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Resume Objectifs Evaluer les modalites d’administration des antiepileptiques (AED) par sonde nasogastrique (SNG) chez des comateux et dresser des recommandations. Methodes Etude des connaissances, attitudes et pratiques concernant les modalites d’administration des AED par SNG (10 questions) pour des infirmiers en reanimation. Resultats Les infirmiers ont repondu comme suit : (1) pour 60 %, la SNG est en silicone et pour 4 % en PVC ; (2) changement de la SNG tous les 5 ± 3 jours ; (3) position de la SNG controlee ; (4) SNG rincee apres chaque utilisation (91 %) ; (5) la forme solide d’AED est la plus utilisee en reanimation ; (6) AED a broyer (100 %) ; (7) puis melange a l’eau de robinet (93 %) ; (8) AED melange aux medicaments associes (62 %) ; (9) AED melange a l’alimentation enterale (56 %) ; et (10) besoin d’une formation sur les modalites d’administration des AED par SNG (62 %). Conclusion La prise en charge du patient comateux sous AED necessite une maitrise des modalites d’administration par SNG.

Introduction. Effective prevention strategies require specific actions during the different phases of ischemia-reperfusion (I-R) injury. The objective of our study is to evaluate the effect of aqueous extract of Hypericum humifusum leaves (HHL) on liver I-R model in Rat. Material and methods. Animals were subjected to 90 min of hepatic ischemia followed by reperfusion (120 min). HHL extract (25 mg/mL/kg) was injected 15 min before reperfusion. To evaluate the effect of HHL extract on I-R, we have monitored transaminases levels, Malondialdehyde (MDA) concentration, histological lesions (apoptosis and necrosis) and compared the results to a reference oxidant vitamin E. Results. The determination of total phenol extracts of HHL was 59.91 ± 0.35 mg of Gallic Acid/g dry plant material with higher antioxidant activity (91.73% ± 1.67) compared to vitamin E (87.42%). Using aqueous extract of HHL, we noted a significant decrease of AST and ALT [1129 UI (585/1995) and 768 UI (335/1375)] compared to no-treated group [5,585.5 UI (5,035/12,070) and 8,099.5 UI (5,040/12,326)] as a decrease in MDA content [85.7% protection (50.9/91.5)]. HHL extract reduce the damage induced by I-R of 48.7% (27/48.7) and 96.1% (95.7/96.5) for necrosis and apoptosis lesions respectively. Conclusion. HHL aqueous extract have potential to protect liver from the damage effect induced by I-R better than vitamin E solution.

The use of cyclosporin in nephrotic syndrome can be considered in cortico-resistance or cortico-dependence. Cyclosporin is an immunosuppressant with a narrow therapeutic range and large pharmacokinetics variability justifying its therapeutic drug monitoring (TDM). The aim of this study was to evaluate the TDM of cyclosporin by the measurement of AUC0-12h in patients with nephrotic syndrome and to study the correlations between the AUC0-12h and the different blood concentrations of cyclosporin. It is a retrospective study from 2009 to 2016. TDM of cyclosporin was carrying out by ARCHITECT®. Determination of the AUC0-12h was made from three samples taken at T0, T60min and T180min obtained by a model of population pharmacokinetics of cyclosporin. A total of 20 patients were evaluated (29 abbreviated kinetics). The median AUC0-12h was 4.76 mg*h/L. Considering the target 5 mg*h/L during the first 6 months, 6 AUC0-12h were sub-therapeutic and 5 supra-therapeutic, no AUC0-12h was in the therapeutic range. Considering the 3 mg*h/L as a target during the following months, 13 AUC0-12h among 18 were supra-therapeutic. A correlation coefficient between the AUC0-12h of cyclosporin and C0 was 0.798. Correlation between AUC0-12h and C2h was 0.909. The median C2h found in our work was 878 ng / mL during the first six months versus 1039 ng / mL in the following months. Our patients are overexposed to cyclosporin and TDM of this drug by determination of AUC0-12h or by C2h would be more interesting than TDM by C0. TDM allows a better individual dose adjustment to avoid especially toxicity of cyclosporin.

Infliximab (IFX) is a chimeric monoclonal antibody which has proven its efficacy in the treatment of inflammatory diseases. However, its efficacy can be limited by the development of anti-IFX antibodies (ATI) resulting in a therapeutic failure of IFX. ATI plasmatic monitoring is then indicated to optimize IFX treatment. The aim of this study was to validate an ELISA (enzyme linked immuno sorbent assay) method of ATI plasmatic monitoring. Methods Assessment of performance was based on the study of correlation and concordance (Bland Altman method) of the absorbances measured by the two readers. ELISA kit validation was made by calculating the accuracy and the exactitude. Results We collected 23 samples. Their mean age was 46 years and sex ratio M/W was 0.92. In nine cases, plasmatic AIT were positive and in 14 cases, they were not detected. Correlation between the two readers showed a correlation coefficient r2 of 99.95%. Concordance limits of the confidence interval 95% were [-112.768%-41.425%] with a bias of -35.671%. Repeatability and reproductibility were checked by a positive control and coefficients of variation were respectively of 5.574% and 14.184%. Limits of detection and quantification were respectively of 0.046 and 0.086. The positive predictive value was 0.5 and the negative predictive value was 1. The sensitivity was 100% and the specificity was 83%. Conclusion The assessment of the performance of the tested microplate reader and the validation of the tested ELISA kit showed good results allowing ATI routine measurement to optimize therapeutic management of patients treated by IFX.

