Ivan Radosavljevic

PREDICT score and CYP2C19 polymorphism independently predict lack of efficacy of clopidogrel in cardiology patients

Sne zana Mugo sa,* Nata sa Djordjevi c, Zoran Bukumiri c, Nina Djukanovi c, Jelena Cuki c, Ivan Radosavljevi c, Dejan Baski c, Dragana Proti c, Marija Zdravkovi c** and Zoran Todorovi c** *Faculty of Pharmacy, University of Montenegro, Podgorica, Montenegro, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, , Faculty of Medicine, University of Belgrade, High Medical School “Milutin Milankovi c”, Belgrade, Public Health Institute, Kragujevac, and **Medical Center “Be zanijska kosa”, Belgrade, Serbia

CYP3A5 Polymorphism In Serbian Paediatric Epileptic Patients On Carbamazepine Treatment

Abstract Carbamazepine exhibits significant inter-individual variability in its efficacy and safety, which leads to unpredictable therapy outcomes for the majority of patients. Although its complex biotransformation depends on CYP3A5 activity, evidence of association between carbamazepine treatment outcomes and CYP3A5 functional variations remains inconclusive. The aim of the present study was to investigate the distribution of two of the functionally important CYP3A5 variants *2 and *3 as well as their effects on carbamazepine dose requirements, plasma concentrations and clearance in a Serbian population. The study involved 40 paediatric epileptic patients on steady-state carbamazepine treatment. Genotyping was conducted using the PCR-RFLP method, and carbamazepine plasma concentrations were determined using the HPLC method. CYP3A5*2 and *3 polymorphisms were found at frequencies of 0.0% and 97.5%, respectively, which corresponds well to previously published data for Caucasians. No differences in CYP3A5*3 allele frequencies were detected among epileptic patients in comparison to healthy volunteers within similar ethnic populations (p>0.08), indicating that CYP3A5 polymorphism does not represent a risk factor for epilepsy development. There was an observed tendency towards lower dosage requirements (mean±SD: 15.06±4.45 mg/kg vs. 18.74±5.55 mg/kg; p=0.26), higher plasma concentrations (mean±SD: 0.45±0.13 mg/kg vs. 0.38±0.03 mg/kg; p=0.47) and lower clearance (mean±SD: 0.14±0.05 mg/kg vs. 0.15±0.01 mg/kg; p=0.79) of carbamazepine in homozygous carriers of CYP3A5*3/*3 compared to heterozygous CYP3A5*1A/*3 Serbians. Because these genotype groups did not differ significantly in terms of their carbamazepine pharmacokinetics parameters, the proposed effects of CYP3A5*3 on carbamazepine metabolism could not be confirmed.

CFTR IVS8 Poly-T Variation Affects Severity of Acute Pancreatitis in Women

BackgroundCystic fibrosis transmembrane conductance regulator (CFTR) is important for normal pancreatic function. Its coding gene is polymorphic, and the variations have been associated with the increased risk for acute pancreatitis. However, their impact on the disease severity is still unknown. Therefore, the aim of our study was to determine the functional importance of common cystic fibrosis transmembrane conductance regulator variations IVS8-poly T, R117H, and M470V for the severity of acute pancreatitis.MethodThe study involved 98 acute pancreatitis patients. The severity of the disease was determined based on the Atlanta Classification system. IVS8-poly T, R117H, and M470V genotyping was performed using PCR-RFLP method.ResultsIVS8-5T, IVS8-7T, IVS8-9T, and M470V alleles were found at the frequencies of 5.7, 75.5, 18.9, and 55.7%, respectively, while R117H was not observed. Among women, the severe form of the disease was more frequent in carriers of at least one IVS8 9T allele (RR for 9T/9T + 9T/non-9T vs. non-9T/non-9T: 2.115; 95% CI: 1.241–3.605). This association was not detected in men and was not affected by M470V. In addition, co-morbidities increased the severity of acute pancreatitis (p = 0.022).ConclusionOur study reveals that IVS8 poly-T variation affects severity of acute pancreatitis in women and that existent co-morbidities worsen the clinical course of the disease.

Clinical and laboratory parameters associated with death in acute pancreatitis

Introduction. Acute pancreatitis is an inflammatory condition having the significant mortality rate in the case of severe forms of disease. The aim of this study was to investigate putative factors of increased mortality with contradictory prior evidence, and to reveal factors that were insufficiently explored previously. Methods. A prospective cohort study with nested case/control design included all adult patients treated for acute pancreatitis in Clinical Center of Kragujevac, Serbia, during the 3-year period (from October 2011 to December 2014). The cases (n=19) were patients who died, while the controls (n=113) were patients who survived. The associations between putative risk factors and the study outcomes were tested by univariate and multivariate logistic regressions, and expressed as crude and adjusted odds ratios (OR) with corresponding 95% confidence intervals (CI). Results. Significant association with the lethal outcome in acute pancreatitis was found for advanced age (adjusted OR 1.12, 95%CI 1.02-1.23), presence of significant comorbidities (adjusted OR 10.62, 95%CI 1.01-111.39), higher interleukin-8 (IL-8) value on third day from onset of symptoms (adjusted OR 1.05, 95%CI 1.02-1.08), use of tramadol and/or morphine (adjusted OR 47.34, 95%CI 3.21-699.08), BISAP score ≥ 3 in the first 24 hours (adjusted OR 48.11, 95%CI 3.14-736.29), and prophylactic use of antibiotics (adjusted OR 0.07, 95%CI 0.01-0.85). Conclusion. Advanced age, significant comorbidities, use of tramadol and/or morphine and more severe disease as assessed by BISAP score can increase the risk for death in acute pancreatitis, while prophylactic use of antibiotics may have a protective role. [Projekat Ministarstva nauke Republike Srbije, br. 175007]

Factors affecting the development of adverse drug reactions to β-blockers in hospitalized cardiac patient population.

