Amantadine+Interferon/Ribivarin in Interferon Non-Responders

RANDOMIZED, CONTROLLED TRIAL WITH INTERFERON-ALPHA (IFN-ALPHA) COMBINED WITH RIBAVIRIN WITH AND WITHOUT AMANTADINE SULFATE IN PRIMARY IFN-ALPHA NONRESPONSIVE PATIENTS WITH CHRONIC HEPATITIS C
     G. Teuber, T. Berg, M. Lafrenz, H. Weidenbach, J. Schoelmerich, P. Wietzke-Braun, J. Pausch, R. Arnold, G. Lock, U. Hopf, S. Zeuzem University Clinic Frankfurt., Germany

Recent pilot studies suggested a beneficial effect of triple therapy with IFN-alpha combined with ribavirin and amantadine in primary IFN-alpha non-responders with chronic hepatitis C (1). The aims of the present study were to evaluate efficacy and safety of IFN-alpha/ribavirin retreatment with or without amantadine sulfate in a large cohort of IFN-alpha non-responsive patients. 134 consecutive IFN-alpha non-responders were enrolled. Patients received IFN-alpha 2b 5 MU daily for 4 weeks, 5 MU tiw for 20 weeks, followed by 3 MU tiw for additional 24 weeks in combination with ribavirin 1000-1200 mg/d (n=70) or with IFN-alpha/ribavirin plus amantadine sulfate 100 mg bid for 48 weeks (n=64). Treatment was discontinued in patients with detectable serum HCV-RNA after treatment week 24. An overall sustained virologic response with undectable serum HCV-RNA levels was observed in 27/134 patients (20.1%). Despite a trend towards a higher sustained virologic response rate in patients receiving triple retreatment compared with those treated with IFN-alpha/ribavirn alone (23.4% vs. 17.1%), the observed differences between the two treatment arms were not significant (p=n.s.). Irrespective of treatment, patients infected with HCV-genotype non-1 were more likely to respond to antiviral retreatment than patients infected with HCV-genotype 1 (38.8% vs. 17.2%, p=0.013). In conclusion, the present study does not confirm an antiviral effect of amantadine in combination with IFN-alpha and ribavirin. The observed relatively high overall sustained virologic response rate may be related to intensified interferon retreatment in combination with ribavirin compared to standard regimens. (1) Brillanti, S. et al: Hepatology 2000; 32: 630-4.

Monocyclic L-nucleosides with type 1 cytokine-inducing activity (ICN 17261)
     Journal of Medicinal Chemistry, 2000 Mar 9, 43(5):1019-28; Ramasamy, KS; Tam, RC; Bard, J; Averett, DR.

Abstract:
A series of 1,2,4-triazole L-nucleosides were synthesized and evaluated for their ability to stimulate type 1 cytokine production by activated human T cells in direct comparison to the known active agent ribavirin. Among the compounds prepared, 1-beta-L-ribofuranosyl-1,2,4-triazole-3-carboxamide (5, ICN 17261) was found to be the most uniformly potent compound. Conversion of the 3-carboxamide group of 5 to a carboxamidine functionality resulted in 1-beta-L-ribofuranosyl-1, 2, 4-triazole-3-carboxamidine hydrochloride (10), which induced cytokine levels comparable to 5 for two of the three type 1 cytokines examined. Modification of the carbohydrate moiety of 5 provided compounds of reduced activity. Significantly, ICN 17261 offers interesting immunomodulatory potential for the treatment of diseases where type 1 cytokines play an important role.