Effect of 9-(1,3-Dihydroxy-2-PropoxymethyI)Guanine and Recombinant Human   Interferon Alone and in Combination on Simian Varicella Virus Infection in Monkeys

Abstract

Treatment of viral infections with combinations of antiviral agents may permit administration of reduced doses of either or both drugs. Lowered doses may reduce associated toxicity. Intravenous administration of substantial doses of either human recombinant beta interferon (rHuIFN-beta) or 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) prevents development of simian varicella virus infection in African green monkeys. Daily doses of 2 X 10(6) U of rHuIFN-beta/kg inhibited clinical disease in monkeys inoculated with simian varicella virus, and doses of DHPG between 20 and 60 mg/kg per day were necessary for similar antiviral effects. Intravenous administration of combinations of rHuIFN-beta and DHPG permitted an approximately 100-fold reduction in the effective dose of rHuIFN-beta and a 10-fold reduction in the effective dose of DHPG. Analysis of data relating to viremia by using the method of the median-effect principle showed the combination of rHuIFN-beta and DHPG was strongly synergistic in treatment of this infection.

Pharmacokinetics and antiviral activity in simian varicella virus-infected monkeys of (R,S)-9-[4-hydroxy-2-(hydroxymethyl) butyl]guanine, an anti-varicella-zoster virus drug

“…The dosage for therapeutic antiviral activity of (±)2HM-HBG administered intramuscularly was between 10 and 30 mg/kg of body weight per day. The effective dosage of (±)2HM-HBG must be, therefore, lower than those of ganciclovir and acyclovir (12,13).…”

“…The pooled, lysed infected-cell antigen from two to urea nitrogen and levels of creatinine, albumin, globulin, four wells was applied, followed by rabbit anti-VZV (20 ,ug total protein, total bilirubin, aspartate aminotransferase, and of immunoglobulin G per well) and alkaline phosphatasealanine aminotransferase in serum. labeled swine anti-rabbit immunoglobulin G (diluted 1:100 Virus inoculation was performed as previously described and applied at 100 ,u1 per well; Orion Diagonstica, Helsinki, (12 For the experiments reported in this paper, treatment was by either the intravenous or intramuscular route. In each experiment, blood was drawn for measurements of hematological and clinical chemical parameters and virus titer on days 3, 5, 7, 9, and, occasionally, 11 postinfection.…”

Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies

“…f. Anti-Epstein Barr virus agent combinations: Lin et al (1989), IFN ␣ , IFN ␥ ϩ AZT against Epstein-Barr virus in vitro. g. Antisimian varicella virus combinations: Soike et al (1987Soike et al ( , 1990 Kahan et al (1991a,b), C S A ϩ Rapa; Vathsala et al (1991), C S A ϩ Rapa; Kahan et al (1993), combinations in vitro and in vivo, brequinar ϩ C S A or ϩ Rapa, two-drug and three-drug combinations; Knight et al (1994) (1994), C S A, Rapa, and brequinar combinations, mice cardiac allografts; Kaji et al (1994), 15-desoxyspergualin ϩ C S A, rat cardiac allografts; Tu et al (1995), C S A, Rapa, and brequinar combinations, mice cardiac allografts; Hamashima et al (1995), donor antigen ϩ C S A or ϩ C S A/sirolimus, rats heart allografts. ii.…”

Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir

“…In vitro studies have demonstrated ganciclovir to have a similar efficacy to aciclovir for the inhibition of VZV infection 22 and it has been demonstrated to have activity against VZV in animal models as well as in BMT patients. 23 This suggests that during periods of ganciclovir use for CMV prophylaxis, the additional use of aciclovir for VZV suppression is unlikely to be necessary.…”