This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Drusano, G. L.
Right arrow Articles by Bilello, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Drusano, G. L.
Right arrow Articles by Bilello, J. A.

Next Article 

Antimicrobial Agents and Chemotherapy, September 1998, p. 2153-2159, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Nucleoside Analog 1592U89 and Human Immunodeficiency Virus Protease Inhibitor 141W94 Are Synergistic In Vitro

G. L. Drusano,1,* D. Z. D'Argenio,2 W. Symonds,3 P. A. Bilello,1 J. McDowell,3 B. Sadler,3 A. Bye,3 and J. A. Bilello1

Departments of Medicine and Pharmacology Albany Medical College, Albany, New York 122081; GlaxoWellcome, Inc., Research Triangle Park, North Carolina 277083; and Department of Biomedical Engineering, University of Southern California, Los Angeles, California 900072

Received 8 December 1997/Returned for modification 7 April 1998/Accepted 30 April 1998

The use of combinations of anti-human immunodeficiency virus (anti-HIV) agents targeted to different molecular targets will most likely result in increased viral suppression and may also delay or prevent the emergence of resistant HIV strains. The purpose of the present study was to develop information on the in vitro anti-HIV activities of combinations of the reverse transcriptase inhibitor 1592U89 and the protease inhibitor 141W94 to help guide the choice of dosages in clinical trials. Triplicate in vitro dose-response matrices were prepared with MT-2 cells infected with HIV type 1 (HIV-1) strain IIIB. In order to account for the effects of protein binding, tissue culture medium with 10% fetal bovine serum was supplemented with the human serum proteins alpha 1 acid glycoprotein (1 mg/ml) and albumin (40 mg/ml). The three-dimensional drug interaction surface for 1592U89 and 141W94 was constructed with the program MacSynergy II. As analyzed relative to a Bliss Independence null reference model, this combination was synergistic, with volumes of synergy exceeding 100 (99% confidence). Analysis of the data set with a fully parametric form of an equation for the quantitation of drug interaction developed by Greco et al. (W. R. Greco, G. Bravo, and J. C. Parsons, Pharmacol. Rev. 47:331-385, 1995) resulted in an interaction term statistically significantly greater than 0.0, indicating true synergy. Both methods concur that this combination is significantly synergistic. These data, with favorable findings from phase I/II trials for each drug alone, suggest that the combination of 1592U89 plus 141W94 should be further evaluated in clinical trials.


* Corresponding author. Mailing address: Department of Medicine, Albany Medical College, 47 New Scotland Ave., Albany, NY 12208. Phone: (518) 262-6330. Fax: (518) 262-6333. E-mail: GLDrusano{at}AOL.com.


Antimicrobial Agents and Chemotherapy, September 1998, p. 2153-2159, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.



This article has been cited by other articles:

  • Sun, L., Sun, S., Cheng, A., Wu, X., Zhang, Y., Lou, H. (2009). In Vitro Activities of Retigeric Acid B Alone and in Combination with Azole Antifungal Agents against Candida albicans. Antimicrob. Agents Chemother. 53: 1586-1591 [Abstract] [Full Text]  
  • Lim, T.-P., Ledesma, K. R., Chang, K.-T., Hou, J.-G., Kwa, A. L., Nikolaou, M., Quinn, J. P., Prince, R. A., Tam, V. H. (2008). Quantitative Assessment of Combination Antimicrobial Therapy against Multidrug-Resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 52: 2898-2904 [Abstract] [Full Text]  
  • Fulco, P. P., Vora, U. B, Bearman, G. M. (2006). Acid Suppressive Therapy and the Effects on Protease Inhibitors. The Annals of Pharmacotherapy 40: 1974-1983 [Abstract] [Full Text]  
  • Afeltra, J., Vitale, R. G., Mouton, J. W., Verweij, P. E. (2004). Potent Synergistic In Vitro Interaction between Nonantimicrobial Membrane-Active Compounds and Itraconazole against Clinical Isolates of Aspergillus fumigatus Resistant to Itraconazole. Antimicrob. Agents Chemother. 48: 1335-1343 [Abstract] [Full Text]  
  • Pereira, C. F., Paridaen, J. T. M. L., van de Bovenkamp, M., Middel, J., Verhoef, J., Nottet, H. S. L. M. (2003). APHS can act synergically with clinically available HIV-1 reverse transcriptase and protease inhibitors and is active against several drug-resistant HIV-1 strains in vitro. J Antimicrob Chemother 51: 1181-1189 [Abstract] [Full Text]  
  • Meletiadis, J., Mouton, J. W., Meis, J. F. G. M., Verweij, P. E. (2003). In Vitro Drug Interaction Modeling of Combinations of Azoles with Terbinafine against Clinical Scedosporium prolificans Isolates. Antimicrob. Agents Chemother. 47: 106-117 [Abstract] [Full Text]  
  • Te Dorsthorst, D. T. A., Verweij, P. E., Meletiadis, J., Bergervoet, M., Punt, N. C., Meis, J. F. G. M., Mouton, J. W. (2002). In Vitro Interaction of Flucytosine Combined with Amphotericin B or Fluconazole against Thirty-Five Yeast Isolates Determined by both the Fractional Inhibitory Concentration Index and the Response Surface Approach. Antimicrob. Agents Chemother. 46: 2982-2989 [Abstract] [Full Text]  
  • Te Dorsthorst, D. T. A., Verweij, P. E., Meis, J. F. G. M., Punt, N. C., Mouton, J. W. (2002). Comparison of Fractional Inhibitory Concentration Index with Response Surface Modeling for Characterization of In Vitro Interaction of Antifungals against Itraconazole-Susceptible and -Resistant Aspergillus fumigatus Isolates. Antimicrob. Agents Chemother. 46: 702-707 [Abstract] [Full Text]  
  • Schmidt, B., Korn, K., Moschik, B., Paatz, C., Überla, K., Walter, H. (2000). Low Level of Cross-Resistance to Amprenavir (141W94) in Samples from Patients Pretreated with Other Protease Inhibitors. Antimicrob. Agents Chemother. 44: 3213-3216 [Abstract] [Full Text]  
  • McDowell, J. A., Lou, Y., Symonds, W. S., Stein, D. S. (2000). Multiple-Dose Pharmacokinetics and Pharmacodynamics of Abacavir Alone and in Combination with Zidovudine in Human Immunodeficiency Virus-Infected Adults. Antimicrob. Agents Chemother. 44: 2061-2067 [Abstract] [Full Text]  
  • Drusano, G. L., D'Argenio, D. Z., Preston, S. L., Barone, C., Symonds, W., LaFon, S., Rogers, M., Prince, W., Bye, A., Bilello, J. A. (2000). Use of Drug Effect Interaction Modeling with Monte Carlo Simulation To Examine the Impact of Dosing Interval on the Projected Antiviral Activity of the Combination of Abacavir and Amprenavir. Antimicrob. Agents Chemother. 44: 1655-1659 [Abstract] [Full Text]