Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Volume 19 , Issue 9
Showing 1-27 articles out of 27 articles from the selected issue
  • Hiroki MIZUGUCHI, Yoichi KAWASHIMA
    1996 Volume 19 Issue 9 Pages 1115-1120
    Published: September 15, 1996
    Released: April 10, 2008
    JOURNALS FREE ACCESS
    Metabolic changes induced by p-chlorophenoxyisobutyric acid (clofibric acid) in hepatic phosphatidylethanolamine (PtdEtn) were studied. The treatment of rats with clofibric acid increased the hepatic concentrations of phosphatidylcholine (PtdCho), PtdEtn and phosphatidylinositol (PtdIns), but not phosphatidylserine (PtdSer). Among the phospholipids, the extent of increase of PtdEtn was the most prominent (1.91-fold on the basis of g liver and 2.73-fold on the basis of whole liver). Of the enzymes which are involved in the synthesis de novo of PtdEtn, the activity of cytidine 5'-triphosphate (CTP) : phosphoethanolamine cytidylyltransferase was reduced by the administration of clofibric acid to rats. The treatment of rats with this drug significantly decreased the serum concentration of free ethanolamine. Clofibric acid enhanced the activity of PtdSer decarboxylase and depressed the N-methylation in vivo of PtdEtn by inhibiting N-methyltransferase. Moreover, clofibric acid significantly depressed the turnover of PtdEtn, which was labeled in vivo with [3H]glycerol. These results suggest that, under the influence of clofibric acid, hepatocytes facilitate the pathway PtdCho→PtdSer→PtdEtn and reduce the turnover of PtdEtn, resulting in an expanded cellular pool of PtdEtn.
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  • Dong-Hyun KIM, In-Seok SHONG, Kyoichi KOBASHI, Myung Joo HAN
    1996 Volume 19 Issue 9 Pages 1121-1125
    Published: September 15, 1996
    Released: April 10, 2008
    JOURNALS FREE ACCESS
    A β-glucosidase (EC 3.2.1.21.) was purified 2500-fold from Bacteroides JY-6, an intestinal anaerobic bacterium of human. The specific activity of the homogeneously purified enzyme was 210 μmol/min/mg protein. The enzyme (Mr 75 kDa) was an monomer whose pI and optimal pH values were 4.6 and 5.5-6, respectively. The best substrates were p-nitrophenyl β-D-glucopyranoside and natural β-bound glucosides, such as prunin and poncirenin. Puerarin, which is a C-glycoside, was weakly effective. However, cellobiose, α-bound glycosides and rhamnoglucosides were not effective. The apparent Kms for prunin and p-nitrophenyl-β-D-glucopyranoside were determined to be 0.08 and 0.19 mM, respectively. The enzyme was strongly inhibited by p-chloromercuriphenylsulfonic acid and reaction products such as p-nitrophenol and glucose.
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  • Naoaki SHIMIZU, Mari NAKAMURA, Minoru AZUCHI, Minoru OKADA, Yutaka KAW ...
    1996 Volume 19 Issue 9 Pages 1126-1129
    Published: September 15, 1996
    Released: April 10, 2008
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    As we previously reported, the cytotoxicity of bleomycin (BLM) toward cultured mammalian cells was extraordinarily potentiated when the cells and BLM were vortex-stirred for a few seconds in the presence of high molecular weight polyacrylic acid (PAA). Cationic and nonionic polymers could not take the place of PAA in potentiating BLM cytotoxicity. The present study revealed that potentiation was sharply dependent on the molecular weight of PAA and a molecular weight of over 106 daltons seemed to be required. Copolymers of acrylic acid (AA) and acrylamide showed some potentiation which was relative to their AA content. It is worth noting that another type of anionic polymer, polymethacrylic acid, did not show any potentiating capacity at all. Polyacrylic sulfonate derivative showed a marginal capacity. The structural requirement for high molecular weight polymers for potentiation of BLM cytotoxicity was demonstrated by the increased uptake of Lucifer Yellow, a non-permeant material. In addition, the ability of permeabilization was not correlated with kinematic viscosity of anionic polymers.
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  • Naoki OKAMURA, Makiko SAKAI, Hiroko ABE, Maki KUWANA, Akiko TSUCHIYA, ...
