Drug Interactions With Zidovudine Phosphorylation in Vitro

Hoggard, Patrick G.; Veal, Gareth J.; Wild, Martin; Barry, Michael; Back, DJ

doi:10.1097/00002030-199411004-00082

Cited by 10 publications

(13 citation statements)

References 14 publications

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“…The antiviral agent ribavirin and the anticancer drug doxorubicin have been previously shown to inhibit phosphorylation of ZDV in PBMCs, Molt 4, U937 and H9 cells in vitro (Vogt et al, 1987;Hoggard et et., 1995). Altered phosphorylation is the most probable explanation for the decreased anti-HIV activity of ZDV in the presence of ribavirin in MT-4 cells (Baba et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

“…Doxorubicin has now been shown to inhibit phosphorylation of both ZDV (Hoggard et al, 1995) and ddC; however the inhibitory effects are not thought to be due to the cytotoxicity of the drug since cell viability, as measured by trypan blue and neutral red uptake is unaffected at the highest concentration used. Although the exact mechanism of inhibition of dideoxynucleoside phosphorylation is not clear, it is unlikely to be a specific inhibitory effect on the kinases involved in the phosphorylation pathways since ddC and ZDV are phosphorylated by different enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…The effects 'of related dideoxynucleosides on ddC phosphorylation in vitro were therefore investigated, as well as the effects of two drugs previously shown to inhibit ZDV phosphorylation; ribavirin and doxorubicin (Hoggard et al, 1995). This type of study is important given that combination therapy is playing an increasingly vital role in the treatment of HIV-infection (Saag, 1994;Murphy, 1995) and patients are often receiving multiple therapies.…”

Section: Introductionmentioning

confidence: 99%

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Zalcitabine (ddC) Phosphorylation and Drug Interactions

Veal

Barry

Back

1995

Antivir Chem Chemother

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SummaryZalcitabine (2',3'-dideoxycytidine; ddC) is an inhibitor of HIV reverse transcriptase. The intracellular metabolism of ddC in peripheral blood mononuclear cells (PBMCs), U937 cells and Molt 4 cells were investigated, and phosphate metabolites were determined by on-line radiometric HPLC. Comparable levels of all three ddC phosphate metabolites were formed in PHA-stimulated PBMCs, U937 cells and Molt 4 cells.Zidovudine (ZDV), didanosine (ddl) and stavudine (d4T) had no significant effect on ddC (O.06JlM) phosphorylation in PBMCs whereas the endogenous nucleoside, cytidine decreased phosphorylation in a concentration-dependent manner (e.g. 41% inhibition of total phosphate formation at 6JlM cytidine, 85% inhibition at 60JlM).The cytotoxic anticancer drug doxorubicin caused a decrease in ddC phosphorylation in U937/Moit 4 cells (e.g. 56% inhibition of total phosphate formation in U937 cells; 55% in Molt 4 cells at a doxorubicin concentration of 60JlM), whilst the antiviral agent ribavirin exhibited no inhibitory effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Zalcitabine (ddC) Phosphorylation and Drug Interactions

Veal

Barry

Back

1995

Antivir Chem Chemother

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“…In vitro studies of drug interactions have proven to be beneficial in predicting which drug combination regimens should be evaluated in a clinical setting (5,6,8). In the present study, we have evaluated in vitro the interactions between TAK-220 and representatives of each class of currently available antiretroviral agents.…”

Section: Tak-220 Is a Ccr5 Antagonist Part Of The New Class Of Anti-mentioning

confidence: 99%

TAK-220, a Novel Small-Molecule CCR5 Antagonist, Has Favorable Anti-Human Immunodeficiency Virus Interactions with Other Antiretrovirals In Vitro

Tremblay

Giguel

Guan

et al. 2005

Antimicrob Agents Chemother

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TAK-220 is a CCR5 antagonist, part of the new class of anti-human immunodeficiency virus type 1 (anti-HIV-1) entry inhibitors. We evaluated the anti-HIV-1 interactions between TAK-220 and various antiretrovirals in vitro. Synergy was observed with all drugs at the 90 and 95% inhibitory concentrations. The favorable drug interactions observed suggest that further clinical evaluation is warranted.New antiretroviral drug regimens are needed, especially for subjects who have failed two or three previous regimens (17). Among potential sites in the human immunodeficiency virus type 1 (HIV-1) replicative cycle, HIV-1 attachment and entry is a particularly promising target (3, 10).TAK-220 is a small molecule that targets the binding of gp120 to the CCR5 coreceptor, is orally bioavailable, and has potent anti-HIV-1 activity in vitro at nanomolar concentrations (9). As with other classes of antiretroviral drugs, attachment-entry inhibitors are likely to be used in combination with other antiretrovirals. Combinations have many potential advantages over monotherapy, including a delay in the emergence of resistant viral variants, increased potency, and broadened coverage against variants that exist in the population (15). Previous studies have shown that the use of combinations in vitro may lead to various outcomes, ranging from synergy to antagonism, and that these outcomes may be predictive of subsequent clinical results (8,(11)(12)(13)(14). Therefore, we studied TAK-220 in combination with various other antiviral compounds in vitro.Peripheral blood mononuclear cells (PBMCs) from HIV-1-seronegative donors were obtained by Ficoll-Hypaque density gradient centrifugation of heparinized venous blood. After 3-day photohemagglutinin assay stimulation, PBMCs were resuspended at a concentration of 1 ϫ 10 6 cells/ml in RPMI 1640 culture medium (Sigma, St Louis, MO) supplemented with 20% heat-inactivated fetal calf serum (Sigma), penicillin (50 U/ml), streptomycin (50 g/ml), L-glutamine (2 mM), HEPES buffer (10 mM), and 10% interleukin-2 in 24-well tissue culture plates (Becton Dickinson, San Jose, CA). Single drugs or combinations of two or three drugs were added to each well by using a fixed ratio among the drugs and the serial dilutions. The drugs were dissolved by using dimethyl sulfoxide for TAK-220 and efavirenz and phosphate-buffered saline for the other drugs. They were added simultaneously with the HIV-1 inoculum (800 to 1,000 50% tissue culture infective doses/10 6 cells), and the plates were incubated at 37°C in a humidified 5% CO 2 atmosphere. Each condition was tested in duplicate, and each experiment was repeated at least twice. Cell-free culture supernatants were harvested and analyzed by an enzyme-linked immunosorbent assay (Du Pont, Wilmington, DE) for HIV-1 p24 antigen production on day 7 of culture. In addition, uninfected drug-treated cytotoxicity controls were maintained at the highest concentration of each agent tested, singly or in combination. No toxicity was observed at concentrations up to 10 M. Cell prolif...

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“…This is because thymidine kinase has a 600-fold higher af®nity for ZDV than d4T. The clinical effect of this interaction was seen in ACTG 290, when the ZDV plus d4T arm was discontinued after interim analysis demonstrated that subjects receiving this combination had signi®-cantly greater decreases in CD4 counts than the other arms [195].…”

Section: Nucleoside Reverse Transcriptase Inhibitorsmentioning

confidence: 99%