The therapeutic effectiveness of two new antiviral agents, 1-(2-fluoro-2-deoxy-P-D-arabinofuranosyl)-5-iodocytosine and 1-(2-fluoro-2-deoxy-p-D-arabinofuranosyl)thymine, was compared with that of acyclovir and vidarabine. In mice inoculated intracerebrally with high 50% lethal doses of herpes simplex virus type 2, nontoxic intraperitoneal or oral treatments with the two new fluorinated antiviral agents were highly effective in reducing mortality. The two drugs were also effective when treatment was begun as late as 48 h after virus inoculation. The relative order of potencies of the drugs when compared on a molar basis or in terms of therapeutic index was 1-(2-fluoro-2-deoxy-3-D-arabinofuranosyl)thymineacyclovir. The new pyrimidine analogs were also found to lack immunosuppressive activity in mice. The combination of 1-(2-fluoro-2-deoxy-p-D-arabinofuranosyl)-5-iodocytosine and vidarabine was the most effective; significantly greater reduction in mortality was achieved with this combination than with either drug alone. Thirty minutes after intraperitoneal treatment with the fluorinated analogs, the drugs (or their metabolites) were transported to the brains of virus-inoculated and normal mice at levels about one-third to two-thirds those in the blood. The levels of 1-(2-fluoro-2-deoxy-3-D-arabinofuranosyl)thymine in the blood or brain were consistently higher than those found with equivalent intraperitoneal doses of the 5-iodocytosine analog.The mouse encephalitis mnodel has been a useful indicator of drug efficacy in the treatment of human herpes encephalitis. This was demonstrated when the results of studies on the effect of vidarabine (ara-A) or 5-iodo-2'-deoxyuridine in mice infected intracerebrally with herpes simplex virus (HSV) (10,12) were compared with those for humans with HSV encephalitis (2,26). Whereas ara-A was effective in mice and in humans, 5-iodo-2'-deoxyuridine was shown to be inactive. Pharmacokinetic studies in mice and humans (at autopsy) later revealed that 5-iodo-2'-deoxyuridine does not cross the blood-brain barrier (10, 13). Two new antiviral agents, 1-(2-fluoro-2-deoxy-,B-D-arabinofuranosyl)-5-iodocytosine (2'-fluoro-5-iodoaracytosine; FIAC) and its thymine analog (2'-fluoro&5-mfthylarauracil; FMAUJ), were previously shown to have potent antiviral activities in cell culture and in mice inoculated intraperitoneally with HSV' type 1 (HSV-1) (8,9,14,24). It was therefore of interest to determine whether these drugs are also effective when virus is inoculated intracerebrally. Other than the route of infection, the efficacy of antiviral agents in the mouse encephalitis model depends on the (i) viral strain; (ii) infectious dose; (iii) time of initiation of treatment; (iv) route of treatment; (v) drug dose and schedule; and (vi) animal species, weight, and age. Several of these variables were examined in this report. In addition, since any evaluation of new antiviral agents in the treatment of human encephalitis within the United States will probably necessitate a comparative double-blind stu...