INDOMETHACIN ENHANCES SERUM 2'5'-OLIGOADENYLATE SYNTHETASE IN PATIENTS WITH HEPATITIS-B AND HEPATITIS-C VIRUS CHRONIC ACTIVE HEPATITIS

Activation of the arachidonic acid metabolism seems to be one of the post-receptor mechanisms by which interferon-alpha induces antiviral protein synthesis. In this study, we evaluated the changes on serum 2'5'-oligoadenylate synthetase levels induced by acute administration of interferon-alpha, indomethacin and interferon-a plus indomethacin in 21 patients with hepatitis B or C virus chronic active hepatitis. Serum samples for 2'5'-oligoadenylate synthetase determination were collected in basal conditions and 8 h after the administration of interferon-alpha, indomethacin and interferon-alpha plus indomethacin. Compared to control value (mean +/- SE) (40.2 +/- 7.9 pg/dl) serum 2'5'-oligoadenylate synthetase concentration was significantly increased 1.5-fold after interferon-alpha (63.4 +/- 11, p<0.001), 2.8-fold after indomethacin (115.5 +/- 21, p<0.001) and 3.7-fold after interferon-alpha plus indomethacin (148.9 +/- 25.1, p<0.001). When patients with different viral infections were considered separately, basal 2'5'-oligoadenylate synthetase concentrations were similar in both HBeAg and HBeAb-positive patients, but about 2-fold higher in hepatitis C virus. Compared to the control value, interferon-alpha caused a 1.5-fold increase in HBeAg- and hepatitis C virus-positive and a 2-fold increase in HBeAb-positive patients. Indomethacin led to a 1.8-fold increase in HBeAg, a 2-fold increase in hepatitis C virus-positive and surprisingly a 6.8-fold increase in HBeAb-positive patients. Simultaneous administration of the two drugs had an additive effect on the 2'5'-oligoadenylate synthetase increase in HBeAg-positive (2.4-fold increase) and a synergistic effect in hepatitis C virus- and HBeAb-positive patients (2.7- and 10.2-fold increase, respectively). Apart from confirming the interaction between arachidonic acid metabolites and interferon-alpha, the results of this study suggest both an altered antiviral response to interferon-alpha in viral chronic active hepatitis and the possibility that nonsteroid anti-inflammatory drugs can enhance the antiviral activity of interferon-alpha. We conclude that the association of interferon-alpha with nonsteroid anti-inflammatory drugs in patients with chronic viral hepatitis, who are non-responders to interferon-alpha alone, should be evaluated, taking into account the possible side effects of nonsteroid anti-inflammatory drugs. (C) Journal of Hepatology.