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Zen Itoh - One of the best experts on this subject based on the ideXlab platform.

  • characterization of multinuclear hepatocytes induced in rats by mitemcinal gm 611 an Erythromycin Derivative
    Toxicologic Pathology, 2008
    Co-Authors: Shuji Hayashi, Zen Itoh, Etsuko Fujii, Atsuhiko Kato, Kazuya Kimura, Keiji Mizoguchi, Masami Suzuki, Tetsuro Sugimoto, Hisanori Takanashi, Satoshi Omura
    Abstract:

    Mitemcinal is an Erythromycin Derivative with motilin agonistic action, developed as a gastrointestinal motor-activating agent. The characteristics of mitemcinal-induced multinuclear hepatocytes (MNHs, hepatocytes with three or more nuclei per cell) from detailed morphological observations together with the results of a study on the mechanisms of MNH formation by combining cytocentrifuge preparations with 5-bromo-2'-deoxyuridine cumulative labeling are reported. MNHs were observed only in rats in the high-dose groups of the subchronic study, with a higher incidence in females and reversibility after twenty-eight days of drug withdrawal, but not observed in dogs. In the chronic study, the incidence increased relative to the dose. Histopathologically, MNHs were preferentially observed in the centrilobular zone, without nuclear atypia or mitotic figures. In the cell kinetic study, the labeling pattern of MNHs included all-positive, all-negative, and mixed labeling patterns of nuclei. The all-negative pattern indicated that the cells were formed by fusion of nondividing cells. The current results indicate that the cell kinetic approach effectively demonstrated the mechanism of mitemcinal-induced MNHs as fusion of hepatocytes and that drug-induced disturbance of mitosis is not involved in the multinucleation of MNHs by mitemcinal.

  • em574 an Erythromycin Derivative improves delayed gastric emptying of semi solid meals in conscious dogs
    European Journal of Pharmacology, 2000
    Co-Authors: Fumihiko Sako, Zen Itoh, Shogo Marui, Nobuhiro Inatomi, Satoshi ōmura
    Abstract:

    The gastroprokinetic effects of de(N-methyl)-N-isopropyl-8,9-anhydroErythromycin A 6,9-hemiacetal (EM574), a non-peptide motilin receptor agonist, were investigated in conscious dogs in a normal state and with experimentally-induced gastroparesis. Gastric emptying of semi-solid meals was assessed indirectly from acetaminophen absorption with simultaneous recording of gastric antral motility. In the normal state, post-prandial intraduodenal administration of EM574 (30 mg/kg) stimulated antral motility and significantly enhanced gastric emptying as potently as did intravenous porcine motilin (0.003 mg/kg/h). Intraduodenal cisapride at 1 mg/kg denal cisapride at 1 mg/kg elicited antral contractions and tended to accelerate gastric emptying but at 3 mg/kg, gastric emptying was not enhanced despite a further increase in the motor index. In dogs with gastroparesis induced by intraduodenal oleic acid or intravenous dopamine, EM574 (0.03 mg/kg) increased antral motility and reversed the delayed gastric emptying completely. Cisapride (1 mg/kg) partially ameliorated the impaired emptying under these conditions. In atropinized dogs, no acceleration of gastric emptying by EM574 was observed. These results indicate that EM574 potently accelerates gastric emptying of caloric meals in dogs in a normal state and with experimentally-induced gastroparesis, and also suggest that the effect is mediated through stimulation of a cholinergic neural pathway.

  • em574 an Erythromycin Derivative is a motilin receptor agonist in the rabbit
    European Journal of Pharmacology, 1997
    Co-Authors: Fumihiko Sato, Zen Itoh, Masahiro Sekiguchi, Shogo Marui, Nobuhiro Inatomi, Akio Shino, Satoshi ōmura
    Abstract:

