DRESS characteristics according to the causative medication.

BACKGROUND: To date, no study has identified a clear relationship between drug and a specific clinical presentation of DRESS. OBJECTIVES: To investigate the particularities of DRESS and analyze the variation of DRESS pattern according to culprit drugs. METHODS: We analyzed cases of DRESS notified to the Department of Clinical Pharmacology at the University Hospital of Monastir over a 15-year period. The statistical study was performed using the comparative and multivariate analysis. RESULTS: DRESS was mostly induced by anticonvulsive agents (27%) followed by allopurinol (26.3%) and antibiotics (24%): For anticonvulsive agents, the occurrence of lymphadenopathy was higher, renal involvement was rare and mild, and positive skin tests were more frequent. The allopurinol group was associated with the patient's older age and a lower incidence of lymphadenopathy and kidney injury. For antibiotics, eosinophilia rate was lower, time to recovery was shorter, and RegiSCAR score was low. The multivariate analysis showed a link of allopurinol with severe renal impairment, antibiotics with short latency period and low RegiSCAR score, and anticonvulsants with high propensity of positive skin test. CONCLUSION: We report the largest African and south Mediterranean cohort of DRESS and evaluated the usefulness of skin tests in identifying the culprit drug. The prominent finding was that latency period and renal involvement may independently differ according to culprit drugs.

Population pharmacokinetic model of isoniazid in patients with tuberculosis in Tunisia.

AIMS: To develop a pharmacokinetic model of isoniazid (INH) concentration taking into account demographic factors and genetic variables [N-acetyltransferase 2 (NAT2) genotype], and to propose an initial INH dosage that could maximize the probability of achieving the desired INH concentration. METHODS: A retrospective analysis was undertaken of INH concentration data collected from patients with tuberculosis in Tunisia. RESULTS: In total, 118 patients were included in this study. The one-compartment model [volume of distribution (V), elimination rate (Ke)] was found to have good predictive performance. Multi-variate analysis showed that NAT2 affected both V and Ke significantly, but age, gender and weight did not. Internal validation of the final model showed correlation of 0.95 between individual predicted INH concentration 3 h after drug intake (C3) and observed C3. External validation showed that percentage mean absolute prediction error and percentage root mean squared error were 9.11% (range 0.62-35.8%) and 11.6%, respectively. Monte-Carlo simulation showed that doses of at least 225 mg/24 h and at least 450 mg/24 h attained a therapeutic concentration in >80% of patients in the NAT2 slow acetylator group and the NAT2 rapid/intermediate acetylator group, respectively. CONCLUSION: The pharmacokinetic model allowed optimization of individual dosing regimens of INH in patients with tuberculosis in Tunisia. This tool may facilitate improved efficacy of INH and prevent its toxicity in this population.

DRESS syndrome following furosemide administration: An unusual association.

INTRODUCTION: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe and rare adverse drug reaction. Several drugs are known to induce DRESS. Furosemide, a sulfonamide loop diuretic drug, is known to induce hypersensitive reactions such as bullous eruptions, acute generalized exanthematous pustulosis and lichenoid eruptions, but rarely DRESS. We describe herein a case of furosemide-induced DRESS that recurred after bumetanide administration. CASE REPORT: A 67-year-old man was admitted to the nephrology department for hypertension, gout and chronic renal failure. He received a multidrug therapy including captopril, nifedipine, allopurinol and furosemide. Six weeks after starting this treatment, he developed a maculopapular itchy and edematous skin reaction, facial edemaand fever. The laboratory findings showed 2200/mm3 of eosinophils (20%). Creatinine clearance decreased from 18.9 to 14.4 mL/min. Lactate dehydrogenase was at 600 IU/L (normal range 190-390 IU/L). Chest X-ray showed an interstitial lung injury. Skin biopsy findings were in accordance with a hypersensitive reaction. Furosemide was withdrawn and symptoms resolved completely three weeks later. A patch test with furosemide performed six weeks later was negative. The patient was given bumetanide, another sulfonamide loop diuretic, with recurrence of symptoms two months later. Bumetanide was withdrawn with a complete resolution of both clinical and biological symptoms within three weeks. CONCLUSION: We add to the literature another case of furosemide-induced DRESS with the particularity of cross reactivity with bumetanide.

Risk factors of isoniazid-induced hepatotoxicity in Tunisian tuberculosis patients.

