Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
23 巻 , 12 号
選択された号の論文の30件中1~30を表示しています
  • Makoto MIYAHARA, Akiko SAITO, Hitoshi ITO, Masatake TOYODA
    2000 年 23 巻 12 号 p. 1399-1405
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    DNA in food will sustain damage by gamma radiation. The detection capability of the high sensitivity comet assay was studied using fluorescence-microscopy. Beef liver was irradiated at a range of 1 Gy to 8 kGy. Single cells were obtained from the irradiated liver, then analyzed by agaros-gel electrophoresis. The pH of the buffer for electrophoresis was pH 13, which is generally utilized for sensitive detection of DNA damage. The pattern formed by DNA was visualized by staining with ethidium bromide. The resulting comets were evaluated with a scale we developed, and Influence Scores were calculated based on the Tice method. It is possible to detect irradiation damage to beef liver at 10 Gy. Together with Influence Score, histogram of comet type is used for detection of irradiation. We elucidated those histograms were useful for distinguishing damage caused by irradiation from that of others.DNA damage can be caused not only by irradiation, but also by the other treatments. Therefore, the respective influences of freezing, preservation, irradiating temperature, atmosphere of irradiation, cooking, and homogenizing devices were also examined.This new comet assay will be a useful method of detecting DNA damage to identify irradiated foods.
  • Ferdinand KOUOH ELOMBO, Miryana REDOSEVICH, Michel POULLE, Jacpues DES ...
    2000 年 23 巻 12 号 p. 1406-1409
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    Human ceruloplasmin (Cp) has been purified from cryoprecipitate-poor plasma as a by-product of the C1-inhibitor production chain. Highly purified Cp was obtained by subsequent ion-exchange chromatography on sulfate-Fractogel EMD and TMAE-Fractogel EMD. Treatments for viral safety included application of the solvent-detergent method and two nanofiltration steps using 35- and 15-nm pore size filters at the end of the precess. Overall antigen yield was 95 (±5)%. Purified human ceruloplasmin was studied by electron spin resonance (ESR) to characterize its different types of copper complexes and to check its antioxidant properties. We distinguished three types of complexes : one type-2 Cu(II) with g⫽=2.25 and A⫽=180 G and two type-1 Cu(II) exhibiting different narrow hyperfine splitting (A⫽=72 G and A⫽=90 G) with close g⫽ (2.20 and 2.21). Purified Cp has a specific activity of 24.5±0.2 mU/mg of proteins. This process provides a method for Cp purification that could be easily integrated into modern plasma fractionation.
  • Maria Fausta OMODEO SALE, Angela Maria RIZZO, Massimo MASSERINI
    2000 年 23 巻 12 号 p. 1410-1413
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    We have investigated the influence of ethanolamine plasmalogens on iron-induced oxidation of arachidonic acid in dipalmitoylphosphatidylcholine (DPPC) vesicles. Lipoperoxidation was induced by the addition of 50 μM FeSO4 and studied above (50 °C) and below (15°C) the gel-to liquid transition temperature of the vesicles, at two different pH values (7.4 or 6.4). The extent of peroxidation was measured as thiobarbituric reactive product formed and the influence exerted by ethanolamine plasmalogens (PEPL) in this process was compared to that of dipalmitoylphosphatidylethanolamine (DPPE) and discylphosphatidylethanolamines (DAPE). The extent of peroxidation of arachidonic acid embedded in DPPC vesicles was similar at the two temperatures and greater at 50°C under acidic conditions. However, the peroxidative process was significantly decreased at 50°C in the presence of PEPL, but not of DPPE or DAPE and the inhibitory effect was enhanced at pH 6.4. The possibility that a different phase distribution of the phospholipids, namely a transition from a lamellar to a hexagonal phase, may play a role in the scavenger effect of ethanolamine plasmalogens is discussed.
  • Hiroshi FUKASAWA, Mitsuhiro YAMAGUCHI, Yuichi HASHIMOTO, Yasuyuki ENDO ...
    2000 年 23 巻 12 号 p. 1414-1417
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    Interaction between a tumor promoter, 12-O- tetradecanoylphorbol 13-acetate (TPA), and ligands of nuclear receptors has been interpreted as the result of crosstalk between the nuclear receptors and oncogenic transcription factor AP-1. We examined the effects of various tumor promoters on transcription mediated by several nuclear receptors (RAR, TR, and ROR) by using thymidine kinase promoter-based reporter systems. TPA-type and other types of tumor promoters (okadaic acid, thapsigargin) enhanced reporter gene transcription independently of the cognate ligands for the receptors. Various kinds of TPA-type tumor promoters, teleocidine and its synthetic derivatives (indolactam, benzolactams) enhanced reporter gene transcription in proportion to their differentiation-inducing activities. Although TPA is known to activate protein kinase C (PKC), some PKC inhibitors did not inhibit the effect of TPA on reporter gene transcription. Interestingly, staurosporin, a strong PKC inhibitor and also a tumor promotor, enhanced the effect of TPA and weakly enhanced the reporter transcription itself. These results suggest this reporter system in useful for the evaluation of effects on the gene expression of various tumor promoters, including non-TPA type.