In this study, we aimed to analyze the trough plasmatic levels (C0) of the antiepileptic drugs (AED) administered by nasogastric tubes (NGT) in comatose patients and to draw up recommendations for therapeutic drug monitoring (TDM) and for the modalities of AED administration by NGT.We conducted a retrospective study on comatose patients addressed over six years and 10 months in Clinical Pharmacology for C0 measurement of AED administered by NGT.In this study, the sex-ratio was 2.38 (44 patients). The patients' median age was 24 years. There was 14.5% of children (≤16 years). Among the 103 samples, C0 measurement concerned valproic acid in 57%, phenobarbital in 28 % and carbamazepine in 15%. Two AED or more were associated in 42% of patients. AED were associated to other drugs in 85% of cases. The AED C0 were subtherapeutic in 71% of cases. C0/Dp lower than recommanded in 65 %. In these samples, 55% presented at least one drug association with the concerned AED. In 45% of the cases, there was no drug association but a non-respect of modalities of AED administration by NGT in patients. The drug monitoring is a useful tool to assess drug-drug interactions and to control modalities of AED administration in comatose patients.

Learning transfer, in medical teaching, remains an essential question and optimizing it is the main preoccupation of every trainer in medical sciences. Some learning methods showed their efficacy as the contextualized learning in the framework of a professional activity or in a situation recalling it in a realistic manner.To describe steps of planning and progress of a session of clarification, illustration, application et participation (CIAP) of pharmacology teaching students from second cycle of medical studies (DCEM) and to assess the session.We performed a descriptive transversal study in April 2017 in the Faculty of Medicine of Tunis. Our work was composed of two parts. The first part consisted in a description of the preparation and the progress of the CIAP session entitled antiepileptic drugs, which is comprised in the pharmacology teaching of the certificate of Neurology to the students of DCEM. The second part consisted in an assessment of knowledge acquisition and the progress of the session by the students.We proceeded to a planning of the session which resulted in a contextualized teaching and induced an active participation and an interactivity of the students. Comparison of the results of the pretest and the posttest showed a statistically significant difference in terms of good responses. The assessment of the session progress was good.Our study demonstrated the feasibility of a session of contextualized teaching session or CIAP of pharmacology and its input in terms of knowledge to the students.

Clopidogrel (clopi) is a prodrug widely prescribed in the management of coronary artery disease and requires the intervention of hepatic cytochrome P450 2C19 (CYP2C19) for its activation. However, there is interindividual variability in response to clopi despite the use of recommended doses. Thus, the studies have highlighted the effect of the CYP2C19 gene polymorphism or Cyp2C19 gene on the response to clopi and particularly Cyp2C19 * 2 which may be associated with an increased risk of major cardiovascular events or MACE.To evaluate the effect of Cyp2C19 * 2 polymorphism on MACE occurrence and hemorrhagic complications in patients treated with clopi.We carried out a descriptive longitudinal study including 71 patients placed under clopi for a minimum duration of one month. Genotyping of the Cyp2C19 allele was performed by conventional polymerase chain reaction (PCR). After a follow-up period of 495 ± 183 days, we performed a statistical analysis to evaluate the association between the Cyp2C19 * 2 polymorphism and the occurrence of MACE or hemorrhagic complications.Among our patients, 51% had an angioplasty, 42% medical treatment and 7% a coronary artery bypass surgery. In our study population, 52% were heterozygous (HTZ), 28% homozygous (HMZ) healthy * 1 / * 1 and 20% HMZ had the loss of function allele * 2 / * 2. The allelic frequency of Cyp2C19 * 2 was 46%. Follow-up mean duration was of 495 ± 183 days. During this period, the prevalence of MACE was 11% and that of hemorrhagic complications was 13%. In our study, we did not observe a significant association between the occurrence of MACE or hemorrhagic complications with the genotype carrying the Cyp2C19 * 2 allele.Among patients treated with clopi, wearing a Cyp2C19 * 2 function loss allele didn't seem to be associated with a significantly higher risk of MACE, nor a significantly lower risk of hemorragic complications. This suggests the necessity of larger studies.

Resume Introduction L’acide valproique (VPA) est un antiepileptique a large spectre. Face a sa variabilite pharmacocinetique et a l’influence de facteurs intrinseques et extrinseques tels que l’observance therapeutique, le suivi therapeutique pharmacologique (STP) du VPA est indique chez l’enfant. Le but de ce travail est d’identifier l’effet de l’observance et du niveau economique (NE) sur les concentrations plasmatiques residuelles (C0) de VPA en milieu pediatrique et sur le rythme des crises epileptiques. Materiel et methodes Etude prospective sur un an (aout 2008-aout 2009) ayant concerne des enfants (âge ≤ 15 ans), regulierement traites par du VPA, qui ont eu un STP du VPA. Ainsi, 276 prelevements provenant de 238 enfants sous VPA ont ete collectes. Les enfants ont ete repartis en 2 groupes comme suit : le groupe 1 (G1) presentant une bonne observance et un questionnaire fiable et le groupe 2 (G2) ayant une mauvaise observance et/ou un questionnaire non fiable. Pour l’evaluation de la variabilite interindividuelle, nous avons correle la C0 a la dose ponderale. Ces groupes 1 et 2 ont ete repartis chacun en fonction de la C0 de VPA. De plus, les patients ont ete repartis en fonction du niveau economique bas, moyen ou eleve. Resultats Le sex ratio garcons/filles etait de 1,3. La mediane d’âge etait de 5 ans +/- 3,9. La moyenne des C0 de VPA etait de 62 μg/mL [0,12-131 μg/mL]. Les C0 etaient dans l’intervalle therapeutique (IT) dans 62 %. Les effets indesirables ont ete notes chez 4,2 % des enfants. G1 representait 70 % des enfants et G2, 30 %. Les C0 etaient dans l’IT dans 67 % du G1 et 51 % du G2 avec une difference significative (p = 0,02). Il n’y avait pas de difference significative dans la repartition des C0 en fonction du NE. Il n’y avait pas de correlation entre la C0 et la dose ponderale. Les crises epileptiques etaient plus espacees chez les enfants ayant des C0 dans l’IT que ceux ayant des C0 en dehors de l’IT (p = 0,002) et dans G1 que dans G2 (p = 0,03). Conclusions L’observance au VPA doit se faire de facon appropriee afin d’optimiser le role du STP. Une bonne observance et une C0 therapeutique permettent de mieux controler les crises epileptiques.

