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Background The P‐glycoprotein (P‐gp) is one of the mechanisms of Imatinib (IM) resistance in chronic myeloid leukemia (CML). P‐gp has been identified as an efflux pump involved in releasing of IM outside CML cells. To date, the P‐gp involvement in the IM resistance development was not completely understood. Therefore, the present study aimed at measuring the P‐gp expression level on lymphocytes from Tunisian patients with CML and correlating this level with a molecular response to IM. Method The expression of P‐gp on peripheral blood lymphocytes from 59 Tunisian patients with CML (27 IM responder patients vs 32 IM non‐responder patients) was evaluated by flow cytometry. Result Our finding showed significantly positive expression of P‐gp in the lymphocytes from the IM non‐responder group when compared to the IM‐responder group (P = .001). In IM non‐responder CML patients, the comparison between CCyR achievers and non‐achievers showed a high mean fluorescence intensity (MFI) of P‐gp expression in patients who did not achieve their CCyR (P = .001). The comparison between patients with primary and secondary resistance to IM showed an increasing MFI value in patients with primary resistance to IM (P = .001). Besides, the comparison between nilotinib‐treated and dasatinib‐treated patients proved a high value of MFI in nilotinib‐treated patients (P = .001). Conclusion The overexpression of P‐gp on lymphocytes has significantly correlated with the failed molecular response to IM in patients with CML.

Resume Introduction Les reactions d’hypersensibilites retardees (HSR) sont parmi les effets indesirables les plus frequents des antiepileptiques. Peu d’etude ont evalue la sensibilite des patch-tests dans le diagnostic des reactions d’HSR aux antiepileptiques. L’objectif de notre etude est d’evaluer la place du patch-test dans le diagnostic positif d’une reaction d’HSR induite par les antiepileptiques. Methodes A partir de la base de donnees de pharmacovigilance du centre regional de pharmacovigilance (CRPV) de Sfax, nous avons inclus des cas d’effets indesirables cutanes de type retarde contemporains a une prise d’un medicament antiepileptique notifies entre le 1 juin 2014 et le 30 avril 2016. Le score d’imputabilite de ces medicaments antiepileptiques, evalue selon la methode francaise d’imputabilite, a ete au moins douteux. Les tests epicutanes ont ete realises en conformite avec les recommandations de l’European Network on Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI). L’interpretation des resultats a ete faite selon les normes adoptees par l’International Contact Dermatitis Research Group (ICDRG). Resultats Dans notre etude, 20 patients ont ete inclus et 23 evenements ont ete observes. Trois antiepileptiques ont ete impliques dans la survenue des reactions cutanees : la carbamazepine dans 11 cas, le phenobarbital dans 10 cas et l’acide valproique dans 4 cas. L’exantheme maculopapuleux a ete observe dans 11 cas, le drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome dans 6 cas, le syndrome de Steven-Johnson dans 2 cas, l’erytheme pigmente fixe dans 2 cas et l’erythrodermie dans 2 cas. Les patch-tests ont ete positifs chez 19 patients (95 %). Une reactivite croisee entre les medicaments antiepileptiques a ete observee dans 4 cas. Cette reactivite a ete entre l’acide valproique et la carbamazepine dans 2 cas, entre l’acide valproique et le phenobarbital dans 1 cas et entre le phenobarbital et la carbamazepine dans 1 cas. Conclusion La realisation des patch-tests s’avere complementaire a l’enquete de pharmacovigilance dans l’identification de l’agent causal dans les reactions d’HSR aux antiepileptiques.

Background This work aimed to evaluate oxidative stress in chronic myeloid leukemia (CML) patients treated with tunisian (IM) vs controls and in CML patients with resistance to IM vs patients without resistance to IM. Methods The study included 40 CML patients and 34 controls. Of 40 patients with CML, 26 patients were developed in resistance to IM. The oxidant/antioxidant markers were evaluated by spectrophotometric methods for all used samples. Results For CML patients, increased malondialdehyde (MDA) and advanced oxidation protein products (AOPP) levels were found compared to controls (P, High malondialdehyde and advanced oxidation of protein products levels were evidenced in chronic myeloid leukemia. Disturbed enzymatic and no enzymatic defenses were found in plasma of chronic myeloid leukemia patients. Patients with resistance to imatinib revealed more pronounced oxidant/antioxidant markers than no‐resistant chronic myeloid leukemia patients. Hydrogen peroxide was incriminated in the disturbed oxidative profile in chronic myeloid leukemia patients with resistance to imatinib.

