Intravenous infusion of cereport increases uptake and efficacy of acyclovir in herpes simplex virus-infected rat brains

Abstract

The outcome of herpes simplex virus (HSV) infections manifesting as encephalitis in healthy or immunocompromised individuals is generally very poor with mortality rates of about 8 to 28% with treatment. The long-term prognosis of survivors is often problematic, posing the need for alternative treatments that may decrease the mortality and morbidity associated with herpes encephalitis. This study addresses one such approach that includes a temporary permeabilization of the blood-brain barrier during treatment with acyclovir (ACV). In these studies we utilized a synthetic bradykinin analog, Cereport (RMP-7), in conjunction with ACV to treat HSV infection of the brain in a rat model. Cereport, infused intravenously via the jugular vein, was shown to increase [(14)C]ACV uptake in both the HSV-1-infected and -uninfected rat brain by approximately two- to threefold, correlating with enhanced efficacy of ACV in various brain compartments. In another series of experiments to determine efficacy, various doses of unlabeled ACV were administered during infusion with RMP-7. The decrease in viral titers in the temporal regions of the brain after 5 days of treatment suggested that this approach enhanced the efficacy of ACV treatment. These data indicated that Cereport infused with ACV enhances both the penetration and efficacy of this drug in the treatment of an experimental HSV-1 infection of the rat brain.

FIG. 1

Replication of HSV-1, E-377, in brains of rats inoculated intranasally. The pathogenesis of HSV-1 infection in rat brain was determined after intranasal inoculation of 2.4 × 10⁴ PFU of HSV-1. Following inoculation, animals were sacrificed on days 1, 2, 3, 4, 5, 6, 7, and 10. Olfactory lobes, cerebral cortex, cerebellum, diencephalon, and pons-medulla were removed, homogenized, and assayed for HSV-1. HSV-1 titers are expressed as log₁₀ PFU/gram of tissue. A value of 1 log₁₀ PFU/g of tissue is the lowest detectable limit.

FIG. 2

Effect of 20 mg of ACV/kg on the replication of HSV-1 in rat brain. The efficacy of 20 mg of ACV/kg administered during infusion with 6 μg of Cereport/ml was determined 7 days after infection in various portions of the rat brain. HSV-1 titers are expressed as the mean log₁₀ PFU/gram of tissue ± the standard deviation. Means reflect values obtained from four animals that survived out of five in each group. A value of 1 log₁₀ PFU/g of tissue is the lowest detectable limit.

FIG. 3

Effect of 40 mg of ACV/kg on the replication of HSV-1 in rat brain. The efficacy of 40 mg of ACV/kg administered during infusion with 6 μg of Cereport/ml was determined 7 days after infection in various portions of the rat brain. HSV-1 titers are expressed as the mean log₁₀ PFU/gram of tissue ± the standard deviation. Means reflect values obtained from three animals that survived out of five in each group. A value of 1 log₁₀ PFU/g of tissue is the lowest detectable limit.

FIG. 4

Effect of 80 mg of ACV/kg on the replication of HSV-1 in rat brain. The efficacy of 80 mg of ACV/kg administered during infusion with 6 μg of Cereport/ml was determined 7 days after infection in various portions of the rat brain. HSV-1 titers are expressed as the mean log₁₀ PFU/gram of tissue ± the standard deviation. Means reflect values obtained from six animals infused with Cereport and seven animals infused with saline (100% survival). A value of 1 log₁₀ PFU/g of tissue is the lowest detectable limit.