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Glutathione S-transferases (GSTs) enzymes are involved in the detoxification of several endogenous and exogenous substances. In this study, we evaluated the effects of two glutathione S-transferase polymorphisms, (GSTM1 and GSTT1) on bipolar disorder (BPD) risk susceptibility in a Tunisian population. These polymorphisms were analyzed in 229 healthy subjects and 109 patients with BPD, using a polymerase chain reaction. Statistical analysis was performed using SPSS 18.0. The relative associations between the GSTs genotypes and BPD were assessed by calculating odds ratios (ORs) and 95% confidence intervals (CLs). The study results demonstrated that individuals with GSTM1 [OR = 1.51, 95% CI: 0.93–2.45, p = 0.081] or GSTT1 [OR = 1.65, 95% CI: 0.95–2.88, p = 0.060] were not associated with the risk of BPD, whereas a significant association was found between individuals with both GSTM1/T1 null genotype and BPD risk [OR = 2.96, 95% CI (1.26–7.03), p = 0.005]. These genotyping finding revealed that the absence of both GSTM1 and GSTT1 activity could be a contributor factor for the development of BPD. [ABSTRACT FROM AUTHOR]

Introduction: The prescribed dose and carbamazepine plasma concentration to achieve the optimal therapeutic efficacy are highly variable from one patient to the other. Our study aimed to determine whether biological parameters may be used as plasma markers that can individually adjust the carbamazepine dose necessary to optimize therapeutic efficacy.Material and Methods: Ninety-four epileptic patients under carbamazepine monotherapy and who have never used combination therapy were recruited from the consecutive admissions at the Department of Neurology "CHU Sahloul" of Sousse Central Hospital in Tunisia from February 2010 to April 2011. The patients were monitored for epilepsy for three years on average. Carbamazepine and 10,11-epoxide-carbamazepine concentrations were analyzed through high-performance liquid chromatography. Simultaneously, therapeutic efficacy was assessed through the annual number of seizures in each patient.Results: Our results showed the absence of any significant correlations between specific dose (mg/kg/day), carbamazepine plasma concentrations and therapeutic efficacy (r = 0.0025, p = 0.30; r = 0.1584, p = 0.38 respectively), whereas both plasma 10,11-epoxide-carbamazepine concentration and 10,11-epoxide-carbamazepine to plasma carbamazepine ratio were closely correlated with therapeutic efficacy (r = 0.34, p = 0.03; r = 0.45, p = 0.008 respectively). The optimum therapeutic response was observed among patients who simultaneously had a plasma concentration of 0.8 μg/ml of metabolite and 5.5 μg/ml of carbamazepine.Conclusions: The results suggest that plasma levels of both carbamazepine and of 10,11-epoxide-carbamazepine must be set to achieve an optimum therapeutic response. [ABSTRACT FROM AUTHOR]

Résumé La présente étude a examiné les relations entre la dose de la carbamazépine (Tégrétol ® ), les concentrations plasmatiques de la carbamazépine (CBZ) et son métabolite 10,11-époxyde-carbamazépine (CBZ-E) et la réponse clinique au traitement de la carbamazépine chez les patients bipolaires tunisiens. Treize patients atteints de troubles bipolaires de type II ont été diagnostiqués comme ayant un trouble affectif. Ces patients recrutés pour cette étude ont été traités avec la carbamazépine pendant 60 jours. L’amélioration de la santé des patients a été évaluée avant et après chaque cycle de deux semaines du traitement par la carbamazépine, à l’aide de l’échelle d’évaluation psychiatrique BPRS (Brief Psychiatric Rating Scale). Les concentrations plasmatiques de la carbamazépine et 10,11-époxyde-carbamazépine ont été déterminées par la chromatographie en phase liquide à haute performance (CLHP). Aucune corrélation significative entre la concentration plasmatique de la carbamazépine, la clairance et l’amélioration de la réponse clinique chez ces patients bipolaires n’a été trouvée. Toutefois, une corrélation significative a été remarquée entre l’amélioration de la réponse clinique constatée par les scores BPRS et de la concentration plasmatique du rapport de 10,11-époxyde-carbamazépine par dose (CBZ-E/D). Malgré la petite taille de l’échantillon de notre étude, nos résultats suggèrent que les variations de la réponse thérapeutique à la carbamazépine observées chez ces patients peuvent être, en partie, expliquées par les différences interindividuelles dans le rapport plasmatique du 10,11-époxyde-carbamazépine par dose (CBZ-E/D). Pour conclure, le paramètre CBZ-E/D pourrait être utilisé comme un bon indicateur de réglage de la stratégie d’adaptation de la dose de la carbamazépine et par conséquent pour l’amélioration de l’état clinique psychopathologique des patients bipolaires. The present study investigated relationships between carbamazepine dose, carbamazepine (Tégrétol ® ) and 10, 11-epoxide-carbamazepine plasma concentrations, and clinical responses to carbamazepine treatment in Tunisian bipolar patients. Twelve patients with bipolar II disorder were diagnosed as having an affective disorder. These patients recruited for this study were treated with carbamazepine for 60 days. Patient health improvement was assessed before and after each cycle of two weeks of carbamazepine therapy, using the Brief Psychiatric Rating Scale (BPRS). Plasma carbamazepine (CBZ) and 10, 11-epoxide-carbamazepine concentrations (CBZ-E) were determined by high-performance liquid chromatography (HPLC). No significant correlations between plasma carbamazepine and clearance-carbamazepine and clinical health improvement among our bipolar patients were found. However, a significant correlation was observed between clinical health improvement given by BPRS scores and 10,11-epoxide-carbamazepine plasma concentration to daily carbamazepine dose ratio (CBZ-E/D). Despite the small sample size of our study, our findings suggest that the carbamazepine therapy response variations observed in our patients may be, in part, explained by the interindividual differences in plasma 10,11-epoxide-carbamazepine concentration to carbamazepine dose ratio (CBZ-E/D). So the CBZ-E/D parameter could be used as a good indicator for adjusting the carbamazepine dose-adaptation strategy and consequently for improving the clinical psychopathological state of bipolar patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the impact of polymorphisms in theEPHX1 (c.416A > G, c.337T > C)and CYP3A4*22genes involved in carbamazepine (CBZ) metabolism and pharmacoresistance among 118 Tunisian patients with epilepsy under maintenance dose of CBZ. These genetic polymorphisms were analyzed by PCR-RFLP. Associations between plasma CBZ concentration, CBZ-E concentration, maintenance doses and metabolic ratio (CBZ-E:CBZ, CBZ-D:CBZ-E) were analyzed with each polymorphism. Both variants ofEPHX1 c.416A > G and c.337T > Care significantly associated with higher metabolic ratio CBZ-E:CBZ and seem to decrease the activity of the epoxide hydrolase. TheCYP3A4*22variant allele is significantly associated with lower CBZ-D:CBZ-E ratio and seems also to be associated with less activity of the cytochrome. Our data suggest that certain polymorphisms of metabolizing enzyme genes could influence inter-individual variability of CBZ metabolism. [ABSTRACT FROM AUTHOR]

