The clinical use of tacrolimus (Tac) is complicated by the large inter-individual variability in its pharmacokinetics as well as by chronic adverse effects on renal function. The main goal of this ...study was to evaluate the potential influence of cytochrome P450 3A5 (CYP 3A5) and ATP-binding cassette transporter B1 (ABCB1) gene polymorphisms on Tac dose requirements and dose-adjusted concentrations in different long-term periods following renal transplantation. Another aim was to investigate whether these polymorphisms affect renal function in late post-transplant period. A total of 91 renal transplant recipients were enrolled for genotyping analysis, and 53 of these entered into a pharmacokinetic-pharmacogenetic study. Allele-specific polymerase chain reaction was used for CYP 3A5 and ABCB1 polymorphism determination. Pharmacokinetic data (dose, trough concentration and dose-adjusted concentration of Tac) and renal function parameters creatinine (Cre) clearance and serum Cre level were analyzed in relation to patient genotype at 6, 12 and 24 months after transplantation. Also, linear regression analysis was performed to evaluate the effect of CYP 3A5 and ABCB1 genotypes on Tac exposure and renal function up to 24 months post-transplant. Individuals carrying the CYP 3A5*1/*3 genotype had higher Tac dose requirements than CYP 3A5*3/*3 carriers at 6, 12 and 24 months after renal transplantation. The results revealed that ABCB1 polymorphism did not influence Tac dose requirements independently. Regression analysis showed that CYP 3A5 influenced the Tac dose-adjusted concentration as well as renal function up to 24 months post-transplant. These findings confirmed that CYP 3A5 polymorphism represents the most important determinant of Tac dose and exposure in the late period following renal transplantation. Furthermore, the obtained results indicate that the decline in renal function may be more pronounced in patients with CYP 3A5*1 in the long-term period after renal transplantation.
Two new natural products, alpha -furanopinguisanol (1) and furanopinguisanone (2), were identified in the liverwort Porella cordaeana(Porellaceae). Although alpha -furanopinguisanol was previously ...reported in the literature, herein, we present arguments that its structure was actually erroneously assigned to a different, related compound. Structure elucidation was accomplished by spectral means (various 1D and 2D NMR experiments, IR, UV, MS) and the structures corroborated by chemical transformations. The relative configuration of the compounds was additionally verified by an analysis of shift changes produced by a lanthanide shift reagent. Immunomodulatory properties of these two compounds were also investigated. Their influence on rat splenocytes (SPCs) was monitored through MTT, trypan blue and neutral red assays, microscopic investigation of cells, comet assay, and protein, RNA and DNA contents. It was shown that, in higher concentration (10 super(-4) M), compound 1 induced a blast-like transformation of SPCs, while in lower ones (10 super(-8) to 10 super(-6) M) it acted as a cytotoxic agent. On the other hand, compound 2 exerted prominent cytotoxicity in all concentrations. It the light of the obtained data, a possible mechanism of action of the two compounds was discussed.
Platelet-rich plasma (PRP) with normal and below-normal physiological concentrations of platelets is designated as diluted PRP (dPRP).
The aims of this study are to evaluate whether bone mineral ...matrix in combination with dPRP possesses osteogenic capacity; and whether the differences in dynamics and osteogenic process pattern depend on different platelet concentrations, to what extent, and also what could be benefits for bone regeneration in clinical practice.
Three types of implants were made: BMM-bone mineral matrix alone; dPRP/10-bone mineral matrix mixed with dPRP (concentration of platelets 10 times lower than physiological level) and dPRP/3-bone mineral matrix mixed with dPRP (concentration of platelets 3 times lower than physiological level). A subcutaneous implantation model in Balb/c mice was used. The implants were analyzed using expression analysis of bone-related genes, histochemical, immunohistochemical and histomorphometrical analysis.
All types of implants induced creation of necessary preconditions for supporting osteogenic processes, but did not induce visible young bone growth. Implant types dPRP/10 and dPRP/3 showed very similar and significantly better stimulatory effects on osteogenic processes than bone matrix alone. In this study, significant ectopic osteogenic potential of concentration of platelets in PRP that are lower than physiological level in blood plasma in combination with bone mineral matrix was demonstrated. Diluted platelet-rich plasma could be a promising and useful adjuvant therapeutic agent in bone regeneration.
