The impediments encountered in the treatment of human brain encephalitis have so far been attributed to the inability of antiviral agents to reach the viral site in the CNS. To circumvent these problems utilization of the brain-specific chemical delivery system (analogous to the NAD forms and is formed from NADH redox system) developed by Bodor and associates is proposed. This system is based on the interconversion of lipophilic dihydropyridines which readily cross the BBB between hydrophilic pyridinium salts which are locked in the brain. The advantages of this system are 1) lower peripheral concentrations of the active agent and consequently reduced systemic toxicity 2) greater efficacy since a lower dose can be given to attain clinically effective cerebral concentrations. The major aim of this proposal is to apply the chemical delivery system to selected antiherpetic agents. The areas of research in Phase I would include synthesis of drug-carrier systems, development of suitable analytical systems, determination of stability in vitro using various matrices to establish the rate at which the free drug is released from the carrier. Evaluation of the lipophilicity and neurotoxicity of drug- carrier systems. In Phase II based on the results from Phase I at least two compounds will be selected for in-depth in vivo distribution and activity studies.