    1996 Volume 19 Issue 9 Pages 1130-1135
    Published: September 15, 1996
    Released: April 10, 2008
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    Mechanisms for the cell-free activation of NADPH oxidase by sodium dodecyl sulfate (SDS) and arachidonate were compared in relation to their responsiveness to short chain diacylglycerols. The plasma membrane and cytosol prepared from guinea pig neutrophils were used for the cell-free system. The activation of NADPH oxidase by SDS was enhanced about 5- to 10-fold by 1, 2-dioctanoylglycerol (diC8), but not by either 1, 2-dihexanoylglycerol (diC6) or 1, 2-didecanoylglycerol (diC10). However, none of these diacylglycerols potentiated the NADPH oxidase activation by arachidonate. The maximal extent of activation by the combination of SDS and diC8 was similar to that by arachidonate alone. In the presence of sufficient amounts of diC8 and SDS, GTPγS potentiated the activation of NADPH oxidase. The potentiating activity of diC8 was preserved in the membrane fraction, not in the cytosol fraction. These results suggest that arachidonate may possess the functions of both SDS and diC8 in the activation. In addition, diC8 and GYPγS seem to independently enhance the NADPH oxidase activation.
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  • Hiroyuki KAMADA, Naoki INOUE, Yuko TAKAOKA, Keiji NAKAGAMI, Hiroshi MO ...
    1996 Volume 19 Issue 9 Pages 1136-1140
    Published: September 15, 1996
    Released: April 10, 2008
    JOURNALS FREE ACCESS
    T cells play a principal role in cellular immunity and govern the regulatory mechanism in humoral immunity. Therefore, T cells play a key role as either effectors or regulators in the immune network. Mizoribine (MZR), an immunosuppressive agent, suppresses both humoral and cellular immunity by acting on both T cells and B cells. In this study, we examined the effect of MZR on various effector T cell-mediated immune responses in mice. MZR prolonged skin graft survival and suppressed a localized graft-versus-host reaction (GvHR) and sheep red blood cell (SRBC)-induced delayed-type hypersensitivity (DTH) reaction. In a collagen-induced arthritic mice model, MZR reduced the arthritic index and the swelling of the hind limbs. Furthermore, MZR suppressed both bone damage and histopathological changes in the hind limbs. Interestingly, MZR markedly suppressed the DTH reaction to type II collagen (CII) but had no effect on anti-CII antibody levels in this arthritic model. In these models, effector T cells such as cytotoxic T lymphocyte (CTL) and TDTH cell play an important part in the development of these reactions. It is suggested that MZR inhibited these reactions via the inhibition of the effector T cell-mediated immune response. Therefore, it is also suggested that the suppressive effect of MZR on clinical rejection and autoimmune disease is based on its suppression of the effector T cell-mediated immune response, that is cellular immunity, in addition to humoral immunity.
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  • Eiko TANAKA, Katsuhiko ASE, Toshiaki OKUDA, Makoto OKUMURA, Katsumi NO ...
    1996 Volume 19 Issue 9 Pages 1141-1148
    Published: September 15, 1996
    Released: April 10, 2008
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    To elucidate the role of basic fibroblast growth factor (bFGF) in the wound healing process, we investigated the ability of the factor to modulate an inflammatory reaction at the wound site and to influence endothelial cells and fibroblasts in vitro. A single, topical application of bFGF to a full-thickness wound of genetically diabetic mice caused an increase in the volume of wound exudate in a dose-dependent manner. bFGF induced the infiltration of a large number of leukocytes in the wound exudate. Transforming growth factor-β (TGF-β) positive cells, such as macrophages, monocytes and fibroblasts, appeared in the granulation tissue in bFGF-treated diabetic mice. These phenomena were comparable to those in normal animals, suggesting that the treatment with bFGF restored the inflammatory response in wound healing of diabetic mice. The effects of bFGF on cell proliferation, migration and angiogenesis were histologically recognized as shown in enhanced granulation tissue formation and neovascularization. It is suggested that bFGF promotes the recruitment of inflammatory cells into the wound site to induce a cascade reaction of growth factors including TGF-β in a wound healing process, and so would accelerate wound healing.
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  • Kazunori URABE, Yasuo MATSUMURA, Hiroshi NONAKA, Manabu NISHIURA, Kohs ...
    1996 Volume 19 Issue 9 Pages 1149-1153
    Published: September 15, 1996
    Released: April 10, 2008
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    The purpose of this study was to investigate whether endogenous angiotensin II has a functional role in renal hemodynamic and excretory changes induced by L-arginine, a substrate for nitric oxide (NO), in anesthetized rats. During the intravenous infusion of L-arginine (50, 100, 200 μmol/kg·min), there was no significant change in systemic or renal hemodynamics, but urine flow and urinary sodium excretion markedly increased in a dose-dependent manner. Simultaneously, L-arginine infusion produced an increase in urinary excretion of NO metabolites, No-2 and NO-3. Treatment with L-158809 {5, 7-dimethyl-2-ethyl-3-[[2'-(1H-tetrazol-5-yl)[1, 1']-biphenyl-4-yl]methyl]-3H-imidazo[4, 5-b]pyridine} (0.3 mg/kg), a selective angiotensin II type I receptor antagonist, caused a reduction in mean arterial pressure, and a rise in renal blood flow and glomerular filtration rate, with no changes in excretory responses. In the presence of L-158809, L-arginine-induced diuretic and natriuretic actions were observed to the same extent as seen in the absence of L-158809. These data suggest that the infusion of L-arginine causes diuresis and natriuresis, possibly via the formation of nitric oxide in the kidney, and that endogenous angiotensin II is not involved in the L-arginine-induced renal actions.