    Abstract This study was performed to examine whether an Erythromycin Derivative, de( N -methyl)- N -isopropyl-8,9-anhydroErythromycin A 6,9-hemiacetal (EM574) is a motilin receptor agonist in the rabbit gastrointestinal tract. EM574 and porcine motilin induced contractions in segments of isolated rabbit intestine with pEC 50 values of 8.26±0.04 and 8.69±0.07, respectively, but not in rat or guinea pig preparations. The sensitivity and efficacy of the response to both compounds in rabbits decreased aborally and was insensitive to pretreatment with atropine or tetrodotoxin, but was markedly suppressed under Ca 2+ -free conditions. EM574 and porcine motilin specifically displaced [ 125 I-Tyr 23 ]canine motilin bound to gastric antral smooth muscle homogenates with pIC 50 values of 8.21±0.13 and 9.20±0.11, respectively. The pEC 50 value for the contractile response and pIC 50 value for the receptor binding for motilin, EM574, Erythromycin A and three other Derivatives correlated well ( r =0.94, P

  • vagus dependent and vagus independent mechanisms of action of the Erythromycin Derivative em574 and motilin in dogs
    Japanese Journal of Pharmacology, 1996
    Co-Authors: Nobuhiro Inatomi, Zen Itoh, Fumihiko Sato, Shogo Marui, Satoshi Omura
    Abstract:

    The motor-stimulating action of de(N-methyl)-N-isopropyl-8,9-anhydroErythromycin A 6,9-hemiacetal (EM574) on the upper gastrointestinal tract was studied in fasted conscious dogs using chronically implanted force transducers and compared with those of porcine motilin and cisapride. EM574 induced gastric phase III-like migrating contractions and increased the plasma motilin levels slightly. The gastric motility induced by low doses of EM574 and motilin was abolished by a 5HT3-receptor antagonist ondansetron and acute vagal blockade, whereas under these conditions, high doses of both agents induced contractions, which were abolished by atropine. Cisapride-induced gastric motility was inhibited by atropine and acute vagal blockade, but not by ondansetron. EM574 did not stimulate gastric secretion in the basal state. These results indicate that EM574- and motilin-induced gastrointestinal motility is attributable mainly to motor-stimulating vagal cholinergic neurons, and 5HT3-receptors are probably involved in the process. At high doses, EM574 and motilin also appear to stimulate cholinergic neurons in a non-vagal pathway, probably the enteric nervous system.

  • em574 an Erythromycin Derivative is a potent motilin receptor agonist in human gastric antrum
    Journal of Pharmacology and Experimental Therapeutics, 1994
    Co-Authors: Minoru Satoh, Takafumi Sakai, Zen Itoh, I Sano, Keiko Fujikura, Haruko Koyama, Kihachi Ohshima, Satoshi Omura
    Abstract:

    Erythromycin and its Derivatives are known to induce phase III-like contractions, which are similar to those induced by motilin, in the human gastrointestinal tract during the interdigestive state, but few detailed in vitro studies have been reported. We evaluated EM574, an Erythromycin Derivative, as a motilin receptor agonist in the human gastric antrum in vitro, using contraction studies of muscle strips and isolated myocytes, receptor binding assay and tissue section autoradiography. EM574 stimulated contractions of muscle strips in a concentration-dependent manner (10(-7)-10(-5) M), and this contractile effect was unaffected by pretreatment with atropine or tetrodotoxin. Isolated myocytes contracted in response to EM574 with a peak shortening at 10(-7) M, which was comparable to the response to motilin. EM574 displaced specifically 125I-motilin bound to smooth muscle homogenates with a Kd value of 7.8 x 10(-9) M, compared with 4.5 x 10(-9) M for motilin. Film autoradiograms showed that 125I-motilin-binding sites were localized in the muscle layers, and that the labeling disappeared in the presence of a 1000 times molar concentration of EM574. We conclude that EM574 directly stimulates smooth muscle cell contraction by acting on motilin receptors in the human gastric antrum in vitro.

Satoshi Omura - One of the best experts on this subject based on the ideXlab platform.