  • Taiko AKAO
    2000 年 23 巻 12 号 p. 1418-1423
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    Glycyrrhizin (1.0 mM GL), glycyrrhetic acid (10 mM GA) and glycyrrhetic acid monoglucuronide (10 mM GAMG), as well as a combination of all components added to medium at the start of growth and at the maximal stage of intestinal flora were cultured for 24 and 12 h, respectively. GL alone enhanced GL β-D-glucuronidase activity about 2.7- to 6.8-fold and was metabolized to between 55 and almost 100% GA. GAMG alone was metabolized to almost 100% GA by GABG β-D-glucuronidase activity. Interstinal flora grown to a maximal stage converted GL to about 15% GA and GAMG to about 13% GA at almost 0 h. GL in combined GL and GA was consumed about 20% at 12 h and about 100% at 24 h under different culture conditions. Metabolite GA and unchanged GA were metabolized to a negligible amount of 3-oxoglycyrrhetic acid, 3α-hydroxyglycyrrhetic acid (3α-hydroxyGA) or both by 3β-hydroxysteroid dehydrogenase and 3α-hydroxyGA dehydrogenase activities. Combined GL and GAMG consumed about 90% and 100% GAMG at 24 h and 12 h, respectively, regardless of culture conditions, and the consumption of GL was non-existent or negligible. Consumption of combined GL, GA and GAMG was similar to that of both combined GL and GA and combined GL and GAMG.It was found that intestinal flora can metabolize GL alone, but does not readily metabolite GL when present among its metabolites containing GL.
  • Atsuhiro TANABE, Chizumi KUMAHARA, Shigehiro OSADA, Tsutomu NISHIHARA, ...
    2000 年 23 巻 12 号 p. 1424-1429
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
  • Kazuyuki KITATANI, Satoshi AKIBA, Takashi SATO
    2000 年 23 巻 12 号 p. 1430-1433
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    The implications of phospholipase D (PLD) in cytosolic phospholipase A2 (cPLA2) activation were studied in a mast cell line, RBL-2H3, upon stimulation with antigen. Antigen-stimulated prostaglandin D2 generation was apparently suppressed by ethanol with a concomitant decrease in phosphatidic acid (PA) formation. The prostaglandin D2 generation was also inhibited almost completely by methyl arachidonyl fluorophosphate (MAFP), an inhibitor of cPLA2, but not by diacylglycerol lipase inhibitor. Furthermore, stimulation with antigen resulted in an increase in lysophosphatidic acid formation, which was suppressed by MAFP in parallel with an increase in PA formation. These results suggest that PA formed by the catalytic action of PLD is used as a substrate for cPLA2. thus PLD regulates cPLA2 activation in antigen-stimulated RBL-2H3 cells.
  • Akira OKU, Kiichiro UETA, KENJI ARAKAWA, Tomomi KANO-ISHIHARA, Mamoru ...
    2000 年 23 巻 12 号 p. 1434-1437
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    T-1095, a derivative of phlorizin, is an orally active inhibitor of Na+ -glucose cotransporter (SGLT). We investigated the acute antihyperglycemic effect of T-1095 in streptozotocin-induced diabetic rats (STZ rats). T-1095 and its metabolite T-1095A inhibited the SGLT activity in brush border membranes prepared from kidneys of both normal and STZ rats, but the latter agent was approximately 10 times more potent than the former. Single oral administration of T-1095 (30-100 mg/kg) dose-dependently induced glycosuria in normal rats. The fed glucose levels in STZ rats were dose-dependently suppressed by single oral administration of T-1095 (3-100 mg/kg), whereas there was only marginal hypoglycemic effect in normal rats. Since there was no effect on blood glucose in nephrectomized STZ rats, inhibition of renal glucose reabsorption rather than intestinal glucose absorption mainly contributes to the antihyperglycemic effect of T-1095. In conclusion, T-1095 is the first orally active agent which has an acute antihyperglycemic action in the absence of endogeneous insulin secretion with a low risk of hypoglycemia and has therapeutic potential for treatment of diabetes mellitus.
  • Rathina Sabapathy THIRUMURUGAN, S. KAVIMANI, Radhey Shyam SRIVASTAVA
    2000 年 23 巻 12 号 p. 1438-1440
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    The antitumour activity of Rhinacanthone (3, 4-dihydro-3, 3-dimethyl-2H-naphtho-[1, 2-B] pyran-5, 6-dione) has been evaluated against Dalton's ascitic lymphoma (DAL) in Swiss albino mice. A significant enhancement of mean survival time of tumour bearing mice and peritoneal cell count in normal mice was observed with respect to the control group. When these Rhinacanthone treated animals underwent i.p. inoculation with DAL cells, tumour cell growth was found to be inhibited. After 14 d of inoculation, Rhinacanthone was able to reverse the changes in the haemotological parameters, protein and packed cellular volume consequent to tumour inoculation.