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  • Masamichi FUKUOKA, Shingo NIIMI, Yu ZHOU, Tetsu KOBAYASHI, Takao HAYAK ...
    1996 Volume 19 Issue 9 Pages 1154-1159
    Published: September 15, 1996
    Released: April 10, 2008
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    We have reported that di-n-butyl phthalate (DBP) caused the depletion of circulating iron, characterized by the release of iron from both haemoglobin (Hb) and transferrin (Tf). The present study investigated whether the erythrocytes from DBP-treated rats were destroyed by nonparenchymal liver cells (NPC, including Kupffer cells) or spleen cells (SC). In the in vivo study, there were observed depletions of Hb in the blood and of iron in the hepatic Tf fraction, as well as an accumulation of iron in the hepatic hemosiderin (Hs) and splenic Tf fractions. In the in vitro study, mono-butyl phthalate (MBP), a metabolite of DBP, caused a depletion of iron in the plasma Tf, although a direct release of iron from Tf was not detectable. When erythrocytes from DBP-treated rats and erythrocytes preincubated with MBP both were incubated with NPC, respectively, the Hb was decomposed and the iron also accumulated in the cell debris. However, when the two kinds of erythrocytes were incubated with SC, respectively, no decomposition of Hb was observed at low and medium doses, but the highest dose induced an accumulation of iron to Tf. Therefore, the NPC may contribute in part to the decomposition of DBP- or MBP-affected erythrocytes.
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  • Yi Rong SHEN, Makoto INOUE, Yuko NAGATSU, Yukio OGIHARA, Masaki ABURAD ...
    1996 Volume 19 Issue 9 Pages 1160-1165
    Published: September 15, 1996
    Released: April 10, 2008
    JOURNALS FREE ACCESS
    We investigated the anti-atherosclerotic action shown by Shosaikoto, a Kampo medicine, using hypercholesterolemic mice. Oral administration of Shosaikoto significantly suppressed the elevation of serum cholesterol in C57BL/6 mice fed a 1.25% cholesterol-enriched diet for four weeks and improved the T cell ratio in peripheral blood, which decreased with the increase of the serum cholesterol level. In addition, Shosaikoto reduced the accumulation of cholesteryl oleate, which alters macrophages into foam cells, after the treatment of macrophages with oxidized or acetylated low density lipoprotein (LDL). Enzymatic study revealed that the treatment of macrophages with oxidized LDL enhanced acyl-coenzyme A : cholesterol acyltransferase (ACAT) activity and markedly reduced neutral cholesteryl ester hydrolase (NCEase) activity. Shosaikoto treatment prevented a decrease in the NCEase activity, however due to the oxidized LDL treatment, although it slightly augmented ACAT activity. Thus, Shosaikoto, which is known to modulate the immune system, improves macrophage and lymphocyte functions diminished by hypercholesterolemia, resulting in an anti-atherosclerotic action.
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  • Keiji KAJIMURA, Yasuhiro TAKAGI, Noboru UEBA, Katsuhiro YAMASAKI, Yosh ...
    1996 Volume 19 Issue 9 Pages 1166-1169
    Published: September 15, 1996
    Released: April 10, 2008
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    We investigated the protective effect of Astragali Radix (AR) by oral administration against Japanese encephalitis virus (JEV) infection in mice, the pharmacological effects of AR extracts (AE) in different origin, and the chemical composition of the AEs. A protective effect was demonstrated in all four AEs used, however, the effective grade for each one was different. In the control group, an increase of hemagglutination inhibition (HI) antibody titer was observed in all mice surviving 25 d after JEV inoculation. However, the increase of HI antibody titer was not observed in some animals administered an AE. In the control group, the rate of HI antibody positive mice was 90% 3 d after JEV inoculation, while the four groups which received the AE had a 30-60% positive rate. In mice which received the AE, the peritoneal exudate cell (PEC) numbers increased significantly compared to the control group. The predominant cell population of PECs in mice receiving the AE was macrophages, and in the PEC, the active oxygen (AO) production was high.From these results, we propose that the protective effect of AE by oral administration is based on a non-specific mechanism during the early stage of infection, before shifting to antibody production, and that mcrophages play an important role in this resistance to JEV infection, e.g., by inducing the production of AO. In the chemical composition of each AE, carbohydrate was the major component.
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  • Mitsutaka SATO, Hiraku ONISHI, Junichi TAKAHARA, Yoshiharu MACHIDA, Ts ...
