r-82913 and Acquired-Immunodeficiency-Syndrome

The pharmacokinetics of oral administration of R 82913, or tetrahydroimidazol [4,5,1-jk]-benzodiazepin-2(1H)-one or -thione (TIBO), was compared with those of intravenous administration in five AIDS patients. TIBO was administered as a single daily 1-h infusion of 100 mg for 29 days and orally as a single daily dose for 14 days with three consecutive regimens of 100, 200, and 100 mg with probenecid (1 g) daily. Each cycle was followed by a wash-out period. Oral bioavailability of TIBO appears to be low and is not improved by the adjunction of probenecid. Trough levels obtained with oral administration systematically remained far below the 90% inhibitory concentration of TIBO against human immunodeficiency virus type 1 (HIV-1). Tolerance of TIBO was excellent. No clinical efficacy could be demonstrated. p24 antigenemia decreased significantly in one patient under intravenous therapy. TIBO derivatives are promising anti-HIV-1 agents in vitro, but improvement of oral bioavailability is needed before implementation of long-term efficacy and tolerability studies. Moreover, rapid emergence of resistance, which has been recently documented, constitutes a major problem with most nonnucleoside reverse transcriptase inhibitors.

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adult; Antiviral Agents; Benzodiazepines; Drug Administration Schedule; Humans; Imidazoles; Infusions, Intravenous; Male; Prospective Studies

The drug sensitivities of human immunodeficiency virus type 1 (HIV-1) isolates from a group of four untreated and seven TIBO R82913-treated patients were determined in a reverse transcriptase (RT) assay. Five of the treated patients harbored HIV-1 isolates with R82913 sensitivity comparable to that of the isolates of untreated patients, ranging from almost 2-fold higher sensitivity to 13-fold lower sensitivity than that of recombinant p66 RT. From one of the seven treated patients, an HIV-1 strain with a 20-fold reduced sensitivity to R82913 could be isolated; and from another patient, a strain with 100-fold reduced sensitivity (resistance) was isolated. The drug-resistant strain in this patient emerged after 3 weeks of treatment and was due to the Y188L mutation in its RT. On passaging the virus in cord blood lymphocytes, but not in CEM cells, the resistant virus was lost in favor of a different HIV-1 strain harboring the wild-type Y188 with a sensitivity to R82913 comparable to that of wild-type p66 RT. In several HIV-1 isolates (from treated and untreated patients), some HIV-2- and CIVgab-specific amino acids were found. One of these substitutions, that is, I/V179D (from an untreated patient), conferred a sevenfold reduced RT sensitivity to R82913.

Topics: Acquired Immunodeficiency Syndrome; Amino Acid Sequence; Base Sequence; Benzodiazepines; Cells, Cultured; DNA Primers; Drug Resistance, Microbial; Genetic Variation; HIV Reverse Transcriptase; HIV-1; Humans; Imidazoles; Molecular Sequence Data; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Sequence Alignment

R 82913, a tetrahydroimidazobenzodiazepinthione (TIBO) derivative with potent activity against human immunodeficiency virus 1 (HIV-1) in vitro, was given to 22 patients with AIDS or AIDS-related complex in a dose-escalating pilot study. Doses of 10 to 300 mg administered daily by intravenous infusion were well tolerated for up to 50 weeks, with no haematological or biochemical evidence of toxicity. Mean OKT4 cell count rose slightly during the second month of treatment when higher steady-state plasma concentrations of the drug were achieved. Median p24 antigen concentration fell by 41% during the first month of therapy. When the rise in p24 antigen before therapy was compared to the fall during treatment, end-point analysis showed a significant difference (p less than 0.03). The combination of potent antiretroviral activity in vitro and the observed effect on HIV p24 antigen and absence of toxicity in vivo indicate that R 82913 and related TIBO derivatives merit further study in the treatment of retroviral infections.

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Complex; Benzodiazepines; CD4 Antigens; Drug Administration Schedule; Gene Products, gag; HIV Core Protein p24; Humans; Imidazoles; Infusions, Intravenous; Leukocyte Count; Middle Aged; Pilot Projects; Viral Core Proteins

Several classes of non-nucleotide analogues (i.e. TIBO and HEPT derivatives) have been identified that specifically interact with the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1). These derivatives inhibit the replication of HIV-1 in various cell lines, including peripheral blood lymphocytes and monocytes/macrophages, at concentrations that are 10,000- to 100,000-fold lower than the cytotoxic concentrations. At the HIV-1 RT level, they appear to interact with a specific allosteric "TIBO" site, which may be functionally and also structurally associated with the substrate binding site. The TIBO and TIBO-like compounds are orally bioavailable. In vivo they sustain plasma drug levels that are well above the concentrations required to inhibit virus replication in vitro.

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Benzodiazepines; HIV-1; Humans; Imidazoles; Reverse Transcriptase Inhibitors; Thymine; Virus Replication

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.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiviral Agents; Benzodiazepines; Colony-Forming Units Assay; Erythroid Precursor Cells; Hematopoietic Stem Cells; Humans; Imidazoles; Zidovudine