title: TIBO R82913, a new HIV-1 inhibiting agent, does not inhibit hematopoietic progenitor cells.
abstract: In progressive stages of infection with human immunodeficiency virus type 1 (HIV-1), the majority of patients develop a pathophysiologically not yet completely explainable bone marrow failure with anemia, leukopenia, and thrombocytopenia. The clinically most widely used HIV-inhibiting antiviral drugs azidothymidine (AZT) and dideoxyinosine (ddI) frequently are hematotoxic to the host, resulting in dose reduction or discontinuation of antiviral therapy. In recent studies, a novel series of benzodiazepine derivatives highly active against HIV-1 was synthesized. These antiviral compounds have a much more favorable therapeutical index than the well-known 2'3'-dideoxyribosides, like AZT. In the experiments presented here, the authors investigated the most promising derivative R82913 [(+)-S-4,5,6,7-tetrahydro-9-chloro-5-methyl- 6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk] [1,4]-benzodiazepin-2(1H)-thione] (TIBO) with regard to its toxicity on bone marrow-derived hematopoietic progenitor cells from six HIV-1+ and HIV- persons, respectively. In methylcellulose assays for hematopoietic colony growth any hematotoxic effects of R82913 in vitro were excluded, as both groups showed no difference of progenitor cell growth with or without the TIBO derivative, even at concentrations 6.7 x 10(4) times higher than the 50% inhibitory concentration for cytopathicity by HIV-1.
authors.affiliation: University of Frankfurt, Department of Hematology, Federal Republic of Germany.
authors.forename: R G
authors.initials: RG
authors.lastname: Geissler
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.forename: O G
authors.initials: OG
authors.lastname: Ottmann
authors.forename: G
authors.initials: G
authors.lastname: Kojouharoff
authors.forename: P
authors.initials: P
authors.lastname: Reutzel
authors.forename: K
authors.initials: K
authors.lastname: Andries
authors.forename: K
authors.initials: K
authors.lastname: Schellekens
authors.forename: D
authors.initials: D
authors.lastname: Hoelzer
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000097:blood*; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D003114:Colony-Forming Units Assay; D015672:Erythroid Precursor Cells / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D007093:Imidazoles; D001569:Benzodiazepines; D015215:Zidovudine; C067413:R-82913