Document 0260
 DOCN  M95A0260
 TI    The inhibition of human immunodeficiency virus type 1 in vitro by a
       non-nucleoside reverse transcriptase inhibitor MKC-442, alone and in
       combination with other anti-HIV compounds.
 DT    9510
 AU    Brennan TM; Taylor DL; Bridges CG; Leyda JP; Tyms AS; MRC Collaborative
       Centre, London, UK.
 SO    Antiviral Res. 1995 Mar;26(2):173-87. Unique Identifier : AIDSLINE
       MED/95328860
 AB    MKC-442, a derivative of the non-nucleoside reverse transcriptase (RT)
       inhibitor 1-[(2-hydroxyethoxy)methyl)-6-(phenylthio)thymidine (HEPT),
       showed potent and selective inhibition of human immunodeficiency virus
       type 1 (HIV-1) replication in vitro, using a range of host-cell/virus
       systems including human peripheral blood mononuclear cells infected with
       primary clinical isolates. MKC-442 was evaluated in combination with the
       nucleoside analogues AZT, ddI and ddC, the non-nucleoside RT inhibitor
       nevirapine, the HIV-1 proteinase inhibitor Ro-31-8959, and the
       alpha-glucosidase 1 inhibitor, MDL-28,574, using a cell viability assay.
       Drug interactions were evaluated by the isobologram technique and by
       calculating combination indices. Notable synergistic inhibition of HIV-1
       replication was observed when MKC-442 was combined with AZT and
       MDL-28,574 and moderate synergy with ddI. In combination with ddC,
       nevirapine or Ro-31-8959, only a slightly better than additive effect
       was observed. Impressive synergy was seen using the three-drug
       combinations of MKC-442, AZT and MDL-28,574 or MKC-442, AZT and
       Ro-31-8959. No additional cytotoxicity was observed as measured by
       [3H]thymidine incorporation by concanavalin A-stimulated peripheral
       blood mononuclear cells, when MKC-442 was combined with any of the
       above-mentioned compounds. The use of MKC-442 in a two- or three-drug
       combination regimen with other RT inhibitors, a proteinase inhibitor or
       an alpha-glucosidase 1 inhibitor should be considered for HIV-1-related
       chemotherapy.
 DE    Antiviral Agents/*PHARMACOLOGY/TOXICITY  Cells, Cultured  Cytotoxicity
       Tests, Immunologic  Didanosine/PHARMACOLOGY  Drug Interactions  Human
       HIV-1/*DRUG EFFECTS  Indolizines/PHARMACOLOGY
       Isoquinolines/PHARMACOLOGY  Leukocytes, Mononuclear/DRUG EFFECTS
       Molecular Structure  Pyridines/PHARMACOLOGY  Quinolines/PHARMACOLOGY
       Reverse Transcriptase/*ANTAGONISTS & INHIB  Uracil/*ANALOGS &
       DERIVATIVES/PHARMACOLOGY/TOXICITY  Zalcitabine/PHARMACOLOGY
       Zidovudine/PHARMACOLOGY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).