Journal of Pharmacobio-Dynamics
Online ISSN : 1881-1353
Print ISSN : 0386-846X
ISSN-L : 0386-846X
14 巻, 9 号
選択された号の論文の7件中1~7を表示しています
  • Satoshi KISHINO, Naonori KOHRI, Ken ISEKI, Katsumi MIYAZAKI, Akikazu N ...
    1991 年 14 巻 9 号 p. 493-499
    発行日: 1991年
    公開日: 2008/02/19
    ジャーナル フリー
    There were remarkable differences in the serum total and unbound concentrations of disopyramide (DP) and mono-N-dealkyldisopyramide (MND), the major metabolite of DP, among patients with arrhythmias. Serum levels of α1-acid glycoprotein (AAG) also varied among the same patients. To predict the unbound DP concentrations, we have obtained the serum concentration-time curves of unbound DP in these patients by means of total DP concentration, DP pharmacokinetic parameters, AAG levels and dissociation constants of DP and MND at specific AAG binding sites. In patients with normal AAG levels, the theoretical values of unbound DP were in good agreement with the measured concentrations. On the other hand, in patients with high AAG levels, the theoretical values could be obtained by correcting the calculated values using both AAG levels of each patient and the equation correlating the unbound DP fraction to AAG concentrations. These findings indicate that patient AAG levels can provide valuable information permitting the rapid estimation of unbound DP concentrations, the pharmacologically active fraction, and the development of effective DP dosage regimens.
  • Matheus SIMANJUNTAK, Tetsuya TERASAKI, Ikumi TAMAI, Akira TSUJI
    1991 年 14 巻 9 号 p. 501-508
    発行日: 1991年
    公開日: 2008/02/19
    ジャーナル フリー
    A participation of bicarbonate exchange system for the transport of acetic acid and the related monocarboxylic acid drugs in the intestinal brush-border membrane vesicles (BBMVs) was investigated. The uptake of [3H] acetic acid at 37°C by BBMVs was markedly stimulated and showed a clear overshoot phenomenon in the presence of outward-directed bicarbonate gradient (pHin = 7.5, [KHCO3]in or [NaHCO3]in = 100 mM ; pHout = 7.5, [K-gluconate]out or [Na-gluconate]out = 100 mM). This uptake process was saturable (Kt = 50.4±4.96 mM and Jmax = 11.6±0.61 nmol/mg protein/10 s) and was inhibited by DIDS (4, 4-diisothiocyano-2, 2'-disulfonic acid stilbene disodium salt) and furosemide, anion exchange inhibitors, and by many monocarboxylates. The initial uptake of [3H] acetic acid was competitively inhibited by salicylic acid, suggesting the common transport between acetic acid and salicylic acid. At lower extravesicular pHs and in the presence of outward-directed bicarbonate gradient (pHin = 7.5, [KHCO3]in = 100 mM ; pHout = 6.0 or 5.0, [K-gluconate]out = 100 mM) where membrane potential was clamped to zero by K+-valinomycin, the uptake of [3H] acetic acid showed an overshoot phenomenon, whereas the uptake was significantly decreased in the presence of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, a protonophore. It was concluded, therefore, that there are one or two mechanisms for the carrier-mediated transport of acetic acid and monocarboxylates related to bicarbonate exchange systems in rabbit intestinal BBMVs : 1) proton gradient independent and bicarbonate exchange system ; 2) proton gradient dependent and bicarbonate exchange system.
  • Chiaki KAMEI, Kazuhiro KITAZUMI, Susumu TSUJIMOTO, Tomokazu YOSHIDA, K ...
    1991 年 14 巻 9 号 p. 509-517
    発行日: 1991年
    公開日: 2008/02/19
    ジャーナル フリー
    The epileptogenic effects of (1R, 5S, 6S)-2-[(6, 7-dihydro-5H-pyrazolo [1, 2-a] [1, 2, 4] triazolium-6-yl)] thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate (LJC10627), a new derivative of carbapenem were studied in comparison with those of imipenem (imipenem/cilastatin), cefazolin and penicillin G. In intraventricular injection in rats, LJC10627 caused no epileptogenic activity at a dose of 32 μg. In contrast, imipenem, cefazolin and penicillin G showed dose-related seizure signs, continuous rhythmic spikes or high voltage spike-wave complexes and convulsive behaviors at doses higher than 10 μg. After intravenous injection of LJC10627, no epileptogenic signs on the electroencephalogram (EEGs) or in behavioral symptoms were observed, even at a dose of 500 mg/kg in rats and 300 mg/kg in rabbits, respectively. By contrast, imipenem/cilastatin provoked severe seizure patterns characterized by high voltage spikes-wave complex and convulsive behavior, both in rats and rabbits, using the same doses of LJC10627. Cefazolin and penicillin G also induced obvious epileptogenic signs in both rats and rabbits after intravenous injection. From these results, it was concluded that LJC 10627, unlike imipenem (imipenem/cilastatin) and cefazolin, dose not elicit epileptogenic activity, and may therefore be safely used for clinical purpose.
  • Shunji KASAI, Shuichi FUJIMOTO, Kazuo NITTA, Hiroyasu BABA, Takehiko K ...
