Journal of Pharmacobio-Dynamics
Online ISSN : 1881-1353
Print ISSN : 0386-846X
ISSN-L : 0386-846X
12 巻, 8 号
選択された号の論文の10件中1~10を表示しています
  • Ikue KANEKO, Yoshinobu FUKUMORI, Tomoaki FUKUDA, Yoshikazu TAKEUCHI
    1989 年 12 巻 8 号 p. 441-447
    発行日: 1989年
    公開日: 2008/02/19
    ジャーナル フリー
    The Pharmacological response intensity of chlorzoxazone (CZX) was measured by the crossed extensor reflex (CER) method in anesthetized rats. The appropriate dose of alpha-chloralose (ACH) was examined to bring about a quantitative effect of CZX. The pharmacodynamics of CZX was also characterized in the anesthetized rats at three different doses of CZX. When rats were anesthetized with ACH at three different doses (80, 110, and 150 mg/kg i.p.), the CER response caused by CZX at the doses of 25, 50, and 75 mg/kg p.o. was depressed dosedependently. Among these three different doses of ACH, 80 and 110 mg/kg gave similar results in describing the pharmacological response induced by CZX with time, whereas a dose of 150 mg/kg of ACH elicited a stronger and longer CZX response than the other two doses. The area under the intensity-time curve also showed the same tendency. These findings suggested that the dose size ranging from 80 to 110 mg/kg of ACH for surgical anesthesia was appropriate to evaluate the quantitative pharmacological response of CZX. Pharmacodynamic analysis offered the results that the dose-normalized biophase levels of CZX were coincident with each other when CZX was given at three different doses under ACH anesthesia at the dose of 80 mg/kg. This suggested that the disposition of CZX in rats obeyed linear kinetics and the theoretical values of CZX-induced response would be predictable. This implied that pharmacological response intensity of CZX was reasonably related to the relative biophase CZX level via Hill's equation.
  • Hideo NAKAGAWA, Yukihiko AIKAWA, Hisashi KITAGAWA
    1989 年 12 巻 8 号 p. 448-455
    発行日: 1989年
    公開日: 2008/02/19
    ジャーナル フリー
    Gelatinases produced by granulation tissue in culture were separated into two fractions when the conditioned medium was chromatographed on diethylaminoethyl-Sephacel ; one contained latent and active gelatinases with molecular weight of about 74 kDa (low-Mr gelatinase), and the other contained an active gelatinase with molecular weight of about 112 kDa (high-Mr gelatinase) as estimated by gel filtration on Sephadex G-150. The former was unbound and the latter was bound to Znchelating Sepharose. Both low-and high-Mr gelatinases, however, occurred in mainly two bands corresponding to molecular weights of 64 and 57 kDa on sodium dodecyl sulfate-substrate polyacrylamide gel electrophoresis. Recombinant human tumor necrosis factor-α (TNF) markedly enhanced the production of gelatinases, especially high-Mr active gelatinase. Dexamethasone and hydrocortisone strongly suppressed TNF-mediated production of high-Mr active gelatinase, whereas indomethacin, piroxicam and mepacrine had no effect. The results suggest that steroidal anti-inflammatory drugs suppress a rapid collagen breakdown in granulation tissue through their inhibitory actions-one of which is the suppression of active gelatinase production enhanced by cytokines including TNF.
  • Teruo TSUCHIYA, Katsuyuki NAGAI, Takamasa YOSHIDA, Tadashi KIHO, Shige ...
