Randomised clinical trial: the benefit of combination therapy with adefovir and lamivudine for chronic hepatitis B.

BACKGROUND: Combination antiviral therapy holds the promise of increasing response rates while decreasing antiviral resistance, but has yet to be shown to be beneficial or necessary in chronic hepatitis B. AIM: To evaluate the benefit of combination therapy with adefovir and lamivudine versus adefovir alone in maintaining virological, biochemical and histological responses. METHODS: Patients with chronic hepatitis B with and without previous lamivudine therapy were randomised to receive adefovir alone (10 mg/daily) or adefovir and lamivudine (100 mg/daily) for up to 192 weeks. Study endpoints were (i) maintained virological (HBV DNA <500 copies/mL), biochemical and histological response, (ii) loss of HBeAg and (iii) loss of HBsAg. RESULTS: A total of 41 patients were enrolled, including 31 HBeAg -positive and 31 treatment-naïve subjects. 30 patients remained on assigned therapy at 192 weeks. The percentage of patients achieving a combined maintained response was higher in the combination than the monotherapy arm, both at week 48 (59% vs. 26%, P = 0.06) and 192 (68% vs. 31%, P = 0.03). At week 192, 76% of the combination vs. 36% of the monotherapy group had loss of HBeAg (P = 0.03). One patient receiving adefovir cleared HBsAg. Adefovir resistance developed in 6 of 19 (32%) monotherapy but none of 22 combination treated patients (P = 0.03). CONCLUSIONS: Extended combination therapy with lamivudine and adefovir is associated with a high rate of long-term virological and biochemical response. Adefovir monotherapy appears to be less effective mainly because of poor initial response and the ultimate development of antiviral resistance (www.Clinical. Trials.gov NCT00023309).

Toxicity of endophyte-infected tall fescue alkaloids and grass metabolites on Pratylenchus scribneri.

ABSTRACT Neotyphodium coenophialum, an endophytic fungus associated with tall fescue grass, enhances host fitness and imparts pest resistance. This symbiotum is implicated in the reduction of stresses, including plant-parasitic nematodes. To substantiate this implication, toxicological effects of root extracts, polyphenolic fraction, ergot, and loline alkaloids from endophyte-infected tall fescue were investigated using Pratylenchus scribneri, a nematode pest of tall fescue. In vitro bioassays and greenhouse studies were used as tests for effects of root fractions and compounds on motility and mortality of this lesion nematode. Greenhouse studies revealed that endophyte-infected tall fescue grasses are essentially nonhosts to P. scribneri, with root populations averaging 3 to 17 nematodes/pot, compared with 4,866 and 8,450 nematodes/pot for noninfected grasses. The in vitro assay indicated that root extracts from infected tall fescues were nematistatic. Polyphenols identified in extracts included chlorogenic acid, 3,5-dicaffeoylquinic acids, caffeic acid, and two unidentified compounds, but these were not correlated with endophyte status, qualitatively or quantitatively. Tests of several ergot alkaloids revealed that ergovaline and alpha-ergocryptine were nematicidal at 5 and 50 microg/ml, respectively, while ergocornine and ergonovine were nematistatic at most concentrations. Loline (N-formylloline), the pyrrolizidine alkaloid tested, was nematicidal (50 to 200 microg/ml). The ecological benefits of the metabolites tested here should assist in defining their role in deterring this nematode species while offering some probable mechanisms of action against plant-parasitic nematodes in general.

Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a form of progressive fatty liver disease that is strongly associated with insulin resistance, which suggests that insulin sensitizing agents such as metformin may be beneficial for NASH. AIM: To assess the effects of metformin on insulin sensitivity, body composition, serum alanine aminotransferase (ALT) levels and liver histology in patients with NASH. METHODS: Patients underwent liver biopsy, metabolic profiling and imaging studies before and at the end 48 weeks of metformin (2000 mg/day) therapy. The primary endpoint was a three-point improvement in the histological NASH activity index. RESULTS: Of 28 patients enrolled, 26 (13 females; average age 44 years) completed 48 weeks of treatment and underwent repeat metabolic studies, imaging and liver biopsy. Thirty per cent achieved a histological response. Most patients lost weight, the average being 6 kg. There was a marked association between weight loss and improvements in NASH activity index and ALT levels (both, P < 0.01). Insulin sensitivity also improved, but the degree of change did not correlate with histological improvement. CONCLUSION: Metformin leads to improvements in liver histology and ALT levels in 30% of patients with NASH, probably by its effects in causing weight loss.