Resume Introduction La toxicite a la lidocaine est d’apparition rapide et directement correlee a ses concentrations plasmatiques. Observation Nous rapportons un cas d’une intoxication neurologique tardive suite a l’instillation de lidocaine lors d’une bronchoscopie. Il s’agissait d’une patiente ayant une bronchiolite obliterante et ayant effectue une bronchoscopie dans le cadre du diagnostic etiologique. La patiente a eu plusieurs instillations de Xylocaine® 2 % (lidocaine). Trois heures et demie apres, elle a presente une crise convulsive tonicoclonique. La patiente a reconvulse 7 heures apres la premiere crise. Le dosage plasmatique de la lidocaine a montre une concentration toxique a H3,5 = 18,32 μg/mL avec une diminution importante de la concentration 24 heures apres. Conclusion Le passage systemique de la lidocaine explique la survenue de cette toxicite neurologique. Notre observation attire l’attention sur la possibilite de survenue de complications avec des doses importantes de lidocaine administrees par instillation. Ainsi, en cas de non respect de la dose de lidocaine, il serait indispensable de surveiller plus attentivement et plus longtemps tous les malades et particulierement ceux ayant une pathologie pulmonaire fibrosante afin d’eviter une eventuelle toxicite tardive.

To evaluate the modalities of administration of antiepileptic drugs (AED) with nasogastric tube (NGT) by nurses and to draw up recommendations.Our study consisted on investigating the modalities of administration of AED's with NGT by nurses during four months. We prepared 10 questions including demographic information. Participation was voluntary and anonymous. The questionnaire was distributed in seven intensive care departments after authorization of each head of the department. Thus, 45 nurses were included.Nurses sex ratio was 1.5 and mean age was 31 years (25 to 37 years). Among the nurses, 60% mentioned that the NGT were silicone made and 4% that they were PVC made. The mean duration before replacing the NGT was thought to be 5±3 days. Among the nurses, 91% affirmed to clear the NGT after each use. All the nurses had agreed that the solid form is the most commonly used pharmaceutical form in the NGT. AED were associated with the enteral feeding solution in 56%. The AED should be crushed before administration for 98% of the nurses even in case of polymedication. Among them, 62% recommended to crush all of the associated drugs together. Before introducing the AED into the NGT, 93% of the nurses reported mixing with tap water. We have noticed that 62% of nurses felt the need to improve their knowledge AED administration with NGT.To optimize AED therapy, modalities of administration by NGT in epileptic comatose patients should be enhanced.

The present work aims to investigate whether the pharmacokinetics of the active metabolite mycophenolic acid (MPA) varies according to the circadian dosing-time of mycophenolate mofetil (MMF). A total of 180 male Wistar rats aged 8 weeks and synchronized for 3 weeks to 12 h light and 12 h dark were used. A single dose of 200 mg/kg of MMF was administrated in rats by i.p route at either of the four different circadian stages (1, 7, 13, and 19 Hours After Light Onset, HALO) (45 rats/circadian time). At each circadian stage, blood samples were collected at 5, 10, 15, 20, 30 min, 1 h, 1 h 30 min, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h and 24 h following drug injection. Plasma MPA concentrations were analyzed for each sample using a validated high-performance liquid chromatography (RP-HPLC) method. Tmax of MPA remained similar whatever the circadian time of injection mean Tmax=30 min). However, the peak of plasma concentration Cmax varied significantly according to the circadian dosing-time. Maximum and minimum Cmax were obtained when MMF was injected at 7 HALO (69.1 μg/ml) and at 19 HALO (22.7 ± 1.74 μg/ml) respectively. AUC0-24 varied significantly according to the circadian-time of injection (166.33 ± 10.54 mg h/L at 7 HALO vs 80.27 ± 2.33 mg h/L at 19 HALO) (p

Objectives: This work is aimed on the study of doxorubicin cardiotoxicity and hepatotoxicity in rats and the evaluation of protective effect of trimetazidine administrated concomitantly with doxorubicin for 3 days. Materials and Methods: Male Wistar rats used were subjected to different types of treatment (3 days); A: Control, B: Doxorubicin treatment and C: Trimetazidine and doxorubicin treatment. After sacrifice, tissular distribution of doxorubicin, cardiac scintigraphy, histological examination of the myocardium, and evaluation of liver function were assessed. Results: Obtained results show that doxorubicin has a high affinity to tissues especially the heart. It causes hepatotoxicity and cardiotoxicity marked by a significant increase of aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) levels and drop of the left ventricular ejection fraction (EF LV ) by scintigraphy. Histological examination showed general alteration of myocardium structure. Concomitant administration of trimetazidine attenuates significantly the cardiotoxicity and hepatotoxity induced by doxorubicin. Conclusion: We have evaluated the protective effect of trimetazidine on an animal model of doxorubicin-induced cardiotoxicity and hepatotoxicity. The evaluation of these effects were assessed by several means; tissular distribution of doxorubicin, histological examination, assessment of liver function, and EF LV by scintigraphy that characterizes the originality of this study.

