Tacrolimus trough level and oxidative stress in Tunisian kidney transplanted patients.

BACKGROUND: The effect of tacrolimus (TAC) on oxidative stress after kidney transplantation (KT) is unclear. This study aimed to evaluate the influence of TAC trough levels of oxidative stress status in Tunisian KT patients during the post-transplantation period (PTP). METHODS: A prospective study including 90 KT patients was performed. TAC whole-blood concentrations were measured by the microparticle enzyme immunoassay method and adjusted according to the target range. Plasma levels of oxidants (malondialdehyde (MDA) and advanced oxidation protein products (AOPP)) and antioxidants (ascorbic acid, glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD)) were measured using spectrophotometry. The subjects were subdivided according to PTP into three groups: patients with early, intermediate, and late PT. According to the TAC level, they were subdivided into LL-TAC, NL-TAC, and HL-TAC groups. RESULTS: A decrease in MDA levels, SOD activity, and an increase in GSH levels and GPx activity were observed in patients with late PT compared to those with early and intermediate PT (p < 0.05). Patients with LL-TAC had lower MDA levels and higher GSH levels and GPx activity compared with the NL-TAC and HL-TAC groups (p < 0.05). CONCLUSION: Our results have shown that in KT patients, despite the recovery of kidney function, the TAC reduced but did not normalize oxidative stress levels in long-term therapy, and the TAC effect significantly depends on the concentration used.

[Multiple drug hypersensitivity in patients with an allergy to antibiotics]. / Hypersensibilité médicamenteuse multiple chez des patients ayant une allergie aux antibiotiques.

INTRODUCTION: Multiple drug hypersensitivity (MDHS) is defined as confirmed drug hypersensitivity (DHS) to 2 or more drugs that are not chemically related. The objective of our study is to describe the cases of MDHS with antibiotics notified to the regional pharmacovigilance service (SRPV) of Sfax (Tunisia). METHODS: Our study is of a descriptive cross-sectional type, focusing on patients who consulted at the SRPV in Sfax during the period between 2013 and 2020 and who presented at least two episodes of DHS occurring at different times (at least one month apart). RESULTS: In our study, we included 29 patients (18 women and 11 men with a mean age of 59 years) who presented 69 sequential MDHS reactions documented either by a positive re-administration in 29 cases or by allergological exploration in 20 case, or by a highly suggestive clinical history in 20 cases. The frequency of MDHS was 1.13%. The drugs involved in the occurrence of these 69 DHS reactions were antibiotics in 55 cases (80%), antiepileptics in 6 cases (9%), NSAIDs in 4 cases (6%) and other drugs in 4 cases (6%) (one case with allopurinol, one case with strontium ranelate and two cases with gliclazide). CONCLUSION: MDHS pose a real problem of therapeutic management. Indeed, these reactions can lead to a difficult choice of drugs with the impossibility of prescribing optimal first-line therapies.

Overexpression of P-glycoprotein and resistance to Imatinib in chronic myeloid leukemia patients.

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.

Relationship of oxidative stress in the resistance to imatinib in Tunisian patients with chronic myeloid leukemia: A retrospective study.

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 < .001; P = .01). Higher catalase (CAT) activity (P = .048) and lower superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, reduced Glutathione (GSH) and vitamin C levels were found in CML patients (P < .001). The comparison between the resistant vs no-resistant CML patients revealed higher MDA level (P = .02) and CAT and SOD activities in IM-resistant patients (P = .04, P = .03). GPx activity was reduced (P = .04). Furthermore, increased mean ratio of MDA/GSH, MDA/GPx, and SOD/(GPx + CAT) was found in IM-resistant patients as compared with no-resistant (P = .01, P = .01, P = .035). The mean ratio of GPx/GSH in the IM-resistant CML patients was lower than in IM no-resistant one (P = .039). For IM-resistant patients, we found negative correlation between MDA level and the ratio SOD/(CAT + GPx) (r = -0.46, P = .002); and positive correlation between SOD and (CAT + GPx) activities (r = 0.38, P = .06) and between GSH level and GPx activity (r = 0.53, P = .01). CONCLUSIONS: Our results have shown a highly disturbed oxidative profile in IM-resistant CML patients as compared to no-resistant. The H2 O2 has a key role in the resistance to IM treatment.

Use of MTHFR C677T polymorphism and plasma pharmacokinetics to predict methotrexate toxicity in patients with acute lymphoblastic leukemia.

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 (ß = 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 (ß = 0.5; R2 = 0.38; p = 0.001) and CT 677 MTHFR genotype (ß = 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.

Potassium Bromate-induced Changes in the Adult Mouse Cerebellum Are Ameliorated by Vanillin.

