Antimicrobial Agents and Chemotherapy, September 1998, p. 2153-2159, Vol. 42, No. 9
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
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
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.
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