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. 1996 May;40(5):1285–1288. doi: 10.1128/aac.40.5.1285

Synergistic inhibition of human immunodeficiency virus isolates (including 3'-azido-3'-deoxythymidine-resistant isolates) by foscarnet in combination with 2',3'-dideoxyinosine or 2',3'-dideoxycytidine.

S Palmer 1, J Harmenberg 1, S Cox 1
PMCID: PMC163311  PMID: 8723486

Abstract

The combinations of foscarnet plus 2',3'-dideoxyinosine and foscarnet plus 2',3'-dideoxycytidine synergistically inhibit the replication of human immunodeficiency virus type 1 isolates, including two 3'-azido-3'-deoxythymidine-resistant isolates. The combination of 2',3'-dideoxyinosine plus 2',3'-dideoxycytidine showed additive inhibition of the majority of the human immunodeficiency virus isolates tested. All three combinations showed pronounced antagonistic cytotoxicity and thus were less toxic to the growth of peripheral blood mononuclear cells than the separate drugs.

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Selected References

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  1. Albert J., Fenyö E. M. Simple, sensitive, and specific detection of human immunodeficiency virus type 1 in clinical specimens by polymerase chain reaction with nested primers. J Clin Microbiol. 1990 Jul;28(7):1560–1564. doi: 10.1128/jcm.28.7.1560-1564.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boucher C. A., Tersmette M., Lange J. M., Kellam P., de Goede R. E., Mulder J. W., Darby G., Goudsmit J., Larder B. A. Zidovudine sensitivity of human immunodeficiency viruses from high-risk, symptom-free individuals during therapy. Lancet. 1990 Sep 8;336(8715):585–590. doi: 10.1016/0140-6736(90)93391-2. [DOI] [PubMed] [Google Scholar]
  3. Böttiger D., Putkonen P., Oberg B. Prevention of HIV-2 and SIV infections in cynomolgus macaques by prophylactic treatment with 3'-fluorothymidine. AIDS Res Hum Retroviruses. 1992 Jul;8(7):1235–1238. doi: 10.1089/aid.1992.8.1235. [DOI] [PubMed] [Google Scholar]
  4. Chou T. C., Talaly P. A simple generalized equation for the analysis of multiple inhibitions of Michaelis-Menten kinetic systems. J Biol Chem. 1977 Sep 25;252(18):6438–6442. [PubMed] [Google Scholar]
  5. Cox S. W., Albert J., Ljungdahl-Ståhle E., Wahren B. Effect of resistance on combination chemotherapy for human immunodeficiency virus infection. Adv Enzyme Regul. 1993;33:27–36. doi: 10.1016/0065-2571(93)90007-z. [DOI] [PubMed] [Google Scholar]
  6. Cox S. W., Apéria K., Albert J., Wahren B. Comparison of the sensitivities of primary isolates of HIV type 2 and HIV type 1 to antiviral drugs and drug combinations. AIDS Res Hum Retroviruses. 1994 Dec;10(12):1725–1729. doi: 10.1089/aid.1994.10.1725. [DOI] [PubMed] [Google Scholar]
  7. Eriksson B. F., Schinazi R. F. Combinations of 3'-azido-3'-deoxythymidine (zidovudine) and phosphonoformate (foscarnet) against human immunodeficiency virus type 1 and cytomegalovirus replication in vitro. Antimicrob Agents Chemother. 1989 May;33(5):663–669. doi: 10.1128/aac.33.5.663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Faulds D., Brogden R. N. Didanosine. A review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection. Drugs. 1992 Jul;44(1):94–116. doi: 10.2165/00003495-199244010-00008. [DOI] [PubMed] [Google Scholar]
  9. Fletcher C. V., Collier A. C., Rhame F. S., Bennett D., Para M. F., Beatty C. C., Jones C. E., Balfour H. H., Jr Foscarnet for suppression of human immunodeficiency virus replication. Antimicrob Agents Chemother. 1994 Mar;38(3):604–607. doi: 10.1128/aac.38.3.604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Harmenberg J., Akesson-Johansson A., Vrang L., Cox S. Synergistic inhibition of human immunodeficiency virus replication in vitro by combinations of 3'-azido-3'-deoxythymidine and 3'-fluoro-3'-deoxythymidine. AIDS Res Hum Retroviruses. 1990 Oct;6(10):1197–1202. doi: 10.1089/aid.1990.6.1197. [DOI] [PubMed] [Google Scholar]
  11. Helgstrand E., Eriksson B., Johansson N. G., Lannerö B., Larsson A., Misiorny A., Norén J. O., Sjöberg B., Stenberg K., Stening G. Trisodium phosphonoformate, a new antiviral compound. Science. 1978 Sep 1;201(4358):819–821. doi: 10.1126/science.210500. [DOI] [PubMed] [Google Scholar]
  12. Jacobson M. A., Causey D., Polsky B., Hardy D., Chown M., Davis R., O'Donnell J. J., Kuppermann B. D., Heinemann M. H., Holland G. N. A dose-ranging study of daily maintenance intravenous foscarnet therapy for cytomegalovirus retinitis in AIDS. J Infect Dis. 1993 Aug;168(2):444–448. doi: 10.1093/infdis/168.2.444. [DOI] [PubMed] [Google Scholar]