Mycophenolate mofetil is a prodrug widely used in renal transplantation to prevent organ rejection. It is hydrolyzed to its active compound mycophenolic acid (MPA). MPA area under the curve (AUC0−12h) is considered the best pharmacokinetic parameter for the estimation of MPA exposition and for prediction of rejection. MPA-AUC requires several blood samples, making it impractical for clinical practice. Therefore, development of a limited sampling strategy (LSS) to estimate MPA AUC0−12h using three blood samples is very helpful for MPA individual dose adjustment. Results of LSS differ according to the patient background and to the drug formulation. Therefore, the purpose of this study was to develop a LSS for the estimation of MPA AUC0−12h in Tunisian renal transplant patients treated with the generic formulation of mycophenolate mofetil (MMF®, MEDIS). The best correlation was achieved by a profile based on three time points C0.5h, C1.5h, and C4h after drug intake: AUC0−12h = 0.414 + 1.210 × C0.5 + 2.256 × C1.5 + 4.134 × C4 (mei = 1.65% and rmse = 5.81%). The correlation between full AUC0−12h and abbreviated AUC0-12h was 0.917. In conclusion, this model provides a reliable and simple equation to estimate MPA AUC0−12h for the generic formulation of mycophenolate mofetil (MMF®).

Introduction In recent years, many marine resources have drew attention in the research for bio-active compounds to develop new drugs and health foods. (1) Marine algae are now considered as a rich source of antioxidants (2). It is known that seaweeds contain numerous bioactive substances that have the ability to lower cholesterol, reduce blood pressure, promote healthy digestion; and antioxidant activity (3). Natural antioxidants are interesting compounds due to their properties which help prevent oxidative stress (4), among other potentially beneficial actions. For instance, several biological effects have been attributed to flavonoids, such as anti-tumoral, anti-inflammatory, anti-ischemic and anti-aggregate plaquetary activities. These activities are believed to be in part related to the antioxidant properties of the compounds, namely in scavenging radical oxygen species (ROS). (5, 6) The cold ischemia constitute a situation of oxidative stress in touch with liberation of oxygenated radicals, these situations incited the researchers to find means for the improvement of the conservation of organs allowing to prolong the durations of the cold ischemia of certain organs (in particular the liver) with conservation of the maximum functional value. However, the constant efforts led by the teams of transplantation to develop transplants, the conservation of organs remains a problem to be resolved. (7) Conservation solution of organ appears as being a stemming to remedy the fatal effects of the ischemia-reperfusion. For our part, we think that seaweeds have not delivered their secrets and yet especially that the marine environment of the Tunisian coast still remains little exploited in spite of the big variety of the fauna and the flora of the coast. We envisage in this work, to study a sort of seaweed collected on the Tunisian quotation in the region of "Chott Meriem" (North West of Tunisia). The purpose of our work is to estimate the capacity of extracts stemming from the green seaweed Ulva lactuca to improve the conservation solution of organs against the hepatic effects of ischemia.

Resume Objectif Chercher s’il y a une relation entre les concentrations de 6-thioguanine nucleotide et des 6-methyl mercaptopurine et l’efficacite clinique et les effets indesirables a travers une population de patients atteints de maladie inflammatoire chronique de l’intestin. Methodes Nous incluons des patients atteins de la maladie de Crohn ou de rectocolite hemorragique (RCH) traites par l’azathioprine pendant une duree minimale de 12 mois. Pour chaque patient, un dosage des metabolites a ete realise. Resultats Nous avons inclus 43 patients atteints de maladie de Crohn et 7 de RCH. L’azathioprine a ete indiquee pour une cortico-dependance dans 23 cas, pour prevenir les recidives post-operatoires dans 10 cas, pour maintenir une remission clinique obtenue par un traitement medical chez 17 patients. Conclusion Notre travail confirme la relation entre la concentration de la 6TGN et la survenue d’une myelo-toxicite.

Imatinib, an antineoplastic drug used to treat certain cancers, has many side effects such as hematologic, neurologic or cutaneous toxicity. These toxicities seem to be due to a high imatinib plasmatic concentration and are frequently controlled by a discontinuation or a dosage reduction of the drug. We report here in 2 cases of cutaneous side effects induced by imatinib in order to demonstrate the necessity of drug monitoring in such cases. In our cases, imatinib is responsible in the occurrence of these side effects. Monitoring plasma levels of imatinib allowed us to judge if levels were toxic or not and to avoid discontinuation of imatinib in some cases.

Resume L'amphotericine B est un antifongique efficace dans le traitement des mycoses systemiques, mais l'intervalle therapeutique est etroit et la toxicite renale importante. Nous proposons dans ce travail de mettre au point et de valider une nouvelle methode de dosage par CLHP de l'amphotericine B dans le plasma. Apres extraction liquide-liquide, la separation est faite par CLHP avec detection UV/visible en utilisant une colonne RP 18 (125 mm), une phase mobile polaire composee d'eau, d'acetonitrile et d'acide acetique (51, 44, 5) (v/v/v) ajustee a pH 3. Le piroxicam est utilise comme etalon interne. Cette methode est lineaire pour des concentrations comprises entre 0,125 μg/mL et 8 μg/mL (r = 0,99). Les limites de detection et de quantification sont respectivement de 0,044 μg/mL et de 0,111 μg/mL. Les coefficients de variations de repetabilite et de reproductibilite sont respectivement de 1,98 a 4,66 % et de 2,69 a 4,95 % pour trois concentrations differentes. Dans ces conditions, le temps d'analyse est inferieur a 10 minutes.

Resume Nous proposons une methode par chromatographie liquide a haute performance (CLHP) pour la quantification rapide de la teicoplanine serique apres deproteinisation, extraction, chromatographie sur une colonne C18 et detection UV-Visible (longueur d’onde : 220 nm). La phase mobile est composee d’un melange compose de tampon phosphate a 20 mmol/L, methanol et acetonitrile, 80/11/9 (v/v/v), ajuste a pH 4. Le sulfamethoxazole est utilisee comme etalon interne. L’etalonnage est lineaire entre 0,5 a 30 μg/ml (r = 0,99). Les limites de detection et de quantification sont respectivement de 0,034 et 0,104 μg/mL, la repetabilite et la reproductibilite de respectivement 1,31 a 2,64 % et 4,46 a 5,72 % a trois concentrations differentes. Le taux de recouvrement varie de 98,14 % a 99,4 % a trois concentrations differentes. Dans ces conditions, le temps d’analyse est inferieur a 12 minutes.

