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.

Implication of the Galectin-3 in colorectal cancer development (about 325 Tunisian patients).

Galectin-3 is a specific soluble lectin of the beta-galactoside family. It plays an important role in cell adherence, proliferation, and differentiation. It has also been shown that galectin-3 expression correlates with tumor progression in several types of cancers. We investigated the involvement of galectin-3 in colorectal cancer development. We performed a comparative immunohistochemical analysis of galectin-3 expression in term of intensity and distribution in normal mucosa, in primary tumor and in metastasis from 200 patients with colorectal cancer selected among 325 cases. We also compared the galectin-3 staining according to the histological subtype (mucinous vs non mucinous), tumoral differentiation and stage of tumor. We showed a strong and diffuse positive staining of galectin-3 in both adjacent and distanced normal mucosa, in well differentiated adenocarcinoma and in metastasis. However, we note a progressive decrease of galectin-3 staining according to the decreasing degree of tumoral differentiation. We also observed a loss of this protein in adenocarcinoma with mucinous component < 50%, where the positive staining was limited only to the well differentiated areas of tumor. These data suggest that galectin-3 play an important role in colorectal cancer progression concerning the non mucinous carcinoma and can be used as a prognostic factor to predict poor outcome of patients. In mucinous subtype, galectin-3 might be implicated in one or many step of its genesis perhaps through the control of cellular adhesion and interaction with mucin produced. Adenocarcinoma with mucinous component <50% would be integrate to mucinous carcinoma, not to non mucinous ones. These investigations could open perspectives for therapeutic means targeted to improve the prognosis of this neoplasm.