  • Aishi KIMOTO, Yasuno HIRANO, Takaya IWAI, Munetoshi SAITOU, Kenichi TO ...
    2000 年 23 巻 12 号 p. 1441-1444
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    The effects of the surfactant secretagogue YM-40461 on the mucociliary transport (MCT) velocity were examined in guinea pigs with induced bronchitis. Guinea pigs were exposed to SO2 gas (900 ppm, 3 h/d) for 5 d. MCT velocity was measured by the movement of a 30% gelatin solution containing Evans blue dye placed on the tracheal mucosal surface. Repeated doses of YM-40461 improved the MCT guinea pigs with bronchitis within 5 d after the completion of SO2 exposure, with an ED50 value of 3.1 mg/kg p.o. At a dose of 10 mg/kg p.o., YM-40461 restored MCT to the control level (98.0% recovery). Ambroxol, bromhexine and salbutamol also improved MCT, but were far less effective than YM-40461. Airway fluid collected from bronchitic animals revealed increased disaturated phosphatidylcholine (DSPC, a major component of surfactants)-to-protein ratio and decreased surface tension produced by YM-40461 treatment (10 mg/kg). These results suggest that YM-40461 ameliorates MCT dysfuction in animals with SO2 gas-induced bronchitis by increasing the DSPC-to-protein ratio in the airway.
  • Junichi KURIHARA, Yoshinobu TAKATA, Shigeo SUZUKI, Yoko OKUBO, Hitoshi ...
    2000 年 23 巻 12 号 p. 1445-1449
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    Orthostatic hypotension was produced in urethane-anesthetized rabbit by a combination of chlorpromazine (0.1 mg/kg, i.v.) and 45° head-up tilt. The effect of midodrine (1 and 3 mg/kg, i.d.) was investigated in comparison with amezinium (10 and 30 mg/kg, i.d.), etilefrine (10 and 30 mg/kg, i.d.) and droxidopa (30 and 100 mg/kg, i.d.). The higher doses of each drug significantly mitigated the chlorpromazine-induced orthostatic hypotension, while none of the lower doses caused a significant effect. The effect of midodrine developed most rapidly; a significant effect was observed 25 min after administration. The order of onset time was midodrine<etilefrine<amezinium<droxidopa. The effect of droxidopa was significant only at 130 to 160 min after administration. The amplitude of effect was in the following order; midodrine=droxidopa≥etilefrine>amezinium. Midodrine (3 mg/kg, i.d.)mitigated orthostatic hypotension induced by prazosin (0.1 mg/kg, i.v.), but not by pentolinium (0.6 mg/kg, i.v.). It is suggested that midodrine competes with chlorpromazine at α1-adrenoceptors and subsequently recovers reflex vasconstriction. Midodrine may be useful to protect patients with impaired baroreflex activity from accidental orthostatic hypotension during treatment with neuroleptics.
  • Kyoji TAGUCHI, Kotomi KANEKO, Takao KUBO
    2000 年 23 巻 12 号 p. 1450-1454
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    The electrical and pharmacological properties of protein kinase C (PKC) and its effect its effect on the single Ca2+ -activated K+ channel (Kca-channel) in the cultured smooth muscle cells of rat mesenteric artery were studied using a patch-clamp technique. The Kca-channel had a slope conductance of 151±7 pS (mean±S.E.) in symmetrical 142 mM K solutions. The high conductance K+ channel, applied to the outer side of membrane patches, was potently inhibited by charybdotoxin (0.1 μM) and tetraethylammonium (0.5 μM), but not by apamin (0.4 μM.). In cell-attached patches, bath application of phorbol 12-myristate 13-acetate (PMA, 2 μM), a PKC activator, inhibited the activity of the Kca-channel in the presence of the Ca2+ ionophore, A 23187 (10 μM). This inhibition was reversed by subsequent application of staurosporine (1 nM), a PKC inhibitor. Application of 1-oleoyl-2-acetylglycerol (OAG, 30 μM), another PKC activator, also inhibited the A 23187-induced activation of the K+ channel, and this inhibition was reversed by staurosporine. In inside-out patches, bath application of PKC (0.2 munits), in the presence of ATP (1 mM) and PMS (1 μM), inhibited the K+ channel. These results indicate that protein kinase C inhibits the Ca2+ -activsted K+ channel of mesenteric artery smooth muscle cells in the rat.
  • Yosie MIZUNUMA, Mizue SUZUKI-KUSABA, Hiroaki HISA, Makoto YOSHIDA, Sus ...
