Postprandial hypoglycaemia due to insulin lispro.
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Biomedical subjects
Publications and source records attributed to E Hosoya.
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The Kampo (Japanese herbal) medicine "Juzen-Taiho-To" (TJ-48), which was prepared by decocting a concoction (formula), contains ten kinds of herbs and has several immunostimulating activities. In order to determine the contribution of each herbal component, the complement-activating and mitogenic activities of the hot water extract as well as the polysaccharide fraction from each herb were tested. Hot water extracts of Glycyrrhizae radix, Astragali radix, and Atractylodes lanceae rhizoma showed significant mitogenic activity whereas that of Cinnamomi cortex showed potent complement-activating activity. However, the exclusion of any single component herb whether active or not on its own did not result in a loss or an increase of the overall activity of TJ-48. The polysaccharide fraction from Glycyrrhizae radix showed the most potent of both activities among the same fractions from the other nine herbs, and reduced both activities after periodate oxidation, thus indicating that the carbohydrate moiety may contribute to both activities.
We studied the effect of TJN-101, a lignan component of Schisandra fruits (Schisandrae fructus), on liver regeneration after partial hepatectomy. TJN-101 was given orally to male Wistar rats 30 min before partial hepatectomy. The mitotic index and the level of DNA synthesis increased after partial hepatectomy and their increase was significantly enhanced by TJN-101. Ornithine decarboxylase (ODC) activity increased in the early stages of liver regeneration and it was also significantly enhanced by TJN-101. Besides, TJN-101 enhanced the increase in hepatic putrescine. These results suggest that TJN-101 stimulates liver regeneration after partial hepatectomy by enhancing ODC activity, which is an important biochemical event in the early stages of liver regeneration.
The acidic polysaccharide fraction (F-5-2) from "Juzen-Taiho-To" (TJ-48), a Kampo (Japanese herbal) medicine prepared by decocting a prescription of 10 kinds of herbs, has potent mitogenic activity. In order to clarify the mitogenic activity, F-5-2 was fractionated by amon-exchange chromatography, and 14 acidic polysaccharide fractions were obtained. Mitogenic activities of these polysaccharides were increasing with their molecular masses and affinities to the anion-exchange column. Methylation analysis and endo-alpha-(1----4)-polygalacturonase digestion showed these polysaccharide fractions to be pectic polysaccharides, many of which consisted mainly of polygalacturonan regions in addition to small amounts of "ramified" regions. Gel filtration showed that the molecular masses of the "ramified" regions of the polysaccharides were similar. High molecular mass polygalacturonic acid showed a weak mitogenic activity. The mitogenic (M-1 and M-2) and non-mitogenic (M-3) polysaccharides from the most active polysaccharide fraction (F-5-2IIh) were further purified by gel filtration. M-2 and M-3 were also shown to be pectic polysaccharides, and the neutral glycosidic linkages in M-2 and M-3 were different from each other. Endopolygalacturonase digestion markedly decreased the mitogenic activity of M-2, however, the "ramified" region of M-2 still showed a weak activity.
Gomisin A (TJN-101) is one of the lignan components isolated from Schisandra Fruits and expected to have some efficacies in clinical treatment of hepatitis. The serum concentrations of TJN-101 and Met. B, which was identified as a demethylenated substance and one of the major metabolites of TJN-101 in rats, were investigated. After intravenous administration at doses of 1.6, 4.0 and 10 mg/kg of body weight, the serum concentration of TJN-101 decreased biphasically, and the terminal elimination half-life at each dose was about 70 min. Dose-dependency was observed for the area under the concentration-time curve (AUC). On the other hand, the serum concentration of TJN-101 increased rapidly and reached maximum within 15 to 30 min when administered orally. This result was supported by the in situ roop method. The Cmax and the AUC values were not exactly dose-dependent, but the values increased with a dose-up of TJN-101. The biotransformation of TJN-101 to Met. B, was very rapid in both intravenous and oral administrations. The AUC value of Met. B after oral administration of TJN-101 at a dose of 1.6 mg/kg was relatively larger than any other dosages. It suggested that TJN-101 was extensively underwent the first pass effect in rats. More than 80% of TJN-101 was bound with rat serum protein in vitro and in vivo. Therefore, it seems to be necessary to pay attention when it was administered concurrently with high protein binding drugs.
