Saad Saguem

Effects of glutathione S-transferase M1 and T1 deletions on epilepsy risk among a Tunisian population

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.

Role of CYP1A2 polymorphisms in breast cancer risk in women

Cytochrome P4501A2 (CYP1A2) is a key enzyme in the etiology of breast cancer (BC). It is involved in breast carcinogen activation [aromatic (AAs) and heterocyclic amines (HAs), polycyclic aromatic hydrocarbons (PAHs)], in the production of beneficial oestrogen [2-hydroxyestrone (2-OHE1)] and in converting arachidonic acid (AAc) to epoxyeicosatrienoic acids (EETs), which have anti-inflammatory properties. Within a hospital-based case-control study, the effect of functional CYP1A2 variants [-3860G/A (rs2069514), -2467T/delT (rs3569413), -163C/A (rs762551)] and their interactions with environmental factors in BC risk was investigated. The study population included 125 BC cases and 43 non-cancer controls. Genotyping was performed in RT-PCR using Taqman assays. The gene-environment interaction was appraised using a case-only study design. We found that the -3860A variant, independently from environmental factors, as well as by interacting with fried foods (p=0.025) and indoor exposure to pollutants (p=0.050), reduced the risk of BC (p=0.025), whereas its interaction with coffee (p=0.045) increased the BC risk. This is the first study indicating that the -3860A variant, by decreasing CYP1A2 activity, modifies BC risk by interacting with environmental factors, thereby supporting the hypothesis that reduced CYP1A2 activity contributes to BC risk in different ways, for example, it may be protective by reducing the activation of pro-carcinogens such as AAs, HAs and PAHs, but would increase risk by reducing the beneficial formation of 2-OHE1 and EETs.

Relationships between pharmacokinetic parameters of carbamazepine and therapeutic response in patients with bipolar disease.

This study aimed to assess the relationship between plasma levels of carbamazepine and its active metabolite 10,11-epoxide-carbamazepine, and the therapeutic response in patients with bipolar disease. Thirteen patients were kept on a fixed individual dose of carbamazepine for 19 weeks under psychiatric care. Steady-state plasma concentrations of carbamazepine and its metabolite 10,11-epoxide-carbamazepine were measured at weeks 4, 12, and 20 by HPLC essay. Simultaneously, the psychopathologic state was assessed using the Brief Psychiatric rating scale (BPRS). Upon correlational analysis, mean BPRS scores did not correlate with the plasma levels of carbamazepine, whereas both mean plasma levels of 10, 11-epoxide-carbamazepine concentrations and 10,11-epoxide-carbamazepine to plasma carbamazepine ratio were closely correlated with mean values of BPRS scores (r = 0.80, p =10(-4), r= -0.89, p =10(-3) respectively). Optimum therapeutic response was observed among patients who had a plasma metabolite level of 1.4 μg/mL and a plasma carbamazepine concentrations of 7 μg/mL simultaneously. These results suggest that both plasma carbamazepine and 10,11-epoxide-carbamazepine levels must be fixed to achieve optimum therapeutic response. In order to reach these conditions, inhibitor drugs (such as valproic acid) or inductor drugs (such as phenobarbital) of epoxyde-hydrolase might be coadministered with the carbamazepine in order to adapt the plasma level of 10,11-epoxide-carbamazepine.

Effects of glutathione S-transferase M1 andT1 deletions on bipolar disorder risk among a Tunisian population

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.

IDENTIFICATION OF 11 POLYCYCLIC AROMATIC HYDROCARBONS AND 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE IN NARGHILE SMOKE

A high-performance liquid chromatography (HPLC) method for the identification of polycyclic aromatic hydrocarbons (PAHs) and 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in narghile smoke is presented. Combustions of 80 g of “maassel” and 20 cigarettes were first initiated by the use of 3 charcoal disks and secondly by an electrical heater in order to study the role of charcoal in the production of PAH in the smoke. PAHs present in the particle smoke were extracted with toluene. This toluene fraction was passed through a silica cartridge and evaporated. The result was analyzed by HPLC coupled with fluorescence detector. In narghile smoke from charcoal combustion, our results show the presence of seven PAHs: phenanthrene, antracene, fluoranthene, chrysene, benzo(a)pyrene, benzo(b)fluoranthene, and benzo(k)fluoranthene, whereas in the narghile smoke from electrical heater only four of these PAHs were detected: phenanthrene, antracene, fluoranthene, and chrysene. Chloroform extractions of narghile smoke and cigarettes smoke from charcoal combustion were also performed in order to detect the presence of NNK. Chloroform samples were then passed through a cation exchange, and the final extracts were analyzed by HPLC using UV detectors. Although the NNK was present in cigarette smoke, this nitrosamine dropped to below detectable limit in narghile smoke.

