Ece Genç

Impact of Genetic Factors (CYP2C9, VKORC1 and CYP4F2) on Warfarin Dose Requirement in the Turkish Population

Warfarin has a narrow therapeutic index and displays marked person‐to‐person variation in dose requirement. Functional polymorphisms at candidate genes can therefore offer utility as biomarkers to individualize warfarin treatment. The main objective of this study was to determine whether and to what extent variability in warfarin dose requirements was determined by polymorphisms in CYP2C9, VKORC1, CYP4F2 (rs2108622) and EPHX1 (rs2292566) in the Turkish population. Patients (n = 107) who had stable doses and international normalized ratio (INRs) at their last three consecutive visits were registered. Their demographic factors, concurrent medications, warfarin‐related bleedings or thromboembolisms, smoking, alcohol intake and weekly green vegetable consumption were recorded. From a blood sample, DNA was isolated and genotyped by real‐time PCR for polymorphisms of CYP2C9, VKORC1, CYP4F2 and EPHX1. A regression analysis was used to determine the independent effects of genetic and non‐genetic factors on warfarin dose optimization. In our study, in addition to age, genetic variants of CYP2C9, VKORC1 and CYP4F2 were found to be significant predictor variables for the maintenance dose for warfarin, explaining 39.3% of dose variability. VKORC1 and CYP2C9 genotypes remain predictor variables of the warfarin dose, and we first found that CYP4F2 (rs2108622) contributes to dose variability in the Turkish population as well. These observations may be of benefit to future translation research with a view to global personalized medicine in regions hitherto understudied such as the Turkish population so as to rationalize initial warfarin dose and reduce the burden of frequent INR measurements.

In vitro effect of pantoprazole on lower esophageal sphincter tone in rats.

AIM To investigate the in vitro effects of pantoprazole on rat lower esophageal sphincter (LES) tone. METHODS Rats weighing 250-300 g, provided by the Yeditepe University Experimental Research Center (YÜDETAM), were used throughout the study. They were anesthetized before decapitation. LES tissues whose mucosal lining were removed were placed in a standard 30-mL organ bath with a modified Krebs solution and continuously aerated with 95% oxygen-5% carbon dioxide gas mixture and kept at room temperature. The tissues were allowed to stabilize for 60 min. Subsequently, the contractile response to 10(-6) mol/L carbachol was obtained. Different concentrations of freshly prepared pantoprazole were added directly to the tissue bath to generate cumulative concentrations of 5 × 10(-6) mol/L, 5 × 10(-5) mol/L, and 1.5 × 10(-4) mol/L. Activities were recorded on an online computer via a 4-channel transducer data acquisition system using the software BSL PRO v 3.7, which also analyzed the data. RESULTS Pantoprazole at 5 × 10(-6) mol/L caused a small, but statistically insignificant, relaxation in the carbachol-contracted LES (2.23% vs 3.95%). The 5 × 10(-5) mol/L concentration, however, caused a significant relaxation of 10.47% compared with the control. 1.5 × 10(-4) mol/L concentration of pantoprazol caused a 19.89% relaxation in the carbachol contracted LES (P < 0.001). CONCLUSION This is the first study to demonstrate that pantoprazole has a relaxing effect in isolated LESs. These results might have significant clinical implications for the subset of patients using proton pump inhibitors who do not receive full symptomatic alleviation from gastroesophageal reflux disease.

Effect of high-fat intake on motor activity, homovanillic acid and 5-hydroxyindoleacetic acid levels in striatum and cortex of rats exposed to stress.

Abstract The aim of the present study was to investigate whether high fat consumption changes the effects of stress on both motor activity performance, striatal and cortical dopamine and serotonin metabolites in rats. The animals were fed either with high fat or standard diet for 4 weeks. Restraint stress lasting for 15 min at +4°C was applied daily to stress-exposed groups. Motor activity performance was measured weekly by using motor activity monitoring systems. At the end of the study, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels of the striatum and cerebral cortex were measured by HPLCEC. It was observed that restraint stress increased locomotor activity and high-fat diet prevented this effect. Stress and high-fat intake had an additive decreasing effect on striatal HVA levels. 5-HIAA levels, on the other hand, were lower in both high fat and high fat + stress groups compared to the stress group. These results suggest that high-fat intake differentially affected the stress response on striatal dopaminergic and serotonergic neurons in rat brain regions studied and this may be related to the effects observed in motor activity performance.

