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

Y. Mizrachi, Arye Rubinstein, Z. Harish, A. Biegon, W. R. Anderson, M. E. Brewster

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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 (AUG), 425 μg x min/g] than equimolar ZDV (AUG, 13.5 μg x min/g). Native ZDV uptake was minimal after 1 h 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 μM 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 μM. Furthermore, syncytia formation was completely suppressed at a ZDV-CDS dose of 0.5 μM (600TCID50) but native ZDV at the same dose was ineffective. Finally, while ZDV (at 0.5 μM) 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.

Original languageEnglish (US)
Pages (from-to)153-158
Number of pages6
JournalAIDS
Volume9
Issue number2
StatePublished - 1995

Fingerprint

Zidovudine
Oxidation-Reduction
Brain
Lymphocytes
In Vitro Techniques
Cell Line
HIV
Anti-Retroviral Agents
Brain Diseases
Giant Cells

Keywords

  • Brain
  • Drug delivery
  • Lymphocytes
  • Neural cells
  • Zidovudine

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Mizrachi, Y., Rubinstein, A., Harish, Z., Biegon, A., Anderson, W. R., & Brewster, M. E. (1995). Improved brain delivery and in vitro activity of zidovudine through the use of a redox chemical delivery system. AIDS, 9(2), 153-158.

Improved brain delivery and in vitro activity of zidovudine through the use of a redox chemical delivery system. / Mizrachi, Y.; Rubinstein, Arye; Harish, Z.; Biegon, A.; Anderson, W. R.; Brewster, M. E.

In: AIDS, Vol. 9, No. 2, 1995, p. 153-158.

Research output: Contribution to journalArticle

Mizrachi, Y, Rubinstein, A, Harish, Z, Biegon, A, Anderson, WR & Brewster, ME 1995, 'Improved brain delivery and in vitro activity of zidovudine through the use of a redox chemical delivery system', AIDS, vol. 9, no. 2, pp. 153-158.
Mizrachi, Y. ; Rubinstein, Arye ; Harish, Z. ; Biegon, A. ; Anderson, W. R. ; Brewster, M. E. / Improved brain delivery and in vitro activity of zidovudine through the use of a redox chemical delivery system. In: AIDS. 1995 ; Vol. 9, No. 2. pp. 153-158.
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AB - 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 (AUG), 425 μg x min/g] than equimolar ZDV (AUG, 13.5 μg x min/g). Native ZDV uptake was minimal after 1 h 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 μM 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 μM. Furthermore, syncytia formation was completely suppressed at a ZDV-CDS dose of 0.5 μM (600TCID50) but native ZDV at the same dose was ineffective. Finally, while ZDV (at 0.5 μM) 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.

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