A randomized, double-blind controlled trial of interferon alpha-2b and ribavirin vs. interferon alpha-2b and amantadine for treatment of chronic hepatitis C non-responder to interferon monotherapy.

BACKGROUND/AIMS: Interferon-based regimens (alone or with ribavairin) are standard therapies for chronic hepatitis C. The aim of this study was to compare a 24-week regimen of interferon alpha-2b + ribavirin (IFN + RIBA) to interferon alpha-2b + amantadine (IFN + AMANT) in non-responders to previous interferon monotherapy. METHODS: In a multi-center, double-blind clinical trial, 118 patients (non-responders to previous interferon monotherapy) were equally randomized into the two arms: interferon alpha-2b (3 MU thrice weekly) and ribavirin (800 mg daily) vs. interferon alpha-2b (3 MU thrice weekly) and amantadine (200 mg daily). RESULTS: After 24 weeks of therapy, HCV RNA became undetectable in 34.8% (95% CI: 23.7-49.2) of IFN + RIBA and 19.6% (95% CI: 10.6-34.7) of IFN + AMANT (P = 0.10). This response was sustained in 3.9% (95% CI: 1.0-14.9) of IFN + RIBA and 0% of IFN + AMANT (P = 0.16). Ten patients from IFN + AMANT (17%) and 12 patients (20%) from IFN + RIBA were discontinued before completion of therapy. Of these, 7% in IFN + AMANT and 12% in IFN + RIBA were discontinued due to adverse effects. CONCLUSIONS: Re-treatment of interferon non-responders with a 24-week course of IFN + AMANT was not associated with any sustained viral eradication. Although IFN + RIBA in this group was associated with a reasonable end of treatment response, relapses were common and sustained responses were low.

Hepatocellular expression of glucose-6-phosphatase is unaltered during hepatic regeneration.

Gluconeogenesis and glycogenolysis are essential hepatic functions required for glucose homeostasis. During the initial phase of hepatic regeneration, the immediate-early genes (IEG) are rapidly expressed, and the IEG RL-1 encodes for glucose-6-phosphatase (G-6-Pase). G-6-Pase is a microsomal enzyme essential for gluconeogenesis and glycogenolysis. This study employs a partial-hepatectomy model to examine the expression and activity of G-6-Pase. After partial hepatectomy, rat hepatic G-6-Pase gene expression is transcriptionally regulated, and mRNA levels are increased approximately 30-fold. However, in contrast to this rapid gene induction, microsomal enzyme activity is unchanged after partial hepatectomy. Western blotting demonstrates that microsomal G-6-Pase protein expression is also unchanged after partial hepatectomy, and similar results are also noted in whole liver homogenate. Thus, despite marked induction in gene expression of the IEG G-6-Pase after partial hepatectomy, protein expression and enzyme activity remain unchanged. These data indicate that, although this hepatocyte IEG is transcriptionally regulated, the physiologically important level of regulation is posttranscriptional. This highlights the importance of correlating gene expression of IEG with protein expression and physiological function.

Hepatic regeneration is associated with preservation of microsomal glucuronidation.

Significant controversy exists regarding the regulation of glucuronidation during the process of hepatic regeneration. We used a partial hepatectomy rat model to elucidate the effects of hepatic regeneration on the various components of the microsomal glucuronidation system. Hepatic microsomes were prepared by standard sucrose density centrifugation, coupled with a modified technique involving Percoll centrifugation. Microsomal uridine diphosphate (UDP)-glucuronosyltransferase (UGT) protein expression and UGT messenger RNA (mRNA) levels were measured by Western and Northern blotting. UGT enzyme activity was determined toward two prototypical aglycones, p-nitrophenol and estrone, in intact and digitonin-treated microsomes. Microsomal uptake of the cosubstrate for all glucuronidation reactions, UDP-glucuronic acid (UDP-GlcUA), was determined using a rapid-filtration assay. Microsomal enrichment after hepatectomy was preserved only when the Percoll method was used. Microsomal UGT protein expression and UGT mRNA levels were unaltered after hepatectomy. UGT enzyme activity toward estrone was unchanged 1 day posthepatectomy compared with sham laparotomy controls. Similarly, p-nitrophenol glucuronide formation was unaffected by hepatic regeneration 1, 2, and 5 days posthepatectomy when digitonin-treated microsomes were used. Glucuronidation of p-nitrophenol in intact microsomes was increased in partial hepatectomy compared with sham-operated controls at 1 and 2 days. This increase was not attributable to changes in microsomal UDP-GlcUA uptake, which was comparable in both groups. We conclude that microsomal glucuronidation, in contrast to other well characterized hepatic metabolic functions, is highly preserved during liver regeneration.