The aim of the present study was to undertake a study on the prevalence of cytochrome P450 2D6 (CYP2D6) poor metabolizer alleles (*3, *4, *5, and *6) on a Montenegrin population and its impact on developing adverse drug reactions (ADRs) of β-blockers in a hospitalized cardiac patient population. A prospective study was conducted in the Cardiology Center of the Clinical Center of Montenegro and included 138 patients who had received any β-blocker in their therapy. ADRs were collected using a specially designed questionnaire, based on the symptom list and any signs that could point to eventual ADRs. Data from patients’ medical charts, laboratory tests, and other available parameters were observed and combined with the data from the questionnaire. ADRs to β-blockers were observed in 15 (10.9%) patients. There was a statistically significant difference in the frequency of ADRs in relation to genetically determined enzymatic activity (P<0.001), with ADRs’ occurrence significantly correlating with slower CYP2D6 metabolism. Our study showed that the adverse reactions to β-blockers could be predicted by the length of hospitalization, CYP2D6 poor metabolizer phenotype, and the concomitant use of other CYP2D6-metabolizing drugs. Therefore, in hospitalized patients with polypharmacy CYP2D6 genotyping might be useful in detecting those at risk of ADRs.

Analysis of Treatment-Related Factors Affecting Mortality in Patients with Severe Necrotizing Acute Pancreatitis

Summary The aim of the paper was to determine the factors related to the initial therapy that may contribute to death from severe necrotizing acute pancreatitis and to analyze their clinical importance as well as possible additive effects. A retrospective case-control study included all adult patients treated for severe necrotizing acute pancreatitis in the Clinical Center of Kragujevac, Serbia, during the five-year period (2006-2010.). The cases (n = 41) were patients who died, while the controls (n = 69) were participants who survived. In order to estimate the relationship between potential risk factors and observed outcome, crude and adjusted odds ratios (OR) with 95 % confidence intervals (CI) were calculated in logistic regression models. Significant association with observed outcome was shown for the use of gelatin and/or hydroxyethyl starch (adjusted OR 12.555; 95 % CI 1.150-137.005), use of albumin (adjusted OR 27.973; 95 % CI 1.741-449.373), use of octreotide (adjusted OR 16.069; 95 % CI 1.072-240.821) and avoiding of enteral feeding (adjusted OR 3.933; 95 % CI 1.118-13.829), while the use of nonsteroidal anti-inflammatory drugs had protective role (adjusted OR 0.057; 95 % CI 0.004-0.805). The risk of death in patients with predicted severe necrotizing acute pancreatitis could be reduced with avoidance of treatment with colloid solutions, albumin and octreotide, as well as with an early introduction of oral/enteral nutrition and use of nonsteroidal anti-inflammatory drugs.

Lack Of PRSS1 And SPINK1 Polymorphisms In Serbian Acute Pancreatitis Patients

Abstract Acute pancreatitis represents an acute nonbacterial inflammation of the pancreas caused by a premature and ectopic activation of pancreatic digestive enzymes. Two of the most important genes in pancreatic autodigestion, PRSS1 and SPINK1, were implicated in the earliest discoveries of the genetic background of pancreatitis. However, the distribution of their variations displays interethnic variability, which could significantly affect the magnitude of their proposed effects on this disease worldwide. The aim of the present study was to investigate the distribution of the most important functional variations of PRSS1 (86A>T and 365G>A) and SPINK1 (101A>G), and their influence on the clinical course of acute pancreatitis in Serbian patients. The study enrolled 81 subjects, the severity of disease course was determined using the Atlanta Classification system, and the genotyping was conducted using a PCR-RFLP method. PRSS1 86A>T and 365G>A SNPs were not observed in the study population, while SPINK1 101A>G was present with the frequency of 0.62% (95% CI: 0.00, 3.83%). Due to extremely low frequencies or absences of examined variations, the proposed effect of these SNPs on the severity of acute pancreatitis could not be confirmed. The results do not support routine genotyping of either PRSS1 or SPINK1 in Serbs.

Risk Factors For Development Of Acute Necrotizing Pancreatitis

Abstract Acute necrotizing pancreatitis (ANP) is a severe form of acute pancreatitis that is associated with high morbidity and mortality. Thus, an adequate initial treatment of patients who present with acute pancreatitis (AP) based on correct interpretation of early detected laboratory and clinical abnormalities may have a significant positive impact on the disease course. The aim of the study was to determine patient- and initial treatment-related risk factors for the development of acute necrotizing pancreatitis. For the purpose of this study a case-control design was chosen, including adult patients treated for AP in the surgical Intensive Care Unit (sICU) of Clinical Center of Kragujevac, from January 2006 to January 2011. The cases (n=63) were patients who developed ANP, while the controls (n=63) were patients with AP without the presence of pancreatic necrosis. The controls were randomly selected from a study sample after matching with the cases by age and sex. Significant association with the development of ANP was found for the presence of comorbidity (adjusted OR 6.614 95%CI 1.185-36.963), and the use of somatostatin (adjusted OR 7.460, 95%CI 1.162-47.833) and furosemide (adjusted OR 2710.57, 95%CI 1.996-56.035) started immediately upon admission to the sICU. This study suggests that comorbidities, particularly the presence of serious cardio-vascular disease, can increase the risk for development of acute necrotizing pancreatitis. The probability for the development of ANP could be reduced by the avoidance of the initial use of loop diuretics and somatostatin.