Effects of reduced glutathione and n-acetylcysteine on lidocaine metabolism in cimetidine treated rats.

The aim of this work was to evaluate the effects of exogenous glutathione (GSH) and N-acetylcysteine (NAC) on the formation of monoethylglycinexylidide (MEGX) from lidocaine in rats with and without the administration of cimetidine. GSH and NAC were administered intraperitoneally (i.p.) (1 mmol/kg) 1 hour before treatment with cimetidine (0.5 mmol/kg) or saline, and 1 hr later all rats were injected i.p. with lidocaine (1 mg/kg). Blood samples were drawn 30 min after the lidocaine injection. MEGX and lidocaine serum concentrations were determined by means of fluorescence polarization immuno-assay using the TDX system. Cimetidine produced a decrease in MEGX levels (from 210 +/- 18 to 164 +/- 13 ng/mL) and a parallel increase in lidocaine levels (from 73 +/- 22 to 172 +/- 47 ng/mL), consistent with cytochrome P-450 3A inhibition. Both GSH and NAC produce a significant decrease in MEGX levels (151 +/- 16 and 139 +/- 14 ng/mL, respectively), but no significant increase in lidocaine levels were found. As compared to the cimetidine group, pre-treatment using either GSH or NAC with cimetidine produced a marked decrease in lidocaine levels (37 +/- 27 and 63 +/- 28 ng/mL, respectively) and no modification of MEGX levels (155 +/- 12 and 165 +/- 22 ng/mL, respectively). These results suggest that GSH and NAC might accelerate the lidocaine metabolism while counteracting the inhibitory effect of cimetidine.

Serum lipid levels during interferon therapy in patients with chronic hepatitis C.

Interferon-alpha (IFN-alpha) may affect lipid metabolism by stimulating hepatic fatty acid synthesis. The aim of this study was to evaluate serum lipid levels during IFN-alpha therapy in patients with biopsy-proven chronic active hepatitis C. A total of 22 patients (18 males and 4 females; age 25-55 years) received 3 MU of recombinant IFN-alpha 2b 3 times a week for 6 months. Serum lipids were determined at baseline and then every month until the end of therapy. All patients had normal serum lipid levels at baseline. No significant level of modification occurred in patients during the therapy. An increase in serum lipid levels during low-dose IFN-alpha therapy seems to be uncommon in hepatitis C virus-infected patients with baseline normal levels.

Detection of anti-HCV IgM antibodies in patients with chronic hepatitis C treated with interferon.

OBJECTIVE: To assess the role of IgM antibodies to hepatitis C virus core protein (anti-HCV IgM) as a marker of chronic HCV infection and as a predictor of successful interferon (IFN) treatment. DESIGN: Anti-HCV IgM levels were evaluated at baseline, during IFN therapy and during a follow-up period. METHODS: Anti-HCV IgM levels were evaluated in 62 patients (47 men and 15 women, aged 25-65 years) with biopsy-proven chronic active hepatitis C. Fifty-one of the patients received alpha-IFN 3 MU three times a week for 6 months and 11 received the same therapy for 12 months. Twenty patients showed a long-term response; fourteen responded but subsequently suffered a relapse; twenty-eight did not respond to the treatment. Follow-up in all patients lasted for at least 6 (mean +/- SD 9.8 +/- 5.4, range 6-29) months after the end of the therapy. RESULTS: Anti-HCV IgM were detected in 35 patients (56.4%) at baseline; no significant differences were observed between the three groups studied. Almost all members of the groups showing a relapse or no response remained positive at the end of therapy and follow-up. In contrast, we observed a progressive disappearance of anti-HCV IgM in patients responsive to interferon therapy over the long term. CONCLUSION: The loss of anti-HCV IgM positivity in patients positive at baseline can predict the long-term response to IFN therapy.

Caffeine clearance in subjects with constitutional unconjugated hyperbilirubinemia.

To investigate the behaviour of caffeine (CAF) in patients with Gilbert's Syndrome (GS), a combined oral loading test of caffeine and chenodeoxycholic acid was performed in 14 healthy subjects and 71 patients with GS. Indocyanine green (ICG) kinetics was tested in 50 subjects with GS and in all control subjects. Fasting serum bile acids (SBA) and clearance after CDCA loading were within normal range in normal and GS subjects. No significant difference in levels either of bilirubin or of SBA was observed in GS cases with normal (52 cases, 488 +/- 63 ml/min) or impaired (19 cases, 338 +/- 30 ml/min) caffeine clearance. Eleven GS cases showed altered ICG clearance. No correlation was found between bilirubin and bile acids, CAF or ICG. Fasting SBA were normal even in cases of CAF or ICG altered kinetics, thus excluding structural damage in unconjugated hyperbilirubinemia. CAF altered kinetics in 27% of GS cases may suggest multiple deficits in the hepatocellular metabolism, thus confirming the heterogeneity of this syndrome.

Lymphoblastoid interferon therapy in chronic hepatitis C: biochemical, virological and histological evaluation of two different doses.

Sixty patients of both sexes with biopsy-proven chronic hepatitis C were randomized to receive lymphoblastoid interferon 3 MU or 6 MU three times weekly for 6 months. A follow-up period of 3 months at the end of the therapy was scheduled. Thirty-two patients (53.3%) normalized alanine aminotransferase at the end of the therapy. Of these, 17 received 3 MU (56.7%) and 15 (50%) received 6 MU. Eighteen of the 32 patients (56.2%) relapsed in the follow-up period after treatment. No significant difference in relapse rate was observed between the two groups. The overall percentage of the non-responder patients was 36.6%. The treatment was discontinued because of non-compliance and/or side effects in six patients (10%): three in the 3-MU group and three in the 6-MU group. An improvement in liver histology was observed in about a quarter of chronic active hepatitis patients whose overall diagnosis changed to chronic persistent hepatitis. Knodell's score system showed a significant improvement (p < 0.05) with regard to peripheral necrosis, fibrosis and total score. HCV-RNA was positive at the beginning in all patients and it became undetectable in almost all responder patients. In some cases there was no correlation between viraemia and biochemical signs of liver disease. Our study shows that 6 MU does not increase the response rate compared to 3 MU. Moreover, the lower dose is able to improve the liver histology and to abolish the HCV viraemia in responder patients.

Biochemical scores could reflect histological activity in chronic hepatitis C.

Eighty-one patients with HCV positive chronic active hepatitis (CAH) were studied to correlate, in multivariate regression analysis, liver tests with the histological activity index (HAI). The median HAI value (9.4) divided the patients into two groups; 44 under the 9.4 value (moderate CAH) and 37 above (severe CAH). Multiple regression improved the significance of nine biochemical parameters related to HAI in univariate analysis, and backward stepwise analysis identified the combination of alanine-aminotransferase (ALT), gammaglobulins (gamma GL), gammaglutamyl transpeptidase (gamma GT) and prolyl-hydroxylase (PH) as the best relationship with HAI (R = 0.520, p < 0.0001). A biochemical activity index (BAI) calculated as: 2.304 + ALT x 0.013 + gamma GL x 1.76 + gamma GT x 0.008 + PH x 0.012 showed the higher significant difference between moderate (7.7 +/- 1.3) and severe (12.2 +/- 2) CAH (p < 0.0001). These results suggest that this BAI could be a pointer for checking activity of chronic liver diseases.