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Biomedical subjects

K Ohata

Publications and source records attributed to K Ohata.

At least 91 records · Page 5Linked to original sources
PubMed1988

Lack of involvement of leukotriene and platelet activating factor in passive cutaneous anaphylaxis in rats.

Possible chemical mediators contributing to 48 hour passive cutaneous anaphylaxis (PCA) in rats were investigated. Forty-eight hour PCA was inhibited considerably by mepyramine and methysergide given intravenously, a finding suggestive of a major role for histamine and serotonin in the reaction. AA-861, a selective 5-lipoxygenase inhibitor did not inhibit the PCA, and leukotriene (LT)D4 or LTE4 and the combination with prostaglandin (PG)E2 had no significant skin reaction. In addition, only small amounts of slow reacting substance of anaphylaxis (SRS-A) were detected in skin fragments, in vitro. Although CV-3988, a selective platelet activating factor (PAF) antagonist, dose-dependently inhibited the PAF-induced skin reaction, the PCA was not affected by treatment with this compound. Indomethacin also had no inhibitory activity on PCA. Thus, sulfidopeptide LTs, PAF and arachidonate cyclooxygenase metabolites probably do not contribute to PCA, at least in rats.

Animals↗
PubMed1988

[Antiallergic effects of mequitazine. 1. In vitro experiments].

The antiallergic effects of 10-(3-quinuclidinylmethyl)phenothiazine (mequitazine) were investigated in vitro. The results obtained were as follows: 1) In the isolated trachea and lung parenchyma of guinea pigs, mequitazine showed a fairly potent antagonistic action against contractions induced by both histamine (Hi) and acetylcholine (ACh). Mequitazine was much less potent in antihistaminic action and slightly more potent in anticholinergic action than ketotifen. The contractions of the preparation by leukotriene (LT) D4 were antagonized by mequitazine, although the potency was moderate, showing an IC50 value of 2.3 x 10(-5) g/ml in the trachea and 5.1 x 10(-5)g/ml in the lung parenchyma. Mequitazine had no effect on the contraction of the trachea by PGF2 alpha, but inhibited that of the lung parenchyma with pA2 = 7.0. 2) Mequitazine (10(-6) g/ml) slightly inhibited the Schultz-Dale reaction of the isolated guinea pig trachea, while ketotifen at the same concentration did not show any effect. 3) The contraction of the isolated guinea pig trachea by Ca2+ influx was slightly inhibited by mequitazine (10(-5) g/ml). 4) Mequitazine competitively inhibited the cyclic AMP-dependent phosphodiesterase activity from the rat lung with a potency of 10 times and 5 times more than those of ketotifen and theophylline, respectively. 5) Mequitazine (10(-6) to 10(-5) M) suppressed both the anaphylactic and phospholipase A2-induced histamine release from the peritoneal cells of rats. 6) Mequitazine (10(-5) g/ml) also inhibited the anaphylactic and Ca ionophore-induced histamine release from the leukocytes of the atopic patients and normal subjects. 7) The anaphylactic releases of histamine, LTB4 and peptide LT from the human lung fragments were dose-dependently inhibited by mequitazine (10(-7) approximately 10(-5) g/ml).

Acetylcholine↗
PubMed1988

[Antiallergic effects of mequitazine. 2. In vivo experiments].

Antiallergic effects of mequitazine were investigated in vivo and compared with those of ketotifen and disodium cromoglycate (DSCG). The results obtained were as follows: 1) Mequitazine in doses of 2 and 5 mg/kg given, p.o., 1 hr prior to antigen challenge inhibited dose-dependently the 48-hr passive cutaneous anaphylaxis in rats. Five mg/kg of mequitazine showed almost the same extent of inhibitory activity as that of 1 mg/kg of ketotifen. An i.v. administration of 1 mg/kg DSCG 1 min before antigen challenge also showed a marked inhibition. 2) The experimental asthma induced by challenge with an i.v. injection of antigen in passively sensitized guinea pigs was fairly inhibited by the pretreatment with 5 mg/kg of mequitazine administered p.o., although 2 mg/kg of this drug showed only a slight inhibition. 3) The experimental asthma induced by aerosolized antigen was also fairly inhibited by the pretreatment with 5 mg/kg of mequitazine given p.o.

Administration, Oral↗
PubMed1988

[Pharmacological studies on the clathrate compound of mobenzoxamine with beta-cyclodextrin. (I). Effects on the digestive system].

