Influence of age and co-medication on the steady-state pharmacokinetics of valproic acid in Tunisian patients with epilepsy.

AIM: Valproic acid (VPA) is a widely prescribed broad-spectrum antiepileptic drug. However, the use of VPA is complicated in clinical practice by its remarkably wide variability of pharmacokinetics. The objective of this study was to investigate the effects of demographic factors and associated therapies on steady-state plasma VPA concentrations in patients with epilepsy. METHODS: This retrospective cohort study was carried out using the routine therapeutic drug monitoring (TDM) database. Stepwise logistic regression analysis was used to compare serum VPA levels in 78 epilepsy patients treated with VPA in association with at least one other drug that could have interacted with CYP2C9, CYP2C19 or UGT enzymes. RESULTS: The frequency of subtherapeutic serum VPA levels was significantly increased with younger age (P<0.02), the number of co-medications (P<0.007) and use of enzyme-inducing co-medications (P<0.02). No significant correlations between VPA dose and trough plasma concentrations were found, as the latter did not increase in proportion to the dose. CONCLUSION: Routine monitoring of VPA serum levels would be extremely useful in epilepsy patients in the pediatric age group and in those who require associated enzyme-inducing medications.

Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis.

SETTING: Antituberculosis drug-induced hepatitis attributed to isoniazide (INH) is one of the most prevalent drug-induced liver injuries. INH is metabolized by hepatic N-acetyltransferase 2 (NAT2) to form hepatotoxins. AIM: To evaluate whether polymorphism of the NAT2 gene was associated with antituberculosis drug-induced hepatotoxicity in Tunisian patients. METHODS: A total of 66 patients with tuberculosis (TB) who received anti-TB treatment were followed prospectively. Their NAT2 genotype was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We identified three single nucleotide polymorphisms (SNPs); 481C to T (NAT2*5B), 590G to A (NAT2*6A) and 857G to A (NAT2*7B). Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. RESULTS: Fourteen patients (21.2%) were diagnosed with anti-TB drug-induced hepatitis. None of the rapid acetylators-type patients have expressed serum aminotransferase elevation. Among patients with hepatotoxicity, slow acetylators-type patients had a higher risk of hepatotoxicity than intermediate acetylators (21.4% vs. 78.6%, P=0.01). Statistical analysis revealed that the frequency of a variant diplotypes, NAT2*5B/5B and NAT2*6A/6A, were significantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity (P=0.01, odds ratio [OR]=7.6 and P=0.029, OR=15, respectively). By contrast, the frequency of the rapid acetylation NAT2*4 allele was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P=0.02, OR=0.18). Moreover, 590G/G genotype was associated with decreased hepatotoxicity (P=0.01); by contrast, homozygous point mutation at position 481 and 590 were associated with a higher risk of hepatotoxicity (P=0.01). CONCLUSION: Our results suggest that the slow-acetylator status of NAT2 is risk factor for INH-induced hepatotoxicity. Moreover, diplotypes, NAT2*5B/5B, NAT2*6A/6A, 481T/T and 590A/A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.

[Relationship between plasma concentrations of valproic acid and hepatotoxicity in patients receiving high doses]. / Relation entre les concentrations plasmatiques d'acide valproïque et la survenue d'une hépatotoxicité.

INTRODUCTION: Valproic acid (VPA) is an anticonvulsivant drug widely prescribed in the treatment of many forms of generalized epilepsy. In literature, the incidence of liver damage induced by AVP is 0.01%. It is potentialized by the combination therapy (phenobarbital, carbamazepine). Severe hepatotoxicity is rare and appears to be independent of dose and to cause a high mortality. METHODS: The aim of our study was to evaluate the relationship between plasma concentrations of AVP and the occurrence of side effects especially hepatotoxicity in patients receiving high doses of AVP. RESULTS: In this period, 425 plasmatic AVP monitoring were carried out in our laboratory. From 128 patients treated by high doses of AVP, only 73 were included in this study. Our work showed that adverse effects in epileptics under high doses of AVP was related to the association of the AVP with other antiepileptic in particular carbamazépine, phenobarbital and benzodiazepines rather than supra-therapeutic plasmatic concentrations of AVP. The association of AVP to major antiepileptics (carbamazépine and or phenobarbital) does not seem to generate an increase in the plasmatic concentration of AVP, which was not associated with a greater risque of adverse effects. CONCLUSION: Consequently, clinical signs of liver toxicity may be present in AVP concentrations generally considered in the therapeutic range especially when used in high doses and or combined with antiepileptic drugs like phenobarbital or carbamazepine.

[Medication adherence of a sample of hypertensive patients in the region of Sfax (Tunisia)]. / Observance médicamenteuse chez un échantillon d'hypertendus dans la région de Sfax (Tunisie).