    2000 年 23 巻 12 号 p. 1455-1457
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    Experiments were carried out to examine whether endogenous angiotensin II (A-II) is involved in the regulation of release of norepinephrine (NE) elicited by the stimulation of spinal sympathetic nerves in pithed rats. It was assessed in terms of the alterations in concentrations of arterial blood plasma A-II and NE elicited by nerve stimulation (5 Hz, 50 V, 1 msec for 45 s) in pithed rats under vehicle or ceptopril (3 mg/kg, i.v.) treatment. Comparative study with pentobarbital anesthetized rats showed that pithing rats have the characteristics of lower basal blood pressure and lower NE level, whereas they have higher basal A-II level. In pithed rats treated with vehicle, pressor response to nerve stimulation was accompanied by increases in both A-II and NE level. In rats treated with captopril, the nerve stimulation caused about 40% lower increases in pressor response and NE level than those observed in rats treated with vehicle. These results suggest that the sympathetic nerve-induced NE release is facilitated by endogenous A-II in pithed rats, and that captopril exerts its inhibitory effect on the pressor response to nerve stimulation through the suppression of this interaction.
  • Yoichi KONDO, Akiko NAKATANI, Koji HAYASHI, Mikio ITO
    2000 年 23 巻 12 号 p. 1458-1464
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    The present study was designed to clarify the effect of low molecular weight (LMW) chitosan (chitosan lactate, average MW : 20000) on the progression of slowly progressive non-insulin-dependent diabetes mellitus (NIDDM) induced by a single i.p. injection of low dose (100 mg/kg) streptozotocin (STZ) to 8-week-old male ICR mice. The non-fasting serum glucose levels of STZ-treated control mice continued to rise throughout the experimental period until 23 weeks after STZ treatment. The 0.2% or 0.8% chitosan (water solution), given as drinking water from prediabetic stage (2 weeks after STZ treatment), markedly prevented the time course-related rise of serum glucose levels of diabetic mice. In addition, the reduction of relative numbers of insulin-immunoreactive cells (β-cells) in the islets of diabetic mice at 24 weeks after STZ treatment was markedly prevented by 0.2% or 0.8% chitosan administration. However, the progression of hyperglycemia in diabetic mice was not affected by 0.2% glucosamine, a monosaccharide of chitosan. The glucose levels of normal mice were not affected by 0.8% chitosan administration. When 0.2% chitosan administration was stopped at 20 weeks, these animals had still maintained significantly lower serum glucose levels, compared to control animals even at 5 weeks after stopping the administration. These results indicate that LMW chitosan prevents the progression of low dose STZ-induced slowly progressive NIDDM.
  • Clelia Akiko HIRUMA-LIMA, Juliano de Souza GRACIOSO, Walber TOMA, Ana ...
    2000 年 23 巻 12 号 p. 1465-1469
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    Aparisthmium cordatum (JUSS.) BAIL. (Euphorbiaceae) is a medium sized tree native to the North Brazilian coastal region, which is known in the State of Para as "ariquena queimosa." To our knowledge it has no popular use. Phytochemical studies of the benzene extract of the bark of A. cordatum yielded a futan diterpene with a clerodane skeleton, called cordatin. Recently, we reported the antiulcerogenic activity of trans-dehydrocrotonin (DHC), another furan diterpene isolated from Croton cajucara bark, in different ulcerogenic models in mice and rats. The aim of the present study was to assess the possible antiulcerogenic activity of cordatin, another compound of the clerodane diterpene group present in A. cordatum bark. When previously administered (p.o.) at the doses of 100 mg/kg, cordatin significantly reduced (p<0.01) gastric injury induced by the indomethacin/bethanechol (78%), ethanol (76%), and hypothermic restraint-stress models (66%) and by pylous ligature (50%) in mice and rats. In the HCl/ethanol-induced gastric ulcer model in mice, at oral dose of 100 and 250 mg/kg, cordatin from A. cordatum significantly reduced (p<0.001) the formation of gastric lesions by 70% and 77%, respectively, when compared to the control. In the pylorus-ligature model, cordatin (p.o.) only decreased the volume of gastric juice compared to the control (p<0.001). When cordatin (100 mg/kg) was administered intraduodenally to mice, significant modifications were found, such as a decrease in gastric acidity compared to the control (p<0.05). In the animals pre-treated with cordatin, free mucus production was not altered when compared with the control group. The results suggest that cordatin from A. cordatum presents a significant anti-ulcer effect when assessed in these induced ulcer models. Although the mechanism underlying this antiulcerogenic effect remains unknown, it seems to be related to an anti-secretory property but the involvement of mucosal defensive mechanisms are not to be ignored. The good yield of cordatin obtained from A. cordatum, as well as its antiulcerogenic activity, suggest that this compound should be submitted to pharmacological research as a potential new antiulcerogenic drug.
  • Yoshiaki IKARASHI, Toshie TSUCHIYA, Masa-aki KANIWA, Akitada NAKAMURA
    2000 年 23 巻 12 号 p. 1470-1476
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    This study examined the osteoblast-like MC3T3-E1 cell responses to poly(DL-lactide) (PDLLA) and poly(L-lactide) (PLLA) with different weight average molecular weight (M.W.). Colony formation of MC3T3-E1 cells on the PLLA with M.W. 270000 or 1370000 was slightly lower than that on glass. The protein, DNA and hydroxyproline (HYP) content and alkaline phosphatase (ALP) activity for cells cultured on the PLLA (M.W. 270000 or 1370000) for 14 d were almost similar to those on glass. In contrast, the ALP activity of the cells cultured on low M.W. PLLA (M.W. 20000) increased. Osteoblast differentiation was simulated by low M.W. PLLA but not by high M.W. PLLA. The addition of low M.W. PDLLA (M.W. 5000 or 10000), L-lactide or L-lactic acid into culture increased the protein, DNA and HYP content and ALP activity for cells at 100 μg/ml. Compared with four chemicals, PDLLA (M.W. 10000) had the strongest simulation effect on the cell. The release of L-lactic acid from PLLA and PDLLA into aqueous solution during incubation only slightly affected cell activity. In a cell-free condition, in the presence of PDLLA, the ALP activity was maintained without inactivation, even after 24 h incubation. Such a phenomenon was not seen with L-lactide and L-lactic acid. This may be a reason why PDLLA has a stronger effect on osteoblast differentiation relative to L-lactic acid. These results suggested that increased osteoblast differentiation was induced by low M.W. PDLLA and PLLA, and these may be used as a effective material in the field of orthopedic and drug delivery systems for the treatment of bone diseases.
  • Shinji TANEDA, Hideyuki HAYASHI, Masakatsu SAKATA, Shin YOSHINO, Akira ...
    2000 年 23 巻 12 号 p. 1477-1480
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    Estrogenic and anti-estrogenic activities of diesel exhaust particles (DEP) were evaluated using yeast cells expressing the human estrogen receptor and the responsive element regulating the expression of the receptor gene for β-galactosidase (Routledge and Sumpter, 1996). It was found that a suspension of whole DEP suspension is not estrogenic but that this preparation possesses the ability to reduce the estrogen-dependent reporter activity. DEP were serially extracted with hexane, benzene, dichloromethane, methanol, and 1 M ammonia, and the estrogenic and anti-estrogenic activities of these preparations were determined. None of the extracts of DEP were estrogenic, but the extracts of benzene, dichloromethane and methanol possessed anti-estrogenic activity, and the activity of estrogen in the presence of hexane extract was slightly decreased. These results indicated that DEP contain heterologous compounds having anti-estrogenic activity. It is thought that those compounds in DEP can modulate the activity of estrogen, leading to the distribution of balance between estrogen and androgen. In this paper, the environmental effects of DEP in relation to the endocrine disrupting effect or organic compounds in DEP are discussed.
  • Eun-Ah BAE, Sun-Young PARK, Dong-Hyum KIM
    2000 年 23 巻 12 号 p. 1481-1485
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    When ginsenoside Rb1 and Rb2 were anaerobically incubated with human intestinal microflora, these ginsenosides were metabolized to 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol (compound K) and 20(S)-protopanaxadiol. Several kinds of intestinal bacteria hydrolyzed these ginsenosides. Eubacterium sp., Strep coccus sp. and Bifidobacterium sp., which more potently hydrolyzed gentiobiose than sophorose, metabolized ginsenoside Rb1 to compounds K via ginsenoside Rd rather than gypenoside XVII. However, Fusobacterium K-60, which more potently hydrolyzed sophorose than gentiobiose, metabolized to compound K via gypenoside XVII. Ginsenoside Rb2 was also metabolized to compound K via ginsenoside Rd or compound O by human intestinal microflora. Eubacterium sp., Streptococcus sp. and Bifidobacterium sp. metabolized ginsenoside Rb2 to compound K via ginsenoside Rd rather than compound O. Fusobacterium K-60 metabolized ginsenoside Rb2 to compound K via compound O.
