Intracerebroventricular and Intraperitoneal Disodium Phosphonoacetate Treatment of Herpes Simplex Virus Type I Experimental Encephalitis in Rats

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Abstract
Herpes simplex virus type 1 (HSV-l) was injected intracerebrally into rats, each with an implanted cannula in the contralateral cerebral ventricle. Either disodium phosphonoacetate (PAA), dissolved in phosphate-buffered saline (PBS) and administered in near maximally tolerable doses, or PBS alone was injected intraperitoneally (ip) or via the cannula (icv) to determine whether circumvention of the blood-brain barrier would yield results superior to those of systemic ip therapy. Mortality, survival times, and concentrations of HSV-l in the brain were compared. Seven of 26 rats given five daily injections of PAA ip starting 2 hr after viral inoculation died, as compared with 15 of 24 given PBS ip. PAA given icv on the same schedule, in doses 250 times smaller, resulted in an equivalent reduction in mortality. Mortality of animals given PAA icv for 11 days was not different from that of animals treated similarly for five days. The death rate was inexplicably higher, however, for animals given therapy ip for 10 days than for those treated for five days. Mortality was the same whether PAA treatment was initiated at 48 or 2 hr, regardless of the mode of administration. When PAA was started at 2 hr, the icv, but not the ip, route increased survival time. PAA reduced HSV-l concentrations in the brain at two days as compared with PBS, but there was no difference between the antiviral effects of PAA injected ip and icv. It was concluded that icv injection of PAA in order to circumvent the blood-brain barrier was not superior to ip injection of PAA.

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