Previous studies have shown controversial results on whether acetylator status causes isoniazid-induced hepatotoxicity (IIH). Moreover, the contribution of CYP2E1, a hepatic enzyme implicated in the formation of hepatotoxins, to the risk of developing IIH remains unclear. The objectives of this study were (i) to assess the quantitative relationship between the level of isoniazid serum concentration and the incidence of IIH and (ii) to evaluate the extent of implication of the N-acetyltransferase-2 (NAT2) and CYP2E1 polymorphisms genes to induce this disorder. Seventy-one patients with tuberculosis receiving a conventional antituberculosis regimen were included. NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction. Three restriction enzymes, RsaI, PstI and DraI were used to detect CYP2E1 RFLP and four different restriction enzymes, KpnI, TaqI, BamHI and Ddel were used to determine NAT2 acetylator status. Therapeutic drug monitoring (TDM) of isoniazid (serum concentration performed 3 h after the morning dose: C3) was performed. Cases of isoniazid-induced hepatotoxicity were diagnosed according to Benichou et al. Receiver Operating Characteristics curve analysis was used to evaluate the relationship between risk factors and the incidence of IIH. Eleven (15.4%) patients have developed IIH. Demographic factors, including age, weight and gender were not associated with the incidence of hepatotoxicity. High serum concentration of isoniazid (C3) was found to be a risk factor of IIH (area under the curve: 0.74, P=0.007, 95% confidence interval (95% CI): 0.56-0.93), with a cutoff value at 3.69 mg l-1 (odds ratio (OR): 13.2, P=0.0007, 95% CI: 2.9-59). Multivariate analysis showed that only a C3 over 3.69 mg l-1 remains a risk factor of IIH. NAT2 and CYP2E1 variants were not found to increase the risk of IIH when analyzed separately. However, combined analysis of the NAT2/CYP2E1 gene polymorphisms showed that patients with both DraI C/D and slow acetylator have an increased risk of IIH compared with other combined NAT2/CYP2E1 genotype profiles (OR: 8.41, P=0.01, 95% CI: 1.54-45.76). Our results suggest that a serum concentration of isoniazid over 3.69 mg l-1 and a combined genotype CYP2E1 DraI(C/D)/slow acetylator are major risk factors for IIH. Therefore, TDM of isoniazid and the determination of both NAT2 and CYP2E1 genotypes could be useful for the prediction and prevention of IIH in Tunisian tuberculosis patients.

Tacrolimus therapeutic drug monitoring in Tunisian renal transplant recipients: effect of post-transplantation period.

BACKGROUND: Most previous studies having focused on therapeutic drug monitoring of tacrolimus in renal transplant recipients have assessed the clinical response of patients. The aim of this study is to investigate the influence of post-transplant delay on tacrolimus dose, trough levels (C0) and dose/C0 ratio in a Tunisian renal transplant population. PATIENTS AND METHODS: A retrospective study including 110 renal transplant patients has been performed. Tacrolimus trough concentrations were adjusted according to the target range proposed by the European consensus conference on tacrolimus optimization. Samples for determination of tacrolimus blood level were subdivided according to the post-transplantation period into three groups. RESULTS: The initial dose required was 0.17 ± 0.05 mg/kg/day during the first 3 months after transplantation. A reduction of 36 and 65% of tacrolimus initial dose during the second (3-12 months) and third period after transplantation (>12 months), respectively, was required to maintain the concentration level within therapeutic range. These results were different from those found in other studies performed in different populations. We hypothesize that these differences in dosing requirement may be due to an interethnic polymorphism in the expression of enzymes involved in tacrolimus metabolism. CONCLUSION: These results could provide a simple therapeutic strategy to optimize tacrolimus prescription after renal transplantation in Tunisian population.

Severe ranitidine-induced anaphylaxis: a case report and literature review.

WHAT IS KNOWN AND OBJECTIVE: Ranitidine is a generally well-tolerated drug, and serious side effects are rare. However, ranitidine-induced anaphylaxis has been reported on rare occasions. We report on such a case and review other cases reported in the literature. CASE SUMMARY: A 36-year-old man with no history of other medications, illnesses or allergic diseases, especially to drugs, consulted our emergency department because of renal colic and epigastric discomfort. He was given 50 mg of ranitidine as a slow intravenous bolus and 20 mg of piroxicam intramuscularly. Within the first minute, the patient developed a cold sweat, trembling, dyspnoea and deterioration of his consciousness. The condition was considered as an anaphylactic shock, and cardiopulmonary resuscitation and inotropic support were immediately commenced. Two days later, he was weaned off the ventilator as he was haemodynamically stable. He was discharged after 7 days. Four weeks later, skin prick tests to ranitidine and piroxicam were performed on the forearm of the patient. He reacted strongly to ranitidine about 10 min later but not to piroxicam. To assess cross-reactivity to other H2- and H1-receptor antagonists in our patient, we subsequently performed prick tests to famotidine, cimetidine and desloratadine and all were negative. WHAT IS NEW AND CONCLUSION: We re-emphasize a potentially serious, albeit very rare, adverse effect of ranitidine and summarize other reported cases. This case demonstrates that commonly used, generally safe drugs may on occasions cause serious adverse effects.