During last years, significant progress was made in the comprehension of the hepatic lesions after Ischemia-Reperfusion episode in order to improve the Results in practice clinical.To avoid or reduce the damage induced by Ischemia-Reperfusion, we developed a model of hepatic Ischemia-Reperfusion with variable periods of reperfusion from 0 to 24 hours. Our study related to rats Wistar males. Six various groups were studied: the first reference group (without neither ischemia and reperfusion), the second group with ischemia of 90 min and without reperfusion and the 3end , 4end, 5end and 6end groups in addition to ischemia, underwent a reperfusion of 30 min, 2h, 6h and 24h respectively. The damage of hepatic Ischemia-Reperfusion was evaluated by a biochemical test based on the proportioning of transaminases and an anatomopathologic study by optical microscopy for the determination of the degree of hepatic attack. The RESULTS obtained seem to show an aggravation of the liver lesions and an increase in the plasmatic rates of AST and ALT in relation with the duration of the reperfusion. Indeed, the maximum of damage was observed after 2 hours of reperfusion. We observed a reduction in the lesions after 6h and 24h of reperfusion. Our work enabled us to describe a simple model of hepatic Ischemia-Reperfusion with functional, biochemical and anatomopathologic tests.

The use of high dose of MTX in the treatment of the leukemia is actually better controlled by renal preparation, control of plasma concentrations and administration of folinic acid. However, High dose MTX has been proven to cause substantial toxicity and have high intra-and inter-patient variability. Population pharmacokinetic analysis is a useful tool for identification of sources of pharmacokinetic variability during anticancer drug development and can aid the design of alternative dosing regimens to enhance their efficacy and safety.The aim of our study is to developed and validate a population pharmacokinetics model of our population. We hereby describe the clinical covariates (age, sex and clearance of the creatinine) that influence MTX pharmacokinetic for predicting optimal dose to reduce MTX toxicity.It is a prospective study achieved between January 2005 to January 2012 in the Service of Clinical Pharmacology. Including 273 patients treated for acute lymphocytic leukaemia 2582 plasma concentration was achieved. The data have been analyzed with Nonmem© software (non linear regression to mixed effect).The age of our patients varied from 2 to 23 years with an average of 13 years. The patients received high dose MTX therapy (1 to 8 g/m2) in 24 hours infusion every 15 days. Three compartiment models describe the pharmacokinetic of MTX. The most important covariables affecting the model were clearance of the creatinine, age and weight. We obtained a good correlation between the predicted and the observed concentrations.The development of population pharmacokinetics model of MTX allows us to propose a therapeutic diagram adapted to every patient according to its morphological and pharmacological features while taking in consideration the therapeutic objective.

Lamotrigine is an effective anticonvulsant drug used in the treatment of epilepsy. It has a narrow therapeutic range, a large inter and intra-individual pharmacokinetic variability and some concentration-dependent side effects.The aim of this study was to develop and validate a new method for lamotrigine quantitation in plasma using HPLC with UV/visible detection.A rapid HPLC-UV method was developed for the determination of lamotrigine in plasma. All solvents used were HPLC grade.After liquid-liquid extraction, chromatographic separation was achieved using an RP 18 (250 mm) column. The mobile phase was composed of acetonitrile and 0.1 M potassium dihyrogenophosphate (25/75) (v/v). Barbital sodium was used as internal standard. This technique was linear over the 2 μg/mL to 50 μg/mL range (r= 0.99). Detection and quantification limits were 0.07 μg/mL and 0.21 μg/mL, respectively. Within-day coefficient of variation (13.37 to 16 %) and day-to-day coefficients of variation (15.68 to 16.63 %) at three different concentrations. Under these conditions, each analysis required no longer than 10 min. We finally evaluated the plasma concentrations of lamotrigine in Tunisian patients treated with this drug.The results found are similar to those previously described and the developed method is repeatable and reproducible. It can be used for clinical applications.

Therapeutic drug monitoring of cyclosporine minimizes the risk of toxicity and acute rejection after transplantation. Areas under the curve (AUCs) rather than trough concentration-based monitoring are recommended. Population pharmacokinetics (PopPK) modeling and Bayesian estimation seem to be the best way to predict cyclosporine disposition and dose requirements to achieve the therapeutic target in an individual patient because of the possibility of predicting cyclosporine AUC using only a few blood samples. Our objectives were to build a PopPk model for cyclosporine in a Tunisian population of HSCT patients and to develop a Bayesian method for the estimation of individual cyclosporine AUC. The PopPk of cyclosporine was studied using nonlinear mixed effects modeling (NONMEM) in 30 patients (index group) receiving cyclosporine on a twice-daily basis. Ten blood samples were collected after steady-state morning cyclosporine dose. Bayesian estimation of individual AUC was made on the basis of three blood concentration measurements in an independent group of 30 patients (test group). A two-compartment model with first-order absorption and a lag time provided the best fitting. The population mean estimate and interindividual variability from the final model for CL, Ka, Tlag, V1, V2, and Q were 25.4 L/h (CV = 38.72 %), 0.214 h−1(CV = 28.5 %), 0.382 h, 10.9 L (85.73 %), 496 L, and 5 L/h, respectively. Covariates had no discernible effects on cyclosporine pharmacokinetics in our population. Bayesian estimation provided an accurate estimation of AUC, although a bias was observed leading to slight underprediction of AUC (bias −1.03 %). A very satisfactory precision was observed (RMSE 12.07 %). We report a PopPK model for cyclosporine in Tunisian HSCT patients. Bayesian estimation using only three concentrations provides good prediction of cyclosporine exposure. These tools allow us to routinely estimate cyclosporine AUC in a clinical setting.