The absorption and excretion of gomisin A (TJN-101) in rats whose livers were injured by carbon tetrachloride (CCl4) were investigated. After intravenous administration of TJN-101 at a dose of 5 mg/kg, the terminal elimination half-life was 1.5 h in the CCl4-treated rats, which was two times that in normal rats. The mean area under the blood concentration-time curve (AUC) value of TJN-101 in the CCl4-treated rats was twice that in normal rats, and this difference was significant (p less than 0.05). Therefore, the total body clearance of TJN-101 in the CCl4-treated rats decreased less than half of that in normal rats. Similar results were observed when it was administered orally. In the CCl4-treated rats, the serum concentration of Met. B, which was identified as a demethylenated substance and one of major metabolites, tended to decrease more than that in normal rats. On the other hand, the cumulative biliary excretion ratio of TJN-101 in 24 h after dosing in the CCl4-treated rats was 2.5 times that in normal rats. The excretion rate of Met. B in the bile in the CCl4-treated rats tended to be delayed. However, the quantitative variance of biliary excretion of Met. B was not found in both groups. The urinary excretion of TJN-101 or Met. B in 72 h after dosing in the CCl4-treated rats was lower than that in normal rats. Similar results were also observed in excretion in the feces.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of cycloheximide, a protein synthesis inhibitor, on hippocampal selective neuronal death was morphologically studied in rats subjected to 10 min forebrain ischemia using a 4-vessel occlusion model. Neuronal damage in the hippocampal CA1 subfield 72 h after ischemic insult was dramatically decreased by the lasting inhibition of protein synthesis through consecutive administration of cycloheximide. Cycloheximide, which was administered once within the first 24 h of recirculation, showed protective action on ischemic cell necrosis and its most potent effect was observed when injected at 12 h of post-ischemia. After 36 h of recirculation, however, treatment with cycloheximide could no longer prevent cell death. The possibility is considered that hippocampal delayed neuronal death following transient ischemia is caused by abnormal protein(s).
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"Juzen-Taiho-To" (TJ-48), which is a kampo (Japanese herbal) medicine prepared by decocting a prescription of ten kinds of herbs, has several immunostimulating activities. In order to characterize the active substances for anti-complementary and mitogenic activities, TJ-48 was fractionated. Anti-complementary activity was observed in the water- and methanol-insoluble fraction (F-2) and the crude polysaccharide fraction (F-5), whereas mitogenic activity was only found in F-5. However, other low molecular mass fractions did not show both activities. Methylation analysis indicated that F-2 mainly contained amylopectin-like polysaccharides. Both Pronase digestion and periodate oxidation decreased the anti-complementary activity of F-2, and the beta-amylase-resistant fraction of F-2 still retained the potent anti-complementary activity. When F-5, which has the most potent of both activities, was further fractionated, only the major acidic polysaccharide fraction, F-5-2, showed potent mitogenic activity. Endo-alpha-(1----4)-polygalacturonase digestion showed that F-5-2 mainly contained pectic polysaccharides, and the endo-polygalacturonase treatment of F-5-2 reduced the mitogenic activity but not the anti-complementary activity. F-2 and F-5 each activated the complement system by a different mode of action.
After oral administration of gomisin A (1) to rats, the bile and urine were collected and treated with beta-glucuronidase and arylsulfatase. Seven metabolites, met B (2), met A-III (3), met E (4), met D (5), met F (6), met G (7), and met H (8) were isolated from the bile treated with the enzymes. Eight metabolites 2-8, and met A-II (9) were isolated from the urine treated with the enzymes. A major metabolite 2, and two minor metabolites 3 and 9 were identified as met B, met A-III, and met A-II, respectively, which are oxidative products of 1 formed by rat liver S9 mix. The structures of five new metabolites 4-7, and 8 were determined on the basis of chemical and spectral studies.
It has been reported that leukotrienes (LTs) may play a role in inflammatory liver diseases, and several inhibitors of LTs show an inhibitory effect on experimental liver injuries. In this study, the effect of Gomisin A (TJN-101), which is a lignan component of schisandra fruits, on the arachidonic acid cascade in macrophages was examined to explain the mechanisms of the inhibitory effect of TJN-101 on liver injuries. The production of leukotriene B4 was suppressed by treatment with TJN-101, while the activity of 5-lipoxygenase was not affected. The release of arachidonic acid from macrophages stimulated with fMet-Leu-Phe or the Ca++ ionophore A23187 was suppressed by treatment with TJN-101. The activity of phospholipase A2 was not affected by treatment with TJN-101. These results suggested that TJN-101 produces an inhibitory effect on the biosynthesis of LTs by preventing the release of arachidonic acid, and it was thought that the preventive effect on the arachidonic acid cascade may be partially associated with the inhibitory effect of TJN-101 on liver injuries.
Effects of Juzen-taiho-toh (TJ-48) on the recovery of hemopoietic systems from radiation injury are analyzed. Female C57BL/6N mice (6-8 weeks old) were irradiated at doses of 1, 2, 3, 5, or 7 Gy from a 60Co source. After irradiation, the mice were given TJ-48 (1.25 g in 100 ml drinking water). Seven days after irradiation, the mice were sacrificed, and bone marrow (both femurs), thymus, spleen, and peripheral blood counts were made. The bone marrow cells were used for fibroblast colony-forming unit (CFU-f), spleen colony-forming unit (CFU-S), granulocyte-macrophage colony-forming unit (CFU-GM), erythroid colony-forming unit (CFU-E), and erythroid burst-forming unit (BFU-E) assays. No difference was observed between the experimental and control groups except for CFU-S counts. In the assay for day-14 CFU-S, the mice injected with TJ-48-treated bone marrow cells showed better general condition (including increased body weight) and heavier spleens with larger and more numerous colonies. The effect of TJ-48 does not seem to be elicited via the hemopoietic microenvironment, because mice that had been given TJ-48 before irradiation at 8 Gy and then injected with syngeneic bone marrow cells did not show enhanced day-14 CFU-S counts. These results suggest that TJ-48 manifests a radioprotective effect by increasing the number and size of day-14 CFU-S.
