Nadia Ben Fredj

Identification of human herpesviruses 1 to 8 in Tunisian multiple sclerosis patients and healthy blood donors

Members of the human Herpesviridae family are candidates for representing the macroenvironmental factors associated with multiple sclerosis (MS) pathogenesis. To verify the possible role of human herpesviruses (HHVs) as triggering or aggravating factors in relapsing–remitting multiple sclerosis clinical outcome, we studied the prevalence of all eight human herpesviruses in whole blood samples collected from 51 MS patients and from 51 healthy controls. The presence of DNA of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella zoster virus (VZV), Epstein–Barr virus (EBV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7) and human herpesvirus 8 (HHV-8) was searched by specific nested polymerase chain reaction. HHVs were significantly more prevalent in the blood of MS patients than in those of the controls (P < 10−4). HSV-1, HSV-2, HCMV and HHV-8 were negative in both MS patients and controls samples. In MS patients, EBV, HHV-7, HHV-6 and VZV were detected in 31.3%, 33.3%, 5.8% and 7.8% of samples, respectively, compared with 3.9%, 9.8%, 1.96% and 1.96%, respectively, of samples from controls. We found a statistically significant difference only for EBV DNA and for HHV-7 DNA prevalence (P < 0.001 and P = 0.03). Although these results indicate lack of apparent association in terms of gender, type of diagnosis, symptoms, disease score and β interferon treatment between EBV or HHV-7 to MS among Tunisian patients, heterogeneity related to genetic polymorphism as well as geographical distribution of the disease and of pathogens may be of significance.

Hypersensitivity to amoxicillin after drug rash with eosinophilia and systemic symptoms (DRESS) to carbamazepine and allopurinol: a possible co‐sensitization

Hypersensitivity syndrome, also known as drug rash with eosinophilia and systemic symptoms (DRESS), is a serious idiosyncratic drug reaction. It is associated with fever, skin eruption, eosinophilia and multiple organ involvement (lymph node enlargement, hepatitis, pneumonitis, renal dysfunction, pancreatitis, myositis, myocarditis, central nervous system manifestations and hyper- and/or hypothyroidism) [1].

Influence of combined CYP3A4 and CYP3A5 single-nucleotide polymorphisms on tacrolimus exposure in kidney transplant recipients: a study according to the post-transplant phase

AIM The present study investigated in Tunisian renal transplant patients, genetic polymorphisms of CYP3A4 -392A>G and CYP3A5 6986A>G and their influence on tacrolimus (Tac) pharmacokinetics during early and late post-transplant (PT) phases and established customized ranges of Tac doses matching the C0 target levels according to CYP3A4 and CYP3A5 genotype combination and the PT phase. PATIENTS & METHODS We included adult Tunisian patients having received Tac for de novo kidney grafts and undergone a therapeutic drug monitoring of Tac by morning C0 monitoring during early (1 to 90 days) and late (over 90 days) PT phases. The genomic DNA was extracted from peripheral blood mononuclear cells using a salting-out procedure. CYP3A4 promoter (rs2740574; -392A>G) and CYP3A5 (rs776746; 6986A>G) SNP genotyping was analyzed using PCR-RFLP. RESULTS Fifty-two patients were enrolled in the study. During the early PT phase, the CYP3A5 polymorphism but not that of CYP3A4, correlates significantly with Tac dose-normalized C0 (C0/D ratio). During the late PT phase, the effect of CYP3A4 polymorphism becomes significant and that of CYP3A5 becomes nonsignificant on Tac C0/D Tac. The mean daily doses (mg/kg) matching therapeutic C0, regardless of the CYP3A genotypes, were 0.16 ± 0.05 and 0.10 ± 0.05 during early and late PT phase, respectively. Carriers of the CYP3A4*1B allele require higher doses to maintain the C0 in the therapeutic range during the two PT phases. However, patients carrying the CYP3A5*1 require significant higher Tac doses, only during the early phase. CONCLUSION Our data support a critical role of the CYP3A5 6986A>G and CYP3A4 -392A>G polymorphisms on the variation of Tac exposure during the early and the late PT phase, respectively. The establishment of customized Tac doses, according to CYP3A4/CYP3A5 genotype combination and the PT time, may allow preventing graft rejection and improving the safety profile of this drug. Further studies are needed to investigate this issue.

Evaluation of the implication of KIR2DL2 receptor in multiple sclerosis and herpesvirus susceptibility

To evaluate the possible effect of cell immunoglobulin-like receptors (KIRs) on viral infection in multiple sclerosis (MS) patients, we performed genotyping of KIR2DL2 and his HLA-C1 ligand and we analyzed the presence of all eight human herpesviruses (HHVs) in 60 MS patients and 112 healthy controls. Significantly higher frequencies were found for KIR2DL2 enhanced in the presence of its ligand HLA-C1 in MS patients. Moreover, a significant association was observed between an increase in HHV risk of infection in KIR2DL2 and HLA-C1 positive patient. Our results confirm a possible effect of KIR2DL2 on viral infection susceptibility in MS patients.

Albendazole-induced associated acute hepatitis and bicytopenia

Abstract Acute hepatitis induced by albendazole is rarely reported. We describe herein an original case of acute hepatitis associated with bicytopenia after albendazole intake. This paper is the first to describe a possible association of a hematologic disorder and acute hepatitis, both induced by albendazole therapy.

