Skip to main content
NCBI home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1997 Oct;41(10):2159–2164. doi: 10.1128/aac.41.10.2159

Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro.

A K Patick 1, T J Boritzki 1, L A Bloom 1
PMCID: PMC164086  PMID: 9333041

Abstract

Nelfinavir mesylate (formerly AG1343) is a potent and selective, nonpeptidic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that was discovered by protein structure-based design methodologies. We evaluated the antiviral and cytotoxic effects of two-drug combinations of nelfinavir with the clinically approved antiretroviral therapeutics zidovudine (ZDV), lamivudine (3TC), dideoxycytidine (ddC; zalcitabine), stavudine (d4T), didanosine (ddI), indinavir, saquinavir, and ritonavir and a three-drug combination of nelfinavir with ZDV and 3TC against an acute HIV-1 strain RF infection of CEM-SS cells in vitro. Quantitative assessment of drug interaction was evaluated by a universal response surface approach (W. R. Greco, G. Bravo, and J. C. Parsons, Pharm. Rev. 47:331-385, 1995) and by the method of M. N. Prichard and C. Shipman (Antiviral Res. 14:181-206, 1990). Both analytical methods yielded similar results and showed that the two-drug combinations of nelfinavir with the reverse transcriptase inhibitors ZDV, 3TC, ddI, d4T, and ddC and the three-drug combination with ZDV and 3TC resulted in additive to statistically significant synergistic interactions. In a similar manner, the combination of nelfinavir with the three protease inhibitors resulted in additive (ritonavir and saquinavir) to slightly antagonistic (indinavir) interactions. In all combinations, minimal cellular cytotoxicity was observed with any drug alone and in combination. These results suggest that administration of combinations of the appropriate doses of nelfinavir with other currently approved antiretroviral therapeutic agents in vivo may result in enhanced antiviral activity with no associated increase in cellular cytotoxicity.

