre-treated with specific inducers of CYPs and NADPH:CYP reductase were used to characterize rat liver microsomal enzymes reducing N-(2-methoxyphenyl)hydroxylamine to o-anisidine. Based on these studies, we attribute most of N-(2-methoxyphenyl)hydroxylamine metabolism to o-anisidine in rat liver to CYP2C, followed by CYP2E1, 2D and 2A. Among recombinant rat CYP enzymes tested in this study, rat CYP2C11 and 2E1, followed by CYP2A2, 2D1/2, 2C12, 3A1/2 and 1A1/2 were the most efficient enzymes metabolizing N-(2-methoxyphenyl)hydroxylamine to o-anisidine.

CONCLUSION: The results found in this study, the first report on the reduction of N-(2-methoxyphenyl)hydroxylamine by rat CYP enzymes, demonstrate that CYP2C, followed by CYP2E1, 2D and 2A are the major enzymes participating in this process in rat liver....

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Journal Article 2010; 31(Suppl 2): 26-35 PubMed PMID: 21187821 Citation  Keywords:  Animals, Antineoplastic Agents:metabolism, Biotransformation:drug effects, Cytochrome P-450 Enzyme System:physiology, DNA Adducts:drug effects, Ellipticines:metabolism, Kidney:metabolism, Liver:metabolism, Lung:metabolism, Male, Microsomes:drug effects, M.   

OBJECTIVE: Ellipticine is a potent antineoplastic agent exhibiting multiple mechanisms of action. This anticancer agent should be considered a pro-drug, whose pharmacological efficiency and/or genotoxic side effects are dependent on its cytochrome P450 (CYP)- and/or peroxidase-mediated activation to species forming covalent DNA adducts. The target of this study was to investigate a role of CYP and peroxidase enzymes in ellipticine oxidative activation in rats, a suitable model mimicking the fate of ellipticine in humans, in details. The contribution of pulmonary and renal CYP- and peroxidase enzymes to ellipticine metabolic activation is investigated and compared with that found in the liver.

METHODS: Ellipticine oxidation and DNA adduct formation in vitro were investigated using microsomes isolated from liver, lung and kidney of rats, either control (untreated) or treated i.p. with a single dose of 40 mg of ellipticine per kg of body weight. HPLC with UV detection was employed for the separation and characterization of ellipticine metabolites. Inhibitors of CYPs and cyclooxygenase (prostaglandin H synthase, COX) were used to characterize the enzymes participating in ellipticine oxidative activation in rat liver, lung and kidney. Ellipticine-derived DNA adducts were detected by 32P-postlabeling.

RESULTS: Using α-naphthoflavone, furafylline and ketoconazole, inhibitors of CYP1A, 1A2 and 3A, respectively, we found that the CYP1A and 3A enzymes play a major role in ellipticine activation to species forming DNA adducts in liver microsomes. Because of lower expression of these enzymes in lungs and kidneys, even after their induction by ellipticine, they play a minor role in ellipticine activation in these extrahepatic tissues. Arachidonic acid, a cofactor of COX, increased ellipticine activation in the microsomes of extrahepatic tissues. In addition, indomethacin, an inhibitor of COX, efficiently inhibited formation of ellipticine-derived DNA adduct in these microsomes. Based on these results, we attribute the higher activation of ellipticine in lung and kidney microsomes to COX than to CYP enzymes.

CONCLUSION: The results demonstrate that whereas CYP enzymes of 1A and 3A subfamilies are the major enzymes activating ellipticine in rat livers, peroxidase COX plays a significant role in this process in lungs and kidneys....

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Journal Article 2010; 31(4): 512-516 PubMed PMID: 20802452 Citation  Keywords:  Animals, Benzhydryl Compounds, Chromatography, High Pressure Liquid, Female, Follicle Stimulating Hormone:blood, Glutamic Acid:metabolism, Gonadotropin-Releasing Hormone:metabolism, Hypothalamus:drug effects, Luteinizing Hormone:blood, Male, Phenols:pharm.   

OBJECTIVES: The aim of present paper was to study the probable role of glutamic acid (GLU) as a mediator of bisphenol A (BPA) effect at the hypothalamic level and its effects on the reproductive axis of prepubertal male rats.

METHODS: Mated Wistar rats were treated with either 0.1% ethanol (control group, n=10) or BPA (BPA group, n=10) in their drinking water until their offspring were weaned at the age of 21 days. The estimated average dose of exposure to dams was approximately 2.5 mg/kg body weight/day of BPA. At the prepubertal stage (35 days of age), the male rats were sacrificed and Gn-RH and glutamic acid (GLU) release, an amino acid involved in Gn-RH secretion, were measured in hypothalamic samples containing medio basal and anterior preoptic area (MBH-APOA), by RIA and HPLC respectively. LH, FSH serum levels were measured by RIA and testosterone by EQLIA.