Background Methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy, but it is associated with serious toxicities in a considerable number of patients. Objectives The aim of the current study was to determine which variables were associated with MTX toxicity in children, adolescents and young adults with ALL. Material and methods In this prospective study, 35 patients with newly diagnosed ALL, treated according to the 58951 European Organization for Research and Treatment of Cancer - Children's Leukemia Group (EORTC-CLG) protocol, were prospectively enrolled. Toxicity data was collected objectively after each high-dose methotrexate (HD-MTX) course. The risk factors of MTX toxicity were determined using multiple linear regression analysis, with age, gender, immunophenotype, risk group, plasma MTX levels, plasma homocysteine (HCY) levels, and MTHFR C677T included as independent variables. Results Twenty-five (71.4%) patients experienced toxicity on at least 1 course of HD-MTX. In the univariate linear regression, the global toxicity score was associated with a significant rise in plasma HCY concentrations within 48 h after MTX administration (β = 0.4; R2 = 0.12; p = 0.02). In the multiple regression model, the global toxicity score was significantly associated with a higher MTX plasma levels at 48 h (β = 0.5; R2 = 0.38; p = 0.001) and CT 677 MTHFR genotype (β = 0.3; R2 = 0.38; p = 0.01). Conclusions Routine monitoring of plasma MTX concentrations is essential to detect patients at a high risk of MTX toxicity. MTHFR C677T genotyping may be useful for predicting MTX toxicity.

Purpose To validate a simplified vancomycin monitoring algorithm in patients on chronic hemodialysis who required intravenous vancomycin for at least 3 weeks. Materials and methods In this prospective study, all hemodialysis patients who were admitted between April 1, 2013, and March 31, 2015, in our unit for suspected or confirmed methicillin-resistant Staphylococcus aureus infection that required vancomycin were enrolled. All patients were categorized into two groups. In group 1 (standard vancomycin dosing algorithm), the maintenance doses of vancomycin were adjusted according to the pre-hemodialysis vancomycin concentrations determined before each hemodialysis session. In group 2 (simplified vancomycin dosing algorithm), pre-dialysis vancomycin trough levels were taken before the 2nd and the 6th session of hemodialysis. Maintenance doses were adjusted according to the residual concentrations of vancomycin. Results A total of 101 blood samples were collected, the average plasma concentration of vancomycin was 13.1 ± 3.8 µg/mL. 64 (63.4%) levels fell out of the therapeutic range. Seven (6.9%) of these exceeded the therapeutic range and 30 (29.7%) were lower. After the loading dose, the average plasma concentration was 11.2 ± 3.4 µg/mL. There were no statistically significant differences between the two groups with respect to the average plasma concentration of vancomycin and the proportion of vancomycin trough levels in the target range. Conclusion The vancomycin dosing algorithm using limited concentration monitoring for hemodialysis patients achieved drug concentrations comparable to those found with more frequent monitoring and resulted in significant cost savings. .

This study investigated the morphological, biochemical and molecular aspects of liver injury in rats after the exposure to difenoconazole and the protective effects of quercetin against hepatotoxicity and genotoxicity induced by this fungicide. Rats were given graded doses of difenoconazole associated or not to quercetin daily for 20 days. Our results showed a significant increase in PLT (platelets) and WBC (white blood cells) in rats treated with higher doses of difenoconazole (1/38 and 1/9 of LD50). However, a significant decrease in Hb (hemoglobin) rate and RBC (red blood cells) number in rats treated with higher doses of difenoconazole (1/38 and 1/9 of LD50) was obtained. Besides, difenoconazole treatment caused an increase in hepatic enzyme activities of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Difenoconazole increased the levels of malondialdehyde (MDA) and advanced oxidation protein products (AOPPs), and decreased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities and vitamin C levels in liver tissues compared to the control group. We also noted a degradation of nucleic acids, testifying difenoconazole genotoxicity. Changes in hepatic tissues were confirmed by histological findings. Co-administration of quercetin (20 mg/kg) improved hematological and biochemical parameters and showed a significant liver protective effect by decreasing MDA levels and producing advanced oxidation protein, along with increased antioxidative enzyme activities and vitamin C levels. Results were confirmed by the improvement of histological impairments. Thus, it appears that quercetin was effective in preventing acute liver injury induced by exposure to difenoconazole.