Journal of Pharmacobio-Dynamics
Online ISSN : 1881-1353
Print ISSN : 0386-846X
ISSN-L : 0386-846X
7 巻, 12 号
選択された号の論文の11件中1~11を表示しています
  • JUNJI HIRATE, ISAMU HORIKOSHI, JUN WATANABE, SHOJI OZEKI
    1984 年 7 巻 12 号 p. 883-890
    発行日: 1984年
    公開日: 2008/02/19
    ジャーナル フリー
    Hypothermal mice were used under the anesthetized condition with ether to clarify the effect of diminished blood circulation on the dispositions of creatinine and urea which are considered to pass through the water-filled pores of biological membranes easily. The total body clearance of each chemical was considerably decreased in hypothermal mice compared with normal mice. This was considered to be caused by the decrease of glomerular filtration rate. The whole-body autoradiograms obtained following intravenous administration of 14C-urea and the rate of muscular blood flow showed that the transfer of urea from blood to muscle was apparently delayed by the decrease of muscular blood flow rate. However, the transfer of creatinine to muscle was not influenced by the change of muscular blood flow rate. This difference between creatinine and urea might be related to the higher permeability of muscular cell membrane to urea than to creatinine.
  • KOJI SHIMIZU, SAKAE AMAGAYA, YUKIO OGIHARA
    1984 年 7 巻 12 号 p. 891-899
    発行日: 1984年
    公開日: 2008/02/19
    ジャーナル フリー
    Effects of combined use of Shosaikoto (one of the famous crude Chinese medicines) and prednisolone were examined in anti-inflammatory effects, using the carrageenan edema and the cotton pellet methods.Shosaikoto and prednisolone were orally given to rats or mice at the dose of 1.1g/kg (corresponding to 10 times the usual human dose) for the former and 1.0, 4.0 and 16.0 mg/kg for the latter. Shosaikoto showed the mild antiinflammatory action and significantly increased the anti-inflammatory effct of prednisolone in both experimental models. In cotton pellet method, combined use of Shosaikoto inhibited the decrease of adrenal weight induced by prednisolone. To clarify the mechanism of combined effcts of prednisolone and Shosaikoto, the effects of Shosaikoto on the blood prednisolone level and on the secretion of endogenous glucocorticoid (corticosterone) were investigated by high performance liquid chromatography. The blood prednisolone level 20 min after the combined administration of Shosaikoto with prednisolone, 16 mg/kg, was about 2 times comparing with that of single administration of prednisolone. The half life period of blood prednisolone after the single administration of prednisolone was about 2 times comparing with that of the combined administration of Shosaikoto with prednisolone. On the other hand, the single administration of Shosaikoto increased the blood corticosterone level 1 h after the administration with significant manner. The increasing activity of Shosaikoto on the anti-inflammatory effect of prednisolone may be explained by its plural actions.
  • NAHOKO KANIWA, NOBUO AOYAGI, KIROYASU OGATA
    1984 年 7 巻 12 号 p. 900-909
    発行日: 1984年
    公開日: 2008/02/19
    ジャーナル フリー
    The programs for the pharmacokinetic models with discontinuous absorption, written in BASIC, were connected to MULTI, which had been proposed for nonlinear least squares for a microcomputer by Yamaoka et al. Using this program (designated as PKMMULTI), the same data sets previously calculated by HFCM, FITISI2and NONLIN were fitted and the finally obtained estimates were in close agreement with those obtained previously. The plasma data of nalidixic acid were also fitted to the pharmacokinetic model with discontinuous absouption, which were suggested to be more valid compared with one compartment model with continuous absorption.
  • RYOHEI HORI, YOSHIHIRO SAITO, MASATO YASUHARA, KATSUHIKO OKUMURA
    1984 年 7 巻 12 号 p. 910-916
    発行日: 1984年
    公開日: 2008/02/19
    ジャーナル フリー
    Following injection of 125I-porcine insulin, 125I-aprotinin, 125I-salmon calcitonin, or 125I-(Asu1, 7-eel calcitonin into rats, high molecular weight (HMW) forms of these peptides were detected in serum or plasma when analyzed by gel chromatography. The conversion into HMW forms occurred after 1) intravenous bolus injection of insulin, aprotinin, or calcitonins, 2) intravenous infusion of insulin or aprotinin, and 3) subcutaneous injection of insulin, indicating that HMW forms were produced in the general circulation not in the subcutaneous tissue. Rechromatography of HMW forms produced in vivo from insulin or aprotinin showed the release of lower moleclar weight component which was eluted at the same position of parent peptide, the immunoreactivity of the released component derived from insulin was almost the same as for insulin. These results suggest that the conversion of peptide drugs into HMW forms is generally occurred in vivo and they play a role as a depot in circulation.
