Ribavirin antagonizes inhibitory effects of pyrimidine 2',3'-dideoxynucleosides but enhances inhibitory effects of purine 2',3'-dideoxynucleosides on replication of human immunodeficiency virus in vitro

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.

Section: Discussionmentioning

confidence: 97%

Zalcitabine (ddC) Phosphorylation and Drug Interactions

Veal

Barry

Back

1995

“…RBV has been shown to be synergistic in combination with ddl, but antagonistic in combination with AZT (Baba et al, 1987;Vogt et al, 1987;Balzarini et al, 1990Balzarini et al, , 1991. This has been attributed to the inhibition of IMP dehydrogenase by RBV, causing on the one hand increased phosphorylation of ddl (through increased IMP levels) and on the other hand decreased phosphorylation of AZT (through increased dTIP pools and feedback inhibition of thymidine kinase).…”

Section: Discussionmentioning

confidence: 99%

“…RBV also enhances the anti-HIV activity of ddl when these two Hao et a/., 1988;Huang et sl., 1990;Balzarini et at. 1991b;Tornevik et a/., 1991;De Glercq, 1992). drugs are combined in vitro and in Vivo (Balzarini et al, 1990(Balzarini et al, , 1991a, whereas it is antagonistic with AZT (Baba et al, 1987;Vogt et al, 1987). These effects are thought to be a result of the effect of RBV on IMP and dTIP pools.…”

Section: Introductionmentioning

confidence: 99%

Intracellular Metabolism of 3′-azido-3′-deoxythymidine and 2′,3′-dideoxyinosine in Combination in the Absence and Presence of Ribavirin

Palmer

Cox

1994

SummaryWe examined the intracellular ph9sphorylation of 3'-azido-3'-deoxythymidine (AZT)Jhd 2',3'-dideoxyinosine (ddl) and the effects on rNTP and dNTP pools when AZT and ddl were incubated separately and in combination in lymphocytes. We also compared the effect of adding ribavirin (RBV) to the two-drug combination of AZT + ddl.AZT and ddl, used singly or in combination, had no effect on the dNTP pools of CEM Iymphoblastoid cells. Neither did the combination of AZT + ddl have any effect on the rNTP pools. RBV, a known inhibitor of IMP dehydrogenase, caused a decrease in GTP and an increase in dTTP whether incubated alone or with the drug combination of AZT + ddl. The addition of AZT + ddl therefore did not alter the effects of RBV upon cellular nucleotide pools.AZT was phosphorylated to a much greater extent than ddl. The activation of ddl to ddA-TP was increased 2-fold in the presence of AZT, whereas AZT phosphorylation was unchanged when combined with ddl. This increase in ddl activation may explain in part the synergistic antiviral activity of the combination of AZT + ddl. The increased activation was not due to increased phosphorylation of ddl resulting from IMP dehydrogenase inhibition.The addition of 10 IlM RBV to the two-drug combination of AZT + ddl did not change the intracellular phosphorylation of AZT or ddl. The activation of ddl to ddA-TP, when combined with AZT, appeared to be maximal and could not be further increased by addition of RBV to this combination.

“…Combination of different anti-HlV drugs may result in diminished toxicity, reduced risk of resistance development and/or synergistic antiviral activity, depending on decreased dosing of the individual drugs, complementarity of mutations in the viral genome and/or action at different target sites in the virus replication cycle. In fact, examples of antiviral synergy (such as ribavirin and ddI) (Baba et al, 1987b), additivity (AZT and acyclovir or gan- ciclovir) (Smith & Pagano, 1991;Medina et al, 1992) and antagonism (ribavirin and pyrimidine dideoxynucleoside analogues such as AZT) (Vogt et al, 1987) have been reported, and in a number of cases the molecular basis for the underlying mechanism of action has been elucidated.…”

Section: 5mentioning

confidence: 99%

The Thiocarboxanilides UC-10 and UC-781 Have an Additive Inhibitory Effect against Human Immunodeficiency Virus Type 1 Reverse Transcriptase and Replication in Cell Culture When Combined with other Antiretroviral Drugs

Balzarini

Clercq

1997

Self Cite

SummaryThe thiocarboxanilides represent a structural class of potent and selective human immunodeficiency virus type 1 {HIV~1}-specific reverse transcriptase {RT} inhibitors. Combinations of the clinical candidate thiocarboxanilides UC-10 {oxime ether derivative} and UC-781 {pentenyloxy ether derivative} with a variety of nucleoside RT inhibitors {NRTls} and non-nucleoside RT inhibitors (NNRTls), two HIV protease inhibitors and one fusion/uncoating inhibitor were evaluated for their inhibitory effects on HIV-1 RT activity and HIV-1 replication in CEM cell cultures. The inhibitory activity of the NNRTls including UC-1 0, UC-781, nevirapine, BHAp, ex-APA, 8-chloro-TIBO, MKC-442 and the quinoxaline HBY 097 against HIV-1 RT was highly dependent on the nature of the template/primer used in the HIV-1 RT reaction. However, fractionary inhibitory concentration (FIe) indexes for all drug concentrations evaluated in the combination experiments of UC-781 and the other NNRTls fell within the range 0.5-1.5. This points to a predominantlyadditive effectof the thiocarboxanilides and other NNRTls in the inhibition of HIV-1 RT. Similar FIC indexes were observed for the combination of UC-781 with the NRTI triphosphotes AZHP, d4T-TP, ddCTP, ddATP and 3TC-TP and the NRTI diphosphate PMEApp against HIV-1 RT. All these drug combinations showed similar additive inhibitory effects on HIV-1 replication in cell culture. Also, the combinations of UC-lO or UC-781 with the protease inhibitors Ro31-8959/008 and ABT 84538.0 and the fusion/uncoating inhibitor 6icyclam JM 3100 showed an additive effect {FIC within the 0.5-1.5 range}. Thus, irrespective of the nature of the drugs, their combination with the thiocarboxanilides proved merely additive. In no case were antagonisticanti-HIV activity or increased cytotoxicity observed. In conclusion, thiocarboxanilides combined with a variety of clinically used anti-HIV agents result in additive anti-HIV activity.