RESULTS: Gn-RH and GLU release decreased significantly in animals exposed to BPA (p<0.001, p<0.01). LH, FSH and testosterone serum levels were also decreased by treatment (p<0.0001).

CONCLUSION: Present results provide evidence that BPA may act at the hypothalamic level to decrease GLU release which in turn may modify Gn-RH secretion altering the normal function of the axis....

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Case Reports 2010; 31(3): 290-296 PubMed PMID: 20588231 Citation  Keywords:  Adult, Anorexia Nervosa:complications, Anxiety:complications, Chronic Disease, Depression:complications, Female, Humans, Menstruation Disturbances:complications, Middle Aged, Phototherapy:methods, Pilot Projects, Sleep-Wake Transition Disorders:complicati.   

OBJECTIVE: To examine the effect of bright light therapy on the sleep-wake rhythm, the menstrual cycle, mood, and key eating pathology symptoms in chronic anorexia nervosa.

METHODS: Five chronic anorectic women (mean duration of illness: 15.3 years) received 5 daily sessions of 30 minutes bright light therapy (10,000 LUX). Participants completed a diagnostic interview and questionnaires at pre-test, post-test and at a three month follow-up.

RESULTS: At follow up there was a slight improvement on core eating pathology, a fair decrease of depressive symptoms and an clinically important improvement on global distress.

CONCLUSIONS: Bright light therapy has on short term a positive effect on the physiological and psychological well being of chronic anorectic women. However, at follow-up the effects were partly lost. It is recommended to enhance the exposure period and repeat the treatment after 3 months....

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Journal Article 2010; 31(2): 238-249 PubMed PMID: 20424590 Citation  Keywords:  Adult, Auditory Cortex:physiopathology, Chronic Disease, Electroencephalography, Female, Follow-Up Studies, Functional Laterality, Humans, Male, Middle Aged, Prospective Studies, Surveys and Questionnaires, Tinnitus:physiopathology, Transcranial Magnetic .   

OBJECTIVE: The pathophysiologic mechanisms of idiopathic tinnitus remain unclear. Low frequency rTMS applied over the auditory cortex has been proposed as a new and causally oriented treatment approach for pathological conditions with abnormal, increased cortical activity including tinnitus with increased activity in the auditory cortex. However available studies are characterized by a positive reports on the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) for treatment of tinnitus, there are few details about the duration of specific treatment effects.

DESIGN: The design of the study was randomized, prospective, placebo-controlled. Right-handed patients were treated with either real or sham 1 Hz frequency rTMS over a period of two weeks. Fifty-two patients with chronic, treatment resistant tinnitus and stable medication were enrolled in the study after giving written informed consent and forty-two patients completed the study and were included in data analysis.

RESULTS: The ability to reduce the symptoms of tinnitus appeared in both randomized groups immediately after the 1 Hz rTMS and sham stimulation phase. There was a significant reduction in both groups of the tinnitus total score on the Tinnitus Handicap Inventory (THI) (real rTMS p=0.005; sham rTMS p=0.049) and Tinnitus Questionnaire (TQ) total score (real rTMS p=0.003; sham rTMS p=0.049). On the THI evaluation scale, in the real rTMS a mild worsening was noted during week 6 in comparison with the state attained in week 2. During the subsequent course of the study a significant reduction of the total score persisted in the case of THI (real rTMS week 14 p=0.033 and borderline week 26 p=0.058). The reduction of symptoms as evaluated using the TQ was significant compared to baseline in the real rTMS group at week 2, 6 and 14 (p=0.003; p=0.024; p=0.022). The group treated with sham stimulation reached significant reduction of symptoms only at week 2 (p=0.049). A comparison of the difference in the recorded values of the total score during follow-up in relation to baseline expressed as a percentage demonstrates the difference in the effect of rTMS and sham stimulation as evaluated by both the basic scales. Graphical analysis of mean patterns of treatment response according to stimulation type shows a similarity between treatment response patterns evaluated by reduction of the total scores using THI and TQ.

CONCLUSIONS: The principal finding of this study is that real 1 Hz rTMS treatment was capable of significantly reducing the total baseline score of basic scales that measure tinnitus severity. This result is important as it proves that significant reduction of symptoms can be achieved even in a group of patients with long-term symptoms resistant to pharmacological treatment....

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