The relationship between pharmacokinetic parameters of carbamazepine and therapeutic response in epileptic patients

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.

Thorax and Abdomen Motion Analysis in Patients with Obstructive Diseases

Objective: We evaluated changes in bronchoconstriction by a new approach based on respiratory inductive plethysmography (RIP) signal analysis. Methods: Thoracic and abdominal motions were recorded (5 min) by uncalibrated RIP in 44 adult subjects with a diagnosis of moderate bronchial obstruction (Obstructive group) and 50 healthy adult controls (Healthy group). In the Obstructive group, two series of measurements were performed before (Obstructive PRE) and after (Obstructive POST) a bronchodilation protocol. Airway resistance (Raw) and lung function data (forced vital capacity (FVC), forced expiratory volume in one second (FEV1 ) and FEV1 /FVC) were measured with a body plethysmograph. A breath-bybreath analysis was performed to calculate distances between normalized thorax and abdomen RIP signals and a mean distance (D) was calculated for each recording. Results: D and Raw were higher in the Obstructive group than in the Healthy group in both PRE and POST conditions. Both D and Raw significantly decreased after bronchodilation in the Obstructive group. D and Raw were also positively and significantly correlated in the Obstructive group in both PRE and POST conditions. Conclusion: D, as calculated from signals recorded by RIP, appears to be a useful non-invasive parameter for continuous monitoring of changes in bronchoconstriction.

Bioavailability and metabolism of rosemary infusion polyphenols using Caco-2 and HepG2 cell model systems

BACKGROUND Rosmarinus officinalis is an aromatic plant used in folk medicine as a result of the therapeutic properties associated with its phenolic composition, being rich in rosmarinic acid (RA) and caffeic acid (CA). To better understand the bioactivity of these compounds, their absorption and metabolism were assessed in human Caco-2 and HepG2 cells, as small intestine and liver models, respectively, using RA and CA standards, as well as a rosemary infusion and ferulic acid (FA). RESULTS Test compounds were partially up-taken and metabolized by Caco-2 and HepG2 cells, although a higher metabolization rate was observed after hepatic incubation compared to intestinal incubation. CA was the compound best absorbed followed by RA and FA, showing metabolites percentages of 30.4%, 11.8% and 4.4% in Caco-2 and 34.3%, 10.3% and 3.2% in HepG2 cells, respectively. RA in the rosemary infusion showed improved bioavailability compared to pure RA. Methyl derivatives were the main metabolites detected for CA and RA after intestinal and hepatic metabolism, followed by methyl-glucuronidates and glucuronidates. RA was also minimally hydrolyzed into CA, whereas FA only was glucuronidated. Rosemary polyphenols followed the same biotransformation pathways as the standards. In addition, phase II derivatives of luteolin were observed. CONCLUSION Rosemary polyphenols are partially metabolized in both the intestine and liver.

Metal–Organic Frameworks as Efficient Oral Detoxifying Agents

Poisoning and accidental oral intoxication are major health problems worldwide. Considering the insufficient efficacy of the currently available detoxification treatments, a pioneering oral detoxifying adsorbent agent based on a single biocompatible metal-organic framework (MOF) is here proposed for the efficient decontamination of drugs commonly implicated in accidental or voluntary poisoning. Furthermore, the in vivo toxicity and biodistribution of a MOF via oral administration have been investigated for the first time. Orally administered upon a salicylate overdose, this MOF is able to reduce the salicylate gastrointestinal absorption and toxicity more than 40-fold (avoiding histological damage) while exhibiting exceptional gastrointestinal stability (<9% degradation), poor intestinal permeation, and safety.

Glutathione S-transferase M1 and T1 polymorphisms and the risk of mild hepatotoxicity induced by carbamazepine in a tunisian population study

BackgroundThe 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.MethodsA 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.ResultsOur 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).ConclusionsOur 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.