Polymorphic CYP2D6 is the enzyme that activates the opioid analgesic tramadol by O-demethylation to its active metabolite O-demethyltramadol (M1). Our objective was to determine the opioid effects measured by pupillary response to tramadol of CYP2D6 genotyped volunteers in relation to the disposition of tramadol and M1 in plasma. Tramadol displayed phenotypic pharmacokinetics and it was possible to identify poor metabolizers (PM) with >99 % confidence from the metabolic ratio (MR) in a single blood sample taken between 2.5 and 24 h post-dose. Homozygous extensive metabolizers (EM) differed from PM subjects by an almost threefold greater (P=0.0014) maximal pupillary constriction (Emax). Significant correlations between the AUC and Cmax values of M1 versus pupillary constriction were found. The corresponding correlations of pharmacokinetic parameters for tramadol itself were weaker and negative. The strongest correlations were for the single-point metabolic ratios at all sampling intervals versus the effects, with rs ranging from 0.85 to 0.89 (p‹0.01). It is concluded that the concept of dual opioid/non-opioid action of the drug, though considerably stronger in EMs, is valid for both EM and PM subjects. This is the theoretical basis for the frequent use and satisfactory efficacy of tramadol in clinical practice when given to genetically non-selected population., O. Slanař, M. Nobilis, J. Květina, R. Mikoviny, T. Zima, J. R. Idle, F. Perlík., and Obsahuje biblografii a bibliografické odkazy
Proteinuria is often used as a surrogate marker in monitoring and predicting outcome in patients with chronic kidney diseases, but it is non-specific. IgAN belongs to the most common primary glomerulonephritis worldwide with serious prognosis. The main aim of this work was to assess differences in urine proteins in patients with IgA nephropathy and to identify abnormal proteins as potential biomarkers of IgA nephropathy or the renal disease. In our pilot project, we selected 20 patients and compared them with 20 healthy volunteers. Protein quantification was performed using iTRAQ (isobaric tag for relative and absolute quantitation) labeling method. The peptides were separated by the isoelectric focusing method (IEF) and nano-LC with C18 column and identified by mass spectrometry using MALDI-TOF/TOF MS. Proteins´ lists obtained from IEF-LC-MS-MS/MS analysis were combined and contained 201 proteins. It was found out that 113 proteins were common in both experiments. 30 urinary proteins were significantly up- or down-regulated in patients with IgA nephropathy. We characterized potential biomarkers such as alpha-1-antitrypsin, apolipoprotein A-I, CD44 antigen or kininogen. Potential biomarkers of IgAN should be validated in further studies., P. Prikryl, L. Vojtova, D. Maixnerova, M. Vokurka, M. Neprasova, T. Zima, V. Tesar., and Obsahuje bibliografii
The pathogenesis of arterial hypertension in autosomal dominant polycystic kidney disease (ADPKD) is complex and likely dependent on interaction of hemodynamic, endocrine and neurogenic factors. We decided to evaluate the role of endothelin (ET1) and nitric oxide (NO) in the regulation of arterial blood pressure (BP) and to determine plasma levels of ET1 and NO in the group of patients with ADPKD. The ADPKD group (18 patients, 6 men + 12 women, mean age 44.611.7 years, with creatinine clearancecorrig > 1.1 ml/s) was compared with a control group of 27 healthy volunteers of comparable age. Plasma levels of ET1 assessed by direct RIA determination in the group of ADPKD patients (11.03±1.8 fmol/ml) were significantly increased (p<0.001) in comparison with the control group (2.660.58 fmol/ml), while no significant differences were observed between normotensive and hypertensive patients in the ADPKD group. Serum levels of NO were evaluated according to the determination of serum levels of their metabolites - nitrites/nitrates. Serum levels of NO in the group of ADPKD patients (39.85±6.38 μmol/l) were significantly higher (p<0.05) in comparison with the control group (22.7±1.20 μmol/l), whereas in the ADPKD group no significant differences were observed between normotensive and hypertensive patients. Thus, our study supports the concept of complex alteration of both vasoconstrictor and vasodilator systems in the pathogenesis of arterial hypertension in ADPKD., M. Merta, J. Reiterová, R. Ryšavá, V. Tesař, M. Jáchymová., and Obsahuje bibliografii
Alcohol use has been identified as a risk factor for the development of osteoporosis. Eight male Wistar rats at two months of age were alcoho-fed (7.6 g 95 % ethanol/kg b.w. per day) to evaluate the effects of long-term administration (three months) of alcohol in drinking water. We have used a dose which is considered to be comparable to a dose of 1 liter of wine or 2.5 liters of 12° beer used in male adults daily. The bones were tested mechanically by a three-point bending test in a Mini Bionix (MTS) testing system. The bones from alcohol-fed rats were characterized by a reduction in bone density as well as in ash, calcium and phosphate content. In alcohol-fed rats the reduction in bone mineral density (10 %) was reflected by about 12 % reduction of mechanical strength of femur (158±5.5 vs. 178±3.2 N/mm2). Alcohol significantly altered femoral cortical thickness. In our experiment alcohol itself did not exert any antiandrogenic effect and it did not produce changes in the weight of seminal vesicles. Liver function test (GGT, ALP, AST) did not differ between alcohol-fed rats and control rats. Alcohol-induced bone loss is associated with increased bone resorption and decreased bone formation. These results document the efficacy of alcohol at the dose of 7.6 g 95 % ethanol/kg b.w. to cause bone loss and loss of bone mechanical strength in intact rats. The results of the present study may be interpreted as supporting the hypothesis of alcohol as a risk factor for osteoporosis., P. D. Broulík ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy