A pro-drug of zidovudine with enhanced efficacy against human immunodeficiency virus.
In an attempt to alleviate the drug-related toxicity of zidovudine in patients with AIDS, a pro-drug of zidovudine, 5'-[(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)oxy]-3'-azido-2',3'- dideoxythymidine (DP-AZT), has been evaluated. Cellular uptake by H9 cells and peripheral blood lymphocytes (PBL) with zidovudine and DP-AZT showed at least a 50% greater intracellular concentration of DP-AZT within 2 hr. DP-AZT was significantly less toxic to murine bone marrow cells as measured by CFU-E assay. The ED50 concentration to inhibit the production of HIV specific p24 antigen was 0.05 microM for DP-AZT whereas zidovudine required 0.125 microM. These results demonstrated that DP-AZT has a higher therapeutic ratio than zidovudine as an anti-HIV-1 agent.
Gogu
S R
SR
Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112.
Aggarwal
S K
SK
Rangan
S R
SR
Agrawal
K C
KC
D000818:Animals; D001853:Bone Marrow; D002461:Cell Line, Transformed; D002463:Cell Membrane Permeability / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003593:Cytoplasm / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
D011355:Prodrugs; D015215:Zidovudine