Improved uptake and retention of lipophilic prodrug to improve treatment of HIV
| Autor: | Milton B. Yatvin, Michael J. Meredith, Wei Li, Mohan A Shenoy |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Drug
Reverse-transcriptase inhibitor viruses media_common.quotation_subject Intercellular transport virus diseases Pharmaceutical Science biochemical phenomena metabolism and nutrition Prodrug Pharmacology Biology Blood–brain barrier Virology Zidovudine Zalcitabine medicine.anatomical_structure medicine Didanosine media_common medicine.drug |
| Zdroj: | Advanced Drug Delivery Reviews. 39:165-182 |
| ISSN: | 0169-409X |
| Popis: | Dideoxynucleosides currently in use for anti-HIV therapy have been found to be inefficient in passing through the blood–brain barrier to enter and maintain therapeutic drug levels in brain, a very significant reservoir of HIV. The low bioavailability of these drugs combined with the bone marrow toxicity of AZT (3′-azido, 3′-deoxythymidine, Zidovudine), resulting in anemia and leukopenia, pancreatitis with ddI (2′,3′-dideoxyinosine, Didanosine) and painful peripheral neuropathy in case of ddC (2′,3-dideoxycytosine, Zalcitabine) are the limiting factors in their use. In addition, the emergence of strains of HIV resistant to AZT, the most commonly used drug, further restricts its use. Thus the control of AIDS and its complications, needs special therapeutic approaches to combat the disease. In order to overcome these limitations, AZT and ddI have been synthesized as ester-linked ceramide- and phosphatidylcholine-linked prodrugs possessing therapeutic attributes lacking in the parent compounds. There is greater uptake and longer retention of these prodrugs in NIH/3T3 cells in vitro. Pretreatment with our prodrugs blocked infection of these cells by Moloney murine leukemia virus (M-MuLV) for an extended period, which the parent drugs failed to do. When human CD4+ HeLa cells were continuously exposed to the AZT prodrug, subsequent infection of these cells by HIV was blocked. Similar results were obtained with NIH/3T3 cells exposed to M-MuLV. AE6C, a prodrug of AZT linked to ceramide via a cleavable ester bond and a six carbon linker, was less toxic to both mouse and human bone marrow progenitor cells than free AZT. Most significantly, the prodrugs concentration was greater and the retention longer, in well known sanctuaries for HIV, such as the brain, testes and thymus. |
| Databáze: | OpenAIRE |
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