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Improved brain delivery and in vitro activity of zidovudine through the use of a redox chemical delivery system

Objective: Improved therapy for AIDS dementia and related encephalopathies may be achieved through enhanced delivery of effective antiretroviral agents to the central nervous system (CNS). Design: A novel chemical delivery system (CDS) was used, which utilized redox trapping of drugs in the brain. This study was aimed at defining the pharmacokinetics of a zidovudine (ZDV)‐CDS as well as establishing its in vitro antiviral efficacy against HIV in both lymphocytes and in a neural cell line. Results: ZDV‐CDS administered parenterally to rats produced significantly higher brain levels of ZDV [area under the curve (AUC), 425 &mgr;g × min/g] than equimolar ZDV (AUC, 13.5 &mgr;g × min/g). Native ZDV uptake was minimal after 1h when analyzed in CEM lymphocytes and in SKNMC neuroblastoma cell line. By contrast, marked uptake of ZDV‐CDS was followed by biochemical conversion of ZDV‐CDS to its main metabolites (ZDV‐CDS quaternary salt, ZDV‐Q+, and native ZDV). These improved uptake profiles were associated with greater in vitro virucidal effect. ZDV‐CDS at 0.5 &mgr;M was 80% more effective than ZDV in suppressing p24 production in a lymphocyte culture infected with 6000 median tissue culture infective doses (TCID50) of the HIV N1T strain and 50% more effective at 0.05 &mgr;M. Furthermore, syncytia formation was completely suppressed at a ZDV‐CDS dose of 0.5 &mgr;M (600TCID50) but native ZDV at the same dose was ineffective. Finally, while ZDV (at 0.5 &mgr;M) is not active in reducing viral replication in an SKNMC neural cell line, the ZDV‐CDS complex significantly suppressed p24 synthesis. Conclusion: The ZDV‐CDS complex is capable of delivering higher ZDV doses to lymphocytes and neural cells, with improved antiretroviral activity.