  • Yoshikazu TASHIRO, Yasuki KATO, Eiji HAYAKAWA, Kuniko ITO
    2000 年 23 巻 12 号 p. 1486-1490
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    The objectives of this study were to develop a method for kinetic analysis of drug transfer to cutaneous blood flow and to evaluate the effect of iontophoresis on drug transfer to cutaneous blood. Cathodal iontophoresis of ketoprofen (non-steroidal anti-inflammatory drug) was conducted to rats (applied electrical current 0.14 and 0.70 mA/cm2; application time 5, 15, 30, 60 and 90 min), and the drug concentrations in skin, cutaneous vein and systemic vein were determined. Transfer rate of ketoprofen from skin to cutaneous blood (RSC) was calculated by moddifying a physiological pharmacokinetic model. The time-course of RSC for 0.70 mA/cm2 showed that the value of RSC was initially increased, following a gradual decrease with time after 30-min application. The effect of electrical current on drug traansfer to cutaneous blood flow was estimated from the comparison to passive diffusion (without electrical current). The RSC value at 30-min application was almost proportional to the electrical current, and the enhancement ratio for 0.14 and 0.70 mA/cm2 was 17 and 73, respectively. Consequently, our results suggest that the change of drug transfer to cutaneous blood flow by iontophoresis may depend on the application period and the magnitude of electrical current.
  • Yoshiharu TOKUNAGA, Mikiro NAKASHIMA, Hitoshi SASAKI, Naoki TOMIYAMA, ...
    2000 年 23 巻 12 号 p. 1491-1496
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    Local distribution into brain tumor and the pharmacokinetics of 4-pyridoxate diammine hydroxy platinum (PyPt), a novel cisplatin derivative, were examined using rats implanted with 9L glioma and compared with cisplatin. PyPt (5.0 mg/kg) and cisplatin (3.5 mg/kg) were administered as selective intracarotid infusions for 30 min to the rats. Dialysates from extracellular fluid (ECF) in tumor and non-tumor brain tissues were collected by simultaneous microdialysis. The amount of platinum was determined by atomic absorption spectrophotometry, as representative of the drug administered. Plasma concentration of total and protein unbound platinum, and urinary excretion amount and tissue distribution of total platinum were also determined. Unbound platinum was accumulated preferentially in the brain tumor tissue ECF aftwer administration, while there was little distribution into normal tissue ECF of the brain. In the brain tumor, the values of the unbound platinum AUC and MRT, where AUC is the area under the concentration-time curve and MRT is the mean residence time, for PyPt were 1.7 and 1.3 times larger than with cisplatin, respectively. The brain tumor distribution coefficient (the ratio of brain tumor ECF platinum AUC to plasma protein unbound platinum AUC) for PyPt (0.85) was higher than that for cisplatin (0.69), indicating that the local amount of platinum distributed into the glioma is enhanced by PyPt rather than by cisplatin. The binding to plasma proteins of PyPt (23%) was lower than that of cisplatin (65%). The total platinum concentration in tissues after administration of PyPt was significantly lower than that of cisplatin in the kidney, liver and spleen. In addition, the urinary excretion amount of total platinum after the administration of PyPt was significantly larger than that of cisplatin. These results suggested that PyPt is easily eliminated by rapid urinary excretion because of its reduced interaction with plasma proteins and poor distribution to the kidney or reticuloendothelial tissues such as the liver and spleen.It is concluded that PyPt is an effective cisplatin derivative for the treatment of gliomas with the added advantage of enhancing local distribution of drug into the brain tumor and reducing its accumulation in the kidney, which has previously caused severe nephrotoxicity.
  • Yoshinori KATO, Hiraku ONISHI, Yoshiharu MACHIDA
    2000 年 23 巻 12 号 p. 1497-1503
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    Highly-succinylated N-succinyl-chitosan (Suc) was fluorescein-labeled, and the labeled product (Suc-FTC) was examined for biodisposition in Sarcoma 180-bearing mice after i.v. and i.p. administration. Suc-FTC injected intravenously was sustained at a high level in the blood circulation and showed little distribution to tissues other than tumor. On the other hand, it took a few hours for Suc-FTC to be transferred to the blood circulation after i.p. administration. There were no marked differences in the distribution of Suc-FTC between i.v. and i.p. administration routes except in the early stage. The urinary excretion of Suc-FTC following both i.v. and i.p. administration was small, but the excretion tended to be suppressed after i.p. administration. Water-soluble Sucmitomycin C conjugate (Suc-MMC) prepared using water-soluble carbodiimide exhibited marked effect at a high dose and suppressed the acute toxic side effect of MMC. Suc-MMC tended to be more toxic at i.p. administration that at i.v. administration. The difference in biodisposition between the two administrations was thought to affect the toxic side effect. The plasma levels of conjugated and free MMCs at 8 h after i.v. administration were higher than those at 8 h after i.p. administration. These suggested more localization of the conjugate in peripheral tissues and less excretion at i.p. administration, which might result in greater toxicity.
  • Toyofumi SUZUKI, Ryo SHIMIZU, Taiyo SUGANUMA, Jun-ichi NISHINO, Kazuo ...
