Zouheir Sahnoun

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.

Pharmacological Studies of Artichoke Leaf Extract and Their Health Benefits

Artichoke (Cynara scolymus) leaf extract was one of the few herbal remedies which the clinical and experimental trials have complemented each other. Both experimental and clinical effects have been verified through extensive biomedical herbal remedy research. Specifically, antioxidant, choleretic, hepatoprotective, bile-enhancing and lipid-lowering effects have been demonstrated, which corresponded with its historical use. Ongoing research seems to indicate that artichoke indeed have medicinal qualities. Most significant appears to be its beneficial effect on the liver. In animal studies, liquid extracts of the roots and leaves of artichoke have demonstrated an ability to protect the liver, with possibly even to help liver cells regenerate. Although research is not yet conclusive, scientists were optimistic that its long-standing use in humans for digestive and bowel problems was indeed justified. It may also play a role in lowering cholesterol and thus help to prevent heart disease. Boiled wild artichoke reduced postprandial glycemic and insulinemic responses in normal subjects but has no effect on metabolic syndrome patients. This article intended to review the wide ranging pharmacological effects of artichoke leaf extract.

Evaluation of efficacy of natural astaxanthin and vitamin E in prevention of colistin-induced nephrotoxicity in the rat model

OBJECTIVE We evaluated the effect of astaxanthin (ASX) and vitamin E (vit E) on colistin methanesulfonate (CMS) induced-nephrotoxicity in rats. METHODS Animals were treated with sterile saline, 300000 or 450 000 IU/kg/day of CMS, CMS + ASX (20 mg/kg), CMS + vit E (100 mg/kg), or CMS + 1 ml/kg olive oil (OO) for 7 days. The plasma/urine creatinine (Cr) level, urine γ-glutamyl-transferase (GGT) level, and renal tissue activities in malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reductase (GSH), as well as renal histology were performed. RESULTS CMS induced a tubular damage, increased the GGT and MDA levels, and decreased the activities of SOD, CAT, GPx and GSH. Co-treatment with ASX or vit E restored all biochemical parameters cited above and improved the histopathological damage. CONCLUSION Nephrotoxicity induced by CMS might be due to oxidative damage. The improvement by ASX or vit E seems to be related to their antioxidant properties.

Microstructure, rheological and wound healing properties of collagen-based gel from cuttlefish skin

Collagen-based biomaterials are of the utmost importance for tissue engineering and regenerative medicine. The aims of the present investigation were to evaluate structural and rheological properties of collagen-based gel obtained from cuttlefish skin, and to investigate its ability to enhance wound healing. Scanning electron microscopy of resulted gel showed a dense fibrillar microstructure with high interconnection network with a smaller pore size. In addition, the rheological characterization of collagen gel showed an excellent reversibility, when subjected to a temperature variation. Moreover, in the wound-healing study, topical application of collagen based gel increased significantly the percentage of wound closure over a period of 12 days, when compared to the untreated and CICAFLORA(®)-treated groups. Wound-healing activity of collagen gel was confirmed by histopathology study. Thus, cuttlefish collagen based gel might be useful as a wound healing agent.

Antioxidant, antibacterial and in vivo dermal wound healing effects of Opuntia flower extracts.

Opuntia ficus-indica flowers are used for various medicinal purposes. The aims of the present investigation were to evaluate biological properties of O. ficus-indica flowers extracts and to investigate its antioxidant and antibacterial activities and its ability to enhance wound healing. The wound healing activity of the mucilaginous and methanol extracts of O. ficus-indica flowers were assessed using excision wound model in rats. After thirteen days of treatment by both extracts, a beneficial effect on cutaneous repair was observed as assessed by the acceleration of wound contraction and remodeling phases. Histopathological studies of the granulation tissue indicated that the derma is properly arranged with the Opuntia flowers extract, compared with the control group. The mucilage extract was more effective than the methanol extract, but both showed significant results compared with the control. Such investigation was supported by the efficiency of the methanolic and mucilage extract as antimicrobial and antioxidant. Indeed, the extracts showed a potential antioxidant activity determined by different test systems, namely DPPH radicals scavenging activity, trolox equivalent antioxidant capacity, reducing power, β-carotene bleaching assay and metal chelating activity and exhibited significant antibacterial activity against almost all tested bacteria.