THE AIM OF THE STUDY: Medication noncompliance is one of the daily problems of the physician. Improving the medication adherence allows better management of hypertension. The aim of this work was to determine the level of compliance for patients with hypertension and to identify factors that determine compliance. METHODS: A cross-sectional study was carried out among a sample of hypertensive patients attending general and specialist practitioners in public or private clinics of Sfax. Two hundred and seventy-three participants had accepted to be interviewed. Patients were identified as noncompliants using a questionnaire developed by the Comité de lutte contre l'hypertension artérielle (CFLHTA). RESULTS: Non-compliance rate was 63.4%. The low level of education was associated with a lower adherence. The monotherapy, the once-daily regimen with fewer number of tablets were associated with a better adherence (p<10(-6)). The welcome and the availability of drugs in the public clinic affect positively the adherence of patients (p<0.0002). A patient very satisfied with his consultation and the explanation given by the doctor about his illness and its treatment had a better adherence (p<0.00003). CONCLUSION: Our study had demonstrated a low compliance with antihypertensive drug therapy. Tunisian health care system should elaborate a management plan which takes into account our particular predictors of compliance to improve adherence to antihypertensive medication.

Investigation of the microcirculation and the state of oxidative stress in the rat after scorpion envenomation.

1. Severe cases of scorpion envenomation (SE) generally show both respiratory and cardiocirculatory dysfunction. However, the pathophysiology of SE remains controversial. In the present study, we tried to explain the pathophysiology of the haemodynamic perturbations and cardiac failure in rats poisoned by the venom of Buthus occitanus tunetanus through a histomorphometric study of myocardial and muscular skeletal microcirculation and analysis of the oxidative stress state in order to evaluate the implication of the inflammatory process in the pathogenesis of SE. 2. Experiments were performed on 96 rats divided into 16 groups (n = 6 in each group). Two groups were used to determine the optimum conditions of venom administration and times when to measure haemodynamic parameters. The B. occitanus tunetanus venom was administered at a dose of 800 microg/kg and tissues were removed 5 and 20 min after envenomation. Six groups were used for histomorphometric study: two control groups, two poisoned groups an two melatonin-pretreated and poisoned groups. The histomorphometric study was performed on isolated hearts and skeletal muscles. The final eight groups of rats (two control groups, two envenomated groups, two control groups pretreated with melatonin and two groups pretreated and envenomated) were used to investigate the state of tissue oxidative stress during SE and to evaluate the anti-oxidant effect of melatonin on rats poisoned with B. occitanus tunetanus venom. This study was based on the determination of tissue malondialdehyde in isolated organs as an indicator of thiobarbituric acid-reactive substances (TBARS). Melatonin was injected at a dose of 5 mg/kg, i.v., 15 min before the administration of serum or venom. Data were compared using analysis of variance and Tukey's test for multiple pair-wise comparisons. 3. Five minutes after venom injection, a significant reduction in the mean relative volume of venules and arterioles in the heart and skeletal muscles of poisoned rats was noted. Twenty minutes after venom injection, these volumes were significantly increased in the heart and skeletal muscles of poisoned rats. Pretreatment of envenomated rats with melatonin resulted in a significant decrease in the mean relative volume of the venules and arterioles in the heart and skeletal muscles 5 and 20 min after venom injection compared with untreated envenomated rats. Investigation of the oxidative stress state showed a highly significant increase in TBARS in poisoned rats compared with control groups 5 and 20 min after venom injection. Melatonin pretreatment of rats poisoned with B. occitanus tunetanus venom resulted in an important and highly significant reduction of TBARS compared with untreated envenomated rats. 4. It appears from the results of the present study that administration of B. occitanus tunetanus venom engendered an excessive myocardial and skeletal muscular vasoconstriction attributed to massive catecholamine release followed by arteriolar and venular vasodilatation. This venous stasis at the muscular microcirculation could be due to myocardiac failure. However, the concomitant presence of arteriolar vasodilatation suggests an inflammatory process in the pathophysiology of SE. This process was suggested by the genesis of a state of oxidative stress in relation to the important lipoperoxidation, which was inhibited by administration of the anti-oxidant melatonin. Thus, melatonin pretreatment seemed to accentuate the first phase of vascular reactivity in envenomed rats and inhibit the second vasodilator phase observed 20 min after administration of the venom.

Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men.

Numerous studies have reported beneficial effects of antioxidant drugs on semen quality, but there is no well-defined therapeutical protocol in male infertility. This study aimed to test the effects of vitamin E and selenium supplementation on lipid peroxidation and on sperm parameters. The study included 54 voluntary and infertile men who produced semen samples for spermiogram and for spectrophotometric measurement of a lipid peroxidation marker, the malondialdehyde (MDA), and produced blood samples for high-performance liquid chromatography assessment of serum vitamin E level. The trial was randomized and open. Twenty-eight men were supplemented daily by vitamin E (400 mg) and selenium (225 microg), during 3 months. The remaining 26 patients received vitamin B (4,5 g/day) for the same duration. Only 20 patients achieved their treatment and returned for control analysis. MDA concentrations in sperm were much less than in seminal plasma and motility and viability were inversely correlated with semen MDA levels. In contrast to vitamin B supplementation, vitamin E and selenium supplementation produced a significant decrease in MDA concentrations and an improvement of sperm motility. The results confirm the protective and beneficial effects of vitamin E and selenium on semen quality and advocate their use in male infertility treatment.