    1996 Volume 19 Issue 9 Pages 1170-1177
    Published: September 15, 1996
    Released: April 10, 2008
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    The water-soluble conjugates of mitomycin C (MMC) with N-succinyl-chitosan (N-Suc-chitosan) and glycol-chitosan (Gly-chitosan), named N-Suc-chitosan-glu-MMC and Gly-chitosan-glu-MMC, respectively, were characterized mainly by the plasma concentration-time profiles of MMC after intraperitoneal administration and their in vivo antitumor effect against P388 leukemia and Sarcoma 180. Before in vivo evaluation, polymer-drug binding characteristics were checked by gel-chromatography. Gel-chromatographs proposed the covalent binding of 1a-(4-carboxybutyryl)-MMC (glu-MMC) with both the polymer supports. The plasma concentration of MMC showed that each conjugate released MMC in vivo at a similar rate. Kinetic analysis suggested that the in vivo drug release should be considerably faster than the in vitro release in the buffer, pH 7.4, alone. In the treatment against P388 leukemia inoculated intraperitoneally, Gly-chitosan-glu-MMC showed the highest increase in life span (ILS) at 10 mg MMC eq/kg. It was lethally toxic at the dose of 20 mg MMC eq/kg, while N-Suc-chitosan-glu-MMC gave the highest ILS value at this dose. Each conjugate exhibited a little larger ILS value than MMC. For the Sarcoma 180 solid tumor inoculated subcutaneously, the polymer characteristics affected the antitumor effect. Namely, with the intravenous injection, Gly-chitosan-glu-MMC hardly exhibited any tumor growth inhibition, but N-Suc-chitosan-glu-MMC showed significant tumor growth suppression. As to the intratumoral administration, the tendency to suppress tumor growth was observed in MMC and both the conjugates.
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  • Taro OGISO, Masahiro IWAKI, Tadatoshi TANINO, Terumi NAGAI, Yuko UEDA, ...
    1996 Volume 19 Issue 9 Pages 1178-1183
    Published: September 15, 1996
    Released: April 10, 2008
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    In order to develop a potential prodrug of indomethacin (IM) which causes less irritation to the gastrointestinal mucosa, the ester prodrugs [butyl ester (IM-BE) and octyl ester (IM-OE)] of IM were synthesized and evaluated for their ulcerogenic activity and hepatic injury after oral administration in rats. Additionally, the kinetics of hydrolysis of the prodrugs were examined to characterize the tissues or organs capable of hydrolyzing the ester bonds. The plasma levels of IM after the oral administration of IM-OE and IM-BE were comparatively low compared with those after IM, with a small bioavailability (2.1 and 15.0%, respectively). Ulcerogenic activity and hepatic injury, expressed by decreased hepatic microsomal enzyme activities, were hardly seen after repeated oral administration of the prodrugs, in contrast with the severely irritating effects of IM alone. Hydrolysis of the prodrugs was adequately described by first-order kinetics. IM-BE was relatively rapidly hydrolyzed in plasma, skin and whole blood, but the hydrolysis in the intestinal mucosa and liver was very slow. The hydrolytic rates for IM-OE were exceedingly small or negligible.These results indicate that the main part of IM-BE and IM-OE administered orally might not be hydrolyzed to IM in the gastrointestinal tract, and that the ester prodrugs themselves were absorbed through the mucosa; also, that the hydrolysis of ester bonds would be carried out mainly in the circulatory system. Consequently, IM-BE seems to be an ideal prodrug of IM.
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  • Kazuyoshi SAGARA, Ichimaro YAMADA, Yuko MATSUURA, Miwako KAWATA, Masah ...
    1996 Volume 19 Issue 9 Pages 1184-1188
    Published: September 15, 1996
    Released: April 10, 2008
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    Gastrointestinal (GI) physiology-regulated beagle dogs (regulated dogs) were regulated by a combined treatment using intramuscular pentagastrin and intravenous atropine sulfate. In the regulated dogs, the gastric pH was shifted to aroung 2, and the GI transit time was prolonged to approximate that in humans. Pranoprofen, an acidic anti-inflammatory agent, was granulated around sucrose seeds, and then coated with low substituted hydroxypropyl cellulose used as a swelling agent to afford plain granules (A-granule). Then, A-granule was coated stepwise with ethyl cellulose used as an outer shell material to afford two kinds of pulsatile release granules (B- ad C-granules). In the dissolution study using pH 1.2 and 6.8 media, A-, B- and C-granules exhibited lag times of 0, 1 and 2 h, respectively. Even in intact beagle dogs, the absorption profiles for A- and B-granules corresponded with those expected from the dissolution profiles. In contrast, the bioavailability of C-granule was only 35% in the intact dogs, but was 55% in the regulated dogs. Thus, the absorption of pranoprofen from pulsatile release granules after a longer lag time should be influenced by the location in the GI tract. Next, a controlled-release (CR) dosage form of pranoprofen was tentatively prepared by combining A-, B- and C-granules at the ratio of 3 : 4 : 3 (w/w in contents of pranoprofen). The bioavailability of the CR dosage form was significantly diminished in the intact dogs, being about 70% as much as that in the regulated dogs. Therefore, the regulated dogs would be superior to the intact dogs in avoiding the underestimation of the bioavailability of a CR dosage form with a pulsatile release property.