    1989 年 12 巻 8 号 p. 456-460
    発行日: 1989年
    公開日: 2008/02/19
    ジャーナル フリー
    The reduction of acute toxicity of paraquat dichloride (PQ) in mice was studied by several sodium sugar sulfates such as dextran sulfate (DS), cellulose sulfate (CS), chondroitin sulfate (CDS), sucrose sulfate (SS) and glucose sulfate (GS). When sugar sulfates (DS, CS, SS or GS, 2 000 mg/kg) were given orally immediately after PQ ingestion (200 mg/kg), the survival rates were 100% respectively on the 14th day after PQ ingestion. In the case of CDS, it was 73%. The effective dose of SS and GS given for the prevention of PQ toxicity in mice after PQ (200 mg/kg) ingestion was more than 400 mg/kg for SS-treated group and more than 800 mg/kg for GS-treated group. The survival rate of these mice was 100% respectively. When GS or SS (2 000 mg/kg) was given orally to mice within 1 h (0, 10, 20, 30 or 60 min) after PQ ingestion (200 mg/kg), the survival rates in an earlier treatment were greater than those in a later treatment. The measurement of serum PQ concentrations in mice suggested that a mechanism for the prevention of PQ toxicity by the administration of sugar sulfates may be inhibition of PQ absorption, and/or stimulation of PQ excretion from intestine. The effectiveness of SS and GS in preventing PQ toxicity was similar to that of DS. These results suggested that SS, GS and DS might serve as an antidote for acute toxicity of PQ.
  • Masumitsu TAKASUGI, Kazuhiko TERAOKA, Kazuo MINAKUCHI, Seiji AKAMATSU, ...
    1989 年 12 巻 8 号 p. 461-467
    発行日: 1989年
    公開日: 2008/02/19
    ジャーナル フリー
    The present study dealt with two objects ; the first object was to examine whether or not lithium uptake in thyroid is modified by the thyroid state and how the intrathyroidal Li affects iodide uptake by the thyroid. Male and female mice were given lithium carbonate (Li) with propylthiouracil (PTU) or thyroxine (T4). Li was measured by a flameless atomic absorption spectrometry. The total Li content in thyroid was unaffected with PTU or T4, however, Li concentration per unit mass was reduced by PTU but unaffected by T4. The thyroid : serum ratio (T/S) of 125I resulted that the T/S became higher when Li concentration per unit mass was lower and vice versa, suggesting that Li uptake is controlled by thyroid states and Li in the gland interferes with the iodide uptake. Serum triiodothyronine (T3) and T4 by radioimmunoassay showed that PTU alone and in combination with Li lowered serum T4, while a high level of T4 by its supplement was suppressed by co-administration of Li. T3 level was lowered by Li alone, but not severely affected by other drugs. The results suggest that Li enhances T4 clearance without T4-T3 conversion. The second object was to examine the effect of combined psychotropic drugs on thyroid function. Carbamazepine (CBZ), haloperidol (HLP) and imipramine (IPA) were given singly or in combination with Li to examine their effects on the T/S of 125I. Only CBZ reduced the T/S but CBZ plus Li had no summative effect. Neither HLP nor IPA affected the T/S, singly or in combination with Li, suggesting that HLP or IPA does not interfere with an iodide pumping machinery. No distinct sex difference was observed in drug effects.
  • Ramasamy KARUNANITHY, Soo Hwa YEO, Sai Leung LEUNG
    1989 年 12 巻 8 号 p. 468-475
    発行日: 1989年
    公開日: 2008/02/19
    ジャーナル フリー
    The relationships between contraceptive activity, hydrophobic character and alkaline hydrolysis rates were studied in three homologous series of norethisterone and levonorgestrel esters. Hydrophobic character was expressed by the high-performance liquid chromatographic retention term, VR (w) or retention volume at 100% aqueous mobile phase. A parabolic and bilinear relationship was shown between log VR (w) and log biological response. No correlation between second-order alkaline hydrolysis rates, K2, measured in 70% (v/v) aqueous dioxan and contraceptive activity was established.
