H. Ghozzi

Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis.

SETTING Antituberculosis drug-induced hepatitis attributed to isoniazide (INH) is one of the most prevalent drug-induced liver injuries. INH is metabolized by hepatic N-acetyltransferase 2 (NAT2) to form hepatotoxins. AIM To evaluate whether polymorphism of the NAT2 gene was associated with antituberculosis drug-induced hepatotoxicity in Tunisian patients. METHODS A total of 66 patients with tuberculosis (TB) who received anti-TB treatment were followed prospectively. Their NAT2 genotype was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We identified three single nucleotide polymorphisms (SNPs); 481C to T (NAT2*5B), 590G to A (NAT2*6A) and 857G to A (NAT2*7B). Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. RESULTS Fourteen patients (21.2%) were diagnosed with anti-TB drug-induced hepatitis. None of the rapid acetylators-type patients have expressed serum aminotransferase elevation. Among patients with hepatotoxicity, slow acetylators-type patients had a higher risk of hepatotoxicity than intermediate acetylators (21.4% vs. 78.6%, P=0.01). Statistical analysis revealed that the frequency of a variant diplotypes, NAT2*5B/5B and NAT2*6A/6A, were significantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity (P=0.01, odds ratio [OR]=7.6 and P=0.029, OR=15, respectively). By contrast, the frequency of the rapid acetylation NAT2*4 allele was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P=0.02, OR=0.18). Moreover, 590G/G genotype was associated with decreased hepatotoxicity (P=0.01); by contrast, homozygous point mutation at position 481 and 590 were associated with a higher risk of hepatotoxicity (P=0.01). CONCLUSION Our results suggest that the slow-acetylator status of NAT2 is risk factor for INH-induced hepatotoxicity. Moreover, diplotypes, NAT2*5B/5B, NAT2*6A/6A, 481T/T and 590A/A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.

Relation entre les concentrations plasmatiques d’acide valproïque et la survenue d’une hépatotoxicité

INTRODUCTION Valproic acid (VPA) is an anticonvulsivant drug widely prescribed in the treatment of many forms of generalized epilepsy. In literature, the incidence of liver damage induced by AVP is 0.01%. It is potentialized by the combination therapy (phenobarbital, carbamazepine). Severe hepatotoxicity is rare and appears to be independent of dose and to cause a high mortality. METHODS The aim of our study was to evaluate the relationship between plasma concentrations of AVP and the occurrence of side effects especially hepatotoxicity in patients receiving high doses of AVP. RESULTS In this period, 425 plasmatic AVP monitoring were carried out in our laboratory. From 128 patients treated by high doses of AVP, only 73 were included in this study. Our work showed that adverse effects in epileptics under high doses of AVP was related to the association of the AVP with other antiepileptic in particular carbamazépine, phenobarbital and benzodiazepines rather than supra-therapeutic plasmatic concentrations of AVP. The association of AVP to major antiepileptics (carbamazépine and or phenobarbital) does not seem to generate an increase in the plasmatic concentration of AVP, which was not associated with a greater risque of adverse effects. CONCLUSION Consequently, clinical signs of liver toxicity may be present in AVP concentrations generally considered in the therapeutic range especially when used in high doses and or combined with antiepileptic drugs like phenobarbital or carbamazepine.

Risk factors for acute decompensation of chronic kidney disease in hospitalized patients in the nephrology department: a case-control study.

OBJECTIVE To investigate risk factors for acute kidney injury (AKI) in hospitalized patients with chronic kidney disease (CKD) a case-control study was conducted in the Nephrology Department of Hedi Chaker University Hospital in Sfax, Tunisia, for a 1-year period. METHODS All patients with baseline renal insufficiency hospitalized for AKI were considered as cases. They were compared with control patients with CKD. A conditional logistic regression model was used to identify independent risk factors for AKI in patients with CKD. RESULTS A total of 58 cases were compared with 114 control subjects. In multivariable models, baseline diabetes, cardiopathy disease, and exposure to non-steroidal anti-inflammatory drugs were independent risk factors for AKI in patients with CKD. However, exposure to calcium channel blockers (CCBs) was associated with decreased risk for AKI on CKD (OR = 0.4; CI 95%: 0.2 - 0.8, p = 0.007). CONCLUSIONS Patients with CKD may benefit from more aggressive cardiovascular screening to prevent episodes of acute kidney injury. More efforts should be made to prevent prescription drug abuse and to demonstrate the role of CCBs in renal protection in these patients.