Effects of the clathrate compound of mobenzoxamine (MBX) with beta-cyclodextrin (MBX-CD), a new gastro-intestinal function modulator, on the digestive system were studied in comparison with those of metoclopramide, domperidone and trimebutine. MBX-CD showed inhibitory effects that were approximately 1/4 times as potent as metoclopramide on both apomorphine- and copper sulfate-induced emesis and about 1/40 times as potent as domperidone on apomorphine-induced emesis in dogs. In rats, MBX-CD enhanced gastric emptying as potently as metoclopramide, and only MBX-CD showed a clear amelioration of the delayed gastric emptying induced by BaCl2. Similarly, only MBX-CD showed an ameliorative effect on small intestinal transport accelerated by BaCl2 in mice. Though both MBX and trimebutine inhibited spontaneous contractions of the isolated guinea pig stomach and rabbit intestine, it seemed that the properties of these effects were different from those of papaverine. On isolated guinea pig ileum, MBX inhibited contractions induced by various agonists equally to or more potently than trimebutine or papaverine. The results suggest that MBX-CD or MBX acts extensively on the gastro-intestinal system for the reason that it has not only the respective properties of the gastro-intestinal function modulators used as the standards, but also its own characteristic effects.

Animals↗
PubMed1988

Effect of AA-861, a selective 5-lipoxygenase inhibitor, on models of allergy in several species.

The effects of 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA-861), a selective 5-lipoxygenase inhibitor, on immunological or non-immunological release of slow reacting substance of anaphylaxis (SRS-A) and histamine and its effects on experimental asthma were investigated. AA-861 showed a dose-dependent inhibition of SRS-A release, with no effect on histamine release from passively sensitized guinea pig, monkey (M. irus) and human lung fragments. An analysis of the anaphylactic diffusate from the human lung fragments, using the combined technique of high performance liquid chromatography and radioimmunoassay, revealed that AA-861 markedly suppresses biosynthesis of the leukotrienes. However, this drug inhibits the release of histamine as well as SRS-A from lung fragments of anaphylactic monkey (M. mulatta) and in the Ca ionophore-stimulated rat peritoneal cavity. AA-861 suppressed the anaphylactically-induced airway resistance in mepyramine- and cimetidine-treated guinea pigs. These results suggest that AA-861 may be clinically effective for treating allergy-related asthma by modulating the 5-lipoxygenase pathway and that an inhibitory mechanism of histamine release by AA-861 may be present in some species.

Animals↗
PubMed1987

Down-regulation of central serotonin S2 receptors after repeated treatment with quinupramine in rats.

The present studies were undertaken to determine whether the repeated administration of quinupramine caused down- or up-regulation of beta-, alpha 2-adrenergic, serotonin S2, imipramine and muscarinic cholinergic receptors, as had been demonstrated for tricyclic and atypical antidepressant drugs. Quinupramine administered at 10 mg/kg (p.o.) twice daily for 10 days caused a down-regulation of serotonin S2 receptors in the frontal cortex of the rat as determined by [3H]ketanserin binding. However, quinupramine did not alter the binding populations of beta-adrenergic, muscarinic cholinergic and alpha 2-adrenergic receptors in the rat brain as determined by the Scatchard analysis of the [3H]ligand binding data. Differing from quinupramine, imipramine caused down-regulation of beta-adrenergic and serotonin S2 receptor bindings, and it caused slight but significant up-regulation of muscarinic cholinergic receptor bindings. These results show that the antidepressant activity of quinupramine is associated with the central serotonin system, but not with the beta-adrenergic system. Accordingly, quinupramine, chemically one of the typical tricyclic antidepressant drugs, seems to be pharmacologically one of the atypical antidepressant drugs, and it was suggested that the central serotonin system plays an important role in the antidepressant activity of quinupramine.

Animals↗
PubMed1987

Effect of butyl 3-(1H-tetrazol-5-Yl) oxanilate (MTB) on immunological or non-immunological histamine and SRS(-A) release from guinea-pig, monkey and human lung tissue.

We investigated the influence of butyl 3-(1H-tetrazol-5-yl) oxanilate (MTB) on the release of histamine and slow reacting substance of anaphylaxis (SRS-A) in vitro. MTB dose-dependently inhibited the release of not only histamine but also SRS-A from passively sensitized guinea-pig lung, while disodium cromoglycate (DSCG) hardly affected either release. MTB also resulted in a dose-dependent inhibition of the release of these mediators from the passively sensitized cynomolgus and rhesus monkey and that from human lung at concentrations similar to those inhibiting the release in the guinea-pig. Relatively lower inhibitory activities on the releases of both mediators from the cynomolgus monkey and human lung, but no effects on those from the rhesus monkey were observed with DSCG. MTB dose-dependently inhibited only SRS release from guinea-pig lung induced by phospholipase A2, although the compound did not show any inhibitory activity on the release of those from the calcium ionophore (A23187)-stimulated one. On the other hand, the release of SRS, but not that of histamine from the lung stimulated with A23187 as well as phospholipase A2 was inhibited by N-(3,4-dimethoxycinnamoyl)-anthranilic acid (tranilast, N-5'). From these results, MTB was a potent inhibitor of the anaphylactic release of the mediators, particularly SRS-A. It was suggested that the inhibitory mechanism of MTB is different from those of DSCG and N-5'.

Animals↗
PubMed1987

Effects of quinupramine on the central monoamine uptake systems and involvement of pharmacokinetics in its pharmacological activities.

