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Abstract
THE COMPARATIVE ABILITY OF NOVEL RIBONUCLEOTIDE REDUCTASE INHIBITORS (RRI) DIDOX (DX) AND TRIMIDOX (TX) TO ENHANCE THE ACTIVITY OF NRTIs DIDEOXYINOSINE (ddI), ABACAVIR (ABC) AND TENOFOVIR (TFV) IN VIVO IN THE MAIDS MODEL OF RETROVIRAL DISEASE
V.S. Gallicchio1, L.R. Sumpter1, C.N. Mayhew1, E.E. Yost1, T.J. Sugg1, M.S. Inayat1, M. Cibull2, H.L. Elford3
1Department of Clinical Sciences, University of Kentucky, Lexington KY, USA
2Department of Pathology, University of Kentucky, Lexington KY, USA, 3Molecules for Health, Inc., Richmond, VA, USA
Preventing deoxynucleotide synthesis to block HIV replication has gained clinical acceptance by hydroxyurea (HU) enhancement of antiviral activity of the non-nucleoside reverse transcriptase inhibitor (NRTI) ddI. Compared to HU, Didox (DX) and Trimidox (TX) inhibit retroviral replication as single agents to a greater extent in several animal models. This report focuses on the ability of ribonucleotide reductase inhibitors (RRIs), with particular attention to DX and TX, to enhance the antiviral activity of NRTIs, dideoxyinosine (ddI), abacavir (ABC), and tenofovir (TFV), in the murine acquired immunodeficient disease (MAIDS) model of retroviral disease. Anti-viral activity was assessed by reduced levels pf proviral DNA, reduced spleen size and decreased IgG levels. Toxicity was measured by complete blood count, histopathology, and bone marrow assays. Treatment started one week post-infection. Mice were treated daily (i.p.) for 8 weeks with HU, DX, TX, ddI, ABC, and TFV alone or in combinations. Suboptimal doses were used to discern positive interaction between RRIs and NRTIs. At doses used, RRIs enhanced activity of ddI, ABC, and TFV reducing infection-induced spleen size increase. DX and TX were more effective than HU and were better tolerated when combined with NRTIs with no adverse signs of toxicity observed. Since the combination of NRTI and RRI produced the optimum regimen, these data support the concept of utilizing RRIs with NRTIs to treat retroviral disease.
The 2nd IAS Conference on HIV Pathogenesis and Treatment
Abstract no.
524
Suggested Citation
" V.S. Gallicchio , et al.
THE COMPARATIVE ABILITY OF NOVEL RIBONUCLEOTIDE REDUCTASE INHIBITORS (RRI) DIDOX (DX) AND TRIMIDOX (TX) TO ENHANCE THE ACTIVITY OF NRTIs DIDEOXYINOSINE (ddI), ABACAVIR (ABC) AND TENOFOVIR (TFV) IN VIVO IN THE MAIDS MODEL OF RETROVIRAL DISEASE.
Poster:
The 2nd IAS Conference on HIV Pathogenesis and Treatment:
Abstract no.
524"
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