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Background: The mass vaccination campaign against SARS-CoV-2 was started in Tunisia on 13 March 2021 by using progressively seven different vaccines approved for emergency use. Herein, we aimed to evaluate the humoral and cellular immunity in subjects aged 40 years and over who received one of the following two-dose regimen vaccines against SARS-CoV-2, namely mRNA-1273 or Spikevax (Moderna), BNT162B2 or Comirnaty (Pfizer-BioNTech), Gam-COVID-Vac or Sputnik V (Gamaleya Research Institute), ChAdOx1-S or Vaxzevria (AstraZeneca), BIBP (Sinopharm), and Coronavac (Sinovac). Material and methods: For each type of vaccine, a sample of subjects aged 40 and over was randomly selected from the national platform for monitoring COVID-19 vaccination and contacted to participate to this study. All consenting participants were sampled for peripheral blood at 3–7 weeks after the second vaccine dose to perform anti-S and anti-N serology by the Elecsys® (Lenexa, KS, USA) anti-SARS-CoV-2 assays (Roche® Basel, Switzerland). The CD4 and CD8 T cell responses were evaluated by the QuantiFERON® SARS-CoV-2 (Qiagen® Basel, Switzerland) for a randomly selected sub-group. Results: A total of 501 people consented to the study and, of them, 133 were included for the cellular response investigations. Both humoral and cellular immune responses against SARS-CoV-2 antigens differed significantly between all tested groups. RNA vaccines induced the highest levels of humoral and cellular anti-S responses followed by adenovirus vaccines and then by inactivated vaccines. Vaccines from the same platform induced similar levels of specific anti-S immune responses except in the case of the Sputnik V and the AstraZeneca vaccine, which exhibited contrasting effects on humoral and cellular responses. When analyses were performed in subjects with negative anti-N antibodies, results were similar to those obtained within the total cohort, except for the Moderna vaccine, which gave a better cellular immune response than the Pfizer vaccine and RNA vaccines, which induced similar cellular immune responses to those of adenovirus vaccines. Conclusion: Collectively, our data confirmed the superiority of the RNA-based COVID-19 vaccines, in particular that of Moderna, for both humoral and cellular immunogenicity. Our results comparing between different vaccine platforms in a similar population are of great importance since they may help decision makers to adopt the best strategy for further national vaccination programs.

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.

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 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.

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.

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.

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.

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.

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.

CyclosporineA (CsA) improves the survival of patients who benefited from transplantation. However, its use is generally limited by its side effects. The aim of our study was to measure, in an experimental model, the changes of the testosterone plasma levels after 21 days of CsA treatment and to explain the mechanism of this modification. After treatment, the levels of CsA, testosterone, corticosterone, transaminases were measured. The cytotoxic effect of CsA was evaluated by microscopic observation. The experimental study showed that CsA had no effect on the plasmatic levels of hepatic enzymes - alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl-transferase - because their plasma concentrations in treated rats did not differ from those of the sham group. The plasma concentration of corticosterone was not modified, the plasma level of testosterone decreased when the dose of cyclosporine was increased to 4 mg/kg/day. The photonic microscope observation showed that the number of Leydig cells was increased and the electronic microscope observation showed mitochondria alteration. The treatment by CsA and trimetazidine did not correct the alteration caused by CsA. N-benzyl-N'-(2-hydrox-3, 4-dimethyloxybenzyl)-pipeazine did not protect the mitochondrial function but partially protected mitochondria structure from the deleterious effect induced by CsA. The decrease of the plasma level of testosterone induced by CsA was due to the inhibition of the mitochondrial 20-22 desmolase which blocked the formation of the testosterone precursor and the destruction of the mitochondria structure.

Introduction The primary aim of this study was to establish the population pharmacokinetic (PPK) model of bupivacaine after combined lumbar plexus and sciatic nerve blocks and secondary aim is to assess the effect of patient's characteristics including age, body weight, sex and drugs co medication (Clonidine and Propofol) on pharmacokinetic parameters. Materials and method A total of 59 patients scheduled for elective lower extremity surgery with combined lumbar and sciatic nerve block using plain bupivacaine 0.5% were included. The total bupivacaine plasma concentrations were measured before injection and after two blocks placement and at selected time points. Monitoring of bupivacaine was made by high performance liquid chromatography (HPLC) with ultraviolet detection. Non-linear mixed effects modeling was used to analyze the PPK of bupivacaine. This pharmacokinetic model was validated using npde package for statistic software R. The simulations confirm that our final model was valid. Results and discussion Two compartment model with first order absorption, two input compartments, a central elimination and peripheral compartment was selected. The Shapiro-Wilks test of normality for normalized prediction distribution errors for this model ( P = 0.837) showed this as a valid model. The description of the quality of the estimate by the graphic diagnostic suggests a good fitting of the final model. The selected model predicts a population clearance of 503 mL/min (residual standard error [RSE] = 16.5%, 95% CI = [534.9–866.9]) with between subject variability of 93.16%. The central and peripheral volumes of distribution were respectively 6850 L and 120 L. The absorption of bupivacaine in two sites Ka1 and Ka2 were 0.00073/min for the lumbar site and 0.0037/min for the sciatic site. Within subject variability WSV% was 30, 3%. Drug Co medication, age, body weight and sex, have no effect on the bupivacaine pharmacokinetics in this studied population. Conclusion The developed model helps us to assess the systemic absorption of bupivacaine at two injections sites.

Objectives: The primary aim of this study was to establish the population pharmacokinetic (PPK) model of bupivacaine after combined lumbar plexus and sciatic nerve blocks and secondary aim is to assess the effect of patient's characteristics including age, body weight and sex on pharmacokinetic parameters. Materials and Methods: A total of 31 patients scheduled for elective lower extremity surgery with combined lumbar and sciatic nerve block using plain bupivacaine 0.5% were included. The total bupivacaine plasma concentrations were measured before injection and after two blocks placement and at selected time points. Monitoring of bupivacaine was made by high performance liquid chromatography (HPLC) with ultraviolet detection. Non-linear mixed effects modeling was used to analyze the PPK of bupivacaine. Results: One compartment model with first order absorption, two input compartments and a central elimination was selected. The Shapiro-Wilks test of normality for normalized prediction distribution errors for this model (P = 0.156) showed this as a valid model. The selected model predicts a population clearance of 930 ml/min (residual standard error [RSE] = 15.48%, IC 95% = 930 ± 282.24) with inter individual variability of 75.29%. The central volume of distribution was 134 l (RSE = 12.76%, IC = 134 ± 33.51 L) with inter individual variability of 63.40%. The absorption of bupivacaine in two sites Ka1 and Ka2 were 0.00462/min for the lumbar site and 0.292/min for the sciatic site. Age, body weight and sex have no effect on the bupivacaine pharmacokinetics in this studied population. Conclusion: The developed model helps us to assess the systemic absorption of bupivacaine at two injections sites.

Tiemonium, an anti-spasmodic drug, can have adverse effects related to its anti-muscarinic effect. Dyskinesia is described with other anti-cholinergic drugs, but there are no reports of dyskinesia associated with tiemonium. We report a reversible orofacial dyskinesia following tiemonium intake (contained in Viscéralgine forte) in a woman with positive rechallenge. She presented these symptoms two times after two separate injections with an interval of 2 months. The case was reported to the Tunisian Centre of Pharmacovigilance.