  • characterization of multinuclear hepatocytes induced in rats by mitemcinal gm 611 an Erythromycin Derivative
    Toxicologic Pathology, 2008
    Co-Authors: Shuji Hayashi, Zen Itoh, Etsuko Fujii, Atsuhiko Kato, Kazuya Kimura, Keiji Mizoguchi, Masami Suzuki, Tetsuro Sugimoto, Hisanori Takanashi, Satoshi Omura
    Abstract:

    Mitemcinal is an Erythromycin Derivative with motilin agonistic action, developed as a gastrointestinal motor-activating agent. The characteristics of mitemcinal-induced multinuclear hepatocytes (MNHs, hepatocytes with three or more nuclei per cell) from detailed morphological observations together with the results of a study on the mechanisms of MNH formation by combining cytocentrifuge preparations with 5-bromo-2'-deoxyuridine cumulative labeling are reported. MNHs were observed only in rats in the high-dose groups of the subchronic study, with a higher incidence in females and reversibility after twenty-eight days of drug withdrawal, but not observed in dogs. In the chronic study, the incidence increased relative to the dose. Histopathologically, MNHs were preferentially observed in the centrilobular zone, without nuclear atypia or mitotic figures. In the cell kinetic study, the labeling pattern of MNHs included all-positive, all-negative, and mixed labeling patterns of nuclei. The all-negative pattern indicated that the cells were formed by fusion of nondividing cells. The current results indicate that the cell kinetic approach effectively demonstrated the mechanism of mitemcinal-induced MNHs as fusion of hepatocytes and that drug-induced disturbance of mitosis is not involved in the multinucleation of MNHs by mitemcinal.

  • vagus dependent and vagus independent mechanisms of action of the Erythromycin Derivative em574 and motilin in dogs
    Japanese Journal of Pharmacology, 1996
    Co-Authors: Nobuhiro Inatomi, Zen Itoh, Fumihiko Sato, Shogo Marui, Satoshi Omura
    Abstract:

    The motor-stimulating action of de(N-methyl)-N-isopropyl-8,9-anhydroErythromycin A 6,9-hemiacetal (EM574) on the upper gastrointestinal tract was studied in fasted conscious dogs using chronically implanted force transducers and compared with those of porcine motilin and cisapride. EM574 induced gastric phase III-like migrating contractions and increased the plasma motilin levels slightly. The gastric motility induced by low doses of EM574 and motilin was abolished by a 5HT3-receptor antagonist ondansetron and acute vagal blockade, whereas under these conditions, high doses of both agents induced contractions, which were abolished by atropine. Cisapride-induced gastric motility was inhibited by atropine and acute vagal blockade, but not by ondansetron. EM574 did not stimulate gastric secretion in the basal state. These results indicate that EM574- and motilin-induced gastrointestinal motility is attributable mainly to motor-stimulating vagal cholinergic neurons, and 5HT3-receptors are probably involved in the process. At high doses, EM574 and motilin also appear to stimulate cholinergic neurons in a non-vagal pathway, probably the enteric nervous system.

  • em574 an Erythromycin Derivative is a potent motilin receptor agonist in human gastric antrum
    Journal of Pharmacology and Experimental Therapeutics, 1994
    Co-Authors: Minoru Satoh, Takafumi Sakai, Zen Itoh, I Sano, Keiko Fujikura, Haruko Koyama, Kihachi Ohshima, Satoshi Omura
    Abstract:

    Erythromycin and its Derivatives are known to induce phase III-like contractions, which are similar to those induced by motilin, in the human gastrointestinal tract during the interdigestive state, but few detailed in vitro studies have been reported. We evaluated EM574, an Erythromycin Derivative, as a motilin receptor agonist in the human gastric antrum in vitro, using contraction studies of muscle strips and isolated myocytes, receptor binding assay and tissue section autoradiography. EM574 stimulated contractions of muscle strips in a concentration-dependent manner (10(-7)-10(-5) M), and this contractile effect was unaffected by pretreatment with atropine or tetrodotoxin. Isolated myocytes contracted in response to EM574 with a peak shortening at 10(-7) M, which was comparable to the response to motilin. EM574 displaced specifically 125I-motilin bound to smooth muscle homogenates with a Kd value of 7.8 x 10(-9) M, compared with 4.5 x 10(-9) M for motilin. Film autoradiograms showed that 125I-motilin-binding sites were localized in the muscle layers, and that the labeling disappeared in the presence of a 1000 times molar concentration of EM574. We conclude that EM574 directly stimulates smooth muscle cell contraction by acting on motilin receptors in the human gastric antrum in vitro.