Glutathione-S-transferases enzymes are involved in the detoxification of several endogenous and exogenous substances. In this present study, we evaluated the effects of two glutathione-S-transferase polymorphisms, (GSTM1 and GSTT1) on epilepsy risk susceptibility in a Tunisian population. These polymorphisms were analyzed in 229 healthy subjects and 98 patients with epilepsy, using a polymerase chain reaction (PCR). Odds ratio (ORs) was used for analyzing results. The study results demonstrated that individuals with the GSTM1 null genotype were at an increased risk of developing epilepsy [OR = 3.80, 95% confidence interval (CI) (2.15-4.78)], whereas no significant effects were observed between individuals with GSTT1 null genotype and epilepsy risk [OR = 1.15, 95% CI (0.62-2.12)]. These genotyping finding revealed that the absence of GSTM1 activity could be contributor factor for the development of epilepsy disease. [ABSTRACT FROM AUTHOR]

• Many anti-tuberculosis drugs are responsible for cases of hepatotoxicity. • The impact of GSTs gene polymorphisms on hepatotoxicity is still limited in Tunisians. • Significant association between GSTM1/T1 null genotype and ATDH. • Association of GSTP1 polymorphism and risk of ATDH. • Genetic analysis could be useful by offering targeted treatments. GST non-functional genotypes can lead to the accumulation of toxic intermediates, resulting in liver damage and increasing susceptibility to ATDH. To investigate the impact of GST Mu (GSTM1), GST Theta (GSTT1) null genotypes, and GST Pi (GSTP1; adenosine (A) > guanine (G), rs1695) variant allele on the development of ATDH in Tunisian patients treated with anti-tuberculosis therapy. This was a case-control study including patients receiving anti-tuberculosis regimen. Cases (n = 23) were tuberculosis patients presenting ATDH during two months of anti-tuberculosis drug therapy. Controls (n = 30) were patients treated for tuberculosis, but presenting no ATDH. Genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism. No statistically significant association was observed between GSTM1 and GSTT1 homozygous null genotypes, and the risk of ATDH. A statistically significant association between GSTM1 and GSTT1 double null genotypes, and the risk of ATDH was found (p = 0.033) between cases and controls. For GSTP1, the distribution of GG homozygous mutant genotype was significantly associated with ATDH compared with the wild and the transition A to G (AA + AG) genotypes. Double deletion of GSTM1 and GSTT1 may predispose to ATDH in a Tunisian population. Moreover, GSTP1 rs1695 (A > G) genotyping can predict susceptibility to developing ATDH. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate whether the glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) null alleles may contribute to carbamazepine-induced hepatotoxicity.Methods: A cross-sectional prospective study was conducted to identify the frequency distribution of GSTM1 and GSTT1 alleles in 129 Tunisian epileptic patients treated with carbamazepine. Null alleles were determined using a Polymerase Chain Reaction. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by standard methods.Results: Our results showed that the frequencies of GSTM1 (-) null allele and GSTT1 null (-) allele were 74.4 and 17.8% respectively. The ALT and AST levels were elevated in 46 (35.7%) and 33 (25.6%) cases. The mean values of ALT and AST were approximately 1.32 and 3.61 times higher than the upper limit of normal levels, respectively. The values of ALT and AST were significantly higher in GSTM1 (-) allele than in GSTM1 (+) (p = 10-3.and 0.004, respectively). The level of ALT was significantly higher in combination of GSTM1 (-)/T1(-) than in combined GSTM1(-)/T1(+) and combined GSTM1(+)/T1(+) (p = 0.2 and 0.03, respectively), and that of AST was significantly higher in combination of GSTM1(-)/T1(-) and in combination of GSTM1(+)/T1(-) than in combination of GSTM1(+)/T1(+) (p = 10-3 and 10-3, respectively).Conclusions: Our findings suggest that the GSTM1 (-) allele may be considered as a key factor for the development of carbamazepine-induced hepatotoxicity. Results related to GSTT (-) allele and elevation in AST levels should be considered with caution as AST may be elevated in other pathophysiological conditions. [ABSTRACT FROM AUTHOR]