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  • Hisakazu OHTANI, Erika HANADA, Koujirou YAMAMOTO, Yasufumi SAWADA, Tat ...
    1996 Volume 19 Issue 9 Pages 1189-1196
    Published: September 15, 1996
    Released: April 10, 2008
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    In establishing a method of electrocardiographic (ECG) measurement for investigating drug-induced ECG changes, we examined the ECG effects and pharmacokinetics of terfenadine (TFN) and quinidine (QND) in rats. The time profiles of the plasma concentration and ECG parameters, such as the QT interval determined from limb lead II (QT-II) and the precordial chest lead (QT-V), heart rate and PR interval, were examined during constant intravenus infusion of TFN (5 or 15 mg/kg/h) or QND sulfate dihydrate (10 or 30 mg/kg/h). Both agents provided significant and concentration-dependent QT prolongation. The plasma concentrations (C-<10>), where 10 ms of QT prolongation was observed, were 1.03 μM for TFN and 5.12 μM for QND, respectively. The calculated plasma unbound concentration of C10 (C10·f) was 10.3 nM for TFN and 3.82 μM for QND, which coincides with previously reported in vitro values of IC50 for potassium channels. The drug-induced QT prolongation was quantitatively reproduced in rats within the clinical concentration range. The usefulness of our methodology for the evaluation of arrhythmogenic hazards of the drugs was also demonstrated.
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  • Masuhiro NISHIMURA, Kiyoshi YAMAOKA, Shinsaku NAITO, Terumichi NAKAGAW ...
    1996 Volume 19 Issue 9 Pages 1197-1202
    Published: September 15, 1996
    Released: April 10, 2008
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    The local disposition of a drug, which is efficiently eliminated by the liver in spite of very high binding with serum albumin, was investigated using BOF-4272 as a model drug in the hepatic perfusion system. Bovine serum albumin (BSA) labeled with Evans Blue was used as the marker of hepatic blood space. The perfusion experiments were carried out at 37°C and at 4°C to evaluate the local disposition in active and inactive livers, respectively. The perfusates included 0, 0.25, 0.5, 1.0 and 4.0% of BSA in the injection of BOF-4272, and 0 and 1.0% of BSA in the injection of Evans Blue. After an instantaneous injection of BOF-4272 or Evans Blue (labeling reagent of BSA), the outflow time profile from the liver was analyzed by curve-fitting based on two-compartment dispersion model. All estimated parameters of BSA were almost the same between 37°C and 4°C, which showed that the blood space in the liver was unaffected by perfusate temperature. The recovery ratio (FH) and the mean transit time (t^-H) of BSA were 100% and about 0.1 min, respectively, both with BSA (1.0%) and without BSA in the perfusate. FH of BOF-4272 increased from 20% to 50% with an increase in the perfusate BSA at 37°C, whereas FH was almost constant (90%) regardless of BSA concentration at 4°C. t^-H of BOF-4272 was almost 0.1 min regardless of BSA concentration at 37°C, whereas t^-H decreased from 0.29 min to 0.17 min at 4°C with an increase in the perfusate BSA. A large elimination (10%) of BOF-4272 was noticed even at 4°C in the presence of perfusate BSA, which demonstrates that the passive transfer of BOF-4272 from BSA to the hepatic tissues is considerably rapid. This efficient transfer is responsible for the large hepatic clearance of BOF-4272 with very high binding with BSA.
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  • Kazuki NAGASAWA, Akiko TSUMURA, Masako NOMIYAMA, Noriaki OHNISHI, Teru ...
    1996 Volume 19 Issue 9 Pages 1203-1209
    Published: September 15, 1996
    Released: April 10, 2008
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    We studied the transport mechanism of pirarubicin (THP) in mononuclear cells (MNCs) obtained from healthy human donors. The THP uptake was time-, temperature-, concentration- and energy (in part)-dependent. The uptake of daunorubicin (DNR) and doxorubicin (ADR) was also concentration-dependent, and the transport of ADR consisted of saturable and nonsaturable components. In cis-inhibition experiments, ADR inhibited both THP and DNR uptake noncompetitively, while DNR showed competitive inhibition of the uptake of THP. The THP uptake rate appeared to be increased by preloading DNR, indicating a trans-stimulatory effect, but not with ADR. These results suggest that THP and DNR were taken up into MNCs via a common carrier-mediated transport system, but that the carrier of ADR might differ from that of THP and DNR. Furthermore, apparent differences in the affinity for the carrier, transport efficacy and substrate specificity of the transporter between MNCs and the human leukemia cell lines (HL60 and K562) were indicated.