Evaluation of colistin nephrotoxicity administered at different doses in the rat model

Abstract Objective: This study evaluated the usefulness of plasma Cystatin C (pCysC) along with urinary neutrophil gelatinase-associated lipocalin (NGAL), γ-glutamyltransferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), aspartate (AST) and alanine (ALT) aminotransferase to monitor colistin nephrotoxicity. Method: Male rats were given intramuscular (i.m.) injections of colistin in doses of 150,000 (G1), 300,000 (G2) and 450,000 IU/kg/day (G3) or normal saline (Control), every 12 h for 7 days. After the 14th injection, animals were placed in metabolic cages and urine samples were collected in the next 12 h. Thereafter, animals were euthanized, blood samples were collected and kidneys were removed for histological assessment. Results: Nephrotoxicity was completely dose-dependent according to pathologic findings. The major insults were acute tubular necrosis in the tubules of G3. No significant change in pCr was observed in all treated groups, but pCysC increased in the G3 compared to the control. In urinary markers, uNGAL level showed a dose dependant increase with significant change in the G2 and G3 groups compared to the control. However, there was no significant change in the AST, ALT, LDH or ALP activities but only GGT increased in the G3 compared to the control. Conclusion: Based on colistin doses used in our experimental study on rat model, histopathologic assessment remains the most accurate way to diagnose colistin nephrotoxicity. pCysC appears to be more reliable than pCr, and uNGAL seems to be the most sensitive factor of colistin nephrotoxicity.

Rhelogical, dermal wound healing and in vitro antioxidant properties of exopolysaccharide hydrogel from Pseudomonas stutzeri AS22.

The in vitro antioxidant activity and the in vivo wound healing performance of the exopolysaccharide EPS22, produced by Pseudomonas stutzeri AS22, were investigated. Antioxidant activity was evaluated by three different tests. The scavenging effect on DPPH radicals at a concentration of 1mg/ml was 80±1.41%. The reducing power reached a maximum of 1.26±0.02 at 2 mg/ml. Moreover, EPS22 showed good chelating ability and chelated almost 88.5±0.7% of ferrous ions at 0.75 mg/ml. The rheological characterization of EPS22 gel (0.5%) showed a pseudoplastic behavior, high elasticity, good mechanical strength and stability with high water-absorption ability. The application of the EPS22 gel on dermal full-thickness excision wounds in a rat model every two days, enhanced significantly wound healing activity and a total closure was achieved after 12 days of wound induction. Further, histological examination of biopsies showed advanced tissue regeneration, characterized by the presence of well-organized stratum of both derma and epidermis.

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.

Effect of Nigella sativa seeds on reproductive system of male diabetic rats

This study aims to investigate the effects of Nigella sativa seeds (NSS) on fertility of male diabetic rats. Animals were divided into 3 groups, one group was kept as control and the two other were rendered diabetic by alloxan (120 mg/kg b.wt). One group was left as diabetic control (Diab) and the second were treated (Diab+N) with 2% of NSS in diet for 30 days. Blood samples were collected for glucose and testosterone levels. Testis, epididymis, prostates and seminal vesicles were removed for sperm parameters and oxidant/antioxidant status. NSS improve semen quantity and mobility, and testosterone levels and testis; they decrease blood glucose and lipid peroxidation product level (LPO) and improve antioxidant activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), lactate dehydrogenase (LDH), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and aspartate and alanine aminotransferase (AST and ALT). NNS as a diet may be beneficial for diabetic fertility.

In Vivo Evaluation of the Anti-Inflammatory Effect of Pistacia lentiscus Fruit Oil and Its Effects on Oxidative Stress

In order to find new topical anti-inflammatory agents, we had recourse to a medicinal plant. This work was designed to determine the topical anti-inflammatory effect of Pistacia lentiscus fruit oil (PLFO), using carrageenan-induced paw edema rat model, and to evaluate its effects on oxidative stress. The topical anti-inflammatory activity of PLFO was compared to Inflocine® and estimated by measuring the diameter of paw edema, for 5 hours at a 1-hour interval. After that the rats were scarified and the inflamed paw tissue was removed for the exploration of some parameters of oxidative stress and histopathology. PLFO showed a significant anti-inflammatory activity in comparison with the Inflocine. The percentages of edema inhibition were 70% and % 51.5% (p < 0.01), respectively, after five hours. The treatment with PLFO and Inflocine led to significant increases (p ≤ 0.05) in the activities of CAT, SOD, and GPX and significant decreases in the MDA level and AOPP activity in the paw tissue after Carr injection, in comparison with the Carr group. Therefore, our findings demonstrate that PLFO might accelerate the development of new drugs which could be used scientifically as a source for natural health products in the treatment of topical inflammation.