Mohamed Lakhal

An animal model of testicular toxicity by cyclosporine: evaluation and protection

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 21u2003days 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 4u2003mg/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.

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.

Adverse Drug Reactions in Older Adults: a Retrospective Study from Pharmacovigilance

PURPOSEnTo assess the adverse drug reactions notified in older adults to pharmacovigilance and to identify the incriminated drugs in their genesis.nnnMETHODSnA retrospective study including 688 notifications of adverse drug reactions to pharmacovigilance in patients aged of 65 years and more, over a period of 16 years and where the responsibility of one drug or more was incriminated in the genesis of the adverse reaction. Imputation was established according to the French method and seriousness according to the World Health Organization (WHO) criteria.nnnRESULTSnSex-ratio W/M was 1.2. Average age was 71.3 years. The average number of administered drugs was 3.64 and polymedication was noted in 30% of cases. Adverse drug reactions were essentially cutaneous and systemic. Incriminated drugs were mainly antibiotics and cardio-vascular drugs. Serious adverse drug reactions were noted in 26%.nnnCONCLUSIONnIn older adults, adverse drug reactions notification to pharmacovigilance is necessary and allows assessing large scale epidemiologic studies to identify iatrogenic risk factors.

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.

Effect of Liver Hypothermic Preservation: Exploration and Protection

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.

Hépatite aiguë sévère au nomégestrol (lutényl

Le Lutenyl® (nomegestrol) est un progestatif de synthese pouvant etre responsable de nombreux effets indesirables de frequence et de gravite variables. Latteinte hepatique est tres rarement rapporteeavec ce medicament. Elle est generalement moderee et de type cholestatique [1]. Aucun cas datteinte hepatique cytolytique imputable a lutilisation du nomegestrol na encore ete rapporte. Le mecanisme physiopathologique de cette atteinte na pas ete elucide.

Convulsion tardive après instillation de lidocaïne pour bronchoscopie

INTRODUCTIONnLidocaine toxicity usually appears rapidly and is directly correlated with plasma concentrations of the drug.nnnCASE REPORTnWe report a case of a late neurologic toxicity occurring after instillation of lidocaine during fibre-optic bronchoscopy. A patient with bronchiolitis obliterans underwent a diagnostic bronchoscopy. She received multiples instillations of Xylocaine(®) 2% (lidocaine). Three and a half hours later, she had a tonic-clonic seizure. Seven hours later, this recurred. Lidocaine plasma levels were in the toxic range at the time of the first seizure (18.32μg/mL) with a significant decrease in the concentration noted 24hours later.nnnCONCLUSIONnThe slow absorption of lidocaine into the blood from the bronchial tree explains the delayed neurologic toxicity. Our observation is a reminder that complications can occur due to high doses of lidocaïne administrated by instillation. Thus, if the recommended dose of lidocaine is exceeded, it is essential to monitor patients closely for a prolonged period, especially those with fibrosing lung disease in order to avoid possible late toxicity.

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

INTRODUCTIONnValproic 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.nnnMATERIAL AND METHODSnA 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).nnnRESULTSnSex 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).nnnCONCLUSIONSnCompliance should be appropriate in order to optimize the TDM rule. A good compliance and a therapeutic TPC allow a better control of epileptic seizures.

Serious Adverse Drug Reactions in Older Adults Notified to Pharmacovigilance

PURPOSEnTo 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.nnnMETHODSnA 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.nnnRESULTSnAdverse 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.nnnCONCLUSIONnSystemic 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.

Orofacial dyskinesia associated with tiemonium

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 2u2003months. The case was reported to the Tunisian Centre of Pharmacovigilance.