  13. Kellam P., Boucher C. A., Tijnagel J. M., Larder B. A. Zidovudine treatment results in the selection of human immunodeficiency virus type 1 variants whose genotypes confer increasing levels of drug resistance. J Gen Virol. 1994 Feb;75(Pt 2):341–351. doi: 10.1099/0022-1317-75-2-341. [DOI] [PubMed] [Google Scholar]
  14. Kong X. B., Zhu Q. Y., Ruprecht R. M., Watanabe K. A., Zeidler J. M., Gold J. W., Polsky B., Armstrong D., Chou T. C. Synergistic inhibition of human immunodeficiency virus type 1 replication in vitro by two-drug and three-drug combinations of 3'-azido-3'-deoxythymidine, phosphonoformate, and 2',3'-dideoxythymidine. Antimicrob Agents Chemother. 1991 Oct;35(10):2003–2011. doi: 10.1128/aac.35.10.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Koshida R., Cox S., Harmenberg J., Gilljam G., Wahren B. Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1. Antimicrob Agents Chemother. 1989 Dec;33(12):2083–2088. doi: 10.1128/aac.33.12.2083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Koshida R., Vrang L., Gilljam G., Harmenberg J., Oberg B., Wahren B. Inhibition of human immunodeficiency virus in vitro by combinations of 3'-azido-3'-deoxythymidine and foscarnet. Antimicrob Agents Chemother. 1989 May;33(5):778–780. doi: 10.1128/aac.33.5.778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Land S., Terloar G., McPhee D., Birch C., Doherty R., Cooper D., Gust I. Decreased in vitro susceptibility to zidovudine of HIV isolates obtained from patients with AIDS. J Infect Dis. 1990 Feb;161(2):326–329. doi: 10.1093/infdis/161.2.326. [DOI] [PubMed] [Google Scholar]
  18. Larder B. A., Darby G., Richman D. D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989 Mar 31;243(4899):1731–1734. doi: 10.1126/science.2467383. [DOI] [PubMed] [Google Scholar]
  19. Medina D. J., Tsai C. H., Hsiung G. D., Cheng Y. C. Comparison of mitochondrial morphology, mitochondrial DNA content, and cell viability in cultured cells treated with three anti-human immunodeficiency virus dideoxynucleosides. Antimicrob Agents Chemother. 1994 Aug;38(8):1824–1828. doi: 10.1128/aac.38.8.1824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Oberg B. Antiviral effects of phosphonoformate (PFA, foscarnet sodium). Pharmacol Ther. 1982;19(3):387–415. doi: 10.1016/0163-7258(82)90074-2. [DOI] [PubMed] [Google Scholar]
  21. Palestine A. G., Polis M. A., De Smet M. D., Baird B. F., Falloon J., Kovacs J. A., Davey R. T., Zurlo J. J., Zunich K. M., Davis M. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med. 1991 Nov 1;115(9):665–673. doi: 10.7326/0003-4819-115-9-665. [DOI] [PubMed] [Google Scholar]
  22. Palmer S., Cox S. Intracellular activation and cytotoxicity of three different combinations of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine. AIDS Res Hum Retroviruses. 1995 Oct;11(10):1227–1233. doi: 10.1089/aid.1995.11.1227. [DOI] [PubMed] [Google Scholar]
  23. Richman D. D. HIV drug resistance. AIDS Res Hum Retroviruses. 1992 Jun;8(6):1065–1071. doi: 10.1089/aid.1992.8.1065. [DOI] [PubMed] [Google Scholar]
  24. Rooke R., Tremblay M., Soudeyns H., DeStephano L., Yao X. J., Fanning M., Montaner J. S., O'Shaughnessy M., Gelmon K., Tsoukas C. Isolation of drug-resistant variants of HIV-1 from patients on long-term zidovudine therapy. Canadian Zidovudine Multi-Centre Study Group. AIDS. 1989 Jul;3(7):411–415. doi: 10.1097/00002030-198907000-00001. [DOI] [PubMed] [Google Scholar]
  25. Sommadossi J. P. Nucleoside analogs: similarities and differences. Clin Infect Dis. 1993 Feb;16 (Suppl 1):S7–15. doi: 10.1093/clinids/16.supplement_1.s7. [DOI] [PubMed] [Google Scholar]
  26. Sundqvist V. A., Albert J., Ohlsson E., Hinkula J., Fenyö E. M., Wahren B. Human immunodeficiency virus type 1 p24 production and antigenic variation in tissue culture of isolates with various growth characteristics. J Med Virol. 1989 Nov;29(3):170–175. doi: 10.1002/jmv.1890290305. [DOI] [PubMed] [Google Scholar]
  27. Wagstaff A. J., Bryson H. M. Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs. 1994 Aug;48(2):199–226. doi: 10.2165/00003495-199448020-00007. [DOI] [PubMed] [Google Scholar]
  28. Wahlberg J., Albert J., Lundeberg J., Cox S., Wahren B., Uhlén M. Dynamic changes in HIV-1 quasispecies from azidothymidine (AZT)-treated patients. FASEB J. 1992 Jul;6(10):2843–2847. doi: 10.1096/fasebj.6.10.1634047. [DOI] [PubMed] [Google Scholar]
  29. Whittington R., Brogden R. N. Zalcitabine. A review of its pharmacology and clinical potential in acquired immunodeficiency syndrome (AIDS). Drugs. 1992 Oct;44(4):656–683. doi: 10.2165/00003495-199244040-00009. [DOI] [PubMed] [Google Scholar]

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