Le methotrexate (MTX) est un antifolique administre a haute dose par voie intraveineuse dans la leucemie aigue lymphoblastique (LAL). Le suivi therapeutique pharmacologique permet de detecter une eventuelle toxicite et de controler le sauvetage par l’acide folinique. Nous rapportons le cas d’un enfant qui a presente un syndrome de Munchausen par procuration s’exprimant par des methotrexatemies toxiques persistantes artificielles. L’enfant, âge de 12 ans et traite pour LAL, recevait des cures de MTX tous les 70 jours. La methotrexatemie etait de 0,15 μmol/L a la 72 e heure de la perfusion. Puis, il a ete mis sous faible dose de MTX per os. Dix jours apres sa derniere cure, il a presente une asthenie, des vomissements et une mucite. La methotrexatemie etait de 2 323 μmol/L et la creatininemie normale. Toute prise medicamenteuse a ete suspendue et un sauvetage par l’acide folinique instaure. Le suivi a montre une disparition des signes de toxicite mais une persistance de methotrexatemies tres elevees. L’enquete a permis l’elimination d’erreurs de dosage et de problemes pharmacocinetiques suggerant une adulteration des prelevements de l’enfant. Ainsi, trois prelevements ont ete effectues : le premier apporte par la mere, le deuxieme apporte par le medecin traitant lui-meme et le dernier realise dans notre laboratoire. Les methotrexatemies etaient respectivement egales a 10 000 μmol/L dans le premier cas et inferieures a 0,02 μmol/L pour les deux autres echantillons. Il a ete envisage qu’il s’agissait d’un cas de syndrome de Munchausen par procuration revele par des methotrexatemies artificiellement toxiques. La mere a ete adressee en psychiatrie.

Ciclosporine (CsA) is an immunosuppressant drug used in bone marrow transplantation in order to extend allograft survival. Despite its efficiency, CsA can expose to therapeutic failure or to toxicity because of underdosing or overdosage. So, many techniques of monitoring CsA in blood were used, the referance one is the chromatographic technique then, the automated techniques: fluorescence polarization immunoassay (FPIA) and chimiluminescent microparticle immunoassay (CMIA). In this study, we aimed to compare the results of CsA concentrations measured by the two automised techniques. Statistical studies showed that the two techniques were repeatable and reproductible. Results obtained by FPIA were slightly higher than those obtained by CMIA but without a significative difference. In conclusion, FPIA technique could be used to measure CsA blood concentration in replacement of CMIA in case of technical problems.

Tacrolimus, an immunosuppressor indicated in solid organ transplantation, has a large inter- and intra-individual variability, a narrow therapeutic index and numerous drug interactions. It is metabolized in the enterocytes and the liver by CYP3A4. Association to enzymatic inhibitors like azole antifungals increase its blood levels and may increase its toxicity directly related to an increase of its blood concentration. We describe in this study four cases of drug interaction between tacrolimus and azole antifungals. These patients were renal transplanted in 2009 and treated with tacrolimus. For fungal infections, azole antifungals were added in these cases. Three were treated by fluconazole and one with voriconazole. By the risk of drug interaction occurrence, tacrolimus doses were decreased by two thirds in one case and by the third in the second case. This association leaded to an increase in tacrolimus concentration (1.33 to 2.45 times the initial concentration) in all patients. Side effects observed in our patients were liver toxicity in two cases, an increase in serum creatinin and an hyperglycemia were notified in all patients. An increase in tacrolimus concentration with about 1.33 times was observed in the case receiving fluconazole intravenously at the dose of 100mg one day out of two and with a tacrolimus doses decrease by two thirds. The patient had impaired renal function before fluconazole introduction. This suggests that in the presence of renal function alteration even low doses of fluconazole with an inhibition of only liver CYPA3A4 (without inhibition of intestinal CYP3A4 and P-gp) leads to an increase on tacrolimus concentration and occurrence of adverse effects related to tacrolimus toxicity. With the co-administration of azole antifugals, it is recommended to adjust tacrolimus dosage on the basis of therapeutic tacrolimus blood monitoring in order to maintain tacrolimus concentration in therapeutic range and to avoid adverse toxic effects.

Frequency of colitis induced by drugs is often under estimated. Antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDS) are usually incriminated. In this study, we classified colitis according to the main responsible drug with a focus on clinical symptomatology, physiopathology, evolution, and complications. We describe colitis due to antibiotics, NSAIDS, laxatives, vasoconstrictive agents, oestroprogestatives, chemotherapy and drugs induced microscopic colitis. The last one represents a particular case; it can be idiopathic, infectious or drugs induced. Its physiopathology is not well known and its diagnosis is based only on histologic criterion. Drug responsibility is easy to determine only for pseudomembranous colitis. In the other cases, chronology is very variable and the clinical, endoscopic and histological elements are rarely specific. Because of the large number of drugs that may induce colitis, it is necessary to search for potentially responsible drugs, especially if there is no obvious cause of the colitis.