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  • Masaharu MIYAGI, Fumiaki ITOH, Fumie TAYA, Nobuhiko ARAI, Masayuki ISA ...
    1996 Volume 19 Issue 9 Pages 1210-1213
    Published: September 15, 1996
    Released: April 10, 2008
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    An ergot alkaloid derivative, cabergoline, and its metabolites were investigated for their affinities for dopamine D1 and D2 receptors in rat striatum in vitro in comparison with those of bromocriptine and pergolide. The affinity for D1 receptors was in the following order : pergolide>des-dimethylaminopropyl cabergoline (FCE21904)>cabergoline≥bromocriptine≥des-methyl cabergoline (FCE27395)≥des-ethylcarbamoyl cabergoline (FCE21590). From the effects of GTP on these affinities for the D1 receptor, cabergoline, some of its metabolites, and pergolide were characterized as agonists in contrast to bromocriptine which was classified as an antagonist. The affinity for D2 receptors was ranked as follows : pergolide≥cabergoline≥FCE27395≥FCE21904>bromocriptine>FCE21590>carboxylic acid-type derivative of cabergoline (FCE21589). The affinity of each compound for the D2 receptor was much higher than that for the D1 receptor. The selectively of cabergoline for the D2 receptor was higher than those of bromocriptine and pergolide. Furthermore, these ergot alkaloids were investigated for eliciting stereotypy after subcutaneous administration to normal rats. Pergolide potently induced stereotypy at doses of 0.5 and 1.0 mg/kg, cabergoline slightly induced it only at a high dose of 2.0 mg/kg, whereas bromocriptine did not induce it at any of the doses tested, 10-40 mg/kg. These results suggest that pharmacological properties of cabergoline for the D1 and D2 receptors differ from those of bromocriptine and pergolide.
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  • Fumio IKEGAMI, Minoru KAMIYA, Yu-Haey KUO, Fernand LAMBEIN, Isamu MURA ...
    1996 Volume 19 Issue 9 Pages 1214-1215
    Published: September 15, 1996
    Released: April 10, 2008
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    Two isoxazolylalanine isomers, β-(isoxazolin-5-on-2-yl)-L-alanine (BIA, 1) and β-(isoxazolin-5-on-4-yl)-L-alanine (TAN-950A, 2) were confirmed to be derived from O-acetyl-L-serine (OAS) and isoxazolin-5-one by cysteine synthases (CSases) with a different ratio in different plant parts. Some properties of this enzyme in the biosynthesis of both isomers are described.
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  • Takahiro SAKAUE, Shuji MATSUMOTO, Seiji TSUBOI, Kazumi OGATA, Shinji O ...
    1996 Volume 19 Issue 9 Pages 1216-1219
    Published: September 15, 1996
    Released: April 10, 2008
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    The administration of acetaminophen (APAP, 500 mg/kg, i.p.) produced liver necrosis and increased aspartate aminotransaminase (AST) activity in serum. The pretreatment of S-(1, 2-diethoxycarbonyl)glutathione isopropyl ester (DCE-Et-GS iPr, 0.5 mmol/kg, p.o.) prevented hepatic necrosis and the elevation of serum AST activity by 99.9%. DCE-Et-GS iPr inhibited APAP-induced hepatotoxicity much more strongly than reduced glutatione (GSH), DCE-GS and other esters of DCE-GS. To clarify this protective effect, the hepatic GSH concentration was determined 2 h after APAP administration. It was found that the DCE-Et-GS iPr administration significantly inhibited the GSH depletion caused by APAP, suggesting that the protective effect of DCE-Et-GS iPr on APAP-induced hepatotoxicity was due, at least in part, to the retention of hepatic GSH level.
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  • Junzo HIROSE, Kaori INOUE, Eiichiro MORIMOTO, Hiroyuki IWAMOTO, Yasuno ...
    1996 Volume 19 Issue 9 Pages 1220-1222
    Published: September 15, 1996
    Released: April 10, 2008
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    Two monoclonal antibodies raised against Pt(II)(1R, 2R-cyclohexanediamine)-DNA were prepared, and the specificity of the monoclonal antibodies against Pt(II)(cyclohexanediamine)-DNA derivatives was determined by competitive enzyme-linked immunosorbent assay. The binding affinity of the monoclonal antibodies is apparently influenced by the cyclohexanediamine moiety of Pt(II)(cyclohexanediamine)-DNA adducts, but the monoclonal antibodies can not bind to the low molecular analogue, Pt(II)(1R, 2R-cyclohexanediamine)-d(GpG), which is the intrastrand binding model compound of Pt(II)(1R, 2R-cyclohexanediamine)-DNA. Therefore, the monoclonal antibodies recognize the macromolecular parts, including DNA duplex, in addition to the cyclohexane moieties of the platinum complexes on Pt(II)(cyclohexanediamine)-DNA adducts.