    2000 年 23 巻 12 号 p. 1504-1510
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    The relstionship between the pharmacokinetics and the pharmacodynamics of eptazocine, a narcotic-antagonist analgesic, was investigated in rats. The analgesic effect of eptazocine (2.5, 5 and 10 mg/kg) following intravenous (i.v) administration was evaluated by both the Randall-Selitto method and the D'Amour-Smith method. The analgesic effects were determined before and at designed intervals for a period of 120 min after eptazocine administration, and are expressed as area under the effect-time curve (AUCE). The plasma concentration of eptazocine was determined by fluorescence HPLC and was analyzed with a two compartment open model using the nonlinear least-squares method. Eptazocine produced a dose-dependent analgesic effect. It was demonstrated that eptazocine has a linear relationship between AUCE and the area under the plasma concentration-time curve (AUC) following i.v. administration for three different doses ranging from 2.5 to 10 mg/kg.
  • Shinya ABE, Kei YAMASHITA, Hiroyuki KOHNO, Yasuhito OHKUBO
    2000 年 23 巻 12 号 p. 1511-1513
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    We investigated the effect of extracellular Ca2+ on the uptake of immunoglobulin G (IgG)-coated normal sheep red blood cells (SRBC) by the mouse peritoneal macrophages. The uptake of SRBC was dose dependently enhanced by Ca2+ concentration. We also investigated the effect of ryanodine on the uptake of SRBC. Ryanodine showed approximately 15% inhibition of the uptake. The activity of transglutaminase (TGase) in the cytosolic fraction of macrophages was enhanced as the Ca2+ concentration increased. The uptake of SRBC decreased by the addition of histamine, a TGase inhibitor. These results suggest that TGase is involved in the receptor-mediated endocytosis system of mouse peritoneal macrophages.
  • Yumi SUGIMOTO, Toshiko NOMA, Tomoko YOSHIKAWA, Jun YAMADA
    2000 年 23 巻 12 号 p. 1514-1516
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    We investigated the effects of the nitric oxide (NO) synthase inhibitor, NG -nitro-L-arginine methyl ester (L-NAME) on hypophagia in rats elicited by α-methyl-5-hydroxytryptamine (α-methyl-5-HT) and 5-carboxamidotryptamine (5-CT) which are suggested to be mediated by the peripheral 5-HT2A and 5-HT7 receptor, respectively. Both α-methyl-5-HT and 5-CT apparently inhibited food intake in food-deprived rats. L-NAME significantly enhanced α-methyl-5-HT-elicited hypophagia, while it inhibited 5-CT-elicited hypophagia. These results suggest that NO is differentialy related to α-methyl-5-HT and 5-CT-induced hypophagia and that NO may play a role in hypo- and hyperphagia.
  • Joon Seok PARK, Jeum Yong KIM, Jae Youl CHO, Jin Seok KANG, Young Hyo ...
    2000 年 23 巻 12 号 p. 1517-1520
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    Wound contraction plays on important role in healing, but in extreme conditions, it may lead to excessive scar formation and pathological wound contracture. To date, the key regulator of excessive contracture is known to be transforming growth factor-beta (TGF-β1). In this study, we have evaluated epidermal growth factor (EGF) antagonism in fibroblast-populated collagen lattice (FPCL)gel contraction, which has been generally used as an in vitro model thought to mimic wound contraction in vivo. As expected, TGF-β1 treatment enhanced normal fibroblast-induced collagen gel concentration in a dose-dependent manner. In contrast, EGF did not affect normal gel formation, but significantly antagonized TGF-β1-induced gel formation (p<0.05 at 100 ng/ml), whereas the other growth factor, platelet-derived growth factor (PDGF), did not altered either normal or TGF-β1-induced gel contractions. Similarly, EGF treatment, but not PDGF, also significantly suppressed TGF-β1 release that was autologously elicited by TGF-β1 treatment (p<0.01 at 100 ng/ml). Therefore, the results suggest that EGF may negatively regulate the role of TGF-β1 through attenuating antologous release of TGF-β1.
  • Yumi SUGIMOTO, Jun YAMADA
    2000 年 23 巻 12 号 p. 1521-1523
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    Effects of the 5-hydroxytryptamine (5-HT)2A receptor agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-amino-propane (DOI) on plasma glucagon levels studied in rats. Systemic injection of DOI induces significant increases in plasma glucagon levels. Hyperglucagonemia induced by DOI was dose-dependently prevented by the 5-HT2A receptor antagonist ketanserin. Adrenodemedullation abolished hyperglucagonemia elicited by DOI. Previous report demonstrated that the peripheral 5-HT2A receptor agonist induces hyperglycemia in rats but does not increase plasma glucagon levels at doses inducing hyperglycemia. Therefore, our findings suggest that DOI-induced glucagon release was elicited by stimulation of the central 5-HT2A receptor, which in turn increasing adrenaline release.
  • Hitoshi SASAKI, Kenzo YAMAMURA, Takahiro MUKAI, Koyo NISHIDA, Junzo NA ...