Introduction L’infliximab (IFX) est anticorps monoclonal chimerique qui a prouve son efficacite dans la prise en charge des maladies inflammatoires chroniques de l’intestin et les affections rhumatismales. Toutefois, son efficacite peut etre limitee par le developpement d’anticorps anti-infliximab (ATI) qui est une des causes de l’echec therapeutique par IFX. D’ou l’interet du dosage plasmatique de l’ATI chez les patients recevant l’IFX afin de guider la prise en charge therapeutique. L’objectif de notre travail etait de valider une technique ELISA (lecteur et kit) de dosage plasmatique des ATI lors de la mise en place de l’activite de routine. Materiels et methodes Nous avons collecte 23 prelevements juste avant la 4e perfusion d’IFX. Le dosage plasmatique des ATI a ete fait par la technique d’ELISA. L’evaluation de la performance de notre lecteur ELISA s’est fondee sur la comparaison des densites optiques mesurees par notre nouveau lecteur et un ancien appareil en se basant sur l’etude de lacorrelation moyennant la courbe de regression lineaire et sur l’etude de la concordance entre les deux lecteurs par la methode graphique de Bland Altman. La validation du kit ELISA s’est effectuee par l’etude de la precision (evaluee par la repetabilite, la reproductibilite ainsi que les limites de detection [LD] et de quantification [LQ]) et l’exactitude (estimee par la valeur predictive positive [VPP], la valeur predictive negative[VPN], la specificite [Sp] et la sensibilite [Se]). Resultats Nous avons collige 23 patients dont la moyenne d’âge etait 46 ans et sex-ratio H/F etait 0,92. Les patients etaient suivis pour polyarthrite rhumatoide, spondylarthrite ankylosante, rhumatisme Psoriasique et maladie de Crohn. Nous avons obtenu 9 prelevements ou les AIT etaient positifs et 14 prelevements ou on n’a pas detecte la presence d’ATI. L’etude de la correlation entre les deux lecteurs a montre un coefficient de correlation r2 de 99,95 %. Les limites de concordance de l’intervalle de confiance a 95 % etaient [−112,768 % −41,425 %] avec un biais de −35,671 %. La repetabilite et la reproductibilite ont ete verifiees par un controle positif teste 3 fois le meme jour pour la repetabilite et 2 jours de suite pour la reproductibilite avec un coefficient de variation respectivement de 5,574 % et 14,184 %. Les LD et LQ etaient de l’ordre de 0,046 et 0,086. Nous avons obtenu une VPP a 0,5 et une VPN a 1. La sensibilite a ete estimee a 100 % et la specificite a 83 %. La cadence etait similaire pour les deux lecteurs. Conclusion L’evaluation de la performance de notre lecteur a revele une bonne correlation et une bonne concordance. La validation de notre kit ELISA a montre une bonne precision, une bonne sensibilite et specificite par rapport au kit de reference. Cependant, vu le cout eleve de cette technique, le nombre de prelevements pour la validation etait limite.

Background/Aims: The principal aim of conservation is to maintain the viability of grafts. This requires the addition of a cellular protector allowing better conservation of the graft. The aim of this work is to evaluate the effect of trimetazidine (TMZ) addition to Wistar rat livers conserved in Krebs-Henseleit solution, compared to the livers preserved only in Krebs-Henseleit solution (24 h at 4°C). Methods: 40 Wistar female rats divided into 5 groups were used: the first group consists of nonpreserved livers, the second consists of livers preserved only in the Krebs-Henseleit solution, and the other 3 groups consist of livers preserved in Krebs solution with different concentrations of TMZ added (16.5, 49.5 and 165 μg/ml). Results: The obtained results show an improvement in the state of the liver in the presence of a high concentration of TMZ, which approaches normal physiological conditions. We note a clear diminution of transaminase activities, as well as an amelioration in metabolic capacities of the liver if the mitochondrial esterase pathway is supported in Wistar rats by a reduction of histological injuries. Conclusion: A TMZ concentration of 165 μg/ml clearly restored the metabolic capacities of the liver. Indeed, TMZ limited the appearance of necrotic areas and almost suppressed apoptotic cells.

Introduction: Posterior reversible encephalopathy syndrome (PRES) is a clinic neuroradiological entity. This syndrome occurs in complex conditions as allogenic bone marrow transplantation, organ transplantation and immunosuppressant therapy such as cyclosporin (CsA). The occurrence of PRES is favored by a high concentration of CsA. Therefore, therapeutic monitoring of CsA is necessary to effects due to overdose. The therapeutic range of CsA is between 150-300 ng/mL. We aimed to present a case PRES induced by CsA in bone marrow transplantation with normal cyclosporine blood concentrations. Case: A 26 years old man received an allogenic bone marrow for bone marrow aplasia in January 2013. He was treated by CsA. Mean CsA dose was 2.57 mg/kg/day. CsA mean blood concentration was 295 ng/mL. After 20 days, our patient presented a complex partial seizure and cortical abnormal. He had no history of head injury, epilepsy or hypertension and there was no family history of neurological or psychiatric disorders. Patient’s blood pressure wasn’t measured. CsA was stopped. He received mycophenolate acid and clonazepam. Seizure and abnormal vision vanished 10 days later. Whereas, the patient developed graft-versus-host disease (GVHD). Then, mycophenolate acid was stopped 1.5 month later and CsA taken back. CsA mean dose was 1.1 mg/kg/day. Mean CsA blood concentration was 167.71 ng/mL. After two months, the patient developed general seizures and in Magnetic Resonance Imaging (MRI) there was a low-density in the subcortical white matter areas. So, CsA was stopped once and for all and the seizures vanished few days later. Conclusion: PRES is responsible for various and no specific neurological symptoms. These symptoms are usually reversible but sometimes fatal. Therapeutic monitoring of CsA was necessary to avoid neurotoxicity depending of concentration but we must remain cautious even if patients have CsA blood concentrations in the therapeutic range.

