SBIR-STTR Award

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 th 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 pyridiniu salts which are locked in the brain.The advantages of this system are1) lower peripheral concentrations of the active agent and consequently reduced systemic toxicity2) 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.National Institute of Neurological Disorders and Stroke (NINDS)

Phase I results demonstrated the feasibility of synthesizing brain-enhanced chemical delivery systems (CDS) for a select group of antiherpetic agents. Based on the successful completion of Phase I studies, analogs of these carrier systems have been proposed for Phase II studies to determine the optimal drug-CDS (D-CDS) combination for delivery to the brain for the purpose of treating herpes encephalitis. The carrier system functions on the basis of an interconversion between a lipophilic dihydropyridine derivative to a hydrophilic pyridinium salt that gets locked in the brain. The advantages of such a system are:(1) clinically effective cerebral concentrations of the active drug are achieved rapidly, resulting in greater efficacy; and(2) reduced systemic toxicity due to lowered peripheral concentrations of the active agent.The objectives of this research are:(1) synthesis of additional analogs of CDS for the antiherpetic agents;(2) in vitro stability determinations in various matrices, evaluation of lipophilicity, and neurotoxicity of these antiviral-CDS;(3) elucidation of the in vivo distribution pattern of these D-CDS in rat and dog models;(4) evaluation of different vehicles for i.v. dosing of D-CDS; and(5) activity evaluations in a rat model of herpes encephalitis using HSV-1 strain. Successful completion of these objectives will identify a candidate drug for clinical and commercial development.

Anticipated Results:
The antiviral DCDS will be used to treat viral encephalitis. Brain-specific delivery should lower peripheral toxicity. The estimated U.S. market for this treatment is $4 to $8 million.National Institute Of Neurological Disorders And Stroke (NINDS)