Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.
Inhibition of SIVmac by zidovudine (AZT) and 2', 3' Dideoxy-2', 3'-didehydrothymidine (D4T) in combination with the membrane-active drug dipyridamole (DPM).
Symp Nonhum Primate Models AIDS. 1990 Nov 28-30;8:57 (abstract no. 41). Unique Identifier : AIDSLINE PRIM8/900041 Fridland A; Robbins B; Connelly MC; Gould R; Marx PA; St. Jude Children's Research Hospital, 332 North Lauderdale, Box; 318, Memphis, TN 38101
Abstract:
D4T and AZT are two major drugs used in the treatment of HIV infections. However the anti-viral activity of these drugs is limited by their ability to form the 5' triphosphate derivatives which are believed to act as chain terminators of reverse transcription. Studies in the SIVmac model could be used to develop strategies to increase the anti-viral effects of these compounds. In this study we report that the in vitro activity of AZT and D4T against SIVmac can be increased by combination with a membrane active compound DPM. Since the anti-viral activity involves the formation of the analog triphosphates, the efficacy of these drugs may be potentiated by increasing their anabolism. In the present study the effect of DPM on the metabolism of AZT and D4T was determined in the human T cell line CCRF-CEM. We found that DPM in a concentration dependent manner increased the intracellular accumulation of the putative active triphosphates of D4T and AZT by 2 to 4 fold. To determine if DPM potentiated the anti-retroviral activity of AZT and D4T we tested DPM in combination with these drugs using the SIVmac model. The 50% inhibitory dose of AZT and D4T against SIVmac in human T cell lines was 0.4 muM and 1.56 muM, respectively. DPM alone was inactive and not toxic up to 100 muM. In these experiments, the activity of D4T and AZT was increased when combined with 1-9muM DPM. For example, 8% and 20% inhibitory activity of D4T and AZT was increased to 25% and 80% inhibition respectively. The overall enhancement ranged from 2 to 4 fold for these combinations. This study demonstrated a correlation between the enhanced accumulation of the active triphosphates of AZT and D4T and their anti-SIVmac activity. The combinations of AZT and D4T with DPM could be of clinical importance for increasing the therapeutic effect at lower dose of these drugs. SIV infection of macaques provides a useful model for the development of new combination for chemotherapy of HIV infections.
Keywords: Animal Cell Line Dipyridamole/*THERAPEUTIC USE Disease Models, Animal Dose-Response Relationship, Drug Drug Evaluation Drug Therapy, Combination Human HIV Infections/DRUG THERAPY Macaca Simian Acquired Immunodeficiency Syndrome/EPIDEMIOLOGY SIV/*DRUG EFFECTS T-Lymphocytes/DRUG EFFECTS/METABOLISM/MICROBIOLOGY Thymine Nucleotides/ADMINISTRATION & DOSAGE/*THERAPEUTIC USE Zidovudine/ADMINISTRATION & DOSAGE/*THERAPEUTIC USE ABSTRACT 910730
M9170953
AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.
Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.