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  • Akira KAMEI
    1996 Volume 19 Issue 9 Pages 1223-1226
    Published: September 15, 1996
    Released: April 10, 2008
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    Two fractions of esterase were partially purified from the soluble fraction of normal human lens. The apparent molecular masses of these enzymes were approximately 200 kDa (esterase-I) and 30 kDa (esterase-II). The optimal pH of esterase-I and esterase-II was 6.0 and 7.5, and their respective optimal temperature were 43°C and 46°C. The Km values of esterase-I and esterase-II for 4-methylumbelliferyl-palmitate were 0.14 and 0.11 μM, respectively. The activity of these enzymes was inhibited by EDTA. The fraction with esterase activity also displayed lipase activity, although it is unknown whether the two enzymes are idnetical.Variation in the activity of these esterases was examined as a function of age for normal lens and as functions of age and coloration for senile cataractous lenses. The normal lenses maintained high enzyme activity up to the 60 age group and their enzyme activity then fell abruptly. In the senile cataractous lenses, enzyme activity was very low as compared to that of normal lenses of similar age. This shows that cataract formation may have a deleterious effect on the catalytic activity of esterase in the lens.
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  • Takahiko FUJIKAWA, Akihiko YAMAGUCHI, Isao MORITA, Hidekatsu TAKEDA, S ...
    1996 Volume 19 Issue 9 Pages 1227-1230
    Published: September 15, 1996
    Released: April 10, 2008
    JOURNALS FREE ACCESS
    The aim of this study is to investigate the pharmacological effect of the stem bark of Acanthopanax senticosus HARMS from Hokkaido (Japanese name : Ezoukogi) in place of the root bark as a restorative tonic on the stress-induced gastric ulcer. in the test, the extract of the stem bark of A. senticosus prepared with hot water was dissolved in water and used for the assay of the protective effect of gastric ulcer (erosion) on stressed rats that were restrained on cold water. The result from a single oral administration of the stem bark of A. senticosus-extract (50, 100 and 500 mg/kg, per day) dissolved in 1 ml distilled water did not show any protective effect on gastric ulcer, but the protective effect was observed in a dose-dependent manner from the oral administration of the extract (50, 100 and 500 mg/kg, per day) for 2 weeks. Pre-administration of the stem bark of A. senticosus-extract in a dose of 500 mg/kg showed the most potent inhibition without affecting either body or adrenal glands weights. Among ether, chloroform, n-butanol and aqueous residue extracts from the stem bark of A. senticosus-extract, the n-butanol extract used for oral administration for 2 weeks showed an obvious inhibition of 61.1% on gastric ulcer, compared with the control group which was treated with distilled water in the same way.Chlorogenic acid and syringaresinol di-o-β-D-glucoside, as the major components of the n-butanol extract, showed a significantly inhibitory effect on gastric ulcer, at 21.4% and 51.3%, respectively. We suggested that the protective effect of the stem bark of A. senticosus on gastric ulcer may be partially due to those of chlorogenic acid and syringaresionol di-o-β-D-glucoside.
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  • Aki NAKAI, Mayumi NISHIKATA, Kenji MATSUYAMA, Masataka ICHIKAWA
    1996 Volume 19 Issue 9 Pages 1231-1233
    Published: September 15, 1996
    Released: April 10, 2008
    JOURNALS FREE ACCESS
    The interaction between simvastatin (SV), a prodrug lactone, HMG-CoA reductase inhibitor which converts to the active hydroxy acid form (SVH) in vivo, and cholestyramine (CT), an anionic exchange resin, was evaluated both in vitro and in vivo.In an in vitro SV-stability study, it was shown that SV degraded gradually to SVH in an aqueous solution at pH 2 and 7. To evaluate the binding ability of SV or SVH to CT, the incubation of 5 μg/ml of SV or SVH solution with 200 mg of CT in various pH (2.0, 5.0 and 7.0) solutions was performed at 37°C for 10 min. After incubation, the concentration of SV decreased by 59.02% (pH 2), 63.90% (pH 5) and 67.36% (pH 7), respectively, and an interaction between SV and CT was suggested. The values were much larger than those expected from the stability test of SV in the absence of CT. SVH was found to bind more strongly to CT. The binding ability of SVH to CT was 66.71% (pH 2), 87.44% (pH 5) and 92.11% (pH 7), respectively. Judging from these results, SV was considered to interact with CT by the following procedure : SV underwent hydrolysis to SVH in aqueous solution, then CT activated the hydrolysis by binding the formed SVH, resulting in a significant reduction in concentration of SV.On the other hand, an in vivo animal experiment also demonstrated a significant reduction (about 50% with AUC) in the concentration of SVH in plasma following the coadministration of SV (500 mg/kg p.o.). and CT (600 mg/kg p.o.), compared with the administration of SV alone. This phenomenon suggested that a combination therapy using SV and CT might result in a smaller cholesterol-lowering effect of SV.