    1991 年 14 巻 9 号 p. 519-525
    発行日: 1991年
    公開日: 2008/02/19
    ジャーナル フリー
    The antitumor activity of mouse polymorphonuclear leukocyte (PMN) treated with a β-1, 3-D-glucan from Alcaligenes faecalis var. myxogenes IFO 13140 (TAK-N) and its carboxymethylated derivative (CM-TAK) was investigated in vitro and in vivo. ICR mouse PMN showed strong cytotoxicity against sarcoma 180 cells and inhibition of the growth of the tumor cells in vitro in the presence of TAK-N but not in the presence of CM-TAK. Since the cytotoxicity induced by TAK-N was almost completely inhibited by catalase, it seems to be mediated by H2O2 production by PMN. On the other hand, TAK-N induced no cytotoxicity in macrophages and neither did CM-TAK in PMN or in macrophage. Intraperitoneal injection of TAK-N into ICR mice induced a large number of PMN and macrophages in the peritoneal cavity. The peritoneal exudate PMN which were harvested at 10 to 72 h after TAK-N injection showed cytotoxicity against sarcoma 180 cells, but the peritoneal exudate macrophages did not. Treatment of sarcoma 180 ascites tumor-bearing ICR mice with TAK-N at a dose of 100 mg/kg prolonged significantly the survival time over that of the control. These results indicate that TAK-N induces PMN cytotoxicity against sarcoma 180 cells not only in vitro but also in vivo. The antitumor effect of TAK-N on sarcoma 180 ascites tumor seems to be derived from PMN stimulated with TAK-N.
  • Hisashi NOMURA, Seigo IWAKAWA, Yoshihiro SAITO, Ryohei HORI, Katsuhiko ...
    1991 年 14 巻 9 号 p. 527-531
    発行日: 1991年
    公開日: 2008/02/19
    ジャーナル フリー
    The effect of experimental ulcers on the binding of human epidermal growth factor (hEGF), β-urogastrone, to plasma membranes isolated from rat gastric mucosa was studied in order to develop hEGF as an anti-ulcer drug. The binding of [125I] hEGF to the gastric plasma membranes was significantly decreased 1 h after treatment with aspirin (300 mg/kg) and after 12 h of water-immersion stress. However, the number of EGF binding sites was increased 12 h after aspirin administration. There was little change in the binding of [125I] insulin to the gastric plasma membranes in response to water-immersion stress. These results indicate that changes in EGF binding to its receptors occur on plasma membranes of the rat gastric mucosa during ulcer.
  • Yutaka ITO, Takeshi FUKUSHIMA, Yoichi SUGAWARA, Osasi TAKAITI, Susumu ...
    1991 年 14 巻 9 号 p. 533-546
    発行日: 1991年
    公開日: 2008/02/19
    ジャーナル フリー
    Metabolic fate of (+)-(1R, 4aS, 10aR)-1, 2, 3, 4, 4a, 9, 10, 10a-octahydro-1, 4a-dimethyl-7-(1-methylethyl)-6-sulfo-1-phenanthrenecarboxylic acid 6-sodium salt pentahydrate (TA-2711), a new anti-ulcer drug, was studied in animals using 14C-TA-2711. The absorption was estimated to be 3.4-7.0% of dose in rats. The plasma radioactivity after oral dosing peaked at 5-6 h in rats and at 2 h in dogs, and their elimination half lives (β) were about 120-130 h. After oral or intravenous administration of TA-2711 to rats, the concentrations of radioactivity in most of the tissues were much lower than that in the plasma, indicating the low transfer of TA-2711 into the tissues from the plasma. In whole body autoradiograms of rats, most of the radioactivity given orally was localized in the gastrointestinal tract. Almost all the radioactivity given orally was excreted to the feces while the urinary excretion was extremely low. The sole and slight metabolite, glucuronide of TA-2711, was detected only in the urine of rats and dogs after oral dosing. During the consecutive oral dosing once a day for 21 d to rats, the plasma levels attained the steady state after administration of drug 7-10 more times. After the final dosing, the patterns of disappearance of radioactivity in the plasma were similar to those in the tissues, and the tissue/plasma ratios of the concentrations were similar to those after single dosing, suggesting no accumulation in rat tissues. More than 96% and about 85% of TA-2711 was bound in vitro to human and rat serum proteins, mainly albumin, respectively. No radioactivity was found in fetus and milk of rats given oral administration.
  • Yutaka ITO, Yoichi SUGAWARA, Osasi TAKAITI, Susumu NAKAMURA
    1991 年 14 巻 9 号 p. 547-554
    発行日: 1991年
    公開日: 2008/02/19
    ジャーナル フリー
    The distribution of (+)-(1R, 4aS, 10aR)-1-2, 3, 4, 4a, 9, 10, 10a-octahydro-1, 4a-dimethyl-7-(1-methylethyl)-6-sulfo-1-phenanthrenecarboxylic acid 6-sodium salt pentahydrate (TA-2711) in stomach was studied after oral administration of 14C-TA-2711 (100 mg/kg) to rats. At 6 h after dosing, most of the radioactivity was found in the lower intestine, caecum and large intestine. However, the radioactivity in the stomach was higher than that in the upper and middle small intestine. The concentration of the radioactivity in the glandular stomach was about 1.5 mg eq. TA-2711/g at 30 min after administration. Thereafter, it decreased gradually to about 60 μg eq. TA-2711/g at 6 h after dosing. In the radioluminograms of 6 and 24 h after dosing, most of the radioactivity was observed on the surface of gastric mucosa. After administration to rats with gastric ulcer induced by acetic acid, higher radioactivity was observed in the ulcerated tissues of the stomach than in the nonulcerated control tissues. In the stomach damaged by ethanol, the concentrations of radioactivity in lesion parts were also higher than those in non-lesion parts. In the microautoradiograms of gastric mucosa damaged by ethanol, the developed silver grains were densely distributed in necrotic tissues.
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