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.Herpes simplex virus (HSV) infections in humans can manifest as a life-threatening disease with high mortality and significant morbidity in survivors. These infections can be caused by either HSV-1 or HSV-2 (2, 46). In neonates, primary infection that occurs during or shortly after birth is usually symptomatic within 1 month and is frequently lethal (42,43,46). Although treatment with either vidarabine or acyclovir (ACV) significantly reduces the mortality rate, up to 15% of those with encephalitis still do not survive (28,42,43,45). In older individuals, encephalitis caused by primary or recurrent HSV infection results in a 70% mortality rate without treatment and an 8 to 28% mortality rate with treatment depending on when treatment is initiated (32,45,46). This disease is characterized by acute necrotizing focal encephalopathy, inflammation and swelling of the brain tissue, and petechiae or larger hemorrhages in the brain (9,26,39,47). Although therapy with either vidarabine or ACV (42, 44) has proven to be effective in reducing mortality rates of HSV encephalitis, the long-term prognosis of the survivors is less than optimal. A few survivors suffer relapses, but many others have learning and memory abnormalities and impairment of general orientation and perceptive-motor skills (12,14,29). This current state of HSV encephalitis-associated mortality and morbidity suggests that alternative approaches to treatment need to be developed.One possible reason for reduced efficacy in the central nervous system (CNS) may be failure of the drug to penetrate the blood-brain barrier (BBB) and enter the CNS tissues. Inefficient penetra...

Potent In Vivo Antiviral Activity of the Herpes Simplex Virus Primase-Helicase Inhibitor BAY 57-1293

“…Our ED 50 of ϳ100 mg/kg t.i.d. for valacyclovir is in good accordance with the findings presented in a recent report in which only acyclovir doses greater than 100 mg/kg were able to reduce mortality in a rat model of HSV infection (2).…”

Correlation between breakdown of the blood–brain barrier and disease outcome of viral encephalitis in mice

“…It has been suggested that investigating means to increase permeability of the BBB to enhance entry of antiviral agents into the CNS may provide a therapeutic strategy for the treatment of viral encephalitis. Such a strategy has proven effective in an animal model of herpes virus infections in the brain in which Acyclovir treatment was administered in conjunction with the use of a synthetic bradykinin analog used to temporarily permeabilize the BBB (Bidanset et al 2001). However, the data presented here, as well as other reports evaluating the connection between BBB permeability and viral encephalitis (Lustig et al 1992;Ben-Nathan et al 2000), would indicate that any therapy aimed at increasing BBB permeability would be contraindicated in BaV and SFV animal models, as well as in individuals infected with related members of the Flavivirus-and Togavirus families of viruses.…”

dNP2 is a blood–brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis

“…Opening the barrier by stimulating tight junctions in the BBB/BSCB, through the use of biological, chemical or physical stimuli, has been the most widely used method of drug delivery. For example, Cereport, a synthetic peptide that can disrupt tight junctions, has been widely studied for BBB permeability and therapeutic approaches 8 9 . The use of high-intensity-focused ultrasound has also been investigated to physically enhance drug delivery into the CNS for therapeutic purposes 10 .…”