Effects of oral administration of Juzentaihoto, a herb drug, on the toxic side effects of cis-diammine dichloroplatinum (CDDP) and combination effects with CDDP on murine bladder tumor (MBT 2) were studied using C3H/He male mice. The following results were obtained; 1. When the mice were treated with the mixture diet of 1% or 0.5% Juzentaihoto before 2 weeks, adverse effects of high dose CDDP (15 or 17.5 mg/kg) which were included with lethal toxicity, renal and hepatic toxicity, and myelosuppression were protected significantly. The administration of 0.5% Juzentaihoto mixture diet markedly shifted the LD50 to the right. Furthermore, the effects of Juzentaihoto were clearly revealed on the histological findings of testis and kidney. 2. On murine bladder tumor, when the mice were treated with the mixture diet of 1% or 0.5% Juzentaihoto and injected CDDP (2.5 mg/kg/week) for 8 weeks, significantly greater inhibition of the tumor growth and prolongation of the survival rate were observed than those in the group of CDDP alone. These results indicates that Juzentaihoto lessens the toxic side effects of CDDP and that it enhances the effects of CDDP experimentally. Juzentaihoto, a kind of Chinese herb medicine, might come under the category of biological response modifiers.
It has been demonstrated that TJ-8007 (Tsumura-Zokumeito, A traditional Chinese medicine) has a protective effect against cerebral anoxia. This study was done to elucidate the protective mechanism of TJ-8007 against cerebral ischemia and anoxia. TJ-8007 (0.3 approximately 3.0 g/kg, p.o.) inhibited the rise in the cumulative mortality rate after ligation of the bilateral carotid artery (BCA) in mice. TJ-8007 also significantly prolonged the survival time at the dose of 3.0 g/kg, p.o. However, TJ-8007 (1.0 or 3.0 g/kg, p.o.) did not affect the mean survival time after ligation of BCA in Mongolian gerbils and the gasping movement in a decapitated mouse head that served as a complete ischemic model. Ifenprodil (30 mg/kg, p.o.) also showed the protective effect only against ischemic death after ligation of BCA in mice. TJ-8007 (1.0 or 3.0 g/kg, p.o.) increased the vertebral blood flow, but showed no effect on the internal carotid blood flow in anesthetized dogs. These results suggest that the mechanism for the cerebral protective effect of TJ-8007 may be due to its ameliorating action on the cerebral circulation.
Some Chinese medicines in Japan have been reported to have not only antitumour effects, but also to offer protection from the adverse effects of anti-tumour agents. However, there is controversy regarding the protective effects of such Chinese medicines against the adverse effects of anti-tumour agents, in this study, we examined the effects of Tsumura Juzentaiho-to (TJ-48) on the toxicity of mitomycin C (MMC) and cisplatin (CDDP). Both the pre-administration of TJ-48 a single time and for seven days shifted the dose response curve and LD50S of MMC and CDDP to the right. Seven days of treatment using TJ-48 delayed deaths due to lethal dose of MMC or CDDP and markedly changed their survival curves. Also, TJ-48 reduced the atrophy of the testis, thymus and spleen caused by MMC. TJ-48 also had beneficial effects on leukopenia, anemia and body weight loss caused by MMC, and increase of BUN and creatinine caused by CDDP. These results indicate that the combined use of TJ-48 may be a new way to in prevent or minimize the toxicity of MMC or CDDP.
The relationship between the focus of cobalt seizures in the cerebral cortex and neuron loss in the hippocampus, as well as the CD50 of pentylenetetrazol was examined in rats. Spike activity in EEG frequently appeared 4 days after cobalt application and reached a peak 8-16 days after cobalt application, which was sometimes accompanied by jerks in the limbs. Changes in the CD50 value showed a two-step pattern, i.e., the first decrease in CD50 appeared one day after application of cobalt and continued at the same value until the fourth day. Then a second gradual decrease of CD50 was observed from the fourth day to eighth day and continued at the same value until 20 days after cobalt application. Neuron loss in the CA1 area of the hippocampus was observed as early as two days after cobalt application and the degree of neuron loss progressively increased until the 20th day. These findings suggest that neuron loss in the hippocampus following cobalt-induced seizures is not a result of generalized convulsions.
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