  • effect of Erythromycin Derivative em523l on human interdigestive gastrointestinal tract
    Digestive Diseases and Sciences, 1993
    Co-Authors: Zen Itoh, Satoshi Omura, Osamu Kawamura, Toshikazu Sekiguchi
    Abstract:

    We investigated the effect of an Erythromycin Derivative, EM523L, on interdigestive gastrointestinal motor activity and plasma motilin concentrations in three healthy volunteers using an infused catheter system. We administered doses of 500, 1000, and 2000 μg of EM523L to each subject as well as physiological saline. EM523L induced interdigestive migrating contractions (IMCs) that originated in the stomach and migrated to the duodenum. This response was noted in all three subjects after each dose of EM523L, while no IMCs were induced by saline. There were no significant differences in the characteristics of the EM523L-induced IMC and the spontaneous IMC. The initiation time, ie, the interval between the start of EM523L infusion and the onset of the IMC became shorter in a dose-dependent manner. Plasma motilin concentrations increased significantly after EM523L administration, suggesting that motilin is involved in the mechanism of IMC induction by this drug.

  • comparison of the motor stimulating action of em523 an Erythromycin Derivative and prostaglandin f2α in conscious dogs
    Japanese Journal of Pharmacology, 1993
    Co-Authors: Nobuhiro Inatomi, Zen Itoh, Hiroshi Satoh, Takashi Satoh, Satoshi Omura
    Abstract:

    The effect of EM523 [de(N-methyl)-N-ethyl-8, 9-anhydroErythromycin A 6, 9-hemiacetal], an Erythromycin Derivative, on gastrointestinal motility was investigated using conscious dogs in the fasting state, and it was compared with those of motilin and prostaglandin F2α (PGF2α). EM523 and motilin given as i.v. infusions induced strong contractions in the stomach that migrated along the intestine. On the other hand, PGF2α stimulated intestinal contractions, but its effect on gastric motility was weak. EM523 had 1/50 the potency of motilin and 6 times the potency of PGF2α for stimulation of intestinal motility. Atropine at 0.1 mg/kg, i.v. strongly inhibited gastrointestinal contractions induced by EM523 or motilin and partly inhibited PGF2α-induced intestinal motility. ICS-205-930, a 5HT3-receptor antagonist, at a dose of 1 mg/kg, i.v. strongly inhibited EM523 or motilin-induced gastric contractions but did not affect the action of PGF2α. Infusion of EM523 at 100 μg/kg/hr induced strong migrating contractions even when motility was depressed by dopamine infusion or laparotomy. Infusion of PGF2α at 300 μg/kg/hr stimulated intestinal but not gastric motility under these conditions. The results of this study indicate that the cholinergic pathway and 5HT3 receptors are involved in EM523 and motilin-induced migrating gastrointestinal contractions, whereas the cholinergic pathway seems to be only partly involved in PGF2α-induced intestinal contractions.

Satoshi ōmura - One of the best experts on this subject based on the ideXlab platform.

  • em574 an Erythromycin Derivative improves delayed gastric emptying of semi solid meals in conscious dogs
    European Journal of Pharmacology, 2000
    Co-Authors: Fumihiko Sako, Zen Itoh, Shogo Marui, Nobuhiro Inatomi, Satoshi ōmura
    Abstract:

    The gastroprokinetic effects of de(N-methyl)-N-isopropyl-8,9-anhydroErythromycin A 6,9-hemiacetal (EM574), a non-peptide motilin receptor agonist, were investigated in conscious dogs in a normal state and with experimentally-induced gastroparesis. Gastric emptying of semi-solid meals was assessed indirectly from acetaminophen absorption with simultaneous recording of gastric antral motility. In the normal state, post-prandial intraduodenal administration of EM574 (30 mg/kg) stimulated antral motility and significantly enhanced gastric emptying as potently as did intravenous porcine motilin (0.003 mg/kg/h). Intraduodenal cisapride at 1 mg/kg denal cisapride at 1 mg/kg elicited antral contractions and tended to accelerate gastric emptying but at 3 mg/kg, gastric emptying was not enhanced despite a further increase in the motor index. In dogs with gastroparesis induced by intraduodenal oleic acid or intravenous dopamine, EM574 (0.03 mg/kg) increased antral motility and reversed the delayed gastric emptying completely. Cisapride (1 mg/kg) partially ameliorated the impaired emptying under these conditions. In atropinized dogs, no acceleration of gastric emptying by EM574 was observed. These results indicate that EM574 potently accelerates gastric emptying of caloric meals in dogs in a normal state and with experimentally-induced gastroparesis, and also suggest that the effect is mediated through stimulation of a cholinergic neural pathway.