The Effect of Rabeprazole on LES Tone in Experimental Rat Model

ABSTRACT Introduction: Despite adequate treatment with proton pump inhibitors (PPIs), symptoms of gastroesophageal reflux disease (GERD) may remain persistent as well as Barretts esophagus may emerge. It may be proposed that the relaxant effect of PPIs on the smooth muscles may lead to resistance of symptoms. The aim of this study is to investigate effects of rabeprazole on the lower esophageal sphincter (LES) pressure with a rat model. Materials and Methods: Sixteen rats were grouped as control and treatment groups. After obtaining LES tissues followed by a 60 min equilibration period for stabilization, contractile response to carbachol was obtained by application of single dose of carbachol to have a final concentration of 10−6 M in the organ bath. After the contractions reached a plateau, concentration-response relationships for rabeprazole were obtained in a cumulative manner in the treatment group. Results: In the carbachol contracted LES preparations; 1.5 × 10−6 and 1.5×10−5 M of rabeprazole caused 6.08% and 11.34% relaxations respectively which were not statistically significant. However, mean integral relaxation value for 4.5 × 10−5 M of rabeprazole was 17.34% and this relaxation was significant compared with controls. Conclusions: In the present study, rabeprazole caused no direct significant change in LES tone in the therapeutic dose range applied to the organ bath. However, rabeprazole at the high dose caused a significant decrease in the LES tone.

Are dopaminergic genotypes risk factors for eating behavior and obesity in adults

Dopamine (DA) is the main modulator of the brain reward system and significantly regulates food intake. The idea that obesity is a neurobiological disease rather than a metabolic disorder, is the basis of the study. Changes in dopamine neurotransmission affect the brain reward system in a direct way. Furthermore, changes in the reward system influence the eating behavior in human. The enzymes monoamine oxidase A (MAOA) and catechol-O-methyltransferase (COMT) terminate the DA function by metabolizing it. In our study, the control group which included 214 individuals and 234 subjects with obesity were investigated for MAOA-u VNTR and COMT (rs4680) polymorphisms. In our study, statistical analysis has showed that in control group Val/Met COMT genotype was significantly higher compared with the patient group (p=0.04). When the groups were compared in terms of eating behavior, the number of the subjects who ate for reward was significantly higher in patient group (p=0.03). Our findings demonstrated that eating behavior might have an effect on obesity and dopaminergic polymorphisms could be risk factors for the development of obesity in Turkish population.

Superiority of ceftriaxon to cefazolin in a rat model of obstructive jaundice: an experimental study.

ABSTRACT Objective: The objective of this study was to evaluate the serum and bile concentrations of cefazolin and ceftriaxone at the third and sixth hours in an experimental obstructive jaundice model and to identify the rate of excretion of these antibiotics into the bile. Material and methods: Thirty-two Wistar albino rats were used in this study. The bile and serum levels of cefazolin were measured at the third hour in the A1 group and at the sixth hour in the A2 group, with cefazolin administered as 5 mg/rat; while the bile and serum levels of ceftriaxone were studied at the third hour in the B1 group and at the sixth hour in the B2 group, with ceftriaxone administered as 5 mg/rat. Results: After 3 hr of cefazolin administration, the serum concentration in the A1 group reached a mean of 1.8 μg/ml, while the bile concentration was 90% of the serum concentration, with a mean of 1.6 μg/ml; whereas in the B1 group, the third-hour serum concentration of ceftriaxone was 18.6 μg/ml, while the bile concentration was found to be as high as 330% of this level, i.e., 56 μg/ml. The serum value of cefazolin decreased to 1.4 μg/ml in the A2 group and ceftriaxone decreased to 3.7 μg/ml in the B2 group at the sixth hour. Conclusions: Although the excretory level of cefazolin and ceftriaxone into the bile reaches therapeutic doses, the duration for which these levels are above those required for bactericidal activity is short. Ceftriaxone is better concentrated in the serum and bile than cefazolin.