Nucleic Acid Research Institute ICN Pharmaceuticals, Inc. Irvine, California 92714
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 12/2006; 284(1):211 - 229. DOI: 10.1111/j.1749-6632.1977.tb21953.x

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    ABSTRACT: Absorption, metabolism, and excretion of [14C]viramidine, a prodrug of ribavirin, were studied in humans following a single oral dose (600 mg). Viramidine was rapidly absorbed, with a time to maximum concentration of the drug in plasma of 1.5 h. Viramidine and ribavirin accounted for only 4.3% and 42% of plasma area under the concentration-time curve (AUC) for radioactivity, respectively, indicating extensive conversion of viramidine to ribavirin, followed by further metabolism of ribavirin. The drug was largely trapped in red blood cells (RBC), with an RBC-to-plasma radioactivity AUC0-infinity ratio of 108. Excretion of total radioactivity in urine and feces accounted for 50.8% and 26.1% of the dose, respectively. The metabolic profile in urine (0 to 24 h) indicated that viramidine was excreted primarily as triazole carboxamide (TCONH2), triazole carboxylic acid nucleoside (TCOOH), and ribavirin with a small amount of unchanged viramidine, which each accounted for 64.1%, 17.0%, 15.7%, and 3.2% of urinary radioactivity, respectively. The amounts of unchanged viramidine (3.4% of dose) and ribavirin (10% of dose) in urine were small after oral administration of viramidine.
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    ABSTRACT: Hepatitis C virus (HCV) infections are treated with interferon alpha plus ribavirin, but it is unknown how ribavirin works against HCV. Ribavirin is a guanosine analogue that can be a substrate for the viral RNA polymerase. HCV is genetically variable, and this genetic variation could affect the polymerase's use of ribavirin triphosphate. Thirteen patients infected with HCV who failed interferon alpha monotherapy and were retreated with interferon alpha plus ribavirin were identified; seven were responders and six were nonresponders to combination therapy. The consensus sequences encoding the 13 polymerases plus seven sequences from treatment-naive controls were determined. The responder sequences were more genetically variable than the nonresponders and controls, the amino acid variations unique to responders had lower BLOSUM90 scores than variations in nonresponders and controls, and the amino acid variations correlated with response to therapy clustered around the RNA-binding channel of the polymerase. These data imply that that the responder enzymes were probably more functionally variable than the nonresponder enzymes. Enzymatic activity was measured for 10 recombinant polymerases; RNA synthesis activity varied by over sevenfold and polymerases from two of the responders used GTP much better than UTP, but technical limitations prevented direct measurement of ribavirin triphosphate use. Because response to combination therapy in these patients was primarily due to addition of ribavirin to the treatment regimen, these data imply that genetic variation in the polymerase may have affected the efficiency of ribavirin incorporation into the viral genome and hence may have modulated ribavirin's efficacy against HCV.
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    ABSTRACT: A considerable amount of information has accumulated during the past 10 years in the search for antiviral agents. Ribavirin and inosiplex are 2 interesting developments to come out of this search. Ribavirin, a synthetic nucleoside, has an unusually wide spectrum of antiviral activity, especially when tested in vitro. A large number of RNA and DNA viruses are sensitive, especially herpes viruses, poxvirus, influenza, parainfluenza, reovirus, togavirus, and RNA tumour viruses. The in vivo antiviral spectrum of activity is much narrower, with activity against herpes virus, influenza, parainfluenza, measles and adenoviruses. However, controlled clinical trials have not been uniformly successful in treating influenza, hepatitis, herpes simplex and herpes zoster. Inosiplex has been shown to have antiviral activity in vivo against influenza, herpes simplex, rhinovirus and vaccinia virus infections. However, antiviral activity has not been consistently demonstrated, and this observation led to further studies which revealed its immunomodulating effects. The accumulated evidence has indicated that inosiplex is more a prohost agent rather than an antiviral drug. Immune functions which are depressed during viral infection can be restored to normal by inosiplex therapy. At present, neither ribavirin nor inosiplex alone has been shown to be uniformly successful in the treatment of human viral diseases. Nevertheless, their potential place in chemotherapy should not be neglected, although further data are needed to determine what this place will be. Whether combining them with other antiviral agents such as interferon, acyclovir, Ara-A, and so on, would produce a potentiation of action and improved antiviral chemotherapy, will be an interesting area for further study.
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