    2000 年 23 巻 12 号 p. 1524-1527
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    The purpose of this study was to investigate the effect of absorption promoters on the ocular membrane permeability of thyrotropin-releasing hormone (TRH) and luteinzing hormone-releasing hormone (LHRH) as model peptides. The permeabilities of TRH and LHRH were measured using a two-chamber glass diffusion cell mounted with isolated ocular membranes of albino rabbits. Saponin, EDTA, benzalkonium chloride and paraben were used as absorption promoters. These promoters enhanced the permeability of hydrophilic molecules through the cornea and conjunctiva. The promoting effects of the absorption promoters on the conjunctival drug penetrations were not as strong as those on the corneal penetrations. The different responses of the corneal and conjunctival drug penetrations to these promoters may be useful in controlling the extent and pathway of the ocular and systemic absorptions of instilled drugs. The promotional effects of absorption promoters on the corneal drug pentration apparently increased with an increase in pentrant molecular weights, although those on the conjunctival drug penetrations did not depend on the molecular weights.
  • Nobuaki SHIRAKI, Akinobu HAMADA, Kazuto YASUDA, Junko FUJII, Kazuhiko ...
    2000 年 23 巻 12 号 p. 1528-1531
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    The objective of this study was to determine whether human immunodeficiency virus (HIV) protease inhibitors (saquinavir, ritonavir and nelfinavir) interact with other HIV protease inhibitors and/or HIV reverse transcriptase inhibitory (zidovudine, didanosine, lamivudine, zalcitabine and sanilvudine). We measured transport of nelfinavir, an HIV protease inhibitor which is known as a substrate for the multidrug resistance transporter P-glycoprotein(P-gp), in an epithelial monolayer model and Ki for P-gp of some drugs by a calcein flux assay. Transport in a basal to apical direction was 2-fold greater than apical to basal flux for nelfinavir, Ki for P-gp of a potent P-gp inhibitor cyclosporin A was 1.09 μM and those of ritonavir and nelfinavir were 111 μM and 28.6 μM, whereas all HIV reverse transcriptase inhibitors gave Ki values. These data show that nelfinavir, which is a substrate for P-gp, inhibits a P-gp function as a drug efflux pump and that HIV reverse transcriptase inhibitors do not inhibit P-gp.
  • Bu-Miin HUANG, Yu-Min CHUANG, Chieu-Fu CHEN, Sew-Fen LEU
    2000 年 23 巻 12 号 p. 1532-1535
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    Extracts from the mycellium of Cordyceps sinensis (CS) were tested to determine the in vitro effect on Leydig cell function. MA-10 mouse Leydig tumor cells were used to conduct the experiments. Results showed that progesterone production gradually increased as the dosage of combined water and ethanol extracted CS increased, and these was a statistically significant difference in progesterone production stimulated by 20 mg/ml of CS extracts compared to the control. The combined water and ethanol extracted CS significantly stimulated MA-10 cell steroid production at 12 and 24 h of incubation. In addition, a protein synthesis inhibitor, cycloheximide, did not block the stimulatory effects of CS extracts on MA-10 cell steroid production or total protein expression. Moreover, the expression of steroidgenic acute regulatory (StAR) protein, which is a critical protein for steroidogenesis, stimulated by CS extracts, could not be detected by Western blot analysis. These data indicate that CS extracts might not induce StAR protein and/or other protein expressions to stimulate steroidogenesis in MA-10 mouse Leydig tumor cells.
  • Fusao KOMADA, Yukiya SAITOH, Haruno KAWABATA, Noriko OHSAKA, Katsuhiko ...
    2000 年 23 巻 12 号 p. 1536-1540
    発行日: 2000/12/01
    公開日: 2008/04/10
    ジャーナル フリー
    In the present study, the levels of SOD activity and Cu, Zn-SOD mRNA in the brain, kidney, liver and eye of normal and Upjohn Pharmaceutics Limited (UPL) rats, a new hereditary cataract model derived from Sprague-Dawley rats, were measured. Although the levels of SOD activity in the eye and brain of UPL rats were significantly decreased compared with those of normal rats 3 and 5 weeks after birth, the levels of SOD activities in the kidney and liver were the same in both groups. The levels of Cu, Zn-SOD mRNA in kidney and liver of UPL rats were the same as those of normal controls. The level of Cu, Zn-SOD mRNA in the brain of normal rats 5 weeks after birth was about twofold greater than that of UPL, and that it the eye of UPL rats 3 weeks after birth was significantly decreased compared with that of normal controls. The sequences of cDNA encoding Cu, Zn-SOD and the sequences of the regulatory region of the Cu, Zn-SOD gene were confirmed to be same in normal and UPL rats.These results indicated that the decreases in levels of SOD activity and Cu, Zn-SOD mRNA in the brain and eye of UPL rat were not due to mutation of the genomic Cu, Zn-SOD gene in UPL rats of differences in the sequence of the regulatory region of the Cu, Zn-SOD gene between normal and UPL rats.
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