The primary goal of this study was to evaluate the influence of cytochrome P450 (CYP) 3A5 (6986A>G) and ABCB1 (3435C>T) polymorphisms on tacrolimus (TAC) dosage regimen and exposure. Second, we ...evaluated the influence of TAC dosage regimen and the tested polymorphisms on renal oxidative injury, as well as the urinary activities of tubular ectoenzymes in a long-term period after transplantation. Also, we aimed to determine the association between renal oxidative stress and tubular damage markers in the renal transplant patients.
The study included 72 patients who were on TAC based immunosuppression. Allele-specific PCR was used for polymorphism determination. We measured the urinary thiobarbituric acid reactive substances (TBARS) and reactive carbonyl derivates (RCD) in order to evaluate oxidative injury, as well as the urinary activities of ectoenzymes (N-acetyl-β-D-glucosaminidase, aminopeptidase N and dipeptidyl peptidase IV) to evaluate tubular damage.
The carriers of CYP 3A5*1 allele required statistically higher daily doses of TAC than CYP *3/*3 carriers, as well as the carriers of C allele of ABCB1 gene compared to those with TT genotype. Also, there were no differences in TBARS, RCD and the activities of ectoenzymes between the patients’ genotypes. Our results showed significant correlations between urinary TBARS and RCD and the ectoenzymes’ activities.
Our findings suggest that CYP 3A5 and ABCB1 3435 polymorphism may affect TAC daily doses, but not the drug’s tubular toxicity. Furthermore, tubular damage may be associated with increased renal oxidative stress.
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The main goal of this study was to evaluate the influence of tacrolimus daily dose (TDD) as well as cytochrome P450 (CYP) 3A5 6986A>G and ABCB1 3435C>T polymorphisms on the ...erythrocytes’ oxidative stress parameters in long-term period after renal transplantation (Tx). Secondly, we investigated whether tacrolimus and/or oxidative injury might have affected renal function or it was independent from both. In order to evaluate erythrocytes’ oxidative stress status in 72 renal transplant recipients and 62 healthy volunteers, we measured the levels of thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) and the activities of superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione reductase (GR) as well. Also, we performed allele-specific PCR to determine CYP 3A5 and ABCB1 polymorphisms. Erythrocytes’ TBARS positively correlated with SOD, GPX and negatively with GFR. Tested polymorphisms affected TDD, but not oxidative stress parameters. TDD positively correlated with GSH and negatively with GFR. Additionally, tacrolimus dose-adjusted trough concentrations positively correlated with GFR and negatively with GPX and GSH. Furthermore, regression analysis showed that TBARS and TDD independently and negatively affected GFR in long term period after Tx. Our findings suggest that tacrolimus may increase erythrocytes’ antioxidative capacity. Regardless, it may be involved in renal function decline in a long-term period after Tx, which seems to be independent from oxidative stress mediated reduction in renal function.
Abstract Background Recent evidence indicates that chronic heart failure (CHF) is accompanied by both activation of the immune system and autonomic imbalance. There is a growing body of evidence that ...increased levels of proinflammatory cytokines and other inflammatory markers have important roles as mediators of disease progression and markers of mortality in patients with CHF. Objective The aim of this study was to investigate connection between autonomic imbalance obtained by analysis of heart rate variability (HRV) and activation of the immune system as measured by serum levels of tumor necrosis factor (TNF)-α in patients with chronic heart failure. Materials and methods This cross-sectional study included 21 patients with CHF and 8 age- and gender-matched healthy control subjects. We assessed HRV by 24-hour electrocardiographic Holter monitoring and measured serum levels of TNF-α using an enzyme-linked immunosorbent assay. Clinical assessment and echocardiography were also performed. Results There was an inverse correlation between serum level of TNF-α and a time-domain parameter of HRV – SDNN ( r = −0.542, p < 0.05). A similar result was found for HRV triangular index, a geometric measure of HRV ( r = −0.556; p < 0.05). The correlation was stronger for subjects with a diabetes mellitus, females, and TNFA2 allele carriers (an “A” at position −308A). The pNN50, indirect marker of cardiac vagal activity, was not significantly associated with serum concentration of TNF-α. Conclusions In conclusion, the results of the present study indicate that increased serum TNF-α level is significantly associated with reduced HRV indices, suggesting that activation of the immune system in patients with CHF is closely related to autonomic imbalance.