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Probably Induced by Cefotaxime: a Report of Two Cases

We report two cases, one of a 52-year-old man and one of a 32-year-old man, who were treated with cefotaxime. On day 23 and day 28 of the treatment, respectively, the patients manifested clinically with fever, pruriginous skin rash, and facial edema. Blood tests showed marked eosinophilia and atypical lymphocytosis for both patients, and hepatic cytolysis only in the second patient. Cefotaxime was discontinued in both patients; the clinico-biological picture improved gradually and completely disappeared approximately 4 weeks later. Six weeks after complete recovery, both patients underwent intradermal testing which was positive to cefotaxime (2 mg/ml) at the 48-hour reading and negative to benzylpenicillin, amoxicillin, and cefazolin at the 20-minute and 48-hour readings. These clinical pictures suggest drug rash with eosinophilia and systemic symptoms (DRESS) induced by cefotaxime. To the best of our knowledge, only one case of cefotaxime-induced DRESS has been reported in the medical literature. Thus, we add two new cases of cefotaxime-induced DRESS and emphasize the usefulness and safety of intradermal testing in establishing the diagnosis.

Limited Sampling Strategy of Mycophenolic Acid in Adult Kidney Transplant Recipients: Influence of the Post-Transplant Period and the Pharmacokinetic Profile

We aimed to develop an accurate and convenient LSS for predicting MPA‐AUC0–12hours in Tunisian adult kidney transplant recipients whose immunosuppressive regimen consisted of MMF and tacrolimus combination with regards to the post‐transplant period and the pharmacokinetic profile. Each pharmacokinetic profile consisted of eight blood samples collected during the 12‐hour dosing interval. The AUC0–12hours was calculated according to the linear trapezoidal rule. The MPA concentrations at each sampling time were correlated by a linear regression analysis with the measured AUC0–12. We analyzed all the developed models for their ability to estimate the MPA‐AUC0–12hours. The best multilinear regression model for predicting the full MPA‐AUC0–12hours was found to be the combination of C1, C4, and C6. All the best correlated models and the most convenient ones were verified to be also applicable before 5 months after transplantation and thereafter. These models were also verified to be applicable for patients having or not the second peak in their pharmacokinetic profiles. For practical reasons we recommend a LSS using C0, C1, and C4 that provides a reasonable MPA‐AUC0–12hours estimation.

Fixed Drug Eruption: Levofloxacin, Another Culprit Drug

775 2012 52 775-777 F drug eruption (FDE) is a pattern of a druginduced cutaneous reaction. It is characterized by skin erythmatous plaques that recur at the same site each time the drug is administered. Several drugs have been associated with an increased risk of inducing such a cutaneous reaction, including nonsteroidal anti-inflammatory drugs, nonopioid analgesics, sedatives, anticonvulsant agents, sulfonamides, and tetracyclines. However, only a few cases of quinoloneinduced FDE have been reported in the literature. Quinolones implicated in these cases are ciprofloxacin, norfloxacin, and ofloxacin. However, levofloxacin was implicated in FDE in only 1 previous case. We report herein a case of levofloxacin-induced FDE with a cross-reactivity to ofloxacin.

Development of Limited Sampling Strategies for the Estimation of Tacrolimus Area Under the Curve in Adult Kidney Transplant Recipients According to the Posttransplantation Time.

Background: Limited sampling strategies (LSS), using few sampling times after dosing, have been used to reliably predict tacrolimus area under the 12-hour concentration–time curve (AUC). Because the pharmacokinetics of tacrolimus is subject to significant changes over the exposure time to this drug, it can be hypothesized that the reliability of the LSS would also change. This study aimed to develop a reliable and practical LSS allowing the estimation of tacrolimus AUC in Tunisian kidney transplant recipients taking into account the posttransplantation time. Methods: Thirty Tunisian patients were enrolled into 3 groups (10 in each group) according to the posttransplantation period: period 1: between 1 day and 3 months, period 2: between 3 and 12 months and period 3 over 12 months, as defined by the European consensus conference on the therapeutic drug monitoring of tacrolimus. Samples were collected just before and 0.5, 1, 2, 4, 6, 8, and 12 hours after tacrolimus administration. The full pharmacokinetic profiles obtained from these timed concentration data were used to choose the best sampling times. Error indices (mean absolute prediction error and the root mean squared prediction error) were used to evaluate the predictive performance. Results: Among the 1-point estimations, the C4-predicted AUC showed the highest correlation with the measured one during period 1 and period 2 (r2 = 0.94 and 0.91, respectively) but not period 3 (r2 = 0.76). The C0-predicted and the measured AUC become less and less correlated from period 1 to period 3 (r2 = 0.81, 0.75, and 0.66), respectively. Only the model including the C0/C2 provided a high correlation between predicted and measured tacrolimus AUC regardless of the posttransplant period (r2 = 0.95, 0.96, 0.98 and root mean squared prediction error = 4.1, 5.8, 4.2 during periods 1, 2, and 3, respectively). Conclusions: Our data clearly indicate that the predictive performance of LSS is prone to change according to the posttransplantation time. A 2–time point LSS was found to be sufficient to predict tacrolimus AUC. The LSS using C0 and C2 is reliable, accurate, and practical to estimate the AUC of tacrolimus regardless of the posttransplantation time.

Codeine-induced acute generalized exanthematous pustulosis without IL36RN mutations

Recent studies have suggested an association between mutations in the IL-36RN gene and the onset of pustular generalized. In the literature, only one case of acute generalized exanthematous pustulosis (AGEP) induced by codeine in a patient with IL36RN mutation has been reported. Herein, we reported an unusual case of AGEP caused by codeine in a patient with a history of psoriasis and confirmed by an oral provocation test. In this case, we have shown that the IL36RN gene mutation is not a constant condition in drug-induced AGEP. Clinicians should be aware of this side effect of codeine especially, in patients with a history of psoriasis. More studies are needed to clarify the association between drug-induced AGEP and IL36RN gene mutations.