Potential protective effects of naringenin against vancomycin-induced nephrotoxicity via reduction on apoptotic and oxidative stress markers in rats.

Vancomycin (VCM), a glycopeptide antibiotic, is a drug widely used in severe infections. However, VCM induce notable nephrotoxic side effects. Naringenin (NAR) is a natural of flavonoid and are known as strongly antioxidant, nefroprotective, antiapoptotic, and anti-inflammatory. The purpose of this study was to determine the potential protective effects of NAR against VCM-induced nephrotoxicity by measuring apoptotic and oxidative stress markers and evaluating histopathological alterations in rats. For this purpose, we used male Wistar albino rats that divided into seven groups: (i) Control [saline, intraperitoneally (i.p.)], (ii) carboxymethyl cellulose (0.5% CMC, orally), (iii) VCM (400 mg/kg, i.p.), (iv) NAR100 (100 mg/kg, orally), (v) VCM + NAR25 (25 mg/kg, orally), (vi) VCM + NAR50 (50 mg/kg, orally), and (vii) VCM + NAR100 (100 mg/kg, orally) groups. VCM administration was started one day after the first treatment of NAR and continued across 7-day. Caspase-3, -8, and-9 activities and malondialdehyde (MDA) and nitric oxide (NO) levels were measured by colorimetric methods in the kidney tissues, creatinine, and blood urea nitrogen (BUN) levels were analyzed based on ELISA in serum. Caspase-3 and -8 activities, NO levels, serum creatinine and BUN levels were significantly higher in VCM group in comparison with VCM + NAR (25, 50, and 100) groups (p < 0.05). Caspase-9 activity and MDA were significantly higher in VCM group compared to VCM + NAR (25 and 50) groups (p < 0.05). Histopathological alterations in VCM group were significantly diminished by administration of NAR, especially NAR 25. In conclusion, NAR 25 and 50 mg have more potent protective effects on VCM-induced nephrotoxicity compared to NAR 100 mg.

Association between serotonin 2A receptor (HTR2A), serotonin transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) gene polymorphisms and citalopram/sertraline induced sexual dysfunction in MDD patients.

Sexual dysfunction (SD) is a troublesome adverse effect of selective serotonin reuptake inhibitors (SSRIs). A variety of mechanisms might be involved in the occurrence of SD but the exact mechanism is still not clear. Genetic variations among patients treated with SSRIs are strong determinants of intolerance and poor compliance. The present study aimed to determine the relationship between serotonin-2A receptor (HTR2A) gene -1438A/G and 102T/C polymorphisms, serotonin transporter gene (SLC6A4) 5-HTT-linked polymorphic region (5-HTTLPR) insertion/deletion variant and brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphisms and the occurrence of SD adverse effect in major depressive disorder patients treated with citalopram (CIT) or sertraline (SERT). The result from this investigation revealed that the -1438A/G and 102T/C polymorphisms appear to be associated with the SD induced by CIT. It was also demonstrated that patients receiving SERT, carrying T allele of HTR2A or L allele of 5-HTTLPR more likely to experience SD. Most important overall finding of the study is the combined effects of -1438A/G, 102T/C, and 5-HTTLPR polymorphisms. In a logistic regression model, the occurrence of SD increased with the number of risky alleles. As compared with subjects receiving SERT with few risky (≤2) alleles, those with had 5-6 alleles had an increased SD risk. After all, according to these findings, -1438A/G, 102T/C, and 5-HTTLPR polymorphisms could be considered as promising pharmacogenetic biomarkers in CIT/SERT treatment in major depressive disorder (MDD) patients to avoid the occurrence of SD.

The relationship between the serotonin 2A receptor gene -1438A/G and 102T/C polymorphisms and citalopram/sertraline-induced nausea in major depressed patients.

OBJECTIVE: The aim of the present study was to determine the relationship between the polymorphisms of -1438A/G and 102T/C in the 5-HT2A receptor (HTR2A) gene and nausea/vomiting as a side effect induced by sertraline (SERT) or citalopram (CIT) in patients with major depressive disorder. METHODS: A total of 128 patients were enrolled, 63 patients received CIT, whereas 65 patients were treated with SERT. Nausea/vomiting were assessed with the UKU Side-effects Rating Scale at baseline and at the end of the second and fourth weeks. Polymerase chain reaction-restriction fragment length polymorphism technique was employed to determine genetic differences. RESULTS: We have found that, in the patients treated with CIT, there was a nominally significant difference in the genotypic distribution associated with -1438A/G polymorphism between patients with and without nausea (X2  = 6.15, p = 0.041). Moreover, logistic regression analysis revealed a significant association between nausea/vomiting as a side effect and -1438A/G polymorphism. That is, patients with the G allele were at a higher risk for developing nausea/vomiting (p = 0.044, odds ratio = 2.213). The 102T/C polymorphism in the HTR2A gene had no significant effect on the nausea/vomiting as a side effect among participants treated with either CIT or SERT. CONCLUSION: The present study suggests the association of the HTR2A gene -1438A/G polymorphism with nausea/vomiting as a side effect related to CIT treatment.

