Vaccines have provided considerable success in preventing viral disease, but they have modest or no therapeutic effect for individuals who are already infected. The assays described include systems for investigating drugs used against herpesviruses, hepatitis viruses, human immunodeficiency viruses, human papillomaviruses, and influenza viruses. Herndier, M. N-MCT inhibited KSHV virion production in lytically induced KSHV-infected BCBL-1 cells with a substantially lower 50% inhibitory concentration (IC50) than those of cidofovir (CDV) and ganciclovir (GCV) (IC50, mean ± standard deviation: 0.08 ± 0.03, 0.42 ± 0.07, and 0.96 ± 0.49 μM for N-MCT, CDV, and GCV, respectively). A prolonged elimination phase seen in vivo, correlates with a long intracellular half-life seen in vitro and allows for efficacy in animal models of virus infection with infrequent dosing or prophylaxis. Furthermore, particular attention has been focused on our understanding of the mechanisms of drug resistance and how that understanding will guide us in the development of more effective antiviral drugs and drug usage. In contrast, zidovudine and foscarnet have synergistic effect and no pharmacokinetic interaction has been detected.
For therapy of resistant mucocutaneous HSV disease, topical trifluorothymidine, and topical or intravenous cidofovir (HPMPC) have yielded encouraging results that warrant further investigation. However, concomitant use of zidovudine and ribavirin is not advised. Although no pharmacokinetic interaction was documented when didanosine was first administered with intravenous ganciclovir, recent studies have shown that concentration of didanosine are increased by 50% or more when coadministered with intravenous or oral ganciclovir. Less established associations have been reported for renal failure [Chapenko 2009,], hemophagocytic syndrome [Marabelle 2010, Dharancy 2008], myocarditis [Leveque 2011], pneumonitis [Yamaguchi 2003], hypogammaglobulinemia [Kano 2004], and arteriopathies [Takatsuka 2003]. ANTIVIRALS aims to introduce 15 ESRs to state-of-the-art knowledge and technology applied in antiviral drug development through both local and network-wide training activities. On day 1, 10 ml of BCBL-1 cells at 2 × 105 cells/ml (in RPMI 1640 medium [Life Technologies, Burlington, Ontario, Canada] supplemented with 10% heat-inactivated fetal bovine serum) were pelleted at 250 × g for 10 min and then washed with 2 ml of phosphate-buffered saline. The latter feature is especially useful for documenting variations in viral DNA load over time.
Ganciclovir has been shown to be phosphorylated in the presence of both the HHV-8 thymidine kinase (open reading frame [ORF] 21) and the HHV-8 phosphotransferase (ORF36) . For example, EBV PK (the product of the BGLF4 gene) phosphorylates a number of different viral and cellular proteins, including the viral DNA polymerase processivity factor BMRF1 (7, 22–24); the latent viral proteins EBNA1 (25), EBNA2 (26), and EBNA LP (27); the EBV immediate early (IE) protein BZLF1 (28); the cell cycle regulatory proteins p27 (29) and pRB (30); nuclear lamin A/C (7, 31); and interferon regulatory factor 3 (IRF3) (32). Very few interaction studies have been undertaken with other antiviral drugs. Coadministration of zalcitabine with the antacid ‘Maalox’ results in a reduction of its absorption. Dapsone does not influence the disposition of zalcitabine. Cotrimoxazole (trimethoprim-sulfamethoxazole) causes an increase in lamivudine concentrations by 43%. Nature continues to be a valuable source for new antimicrobial and anticancer pharmaceuticals (20, 21).
Some studies showed that interferons can reduce drug metabolism but only a few studies have evaluated the pathways involved. Further studies are required to better understand the clinical consequences of drug interactions with antiviral drugs. Molluscs make antiviral compounds that are active against a range of human viruses, which may reflect the inability of their innate immunity to tailor responses to specific viral pathogens.