Journal of Pharmacobio-Dynamics
Online ISSN : 1881-1353
Print ISSN : 0386-846X
ISSN-L : 0386-846X
Volume 15, Issue 7
Displaying 1-6 of 6 articles from this issue
  • Atsushi KURIHARA, Masafumi HISAOKA, Naoji MIKUNI, Katsuo KAMOSHIDA
    1992 Volume 15 Issue 7 Pages 325-332
    Published: 1992
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    The neurotoxic potential of panipenem/betamipron (PAPM/BP), a new carbapenem antibiotic, was compared with that of imipenem/cilastatin (IPM/CS). The drug concentration in cerebrospinal fluid (CSF) at the onset of epileptogenic electroencephalographic (EEG)-activity and the drug distribution into the central nervous system (CNS) were evaluated. Epileptogenic reactions correlated well with drug levels in CSF, but not with drug levels in circulating plasma. The concentration of PAPM in CSF at the onset of epileptogenic EEG-activity was almost twice that of IPM, suggesting that neurotoxic activity of PAPM is about half that of IPM. In addition, in terms of incidence percent for the epileptogenic EEG-activity, PAPM/BP was found to be less toxic than IPM/CS within the dose of 1.0-1.2 g/kg. Concentrations of PAPM in CSF and brain extracellular fluid after PAPM/BP i.v. infusion were comparable with those of IPM after IPM/CS infusion, indicating the similar characteristics of distribution into the CNS for the two antibiotics. From these results of pharmacologic effects and drug distributions, it is suggested that the neurotoxicity of PAPM/BP is less than half that of IPM/CS.
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  • Shinichi KORA, Mineo SADO, Haruhiko KOIKE, Hiroshi TERADA
    1992 Volume 15 Issue 7 Pages 333-338
    Published: 1992
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    Ca2+-Induced membrane damage of energized mitochondria has been proposed to be due to lipid peroxidation induced by Ca2+. To examine this possibility, we studied the effects of the radical scavenger, 3, 5-di-tert-butyl-4-hydroxytoluene (BHT), and its derivative, 3, 5-di-tert-butyl-4-methoxytoluene (MeO-BHT), on membrane damage of respiring mitochondria induced by Ca2+ in the presence of inorganic phosphate. Both compounds inhibited Ca2+-induced damage almost completely at 20 μM, and their effects were identical, although MeO-BHT had no radical scavenging ability. These results indicate that the protective effects of BHT and MeO-BHT are not due to their radical scavenging ability. Thus, free radicals are concluded not to be involved in Ca2+-induced membrane damage of mitochondria.
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  • Akihisa YOSHIMI, Hiroyuki HASHIZUME, Satoshi TAMAKI, Hirokazu TSUDA, F ...
    1992 Volume 15 Issue 7 Pages 339-345
    Published: 1992
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    The relationship between physicochemical properties and oral absorption was investigated in prodrugs for the oral delivery of disodium cromoglycate (DSCG). To improve the lipophilicity of DSCG, various lipophilic moieties were introduced into the twin carboxyl groups. However, this did not lead to improved oral absorption in rabbits because of loss of water solubility, in spite of improved lipophilicity. Water-soluble prodrugs, in which an amino acid was introduced into a hydroxy group by ester linkage in addition to ethyl residues at twin carboxyl groups of DSCG, were synthesized and examined for oral absorption and rats. The oral absorption of these prodrugs was affected by the species of amino acids introduced as a water-soluble moiety. Therefore, we examined the relation between the oral absorption of water-soluble prodrugs and the hydrolysis rate of the amino acid moiety. A good linear correlation was obtained between the oral absorption and the hydrolysis rate constant catalyzed by digestive enzymes, trypsin or α-chymotrypsin. It was thus concluded that the amino acid moiety of water-soluble prodrugs must be rapidly hrdrolyzed to a permeable lipophilic prodrug still possessing the ethyl moiety at twin carboxyl groups in the small intestinal tract for good oral absorption.
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  • Taro OGISO, Masahiro IWAKI, Tadatoshi TANINO, Hidenari OUE
    1992 Volume 15 Issue 7 Pages 347-352
    Published: 1992
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    The percutaneous (p.c.) absorption of pindolol, a β-blocker, through rabbit skin was examined by in vitro and in vivo studies. Additionally, for practical use of the transdermal system (TTS), a trial for sustaining a suitable plasma concentration of pindolol by using a rate-controlling membrane and for describing plasma drug levels after p.c. application by using a simple pharmacokinetic model was tested. As a result, the drug penetrated through rabbit skin in vitro at a zero-order rate. In vivo, the drug was also absorbed through the skin from a gel base with or without enhancers. The gel preparation with Azone (Rp. 2) gave high plasma levels of pindolol. The transdermal system produced with Rp. 2 and a rate-controlling membrane (Hipore 4050) provided relatively constan plasma levels for 48 h. The model presented could describe the time course of plasma pindolol concentrations following p.c. application of the systems.
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  • Masatoshi BEPPU, Atsushi MIZUKAMI, Kiyomi KIKUGAWA
    1992 Volume 15 Issue 7 Pages 353-358
    Published: 1992
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    Human erythrocytes treated with diamide (0.2mM) or N-ethylmaleimide (0.1 mM) at 37°C for 1 h were susceptible to binding of anti-band 3 immunoglobulin G autoantibody and hemoglobin. A definite degree of cell modification appeared to be required for the effective bindings since the cells treated with the reagents above these concentrations were less susceptible. The enhanced binding activities of the cells treated with diamide were abolished on treatment with dithiothreitol. Partial blocking of SH groups of the membrane proteins but not disulfide-mediated protein cross-linking may be essential for the formation of band 3 senescent antigen, which may not be a neo-antigen formed by chemical modification of band 3 but an antigen formed by topological alterations of the molecules in the membrane.
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  • Hideji TANAKA, Tatsuhiko KANEKO
    1992 Volume 15 Issue 7 Pages 359-366
    Published: 1992
    Released on J-STAGE: February 19, 2008
    JOURNAL FREE ACCESS
    A competitive radioimmunoassay (RIA) and a sandwich enzyme-linked immunosorbent assay (ELISA) for the measurement of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rat serum was developed using polyclonal antibody obtained by immunizing rabbits with rhG-CSF. The anti-rhG-CSF antibody did not recognize other colony-stimulating factors or interleukins. RIA and ELISA gave satisfactory reproducibility as judged by intra- and inter-assay precision. Good agreements between the RIA, ELISA and bioassay were observed with rat serum samples after administration of rhG-CSF. The competitive RIA and sandwich ELISA described here appear to be as equally useful as the bioassay in studying the pharmacokinetics of rhG-CSF in animals.
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