3-DRUG COMBINATION OF MKC-442, LAMIVUDINE AND ZIDOVUDINE IN-VITRO - POTENTIAL APPROACH TOWARDS EFFECTIVE CHEMOTHERAPY AGAINST HIV-1

Citation
G. Piras et al., 3-DRUG COMBINATION OF MKC-442, LAMIVUDINE AND ZIDOVUDINE IN-VITRO - POTENTIAL APPROACH TOWARDS EFFECTIVE CHEMOTHERAPY AGAINST HIV-1, AIDS, 11(4), 1997, pp. 469-475
Citations number
28
Categorie Soggetti
Immunology,"Infectious Diseases
Journal title
AIDSACNP
ISSN journal
02699370
Volume
11
Issue
4
Year of publication
1997
Pages
469 - 475
Database
ISI
SICI code
0269-9370(1997)11:4<469:3COMLA>2.0.ZU;2-V
Abstract
Objectives: MKC-442 (6-benzyl-1-ethoxymethyl-5-isopropyluracil), a pot ent nonnucleoside reverse transcriptase inhibitor, is a promising cand idate for the treatment of HIV-1 infection and is now undergoing clini cal trials. We studied the in vitro activity of MKC-442 against HIV-1 replication in a three-drug combination regimen with zidovudine (ZDV) and lamivudine (3TC). Methods: Drug-drug interactions in MT-4 cells an d peripheral blood mononuclear cells (PBMC) infected with HIV-1(IIIB) were evaluated. The multiple drug effect analysis based on the median effect principle was applied, and the combination indices were calcula ted using a computer software program. The occurrence of viral breakth rough was investigated during a long-term culture of HIV-1-injected MT -4 cells. Results: When MKC-442 was combined with 3TC and ZDV, they sy nergistically suppressed HIV-1 replication in MT-4 cells over a wide r ange of doses irrespective of the endpoints for synergy calculations. Similar results were also obtained In PBMC. An arbitrary combination r atio of 10 : 100 : 1 for MKC-442 : 3TC : ZDV showed stronger synergism than any other ratios examined. As a result of synergy in the three-d rug combination, the dose of each drug could be reduced by four- to 24 -fold. The three-drug combination markedly delayed or even completely suppressed HIV-1 replication at least for 40 days. Virus emerged in th e presence of three drugs at lower doses, although it did not contain any amino-acid mutations in the sequenced reverse transcriptase region and did retain full sensitivity to all three drugs. Conclusions: Our results demonstrate a potential efficacy of MKC-442 in combination wit h 3TC and ZDV, and the three-drug combination should be considered for treatment of AIDS patients.