  • KATSUHIKO OKUMURA, YOSHIHIRO SAITO, MASAO YASUHARA, RYOHEI HORI
    1984 年 7 巻 12 号 p. 917-922
    発行日: 1984年
    公開日: 2008/02/19
    ジャーナル フリー
    Studies were undertaken to investigate the site and conversion mechanism of exogenous peptides into high molecular weight (HMW) forms when administered in vivo. Functional nephrectomy reduced the conversion of aprotinin into HMW form in circulation whereas incubation of aprotinin in kidney homogenate in vitro resulted in an increase in HMW component, indicating that the kidney participates in conversion of aprotinin into HMW form. Incubation of aprotinin in rat serum showed that HMW forms can be produced in blood. Analysis of molecular weight of the components produced in vivo and in serum in vitro demonstrated that they consist of heterogeneous mixture and that the components produced in vitro resemble those produced in vivo. Incubation of (Aus1, 7)-eel calcitonin, which lacks intramolecular disulfide disulfide bonds, in serum did not result in the production of HMW form, whereas incubation of three other peptides having intramolecular disulfide bonds did, suggesting that conversion mechanism of peptide drugs into HMW forms in blood is mainly by thiol-disulfide interchamge reaction between peptides and serum protein.
  • SAKAE AMAGAYA, ETSUKO SUGISHITA, YUKIO OGIHARA, SUSUMU OGAWA, KENZO OK ...
    1984 年 7 巻 12 号 p. 923-928
    発行日: 1984年
    公開日: 2008/02/19
    ジャーナル フリー
    Anti-inflammatory of the stereoisomers, 18α and 18β-glycyrrhetinic acid (18α and 18β-GA), obtained from Glycyrrhizae Radix, was investigated by using carrageenan-induced edema in mice and 18α-GA was found to be more active than 18β-GA. Therefore, to clarify the difference of action of 18α and 18β-GA, the inhibitory effects of both stereoisomers on the cotton pellet granuloma formation in adrenalectomized rats and on the reduction of steroidal compounds by Δ4-5β-reductase in the microsome fraction of rat liver were investigated. 18α-GA, 30 mg/kg p.o., showed the similar antigranulomatous action in normal and adrenalectomized rats. On the other hand, 18β-GA, 30 mg/kg p.o., which exhibited the inhibitory effects in normal rats, showed no action in adrenalectomized rats. More than 50% of inhibitory effects of 18α and 18β-GA on the 5β-reduction of testosterone and cortisol were recognized by an equimolar ratio of steroids to 18α or 18β-GA. From these results, the activity of 18α-GA is similar to that of glucocorticoid and the difference of action between 18α and 18β-GA could be explained by its stereochemical structure of D/E trans conformation. In addition to the glucocorticoid action, 18α-GA inhibited the inactivation of endogenous glucocorticoid in liver, which is also recognized by the application of 18β-GA.
  • JUNJI HIRATE, ISAMU HORIKOSHI, JUN WATANABE, SHOJI OZEKI, SUMI NAGASE
    1984 年 7 巻 12 号 p. 929-934
    発行日: 1984年
    公開日: 2008/02/19
    ジャーナル フリー
    To clarify the role of albumin in the dispositions of drugs by in vivo experiment, analbuminemic rats were used and plasma-level analyses and whole-body autoradiography following intravenous administration of 14C-salicylic acid were carried out. The distribution volume of salicylic acid in analbuminemic rats (650±33 ml/kg) was remarkably larger than that in normal rats (180±3 ml/kg) (p <0.01). Whole-body autoradiograms demonstrated that transfer of salicylic acid from the blood to the liver, muscle and brain, especially to the liver, may be increased in analbuminemic rats. The increased distribution may be explained by the lack of plasma albumin, since the distribution of salicylic acid depends in part on plasma albumin binding. The total body clearance of salicylic acid in analbuminemic rats (12.2±1.4 ml/min/kg) was about 3.2 times that in normal rats (3.8±0.1ml/min/kg) (p <0.01), suggesting that metabolic clearance and/or renal clearance is enhanced in analbuminemic rats. Increased extraction by the liver and/or the kidney due to increased free fraction in total (bound and unbound) plasma salicylic acid assumed to be responsible for this result.