Genotype and Allele Frequency of CYP3A4 -392A>G in Turkish Patients with Major Depressive Disorder.

OBJECTIVES: Genetic polymorphisms may help for individualized drug dosing and improved therapeutics. CYP3A4 is responsible for the metabolism of more than 50% of the commonly used drugs and metabolizes typical antipsychotic medications and antidepressant drugs. The objective of the study was to assess the genotype and allele frequencies of CYP3A4 -392A>G in Turkish patients with major depressive disorder receiving any SSRIs and to compare these results with the frequencies of other ethnic groups. MATERIALS AND METHODS: Genotyping analyses of CYP3A4 -392A>G was conducted on 84 Turkish patients using the PCR-RFLP technique. RESULTS: The allele frequencies were found as 0.982 (A) and 0.018 (G) for CYP3A4 -392A>G. The genotype frequencies were determined as 0.976 (AA), 0.012 (AG), and 0.012 (GG). The genotype frequencies were consistent with the Hardy-Weinberg equilibrium. CONCLUSION: The genotype and allele frequencies of CYP3A4 -392A>G were determined to be low in Turkish patients with major depressive disorder receiving SSRIs. Furthermore, the results of the study were compared with those of other ethnic groups and they displayed pronounced differences among other ethnic groups, especially black subjects.

Influence of CYP2B6 and CYP2C19 polymorphisms on sertraline metabolism in major depression patients.

BACKGROUND: Genetic polymorphisms in CYP2B6 and CYP2C19 may cause variability in the metabolism of sertraline, a widely used antidepressant in major depressive disorder treatment. OBJECTIVE: This study investigates the impact of CYP2B6*4 (785A > G), CYP2B6*9 (516G > T), CYP2B6*6 (516G > T + 685G > A) CYP2C19*2 (685G > A), CYP2C19*17 (-3402C > T) polymorphisms on plasma concentrations of sertraline and N-desmethyl sertraline in major depression patients treated with sertraline [n = 50]. SETTING: Participants were patients who admitted to an adult psychiatry outpatient unit at a university hospital. These were DSM-IV major depression diagnosed patients with a stable sertraline medication regimen [for at least one month]. METHODS: CYP2B6*4 (rs 2279343; 785A > G), CYP2B6*9 (516G > T; rs 3745274), CYP2B6*6 (516G > T + 685G > A) CYP2C19*2 (rs 4244285; 685G > A), CYP2C19*17 (rs 11188072; -3402C > T), polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymorphism. Plasma concentrations were measured by high-performance liquid chromatography in patients treated with SERT. MAIN OUTCOME MEASURE: The distribution of CYP2B6*4, *6, *9 and CYP2C19*2, *17 among patient group and the association between genotype and sertraline metabolism. RESULTS: Sertraline, N-desmethyl sertraline, N-desmethyl sertraline/sertraline and dose-adjusted plasma concentrations were statistically compared between individuals with wild-type and variant alleles both for CYP2B6 and CYP2C19 enzymes. The mean N-desmethyl sertraline/sertraline value, was significantly lower in all subgroups with *6 and *9 variant alleles (p < 0.05). Sertraline/C values were significantly higher (p < 0.05) and N-desmethyl sertraline/C values were lower in all subgroups with *6 and *9 variant alleles compared to wild-type subgroup. CONCLUSION: CYP2B6*6 and *9 variant alleles had a significant decreasing effect on sertraline metabolism in major depression patients which might result as variations in sertraline therapy.

CAT C-262T and GPX1 Pro198Leu polymorphisms in a Turkish population.

Oxidative stress is believed to play an important role in the pathogenesis of considerable number of complex diseases. The antioxidant enzymes catalase (CAT) and glutathione peroxidase (GPX) are important components of cell defense against oxidative stress, and polymorphisms in the genes which regulate their expression may contribute to differences in susceptibility of individuals to oxidative damage caused by reactive oxygen species. The aim of this study was to assess the distribution of CAT C-262T and GPX1 Pro198Leu genotypic variants in a Turkish population. Genotyping analyses of CAT and GPX1 were conducted in 250 unrelated, healthy volunteers by the PCR-RFLP assay. The allele frequencies were 0.784 (C) and 0.216 (T) for CAT and 0.636 (C) and 0.364 (T) for GPX1 Pro198Leu. The genotype frequencies were 0.632 (CC), 0.304 (CT), and 0.064 (TT) for CAT and 0.416 (CC), 0.44 (CT), and 0.144 (TT) for GPX1 Pro198Leu. The genotype frequencies did not deviate from Hardy-Weinberg equilibrium. The results are compared with those of other reported populations. They showed marked ethnic group differences.