Enhanced efficacy of the acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine in combination with beta-interferon against herpes simplex virus type 2 in mice

Abstract

The acyclic nucleoside 9-(1,3-dihydroxy-2- propoxymethyl )guanine (DHPG) and natural mouse interferon beta ( MuIFN -beta) were evaluated for their efficacy alone and in combination against herpes simplex virus type 2 systemic infections in mice. Intraperitoneally infected animals were treated once a day with the drugs at various concentrations for 5 days starting 24 h after inoculation. DHPG was injected subcutaneously at doses of 0.7 to 6 mg/kg. MuIFN -beta was given intraperitoneally at doses ranging from 3 X 10(3) to 3 X 10(4) IU per mouse. For DHPG alone, the effective dose at which 50% of the mice survived (ED50) was greater than 6 mg/kg. However, when given in combination with an ineffective dose of MuIFN -beta (10(4) IU per mouse), the ED50 for DHPG was 0.8 mg/kg. In addition, at the highest dose tested, MuIFN -beta alone had no protective activity against herpes simplex virus type 2 (ED50, greater than 3 X 10(4) IU per mouse). However, when given in combination with a marginally effective dose of DHPG (2 mg/kg), the ED50 for MuIFN -beta was less than 3 X 10(3) IU per mouse. Calculation of the fractional protective dose index (less than 0.23 where values of less than or equal to 0.5 are considered synergistic) indicates an enhanced protective interaction by the combination of the two drugs. These results represent the first time that potentiation of the antiviral activity of an acyclic nucleoside by interferon has been demonstrated in animal studies.