[Allergy to betalactams: myth and realities]. / Allergie aux bêtalactamines : mythe et réalités.

Allergic reactions to penicillins have been reported since the 1950s, shortly after their introduction as therapeutic agents. An increasing number of reported anaphylactic reactions and other adverse effects proved this to be a serious public health problem. Fifty years later, betalactam-induced hypersensitivity is the most frequent cause of drug reaction and has been the source of a great number of publications. Clinically, betalactam-induced allergic reactions may be immediate or non-immediate according to the time interval between drug intake and the occurrence of symptoms. The diagnosis of betalactam hypersensitivity is based on skin tests methods, in vitro tests and drug provocation test. There are three classical methods for skin testing: prick, intradermal, and patch. These tests are still the most sensitive techniques. In vitro tests, mainly based on the quantification of IgE antibodies to betalactams by immunoassay (Fluorescent Enzyme Immunoassay [FEIA]), may sometimes yield useful complementary information. Drug provocation tests must be performed with the required caution and the adequate indication. Algorithms are available for both immediate and non-immediate reactions to provide a practical approach for patient evaluation. They are based on the following data: clinical history, skin tests, FEIA, and drug provocation tests. Finally, cross reactivity between betalactams has been reported, especially between penicillins and cephalosporins. Their frequency was long over-estimated, but recent evidence, indicates that cross reactivity between betalactams has become rare. Administration of cephalosporins in patients with a history of penicillin allergy requires performing skin testing with penicillin, the probably allergenic drug, and the cephalosporin to be prescribed.

Les effets indesirables medicamenteux : experience de l'unite de pharmacovigilance de Monastir

Introduction : Les effets indesirables medicamenteux representent une cause importante de morbidite voire de mortalite. Notre etude a pour objectifs d'analyser les aspects epidemiologiques; cliniques et chronologiques des effets indesirables et de cerner les differents medicaments impliques dans l'apparition d'effets indesirables. Materiel et methodes : Etude retrospective portant sur toutes les observations notifieesa l'unite de pharmacovigilance de Monastir pendant 45 mois (de avril 2004 a decembre 2007). L'imputabilite medicamenteuse a ete etablie selon la methode de Begaud et al. Resultats : Nous avons ete sollicites pour etablir l'imputabilite medicamenteuse de 277 evenements. L'origine medicamenteuse a ete retenue pour 157 patients (56;6). Il s'agissait de 77 hommes et 80 femmes. L'age des patients a varie de 1 a 87 ans avec une mediane de 39 ans. La majorite des effets imputes aux medicaments etaient des manifestations cutanees (70;7) suivies des effets indesirables hepatiques (10;2). Les autres evenements etaient a type de syndrome pseudo parkinsonien; des reactions anaphylactiques et hematologiques. Les beta-lactamines etaient les plus incriminees aux manifestations cutanees (35); suivies des autres anti-infectieux (30). Conclusion : Nous avons mis en evidence une predominance des effets indesirables cutanes et une implication accrue des anti-infectieux dans la survenue de ces effets

[Adverse effects of antitubercular drugs: epidemiology, mechanisms, and patient management]. / Les effets indésirables des antituberculeux: épidémiologie, mécanismes et conduite à tenir.

Tuberculosis, what ever its localization, is an infectious disease which can be totally cured by combining antitubercular drugs. Current therapeutic regimens with isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin have proved successful in treating tuberculosis. However, they are associated to a high rate of adverse effects that can lead to therapeutic failure. Understanding the nature and the severity of these adverse effects allows for their appropriate management. Toxic neuropathy and hepatitis are the most common adverse reactions to isoniazid. Rifampicin is generally well tolerated but some severe immuno-allergic reactions may occur in case of intermittent regimen. Pyrazinamide-induced liver injury is rare but sometimes lethal. Joint affections, usually due to hyperuricemia, are more frequent but easily manageable. The major adverse effect related to ethambutol is ocular optic neuropathy. It occurs dose-dependently and can be irreversible. Finally, administration of streptomycin is potentially associated with renal and cochleo-vestibular toxicity that might be milder than when induced by other aminoglycosides. The management of antituberculosis-induced adverse effects depends on parameters related to the adverse effect itself and to the administrated drug.