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  • Toshiyuki YAJIMA, Tetsuya HASEGAWA, Kazuhiko JUNI, Mineo SANEYOSHI, Ta ...
    1996 Volume 19 Issue 9 Pages 1234-1237
    Published: September 15, 1996
    Released: April 10, 2008
    JOURNALS FREE ACCESS
    Nasal absorption of 2', 3'-didehydro-3'-deoxythymidine (D4T) and its esters (5'-acetyl D4T : C2-D4T and 5'-hemisuccinyl D4T : Suc-D4T) was investigated in rats. Bioavailability of D4T following intranasal (i.n.) administration was 98.0%, and the elimination from plasma was as rapid as that following intravenous administration of D4T. There seemed to be complete and rapid absorption of D4T from the nasal cavity. The plasma concentration-time profile of D4T following i.n. administration of C2-D4T was almost the same as that after administration of D4T itself. This suggests that C2-D4T was rapidly absorbed from the nasal cavity, and that some amount of dosing C2-D4T was hydrolyzed to D4T before entering the systemic circulation. In contrast, Suc-D4T showed slower absorption in the i.n. administration, and the plasma D4T level was maintained for a long period.
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  • Yasuhiro OHNISHI, Sayuki TAKAGI, Toshihiro MIURA, Masaru USAMI, Mami K ...
    1996 Volume 19 Issue 9 Pages 1238-1240
    Published: September 15, 1996
    Released: April 10, 2008
    JOURNALS FREE ACCESS
    The oral administration of the water extract of Ginseng Radix (GR) to normal and epinephrine-induced hyperglycemic mice caused a significant decrease in the blood glucose level 4 h after its administration. The hepatic content of facilitative glucose transporter isoform 2, liver type glucose transporter (GLUT2) protein content from mouse liver significantly increased in the orally GR-treated normal and epinephrine-induced hyperglycemic mice compared to that in the controls. These results suggest that the hypoglycemic activity of GR is presumably due, at least in part, to the increment of GLUT2 protein content.
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  • Johji YAMAHARA, Hiroshi SHIMODA, Hisashi MATSUDA, Masayuki YOSHIKAWA
    1996 Volume 19 Issue 9 Pages 1241-1243
    Published: September 15, 1996
    Released: April 10, 2008
    JOURNALS FREE ACCESS
    Potent immunosuppressants, the dimeric sesquiterpene thioalkaloids, 6-hydroxythiobinupharidine (2), 6, 6'-dihydroxythiobinupharidine (3), 6-hydroxythionuphlutine B (5) and 6'-hydroxythionuphlutine B (6), were isolated from a natural medicine, Nupharis Rhizoma, the rhizoma of Nuphar pumilum (TIMM.) DC., through bioassay-guided separation together with five quinolizidine alkaloids (8, 9, 10, 11, 12). Dimeric sesquiterpene thioalkaloids (2, 3, 5, 6) were found to significantly inhibit anti-sheep erythrocyte plaque forming cell formation in mice spleen cells at 10-6 M concentration. At this concentration, 2, 5 and 6 were found to exhibit no cytotoxicity to mice spleen cells, and 3 also showed only a little cytotoxicity. In addition, the inhibitory activity of several Nuphar alkaloids, dimeric sesquiterpene thioalkaloids (1, 4, 7, 8), and monomeric sesquiterpene alkaloids (9, 10, 11, 12) on anti-sheep erythorocyte plaque forming cell formation was examined and some structural requirement of Nuphar alkaloid for immunosuppressive activity was determined.
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  • Kenji YAMADA, Takeharu MIURA, Yoshihiro MIMAKI, Yutaka SASHIDA
    1996 Volume 19 Issue 9 Pages 1244-1246
    Published: September 15, 1996
    Released: April 10, 2008
    JOURNALS FREE ACCESS
    We found that inhaling chamomile oil vapour decreased restriction stress-induced increases of plasma ACTH level in ovariectomized rat. The plasma ACTH level decreased further when diazepam was administered along with inhaling chamomile oil vapour. Flumazenile blocked the decrease in plasma ACTH level induced by inhaled chamomile oil vapour.
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