Full Text

The Full Text of this article is available as a PDF (1.0 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alley M. C., Scudiero D. A., Monks A., Hursey M. L., Czerwinski M. J., Fine D. L., Abbott B. J., Mayo J. G., Shoemaker R. H., Boyd M. R. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 1988 Feb 1;48(3):589–601. [PubMed] [Google Scholar]
  2. Carter W. H., Jr, Wampler G. L. Review of the application of response surface methodology in the combination therapy of cancer. Cancer Treat Rep. 1986 Jan;70(1):133–140. [PubMed] [Google Scholar]
  3. Condra J. H., Schleif W. A., Blahy O. M., Gabryelski L. J., Graham D. J., Quintero J. C., Rhodes A., Robbins H. L., Roth E., Shivaprakash M. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature. 1995 Apr 6;374(6522):569–571. doi: 10.1038/374569a0. [DOI] [PubMed] [Google Scholar]
  4. Deminie C. A., Bechtold C. M., Stock D., Alam M., Djang F., Balch A. H., Chou T. C., Prichard M., Colonno R. J., Lin P. F. Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication. Antimicrob Agents Chemother. 1996 Jun;40(6):1346–1351. doi: 10.1128/aac.40.6.1346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Eron J. J., Jr, Johnson V. A., Merrill D. P., Chou T. C., Hirsch M. S. Synergistic inhibition of replication of human immunodeficiency virus type 1, including that of a zidovudine-resistant isolate, by zidovudine and 2',3'-dideoxycytidine in vitro. Antimicrob Agents Chemother. 1992 Jul;36(7):1559–1562. doi: 10.1128/aac.36.7.1559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gaumont Y., Kisliuk R. L., Parsons J. C., Greco W. R. Quantitation of folic acid enhancement of antifolate synergism. Cancer Res. 1992 Apr 15;52(8):2228–2235. [PubMed] [Google Scholar]
  7. Greco W. R., Bravo G., Parsons J. C. The search for synergy: a critical review from a response surface perspective. Pharmacol Rev. 1995 Jun;47(2):331–385. [PubMed] [Google Scholar]
  8. Jacobsen H., Hänggi M., Ott M., Duncan I. B., Owen S., Andreoni M., Vella S., Mous J. In vivo resistance to a human immunodeficiency virus type 1 proteinase inhibitor: mutations, kinetics, and frequencies. J Infect Dis. 1996 Jun;173(6):1379–1387. doi: 10.1093/infdis/173.6.1379. [DOI] [PubMed] [Google Scholar]
  9. Johnson V. A., Barlow M. A., Merrill D. P., Chou T. C., Hirsch M. S. Three-drug synergistic inhibition of HIV-1 replication in vitro by zidovudine, recombinant soluble CD4, and recombinant interferon-alpha A. J Infect Dis. 1990 Jun;161(6):1059–1067. doi: 10.1093/infdis/161.6.1059. [DOI] [PubMed] [Google Scholar]
  10. Johnson V. A., Merrill D. P., Chou T. C., Hirsch M. S. Human immunodeficiency virus type 1 (HIV-1) inhibitory interactions between protease inhibitor Ro 31-8959 and zidovudine, 2',3'-dideoxycytidine, or recombinant interferon-alpha A against zidovudine-sensitive or -resistant HIV-1 in vitro. J Infect Dis. 1992 Nov;166(5):1143–1146. doi: 10.1093/infdis/166.5.1143. [DOI] [PubMed] [Google Scholar]
  11. Johnson V. A., Merrill D. P., Videler J. A., Chou T. C., Byington R. E., Eron J. J., D'Aquila R. T., Hirsch M. S. Two-drug combinations of zidovudine, didanosine, and recombinant interferon-alpha A inhibit replication of zidovudine-resistant human immunodeficiency virus type 1 synergistically in vitro. J Infect Dis. 1991 Oct;164(4):646–655. doi: 10.1093/infdis/164.4.646. [DOI] [PubMed] [Google Scholar]
  12. Lambert D. M., Bartus H., Fernandez A. V., Bratby-Anders C., Leary J. J., Dreyer G. B., Metcalf B. W., Petteway S. R., Jr Synergistic drug interactions of an HIV-1 protease inhibitor with AZT in different in vitro models of HIV-1 infection. Antiviral Res. 1993 Aug;21(4):327–342. doi: 10.1016/0166-3542(93)90011-7. [DOI] [PubMed] [Google Scholar]
  13. Larder B. A., Kemp S. D., Harrigan P. R. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science. 1995 Aug 4;269(5224):696–699. doi: 10.1126/science.7542804. [DOI] [PubMed] [Google Scholar]
  14. Mascolini M. Outing HIV (or, the tailor retailored). J Int Assoc Physicians AIDS Care. 1996 Sep;2(9):29–56. [PubMed] [Google Scholar]
  15. Merrill D. P., Moonis M., Chou T. C., Hirsch M. S. Lamivudine or stavudine in two- and three-drug combinations against human immunodeficiency virus type 1 replication in vitro. J Infect Dis. 1996 Feb;173(2):355–364. doi: 10.1093/infdis/173.2.355. [DOI] [PubMed] [Google Scholar]
  16. Molla A., Korneyeva M., Gao Q., Vasavanonda S., Schipper P. J., Mo H. M., Markowitz M., Chernyavskiy T., Niu P., Lyons N. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat Med. 1996 Jul;2(7):760–766. doi: 10.1038/nm0796-760. [DOI] [PubMed] [Google Scholar]
  17. Pagano P. J., Chong K. T. In vitro inhibition of human immunodeficiency virus type 1 by a combination of delavirdine (U-90152) with protease inhibitor U-75875 or interferon-alpha. J Infect Dis. 1995 Jan;171(1):61–67. doi: 10.1093/infdis/171.1.61. [DOI] [PubMed] [Google Scholar]
  18. Patick A. K., Mo H., Markowitz M., Appelt K., Wu B., Musick L., Kalish V., Kaldor S., Reich S., Ho D. Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease. Antimicrob Agents Chemother. 1996 Feb;40(2):292–297. doi: 10.1128/aac.40.2.292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Prichard M. N., Shipman C., Jr A three-dimensional model to analyze drug-drug interactions. Antiviral Res. 1990 Oct-Nov;14(4-5):181–205. doi: 10.1016/0166-3542(90)90001-n. [DOI] [PubMed] [Google Scholar]
  20. Sørensen A. M., Nielsen C., Mathiesen L. R., Nielsen J. O., Hansen J. E. Evaluation of the combination effect of different antiviral compounds against HIV in vitro. Scand J Infect Dis. 1993;25(3):365–371. doi: 10.3109/00365549309008512. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES