Ribavirin Virazole

Structural Formula Ball-and-Stick Model Space-filling Model

Year of discovery: 1970 (ICN); Year of introduction: 1980 (for RSV in children); 1998 (in combination with interferon for HCV); Drug category: Nucleoside antimetabolite/antiviral; Main uses: For the treatment of hepatitis C (HCV) in combination with interferon-a or peginterferon-a; Other brand names: Rebetol, Copegus, Cotronak, Ribasphere. Sold as a generic drug since 2005; Related drugs Viramidine, HCV-796 (Wyeth & Viro-Pharma), Peginterferon-a.

Ribavirin, a broad-spectrum antiviral compound discovered in 1970, is currently a firstline therapy against hepatitis C in combination with interferon-a. Transmission of the Hepatitis C virus (HCV) requires its introduction into the bloodstream (e.g., by blood transfusion or intravenous drug use). The disease affects nearly 200 million people worldwide, including 4 million in the US. Individuals infected with hepatitis C usually show few if any symptoms within the first six months, making detection of the disease difficult. If left untreated, HCV infection eventually can lead to serious liver damage (cirrhosis) or cancer over a period of years (10-20). Liver failure in HCV infected individuals is the main reason for liver transplants in the US.

Ribavirin was first synthesized and shown to be active against a number of RNA and DNA viruses in the 1970s. It was first approved for the treatment of severe respiratory syncytial virus (RSV) infections in children in 1989. Following the discovery of the hepatitis C virus, ribavirin was tested as monotherapy in HCV infected individuals, but even prolonged administration did not result in the clearance of the virus. However, the combination of ribavirin with interferon-a (INF-a), a natural protein synthesized by immune cells in response to viral infections, led to clearance of HCV infection in many of the patients so treated.' The combination of INF-a and ribavirin is strongly synergistic, since either agent alone is relatively ineffective. Recently, peginterferon-a (INF-a covalently coupled to polyethyleneglycol) has been introduced as an improvement over INF-a that requires only weekly dosing because it is inactivated more slowly in vivo.2 Also, a prodrug for ribavirin, viramidine, is currently undergoing Phase III clinical trials. Viramidine (shown below) is eliminated from the body more rapidly than ribavirin and is expected to have fewer side effects.

ho"" 'oh nh Viramidine

Although the mechanisms of action of INF-a and ribavirin have not been established, it is possible that ribavirin diminishes the rate of viral replication sufficiently to allow more effective destruction of infected cells by INF-a-activated immune cells.3

The INF-a/ribavirin therapy of HCV is successful for about 90% of patients who have been infected for less than six months (acute phase) and successful in about 50% of those patients who have been infected for more than six months. Because the large doses used in ribavirin/INF-a therapy cause serious side effects (e.g., hemolytic anemia and flu-like symptoms), safer therapies are still needed. A potent HCV polymerase inhibitor, HCV-796, is currently in Phase II clinical development for the treatment of HCV in combination with peglNF-a, with and without ribavirin.

v HCV-796

1. N. Engl. J. Med. 1998 339, 1485-1492; 2. N. Engl. J. Med. 2006 355, 2444-2451; 3. Nature 2005 436, 967-972; Refs. p. 176

v HCV-796

1. N. Engl. J. Med. 1998 339, 1485-1492; 2. N. Engl. J. Med. 2006 355, 2444-2451; 3. Nature 2005 436, 967-972; Refs. p. 176

0 0

Post a comment