Our study investigates association between Galectin-3 levels and adverse left ventricular remodelling (LVR) at six months. Fifty-seven patients following first acute myocardial infarction (AMI) were ...enrolled in this study and blood samples collected on day 1 from the femoral vein and artery, the right atrium near the coronary sinus and the aortic root, and on day 30, from the cubital vein. Patients with LVESV ≥20% at six months, were included in the LVR group. On day 1, Galectin-3 plasma levels in the femoral vein (10.34 ng/ml ± 3.81 vs 8.22 ng/ml ± 2.34, p = 0.01), and near coronary sinus (10.7 ng/ml ± 3.97 vs 8.41 ng/ml ± 2.56, p = 0.007) were higher in the LVR group. Positive correlations between Galectin-3 levels from aortic root and coronary sinus, aortic root and femoral vein, and coronary sinus and femoral vein, were observed in both groups. On day 30, Galectin-3 concentration in the cubital vein was an independent risk factor of LVR six months post-AMI, demonstrating 1.5-fold increased risk. Day-30 Galectin-3 also showed positive correlations with echocardiography parameters indicative of diastolic and systolic dysfunction. Determining Galectin-3 plasma concentration on day 30 following AMI could have beneficial prognostic value in predicting LVR.
This study was conducted to determine the effect of
and
genetic polymorphisms on the pharmacokinetics of propofol in children of different sexes and ages who undergone total intravenous anesthesia ...(ТIVA) and deep sedation during diagnostic and therapeutic procedures.
The prospective study included 94 children, ASA I-II status, 1 to 17 years of age, who undergone standard anesthetic protocol for TIVA, which implied the continuous use of propofol. Before the administration of propofol, venous blood was sampled to determine the presence of genetic variations in
and
gene using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). From each patient included in the study blood samples were taken: 10 mins after the induction of anesthesia, immediately before the discontinuation of the propofol infusion, 10 mins after discontinuation of the propofol infusion and 20 mins after discontinuation of the propofol infusion to determine the pharmacokinetics of the drug in the plasma of the subjects The plasma propofol concentration was determined by HPLC analytical technique.
genotype is an independent predictor of the propofol concentration in children immediately after the end of the continuous infusion and 10 mins afterwards. In the carriers of the polymorphic
C allele, the propofol distribution constant was higher. The carriers of the polymorphic
T allele received a significantly lower overall and initial dose of propofol. Unlike polymorphism of the
gene, the tested
and
gene polymorphisms are not independent predictors of the pharmacokinetics of propofol.
Further investigations of
and
and other genes that participate in propofol metabolism as well as detailed analyses of the general conditions, administered therapies and associated diseases could explain the large interindividual variability of propofol metabolism in children.
The present study aimed to evaluate the protective action of thymol towards l-arginine-induced acute pancreatitis (AP) by studying the function of rat peritoneal immune cells.
Rat peritoneal exudate ...cells (PECs), obtained 24 h after the injection of l-arginine (350 mg/100 g of b.w.), were evaluated for mitochondrial activity (MTT assay), adherence capacity (methylene-blue assay), and phagocyte enzyme activity (myeloperoxidase, MPO, assay). The activity of α-amylase and free MPO, as well as the concentration of reactive oxygen species (ROS, i.e. O2−), were determined in the peritoneal exudate fluid. Also, serum α-amylase activity determination and pancreatic tissue pathohistological analysis were performed.
The administered thymol (50 and 100 mg/kg, per os) caused a significant decrease in the PEC mitochondrial activity and adherence capacity when compared with these functions of PECs isolated from rats with AP. A decrease in cellular MPO activity, as well as in the levels of ROS, α-amylase, and free MPO in peritoneal exudates was found in animals treated with thymol compared to the control animals with AP. Additionally, thymol administration prevented an increase in serum α-amylase activity, accompanied by the decrease in pancreatic tissue damage that follows l-arginine application.
The present results showed that thymol exerts significant immunomodulatory properties and a potential to silence PEC functions in inflammatory conditions such as the AP induced by l-arginine.
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