  • Toshio FUJIYOSHI, Masaharu DOZEN, Kenro IKEDA, Sachiko OHISHI
    1989 年 12 巻 8 号 p. 476-482
    発行日: 1989年
    公開日: 2008/02/19
    ジャーナル フリー
    The relationship between the kaolin-induced writhing reaction and production of arachidonate metabolites (PGs) in mice was studied. PGs were released into the peritoneal cavity after intraperitoneal injection (i.p.) of kaolin (2.5 mg/mouse) with a peak at 5 min. About 80% of the total amount was 6-keto-PGF. There was a significant correlation (r=0.8237, p<0.001) between the number of writhes and the amount of 6-keto-PGF. The writhing reaction induced by kaolin was significantly inhibited by simultaneous injection of soybean trypsin inhibitor (SBTI ; 2.5 mg/mouse) and increased by simultaneous injection of captopril (50μg/mouse). The writhing reaction induced by kaolin which was inhibited by oral administration of indomethacin (1 mg/kg) was restored by exogenous i.p. injection of PGI2-Na (2-10ng/mouse). Indomethacin, ibuprofen and alminoprofen inhibited the writhing reaction and reduced the level of peritoneal 6-keto-PGF in parallel manner. Tiaramide, pentazocine and morphine inhibited the writhing reaction without reducing the revels of 6-keto-PGF. These results differentiate the site of action of these analgesics. They suggest that the mechanism of the kaolininduced writhing reaction in mice involves a synergic pain caused by simultaneously released bradykinin and PGI2. This model is a useful tool which allows differentiation of mode of action of analgesics by simultaneous determination of the writhing response and peritoneal 6-keto-PGF.
  • Toshio FUJIYOSHI, Izumi HAYASHI, Sachiko OHISHI
    1989 年 12 巻 8 号 p. 483-487
    発行日: 1989年
    公開日: 2008/02/19
    ジャーナル フリー
    A mechanism of writhing reaction induced by kaolin, a known activator of factor XII, was studied. Kaolin induced a distinct writhing response, when injected intraperitoneally into mice (2.5 mg/mouse). The response disappeared in 15 min, but it was reproduced by intraperitoneal injection of captopril, 20μg, into mice who had received the injection of kaolin 60 min before. This later response as well as the early one was not produced when mice were pretreated with bromelain (10mg/kg, intravenously), 30 min before the kaolin administration. Therefore we determined if bromelain, a known depleter of plasma prekallikrein and a high molecular weight (HMW) kininogen, depletes those in mice. Plasma was collected from mice with or without pretreatment of bromelain, and kinin release of these plasma samples was examined by action of kaolin. The bromelain-treated mouse plasma released kinin amount of less than detection limit when activated with kaolin, whereas normal plasma released about 300ng/ml of kinin of bradykinin equivalent as assessed by rat uterus contraction. Furthermore, activation of prekallikrein by kaolin was observed in mouse plasma as amidase activity to produce fluorescence from the synthetic substrate. It was completely diminished in the presence of soybean trypsin inhibitor. These results suggest that bromelain could deplete the HMW-kininogen in mouse plasma in the same way as in rat plasma. Furthermore, it is assumed that the kinin released from HMW-kininogen by kaolin could be responsible for inducing the writhing response.
  • Ikuo YAMAMOTO, Hiroshi GOHDA, Shizuo NARIMATSU, Hidetoshi YOSHIMURA
    1989 年 12 巻 8 号 p. 488-494
    発行日: 1989年
    公開日: 2008/02/19
    ジャーナル フリー
    Biological formation of cannabielsoin (CBE) from cannabidiol (CBD) was studied in the guinea pig, mouse, rat and rabbit in vitro. Emphasis was placed on the elucidation of this formation mechanism. The enzyme activity of CBE formation was localized in hepatic microsomes. The enzymatic reaction required nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen, and showed an optimal pH around 7.3. The microsomal CBE-forming activities decreased in the following order ; guinea pig>mouse≥rabbit≥rat. The CBE formation in the guinea pig hepatic microsomes was suppressed with various inhibitors of cytochrome P-450 such as SKF 525-A, α-naphthoflavone and carbon monoxide, but not by disodium ethylenediamine tetraacetate. When in-cubated with the microsomes either in the presence or absence of NADPH, a synthetic epoxide of CBD, 1S, 2R-epoxy-CBD-2', 6'-diacetate was easily and exclusively converted to CBE. On the other hand, 1R, 2S-epoxy-CBD was not changed to CBE at all, but to several oxidized metabolites. These results suggest that CBD is biotransformed to 1S, 2R-epoxy-CBD with hepatic microsomal monooxygenase system including cytochrome P-450, and the epoxide is immediately converted to CBE.