OBJECTIVE: The current study aimed to elucidate the effect of vanillin on behavioral changes, oxidative stress, and histopathological changes induced by potassium bromate (KBrO3), an environmental pollutant, in the cerebellum of adult mice. METHODS: The animals were divided into four groups: group 1 served as a control, group 2 received KBrO3, group 3 received KBrO3 and vanillin, and group 4 received only vanillin. We then measured behavioral changes, oxidative stress, and molecular and histological changes in the cerebellum. RESULTS: We observed significant behavioral changes in KBrO3-exposed mice. When investigating redox homeostasis in the cerebellum, we found that mice treated with KBrO3 had increased lipid peroxidation and protein oxidation in the cerebellum. These effects were accompanied by decreased Na+-K+ and Mg2+ ATPase activity and antioxidant enzyme gene expression when compared to the control group. Additionally, there was a significant increase in cytokine gene expression in KBrO3-treated mice. Microscopy revealed that KBrO3 intoxication resulted in numerous degenerative changes in the cerebellum that were substantially ameliorated by vanillin supplementation. Co-administration of vanillin blocked the biochemical and molecular anomalies induced by KBrO3. CONCLUSION: Our results demonstrate that vanillin is a potential therapeutic agent for oxidative stress associated with neurodegenerative diseases.

Modulatory effects of quercetin on liver histopathological, biochemical, hematological, oxidative stress and DNA alterations in rats exposed to graded doses of score 250.

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.

Optimization of therapeutic drug monitoring of vancomycin in patients with chronic hemodialysis
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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.
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[Epicutaneous patch testing in delayed drug hypersensitivity reactions induced by antiepileptic drugs]. / Place du patch-test dans le diagnostic des réactions d'hypersensibilités retardées induites par les antiépileptiques.

INTRODUCTION: Antiepileptic drugs are widely used and are associated with numerous side effects including skin eruptions. Epicutaneous tests have been used with variable success in skin drug reactions. The purpose of this study was to evaluate the profitability of epicutaneous tests in delayed hypersensitivity reactions induced by antiepileptic drugs. METHODS: We analyzed all cases of allergic skin reactions to antiepileptic drugs notified in regional pharmacovigilance center of Sfax (Tunisia) between June 1, 2014 and April 30, 2016. The imputation score, determined using the French imputation method, should be at least doubtful. Patch-tests were performed in accordance with the general Europen network on Drug Allergy/European Academy of Allergy and Clinical Immunology (ENDA/EAACI) guidelines. Patch-tests were read according to the generally accepted criteria of the International contact dermatitis research group (ICDRG). RESULTS: In our study, 20 patients were included, among which 23 events were observed. The drug involved in delayed hypersensitivity reactions was carbamazepine in 11 cases, phenobarbital in 10 cases and valproic acid in 4 cases. The clinical reactions caused by the drug were classified as maculopapular exanthema (11 cases), DRESS syndrome (6 cases), Stevens-Johnson syndrome (2 cases), fixed drug eruption (2 cases) and erythroderma (2 cases). Patch-tests were positive in 19 patients (95 %). Cross-reactivity between antiepileptic drugs was observed in 4 cases: between valproic acid and carbamazepine in 2 cases between valproic acid and phenobarbital in 1 case and between phenobarbital and carbamazepine in 1 case. CONCLUSION: In this study, patch testing was a safe and useful method in confirming the culprit drug in delayed hypersensitivity reactions induced by antiepileptic drugs.

Bioequivalence evaluation of glibenclamide 5-mg tablets: diabenil® and daonil® (in 24 healthy volunteers).

BACKGROUND: Prescription of generic products is a way to reduce health expense. Bioequivalence is the most appropriate procedure to evaluate the quality and therapeutic efficacy of a generic product. Generic prescriptions are a strategic choice in Tunisia. OBJECTIVE: We expose in this work, a bioequivalence study witch compare a generic (test) product: DIABENIL* manufactured by a Tunisian pharmaceutical industry Dar Essaidaly to the innovative (reference) product: DAONIL* of Aventis pharma laboratories. METHODS: The bioequivalence of two glibenclamide 5-mg tablets was determined in healthy human, adult volunteers after a single dose in a randomized cross-over in double blind study. Test and reference were administered to twenty-four healthy volunteers of both sexes after overnight fasting. In total, 15 Blood samples were collected before and following the administration of the drug. Serum concentrations of glibenclamide were determined by validated HPLC method. The pharmacokinetic parameters AUC0t, AUC0 , Cmax and tmax were tested for bioequivalence. RESULTS: All parameters showed bioequivalence between both formulations as their confidence intervals were within the bioequivalence acceptable range of 0.80-1.25 limits. CONCLUSION: We conclude that the two formulations exhibited comparable pharmacokinetic profiles and that the two products can be considered interchangeable in medical practice.