  • em574 an Erythromycin Derivative is a motilin receptor agonist in the rabbit
    European Journal of Pharmacology, 1997
    Co-Authors: Fumihiko Sato, Zen Itoh, Masahiro Sekiguchi, Shogo Marui, Nobuhiro Inatomi, Akio Shino, Satoshi ōmura
    Abstract:

    Abstract This study was performed to examine whether an Erythromycin Derivative, de( N -methyl)- N -isopropyl-8,9-anhydroErythromycin A 6,9-hemiacetal (EM574) is a motilin receptor agonist in the rabbit gastrointestinal tract. EM574 and porcine motilin induced contractions in segments of isolated rabbit intestine with pEC 50 values of 8.26±0.04 and 8.69±0.07, respectively, but not in rat or guinea pig preparations. The sensitivity and efficacy of the response to both compounds in rabbits decreased aborally and was insensitive to pretreatment with atropine or tetrodotoxin, but was markedly suppressed under Ca 2+ -free conditions. EM574 and porcine motilin specifically displaced [ 125 I-Tyr 23 ]canine motilin bound to gastric antral smooth muscle homogenates with pIC 50 values of 8.21±0.13 and 9.20±0.11, respectively. The pEC 50 value for the contractile response and pIC 50 value for the receptor binding for motilin, EM574, Erythromycin A and three other Derivatives correlated well ( r =0.94, P

Retno S. Sudibyo - One of the best experts on this subject based on the ideXlab platform.

  • Biosintesis A6\u277-AnhidroeritromisinMelalui Penghambatan Reduksi Enoil Oleh Isoniazid Pada FERMENTASI Saccharopolyspora erythraea ATCC 11635
    [Yogyakarta] : Universitas Gadjah Mada, 2003
    Co-Authors: Retno Arianingrum, Umar A. Jenie, Retno S. Sudibyo
    Abstract:

    ABSTRACT The biosynthesis of new Erythromycin Derivative has been carried out by adding of isoniazid (INH) into fermentation of Saccharopolyspora erythraea ATCC 11635. INH was added to inhibit the enoyl-reduction process in the fourth step of 6- deoxyerythronolid B (6-DEB) biosynthesis, so in the last process was expected to produce Av-anhydroErythromycin which more stable in acidic condition than Erythromycin. The isolating new metabolites: A-KG was obtained from the shake fermentation with additional INHwhile B-F and D-F were from the fermentor with additional INH. The optimum concentration of additional INH was 0,2%. Based on the FT-IR spectrograms analysis, it was indicated that the B-F and D-F were Erythromycin Derivatives which have a C=C bond at 06,2 position. This bond is possible to form a conjugation system which result in an enol-form of C=0 at C-9. These new metabolite kept on having acid stability and antibiotic activity in lower pH up to 3which were much better than those of Erythromycin A. Key words: isoniazid, enoyl reduction, Sacchapolyspora erythraea ATCC 11635, d6,7-anhydroerythromyci

  • Analysis of acid resistance of 6,6\u277-anhydroErythromycin D using FT-IRFT-IR spectrometric approach and microbial test
    [Yogyakarta] : Universitas Gadjah Mada, 1999
    Co-Authors: Retno S. Sudibyo, Umar A. Jeniel, Winarto Haryadi
    Abstract:

    c16-7-AnhydroErythromycin D has been resulted from fermentation of Saccharopolyspora erythraea ATCC 11912 with additional isonicotinic hydrazide (INH) in order to produce an acidic resistant Erythromycin Derivative. The acid resistance analysis was carried out to the product, in series of pH, using FT-IR spectrometric approach and microbial test. The IR spectrogram showed the stability of the appearance of Câ-carbonyl group of the product under acidic condition (pH 3-5). This results were supported by the microbial tests. Keywords: Ab.7-AnhydroErythromycin D - FTIR-spectrophotometric analysis - Microbial test

Perpustakaan Ugm I-lib - One of the best experts on this subject based on the ideXlab platform.