  • Shoji FUKUSHIMA, Yoshiki HAYASHI, Takeo KAWAGUCHI, Mika KANEKO, Masahi ...
    1989 年 12 巻 8 号 p. 495-502
    発行日: 1989年
    公開日: 2008/02/19
    ジャーナル フリー
    Hydrolysis of 3', 5'-dioctanoyl-5-fluoro-2'-deoxyuridine (FdUrd-C8), a lipophilic prodrug of 5-fluoro-2'-deoxyuridine (FdUrd), 3'-octanoyl-5-fluoro-2'-deoxyuridine (3'-octanoyl FdUrd) and 5'-octanoyl-5-fluoro-2'-deoxyuridine (5'-octanoyl FdUrd) in the rabbit and human plasma and release of FdUrd-C8 and its hydrolyzed species from Lipiodol Ultra-Fluid (Lipiodol), an oily lymphographic agent, containing FdUrd-C8 were examined. The rates of hydrolysis of FdUrd-C8, 3'-octanoyl FdUrd and 5'-octanoyl FdUrd in the rabbit plasma were fast and almost the same among the three compounds ; half lives were 2.4, 3.6 and 3.9 min for 5'-octanoyl FdUrd, FdUrd-C8 and 3'-octanoyl FdUrd, respectively. In the human plasma, however, the rates of hydrolysis were much different among the three compounds and were slower than those in the rabbit plasma ; half lives were 11.5, 130 and 1020 min for 5'-octanoyl FdUrd, FdUrd-C8 and 3'-octanoyl FdUrd, respectively. Ratios of the rate constant of 5'-octanoyl FdUrd to that of 3'-octanoyl FdUrd were 1.6 and 85.7 in the rabbit plasma and in the human plasma, respectively. In a release study, although detected species in a release medium were different between the rabbit plasma and the human plasma and the amount of each species reflected the characteristics of esterase in each plasma, the total amounts of compounds released were almost the same both in the rabbit plasma and the human plasma. The existence of bovine serum albumin in a release medium increased the amount of compounds released from a Lipiodol solution to a greater extent than the existence of porcine liver esterase in the release medium. The FdUrd-C8 content in Lipiodol affected the duration of release but not the amount of compounds released.
  • Yorishige IMAMURA, Hiroko ABE, Yuichiro KOJIMA, Masaki OTAGIRI
    1989 年 12 巻 8 号 p. 503-507
    発行日: 1989年
    公開日: 2008/02/19
    ジャーナル フリー
    The in vivo and in vitro bindings of (-)-hydroxyhexamide, a major metabolite of acetohexamide, to rabbit serum were examined by using an ultrafiltration method. The in vivo serum protein binding of (-)-hydroxyhexamide was much lower than the in vitro serum protein binding. The in vitro serum protein binding of (-)-hydroxyhexamide was strongly displaced by the addition of acetohexamide. Furthermore, the in vitro serum protein binding of (-)-hydroxyhexamide in the presence of acetohexamide and (-)-hydroxyhexamide at the same concentrations as those found 1.0 h after acetohexamide administration was approximately similar to the in vivo serum protein binding of (-)-hydroxyhexamide. These results lead us to conclude that acetohexamide, the parent drug of (-)-hydroxyhexamide, plays an important role in the in vivo serum protein binding of (-)-hydroxyhexamide.
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