Monitoring athletes’ hydration status and sleep patterns during Ramadan observance: methodological and practical considerations

Abstract During Ramadan, dehydration and disturbed sleep patterns are common, so accurate reliable methods for the assessment of hydration and sleep of athletes are necessary to maintain performance. The purpose of this review is: (1) to identify appropriate tools/methods for monitoring hydration status and sleep in sports people; (2) to discuss which of these tools/methods can be confidently used by sport scientists and trainers during Ramadan; and (3) to discuss the possible link that may exist between sleep and hydration status. Several markers of hydration status are currently used and include body mass, plasma/serum osmolality, dilution techniques, and neutron activation analysis. Used in an appropriate context, all can be indicative of the hydration status in the laboratory. In the field, monitoring hydration status in physically active individuals and athletes may be performed using a combination of body mass with some measure of urine concentration (e.g. urine osmolality, urine-specific gravity, urine color) and sensation of thirst. During Ramadan, appropriate timing of sample collection and the use of reference methods in future studies are warranted. In the field, careful use of body mass in conjunction with urine indices may be used to monitor the hydration status of subjects practicing physical activity during Ramadan. There is a need for the use of polysomnography or actigraphy for sleep assessment during Ramadan in future laboratory-based studies of athletes. However, in the field, monitoring sleep–wake patterns may be performed using actigraphy and/or the PSQI questionnaire.

Influence of age and co-medication on the steady-state pharmacokinetics of valproic acid in Tunisian patients with epilepsy

AIM Valproic acid (VPA) is a widely prescribed broad-spectrum antiepileptic drug. However, the use of VPA is complicated in clinical practice by its remarkably wide variability of pharmacokinetics. The objective of this study was to investigate the effects of demographic factors and associated therapies on steady-state plasma VPA concentrations in patients with epilepsy. METHODS This retrospective cohort study was carried out using the routine therapeutic drug monitoring (TDM) database. Stepwise logistic regression analysis was used to compare serum VPA levels in 78 epilepsy patients treated with VPA in association with at least one other drug that could have interacted with CYP2C9, CYP2C19 or UGT enzymes. RESULTS The frequency of subtherapeutic serum VPA levels was significantly increased with younger age (P<0.02), the number of co-medications (P<0.007) and use of enzyme-inducing co-medications (P<0.02). No significant correlations between VPA dose and trough plasma concentrations were found, as the latter did not increase in proportion to the dose. CONCLUSION Routine monitoring of VPA serum levels would be extremely useful in epilepsy patients in the pediatric age group and in those who require associated enzyme-inducing medications.

Oxidative Stress in Tunisian Patients With Acute Lymphoblastic Leukemia and Its Involvement in Leukemic Relapse

The aim of the present study was to evaluate in patients with acute lymphoblastic leukemia (ALL), the oxidative status and antioxidant defense and its involvement in the relapse of ALL. The plasmatic levels of malondialdehyde, advanced oxidation of protein products and reduced glutathione (GSH), and the plasmatic activities of catalase, superoxide dismutase (SOD), and glutathione peroxidase were determined in 34 patients who were newly diagnosed with ALL and compared with 92 healthy individuals. The plasmatic concentrations of malondialdehyde and advanced oxidation of protein products were higher in ALL patients than in controls and increased during chemotherapy. A decrease in glutathione peroxidase activity and an increase in catalase and SOD activities and GSH plasma levels were observed in ALL patients, as compared with sex-matched controls. Moreover, SOD activity and GSH levels were significantly correlated with the relapse of ALL patients. These data suggest the involvement of oxidative stress in acute lymphoid leukemias and leukemic relapse.

Polysaccharides extraction from Opuntia stricta and their protective effect against HepG2 cell death and hypolipidaemic effects on hyperlipidaemia rats induced by high-fat diet

Abstract The aim of this study was to analyse cytoprotective effect of polysaccharides compound from Opuntia stricta (O. stricta) cladode (POS) in vitro including its radical scavenging activities and protective effects against hypercholesterolaemia. Our results showed that glucose was the dominant monosaccharides (30.35%). Arabinose, pyranose, fructose, galactose, glucose, sorbitol, S-inositol, M-inositol, trehalose and saccharose found in this species. O. stricta polysaccharides did not cause any cytotoxic effect on HepG2 cells within the range of concentrations tested (0–400 μgml−1). Pre-treatment of HepG2 cells with POS (100 μgml−1) significantly (p < .05) protected against cytotoxicity induced by DPPH and ABTS radicals. The POS showed strong antioxidant potential in vitro. The results indicated also that POS significantly prevented hypercholesterolaemia-induced elevation of serum biomarkers and induced increase in serum lipid profile. Moreover, the hypercholesterolaemia characterised by elevated lipid peroxidation (MDA) and reduced antioxidant enzyme defences (SOD, CAT and GPx) was restored by POS treatment.