Resume Contexte Le paracetamol est un antalgique et antipyretique largement utilise et generalement bien tolere. La litterature ne rapporte que tres peu de reactions allergiques franches a ce medicament. Materiels et methodes Nous avons mene une etude retrospective sur 119 cas d’allergie au paracetamol notifies au centre national de pharmacovigilance (CNPV) tunisien entre septembre 1990 et septembre 2000, et valides selon la methode de Begaud et al. (1985). Resultats Notre population est formee de 64 femmes et 55 hommes âges de 1 mois a 70 ans. Des antecedents d’allergie ou d’atopie ont ete trouves chez de nombreux patients dont 10 cas d’allergie au paracetamol et 6 cas d’allergie a l’aspirine. Le paracetamol a ete pris en automedication dans 50 % des cas et associe a d’autres medicaments dans 68 % des cas. Le type de lesion a ete variable avec predominance d’urticaire dans 34,4 % des cas, d’eruption maculo-papuleuse dans 30,2 % des cas et d’erytheme pigmente fixe dans 12,6% des cas. Certaines lesions etaient graves, telles qu’un syndrome de Lyell ou un choc anaphylactique. L’evolution a ete favorable dans presque tous les cas. Le paracetamol a ete contre-indique definitivement chez les patients dans les cas ou le score d’imputabilite etait eleve ou moyen. Conclusion Ainsi, l’allergie au paracetamol est assez rare mais est loin d’etre exceptionnelle. Plusieurs facteurs de risque semblent intervenir et en particulier la notion d’allergie connue a ce medicament et celle a l’aspirine.

Mitotane provided serious side effects and low doses seemed to be tolerated. Determination of mitotane concentration in plasma is recommended. We report the case of toxic plasma levels with low doses of mitotane in a 47-year-old man with adrenocortical cancer.

Resume Le voriconazole est un antifongique de deuxieme generation largement indique dans le traitement de l’aspergillose invasive. Ce medicament est relativement bien tolere. Neanmoins, il presente quelques effets indesirables dont l’hepatotoxicite, la photosensibilite, les rashs cutanes et les troubles visuels. Les hallucinations ont ete egalement rapportees comme effets indesirables. Cependant, les hallucinations auditives ont ete rarement observees et semblent secondaires a des concentrations toxiques de voriconazole. Nous rapportons dans ce travail un cas d’hallucination auditive avec un suivi therapeutique des concentrations plasmatiques de voriconazole. Il s’agit d’un patient âge de 38 ans, traite par du voriconazole par voie intraveineuse pour aspergillose pulmonaire. Sept jours apres le debut du traitement, le patient presente soudainement des hallucinations auditives associees a une incoherence et une desorientation temporospatiale. La determination des concentrations plasmatiques du voriconazole de facon concomitante a l’apparition des hallucinations a montre une concentration plasmatique residuelle (C 0 ) de 7,5 μg/mL (intervalle therapeutique : 1,4–1,8 μg/mL) et une concentration au pic (C pic ) de 9,83 μg/mL (intervalle therapeutique : 2,1–4,8 μg/mL). Le voriconazole a ete arrete et deux jours apres, il y a eu une disparition complete de la symptomatologie avec une diminution importante et concomitante de la concentration plasmatique du voriconazole (C 0 = 0,11 μg/mL et C pic = 2,17 μg/mL). Ainsi, nous avons implique le voriconazole dans l’apparition de ces hallucinations, vu l’apparition soudaine des hallucinations associees a des concentrations toxiques de voriconazole et l’importante diminution des concentrations de voriconazole concomitantes a l’arret de ce medicament et a la disparition des symptomes.

Tacrolimus is a calcineurin inhibitor primarily metabolized by CYP3A4 and secondarily by CYP3A5. Several drugs can modify tacrolimus blood levels as calcium channel blockers (CCBs). Interaction with nicardipine was reported in some cases. A man with a history of malignant arterial hypertension treated with nicardipine, underwent kidney transplantation. After transplantation, he was treated with tacrolimus, mycophenolate mofetil and corticoids. Therapeutic drug monitoring of tacrolimus was done regularly showing a mean trough concentration (C0) of 24.39 ng/mL with some concentrations reaching 52 ng/mL. After changing nicardipine by prazosine, the first tacrolimus C0 after stopping nicardipine was 3.2 ng/mL. Increase of tacrolimus trough concentrations is due to the inhibition of CYP3A4. Very high levels of tacrolimus suggest the non expression of CYP3A5. Thus, because of the possible lack of the secondary pathway, therapeutic drug monitoring of tacrolimus is highly recommended at the introduction of CCBs and also at its stopping.

Valproic acid (VA) is a widely used antiepileptic drug. Because of its pharmacokinetic variability and the influence of intrinsic and extrinsic factors such as the treatment compliance, VA therapeutic drug monitoring (TDM) is recommended in children. The aim of this study is to evaluate the effect of treatment compliance and the economic level on VA tough plasmatic concentration (TPC) and epileptic rhythm in children.A one-year prospective study (August 2008-August 2009) concerning children (age≤5 years) regularly treated by VA who had a VA TDM. So, 276 plasmatic samples from 238 children were collected. The children were divided in two groups as following: the group 1 (G1) presenting a good compliance and a reliable questioning and the group 2 (G2) presenting a bad compliance and a non reliable questioning. We evaluated the interindividual variability by correlating the TPC to the dose. Then, we divided the hole group in function of their economic levels (low-medium-high).Sex ratio male/female was 1.3. Median age was 5 years+/-3,9. The mean TPC was 62 µg/mL [0.12-131 µg/mL]. VA TPC were in the therapeutic range (TR) in 62%. Adverse drug reactions were noted in 4.2% of the children. G1 represented 70% of the children and G2, 30%. The TPC were in the TR in 67% of G1 and 51% of G2 (p=0.02). There was a significant difference between the TPC in G1 and G2 (p=0.02).There was no significative difference in the TPC in function of the economic levels. There was no correlation between TPC and the administered doses. The epileptic seizures were more spaced in children with therapeutic TPC than those with TPC in the TR (p=0.002) and in G1 than in G2 (p=0.03).Compliance should be appropriate in order to optimize the TDM rule. A good compliance and a therapeutic TPC allow a better control of epileptic seizures.

Vancomycin penetrates poorly through the blood-brain barrier. Determination of vancomycin concentration in plasma is recommended. In contrast, its determination in cerebrospinal fluid (CSF) is rarely performed. We report the case of a 74-year-old man with post traumatic meningitis with vancomycin concentration measured in CSF.