The effects of a new tricyclic antidepressant drug, quinupramine, on the monoamine uptake of rat brain homogenate preparations were studied in comparison with imipramine. Pharmacokinetic studies on quinupramine and imipramine in plasma and brain were also performed in rats after a single oral administration. Quinupramine had few effects on the noradrenaline and serotonin uptake both in in vitro and ex vivo models. After the administration of [3H]quinupramine, the unchanged drug was estimated as 60-75% of the total radioactivity in the cerebral cortex. Imipramine and desipramine preferentially inhibited the uptake of serotonin and noradrenaline, respectively, in vitro. After the administration, imipramine showed a marked inhibitory effect on noradrenaline uptake. A considerable amount of desipramine but not imipramine could be detected in the brain and plasma after the administration of [3H]imipramine. These results demonstrate that 1) the antidepressant activity of quinupramine cannot be attributed to inhibition of monoamine uptake, 2) unchanged quinupramine penetrates into the CNS and affects some of the processes of neurotransmission and 3) the pharmacological activities of imipramine, when administered orally, may be attributed to desipramine, the metabolite formed.

Animals↗
PubMed1987

Binding characteristics of [3H]quinupramine to rat brain membrane fractions.

The binding characteristics of [3H]quinupramine to rat brain membrane fractions were studied. The specific binding of [3H]quinupramine to rat brain membrane fractions was stable, reversible and saturable. Scatchard analysis of the data from saturation experiments indicated that the specific binding was a single population with an affinity (KD) of 3.04 nM, a maximal binding site number (Bmax) of 714 fmol/mg protein, and a Hill coefficient (nH) of 1.08. Compounds known to inhibit muscarinic cholinergic receptors such as atropine and quinuclidinyl benzilate were the most potent competitors of [3H]quinupramine binding. When the drug potencies in inhibiting [3H]quinupramine binding were tested in the presence of 10 nM atropine, mianserin was the most potent competitor. Studies of the subcellular fractions showed that there was an enrichment of [3H]quinupramine binding sites in the synaptosome fraction. The regional distribution study revealed the highest densities of binding sites in the cerebral cortex and the lowest in the cerebellum. Thus, the specific binding of [3H]quinupramine observed here can be accounted for by both muscarinic cholinergic and serotonin S2 receptors.

Animals↗
PubMed1986

Syntheses of 5,6,7- and 5,7,8-trioxygenated 3',4'-dihydroxyflavones having alkoxy groups and their inhibitory activities against arachidonate 5-lipoxygenase.

Arachidonate 5-lipoxygenase plays a pivotal role in the biosynthesis of leukotrienes. Cirsiliol (3',4',5-trihydroxy-6,7-dimethoxyflavone), a selective inhibitor of the enzyme, was derivatized by introducing alkyl groups of various chain lengths at positions 5, 6, 7, and 8 of the A ring of the flavone skeleton. Modification of the positions 5 and 6 with an alkyl group of 5-10 carbons markedly decreased the IC50 values for 5-lipoxygenase inhibition to the order of 10 nM. As tested with 5- or 6-hexyloxy derivatives, a relatively selective inhibition of 5-lipoxygenase was shown. Inhibition of 12-lipoxygenase required much higher concentrations of these compounds, and cyclooxygenase was not inhibited. Modification of positions 7 and 8 did not increase the inhibitory effect of most flavone compounds.

Arachidonate Lipoxygenases↗
PubMed1986

Effects of the new antiallergic drug 11-oxo-11H-pyrido[2,1-b] quinazoline-2-carboxylic acid on type I allergic reactions.

Antiallergic effects of the newly synthesized, quinazoline derivative 11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid (Sm 857) were investigated. The following results were obtained. 1. Anaphylactic and non-immunologic histamine and slow reacting substance of anaphylaxis (SRS-A) release from guinea pig lung fragments was dose-dependently inhibited by 10(-6)-10(-4) and 10(-7) -10(-4) g/ml of Sm 857, respectively. Similar inhibition of the mediator release by the compound was obtained from the experiments of passively sensitized monkey and human lung fragments by antigen. 2. Seven-day passive cutaneous anaphylaxis of guinea pigs was not inhibited at 1-20 mg/kg (i.v.) of Sm 857, but inhibited at 20-100 mg/kg (p.o.) in some experiments without dose dependency. 3. Cutaneous anaphylaxis and histamine-induced cutaneous reaction in guinea pigs were hardly affected by the treatment of 50 and 100 mg/kg (p.o.) of Sm 857. 4. Passive systemic anaphylaxis in guinea pigs was not inhibited at 50-200 mg/kg (p.o.) of Sm 857. 5. Arthus reaction in rabbits was slightly and dose-dependently enhanced at 50-200 mg/kg given twice p.o. 6. Sm 857 (10(-6)-10(-4) g/ml) exhibited antispasmogenic activity against histamine and leukotriene D4 in isolated human bronchi and guinea pig trachea, however, this activity is attributable to non-specific musculotropic smooth muscle relaxation. From these results it may be concluded that Sm 857 exerts preferential effect on the respiratory system and that it might be useful in allergic asthma.

Animals↗