Document 0790
 DOCN  M9650790
 TI    Efficacy of constant infusion of A-77003, an inhibitor of the human
       immunodeficiency virus type 1 (HIV-1) protease, in limiting acute HIV-1
       infection in vitro.
 DT    9605
 AU    Bilello JA; Bilello PA; Kort JJ; Dudley MN; Leonard J; Drusano GL;
       Department of Medicine, Albany Medical College, New York 12208,; USA.
 SO    Antimicrob Agents Chemother. 1995 Nov;39(11):2523-7. Unique Identifier :
       AIDSLINE MED/96139551
 AB    A-77003, a human immunodeficiency virus type 1 (HIV-1) protease
       inhibitor, is effective for both acute and chronic infection in vitro
       and was evaluated clinically by continuous intravenous infusion
       administration. The minimum effective dose (the concentration required
       to completely inhibit viral replication) was determined in vitro in a
       population of uninfected (99%) and HIV-infected (1%) cells exposed to
       A-77003 by continuous infusion in hollow-fiber bioreactors. The
       production of infectious HIV and release of p24 antigen from infected
       cells were completely inhibited in cultures exposed to A-77003 at or
       above a concentration of 0.5 microM. Measurement of unintegrated HIV-1
       DNA synthesis and flow cytometric analysis for cells expressing HIV p24
       antigen demonstrated that the spread of HIV to uninfected cells was also
       blocked at 0.5 microM A-77003. Dose deescalation to 0.25 microM or
       removal of A-77003 resulted in the limited spread of the virus
       throughout the culture, the resumption of viral DNA synthesis, and
       release of p24. HIV produced after exposure to 0.5 microM A-77003 was
       noninfectious for a period of 72 h after the removal of the drug.
       Addition of 1 mg of alpha 1-acid glycoprotein per ml to this in vitro
       system completely ablated the anti-HIV effect of 0.5 microM A-77003.
       These data suggest that determination of the minimum effective dose
       under conditions which simulate human pharmacodynamic patterns may be
       useful in determining the initial dose and schedule for clinical trials.
       However, other factors, such as serum protein binding, may influence the
       selection of a therapeutic regimen.
 DE    Antiviral Agents/ADMINISTRATION & DOSAGE/*PHARMACOLOGY  Cell Line
       Dose-Response Relationship, Drug  DNA, Viral/BIOSYNTHESIS  Flow
       Cytometry  Human  HIV Core Protein p24/METABOLISM  HIV Protease
       Inhibitors/ADMINISTRATION & DOSAGE/*PHARMACOLOGY  HIV-1/*DRUG
       EFFECTS/PHYSIOLOGY  Methylurea Compounds/ADMINISTRATION &
       DOSAGE/*PHARMACOLOGY  Orosomucoid/METABOLISM/PHARMACOLOGY  Polymerase
       Chain Reaction  Pyridines/ADMINISTRATION & DOSAGE/*PHARMACOLOGY
       T-Lymphocytes/VIROLOGY  Virus Replication/DRUG EFFECTS  JOURNAL ARTICLE

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