Rim Charfi

Methotrexate Side Effects: Review Article

Methotrextae (MTX) is an antifolate first developed to treat certain types of cancer. It was used at higher doses as a cancer therapy and since 1990 it is used at much lower doses to treat rheumatic diseases [1]. Side effects of MTX high dose (MTX-HD) may be life threatening, however those of various doses of oral MTX are variable because of the interindividual variability of gastrointestinal absorption of this drug. Bone marrow, gastrointestinal mucosa and hair are particularly vulnerable to the effects of MTX, secondary to their high rate of cellular turnover [2] and because MTX concentration is inversly proportianal to renal clearance [2], renal toxicity is frequent with MTX-HD.

The Val158Met COMT polymorphism is a modifier of the age at onset in Parkinson's disease with a sexual dimorphism

The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinsons disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.

Delayed Elimination of Methotrexate in a Patient Receiving Ciprofloxacin

High-dose methotrexate (HD-MTX) is indicated in neoplasic diseases. It is administrated at doses above 500 mg/m2 in association with alkaline hyperhydratation and folinic acid in order to interrupt the antifolinic activity of this chemotherapy.[1,2] It has several toxic side effects as mucosal ulcer, hepatitis and renal impairment.[2] This toxicity may be exacerbated by a delayed elimination of HD-MTX. Many factors may lead to the delayed elimination of HD-MTX such as renal impairment, third space fluid collections and drug-drug interactions. Non steroidal anti-inflammatory drugs (NSAIDs), probenicid, penicillin and sulfamethoxazole-trimethoprim are the most responsible of drug interactions with MTX.[3] We report herein a rare case of delayed elimination of HD-MTX associated with administration of ciprofloxacin.

Interaction médicamenteuse entre le tacrolimus et la théophylline chez un greffé rénal : à propos d’un cas

Le tacrolimus est un immunosuppresseur largement indiqué dans la greffe d’organes solides. [1] C’est un médicament métabolisé au niveau du foie par le CYP 450 3A4. De nombreuses interactions médicamenteuses sont observées avec les inducteurs et les inhibiteurs enzymatiques du système cytochrome P450, [2] entraînant dans le premier cas un risque de rejet de greffe par diminution des concentrations sanguines du tacrolimus et dans le second un risque de toxicité par augmentation de ses concentrations sanguines. Les principaux inducteurs enzymatiques interagissant avec le tacrolimus sont les anticonvulsivants, la rifampicine et les extraits de millepertuis. [2,3] Concernant les inhibiteurs enzymatiques, il s’agit essentiellement de macrolides, antiprotéases, antifongiques azolés, antagonistes calciques, amiodarone et inhibiteurs de la pompe à protons. [2,3] Nous rapportons dans ce travail un cas d’interaction médicamenteuse très rarement observé, entre le tacrolimus et la théophylline.

Vancomycin Therapeutic Drug Monitoring in Cerebrospinal Fluid

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.

Contribution of Therapeutic Monitoring in the Assessment of Toxic Adverse Effects of Mitotane: a Case Report

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.

Suivi thérapeutique de l’acide valproïque chez l’enfant : étude prospective de l’effet de l’observance et du niveau économique sur les concentrations plasmatiques résiduelles et les crises épileptiques

INTRODUCTION 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. MATERIAL AND METHODS 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). RESULTS 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). CONCLUSIONS 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.

Raccourcissement accidentel du temps de perfusion de méthotrexate à haute dose : cas clinique et revue de la littérature

Methotrexate (MTX) is a folic acid antagonist used at high-dose intravenously on 24 hours (24h) in the treatment of the acute lymphoblastic leukemia (ALL). To prevent potential toxicity, MTX is usually administered following the application of preventive measures. We report a case of an accidental shortening time for high dose MTX infusion and a literature review of accidental intoxications by the MTX. This case illustrates the importance of the respect of MTX high dose infusion time and the major role played by the therapeutic drug monitoring.

Serious Adverse Drug Reactions in Older Adults Notified to Pharmacovigilance

PURPOSE To report the serious adverse drug reactions (ADRs) in older adults notified to pharmacovigilance, to identify the incriminated drugs and to search for risk factors of occurrence. METHODS A retrospective study including 106 serious adverse drug reactions notified to pharmacovigilance in patients aged of 65 years and more, over a period of 16 years. Imputation was established according to the French method and seriousness according to the World Health Organisation (WHO) criteria. RESULTS Adverse drug reactions were essentially systemic. Incriminated drugs were mainly antibiotics, allopurinol and cardio-vascular drugs. Gender, age and number of administered drugs did not seem to be risk factors of serious ADRs occurrence. Among older adults, 4% died further to a serious ADRs. CONCLUSION Systemic notification to pharmacovigilance will allow a better analysis of risk factors of serious ADRs occurrence and to insure safety and health to the older adults.