  • SHIGETOSHI SUZUKI, KOHEI KIKKAWA, MIKIO YAMAZAKI
    1984 年 7 巻 12 号 p. 935-942
    発行日: 1984年
    公開日: 2008/02/19
    ジャーナル フリー
    Fumitremorgin A (FTA), a neurotropic mycotoxin induced dose-dependent abnormal behaviors, including tremor, clonic convulsion, kangaroo posture and tonic exensor convulsion in the mouse. FTA-induced tinic extensor convulsion was markedly suppressed by anticonvulsant, e.g. phenobarbital, phenytoin. Phenobarbital, trimethadione, valproic acid and mephenesin decreased the occurrence of abnormal behaviors induced by FTA. Although pentylenetetrazol-induced tonic extensor convulsion was not affected by antipsychotic drugs (dopaminergic drugs) except chlorpromazine, FTA-induced abnormal behaviors were inhibited by antipsychotic drugs, e.g. chlorpromazine, haloperidol. Chlordiazepoxide, diazepam and muscimol inhibited FTA-induced abnormal behaviors. These findings suggest that both dopaminergic and γ-aminobutyric acid (GABA)-ergic systems are involved in FTA-induced abnormal behaviors. FTA-induced abnormal behaviors may be useful as a common experimental model for the primary evaluation of anticonvulsants, antipsychotic drugs and anxiolytic drugs.
  • KAZUHIKO SAKAI, NEE HASHIMOTO, SHIGEO SUZUKI, MASUKO SUZUKI
    1984 年 7 巻 12 号 p. 943-950
    発行日: 1984年
    公開日: 2008/02/19
    ジャーナル フリー
    Macrophages (Mφ) and polymorphonuclear leukocytes (PMN) were obtained from C3H/He mice which had received intraperitoneal administration of an acidic fraction of bakers' yeast mannan (WAM025), 150 mg/kg/d, for 5d and the cells were investigated for their cell-injuring effect against MM46 tumor cells in vitro. The Mφ displayed a marked cytolytic effect in the range of effector cells to target cells ration of 100 to 200 with concomitant increase of lysosomal enzyme and active oxygen production. On the other hand, the PMN did not show the cytolytic effect, and the enhancing effect of the lysosomal enzyme activity was also very low, while these cells produced larger amounts of active oxygens and interleukin-1 (IL-1) than did the Mφ.
  • KATSUSHIGE GOMI, MAKOTO MORIMOTO, NOBUHIRO NAKAMIZO
    1984 年 7 巻 12 号 p. 951-961
    発行日: 1984年
    公開日: 2008/02/19
    ジャーナル フリー
    The antitumor activity of recombinant human interferon-β (ReIFN-β) against 2 human melanomas, Mela3 and SK-MEL-26 cells, transplanted into nude mice was examined, comparing with that of natural interferon-β (IFN-β). The growth of Mela3 and SK-MEL-26 cells was inhibited significantly by the daily intravenous injection of 108 units(U)/kg of ReIFN-β for 10 d starting from day 0. The effect of ReIFN-β decreased when its administration was started from the established stage of tumor development. Intravenous injection of 107 U/kg of ReIFN-β or IFN-β did not significantly inhibit the growth of Mela3 cells. Mela3 cells, prepared from Mela3-bearing mice which had been injected 108 U/kg of ReIFN-β intravenously for 10 d, showed the slight resistance to ReIFN-β in vitro. Intratumoral injection of 107 U/kg of ReIFN-β in the established stage of tumor development inhibited the growth of Mela3 and SK-MEL-26 cells significantly. This effect of ReIFN-β was almost equivalent to that of IFN-β. From the histologocal examination, these effects of intratumoral injection of ReIFN-β or IFN-β were suggested to be mediated by their direct anticellular activities, but not by immunological activities. These results indicate that the in vivo antitumor activity of ReIFN-β was not essentially affected by the deficiency of carbohydrate.
  • MITSUZI YOSHIDA, SEIICHI ISHIZUKA, AKIO HOSHI
    1984 年 7 巻 12 号 p. 962-968
    発行日: 1984年
    公開日: 2008/02/19
    ジャーナル フリー
    Induction of cell differentiation by twenty-one derivatives of vitamin D3 and their binding affinity for the receptor of 1α, 25-dihydroxyvitamin D3 an active vitamin D3 metabolite, were examind using HL-60 human promyelocytic leukemia cells and chick intestinal cytosol, respectively. 1α, 24(R)-dihydroxy-26-chlorovitamin D3 is found to be more active than 1α, 24(R)-dihydroxyvitamin D3 and 1α, 25-dihydroxyvitamin D3 in the two abilities to induce the differeniation and to bind to the receptor. the results suggest that a hydroxy group at C-1 position of vitamin D3 and a hydroxy or oxo group at C-25 or C-24 position are essential for both abilities. In diastereoisomers of 1α, 25-dihydroxyvitamin D3-26, 23-lactone, synthesized (23S, 25S)1α, 25-dihydroxyvitamin D3-26, 23-lactone was more active in both abilities than the natural metabolite, (23S, 25R)1α, 25-dihydroxy-vitamin D3-26, 23-latone, which shows anti-vitamin D action.
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