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Biomedical subjects

M Kagoshima

Publications and source records attributed to M Kagoshima.

At least 37 records · Page 2Linked to original sources
PubMed1997

Effect of Y-24180, a long-acting antagonist to platelet-activating factor (PAF), on PAF-induced reactions: a relationship between the partial structure of the compound and its duration of the action.

(+/-)-4-(2-Chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dime thy l-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (Y-24180) is a platelet-activating factor (PAF) antagonist, being similar to WEB 2086. One of the structural differences between the two PAF antagonists is the presence of a methyl substituent in Y-24180 at the 6-position of its ring system. Orally administered Y-24180 and WEB 2086 both dose-dependently prevented PAF-induced airway hyperresponsiveness (ED50: 0.0010 and 0.019 mg/ kg, respectively) and bronchoconstriction (ED50: 0.0014 and 0.024 mg/kg, respectively) in guinea pigs. Against the bronchoconstriction, here, the inhibitory effect of Y-24180 was significantly more potent and longer acting than that of WEB 2086. On the other hand, Y-24180 (10 mg/kg, p.o.) showed insignificant effects on the bronchoconstriction induced by leukotriene D4, histamine, serotonin, acetylcholine, arachidonic acid, or bradykinin. In an in vitro test, Y-24180 and WEB 2086 inhibited the PAF-induced aggregation of the rabbit washed platelets in a concentration-dependent manner (IC50: 1.2 and 64 nmol/l, respectively). Compared with desmethyl-Y-24180 and WEB 2086, Y-24180 and methyl-WEB 2086, both of which have a methyl substituent on the 6-position of their thienodiazepine ring, exhibited a longer acting suppressive effect on PAF-induced bronchoconstriction and significantly more stable binding to the PAF receptor after the washing-out procedure of the test compounds from platelets. Therefore, the 6-methyl substituent should be responsible for the PAF receptor binding stability of Y-24180, namely, for its long-acting anti-PAF effects in vivo. These results indicate that Y-24180 possesses the specific and long-acting PAF antagonistic effects in the airway.

Acetylcholine↗
PubMed1997

Suppressive effects of Y-24180, a long-acting antagonist for platelet-activating factor, on allergic pulmonary eosinophilia in mice.

We studied the effects of (+/-)-4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethy l-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (Y-24180), a long-acting antagonist for platelet-activating factor (PAF), on antigen-induced eosinophil infiltration and interleukin-5 (IL-5) release in the bronchoalveolar lavage fluid (BALF) of mice. Mice actively sensitized with ovalbumin (OA) were challenged by injecting intratracheally OA 3 times every fourth day. Both the number of eosinophils and level of IL-5 were significantly increased in the BALF 24 hr after the last OA challenge. Either Y-24180 or prednisolone was orally administered once a day for 10 days beginning one day before the first OA challenge. WEB2086, another PAF antagonist, was orally administered once or twice a day for 10 days. Y-24180 (0.3 - 3 mg/kg) suppressed the eosinophil infiltration in a dose-dependent manner and suppressed the IL-5 release at the highest dosage. Prednisolone (10 mg/kg) significantly suppressed both the eosinophil infiltration and IL-5 release. In contrast, WEB2086 affected neither the eosinophil infiltration nor IL-5 release when administered once a day (10 - 100 mg/kg/day). This drug never affected the IL-5 release but significantly suppressed eosinophil infiltration even when administered twice a day (30 - 200 mg/kg/day). These results indicate that the suppressive effect of Y-24180 on allergic pulmonary eosinophilia is due to not only to its long-lasting PAF-antagonism but also due to its suppressive effect on IL-5 release.

Animals↗
PubMed1997

Anti-inflammatory and ulcerogenic effects of 3-(N,N-diethylamino) propylindometacin HCl.

AIM: To study anti-inflammatory effects of a novel indometacin ester, 3-(N,N-diethylamino) propyl-indometacin HCl (prodrug) and its ulcerogenicity in fats. METHODS: Carrageenin (Car)-induced paw edema and ulcer index were examined. RESULTS: Car-induced paw edema was inhibited by 36.6% (P < 0.01) at 3 h and 34.6% (P < 0.01) at 5 h after a single i.p. injection of the prodrug 7.09 mg.kg-1. On the same molar basis, indometacin (Ind) 5 mg.kg-1 i.p. inhibited edema by 45.6% at 3 h and 39.2% at 5 h, however, there was no statistical significant difference (P > 0.05) between the edema-inhibitory effect of the prodrug and that of Ind. The dose 10 micrograms/paw exhibited 64% inhibition of the swelling, the prodrug > 10 micrograms/paw showed no additional inhibition of swelling; the acute gastric lesion properties of the prodrug were much lower than those of Ind 6 h after p.o. CONCLUSION: The prodrug is a potent anti-inflammatory agent with lower ulcerogenicity in the stomach.

Animals↗
PubMed1996

Effect of Y-24180, a platelet-activating factor-receptor antagonist, on the antigen-induced airway microvascular leakage in guinea pigs.

The inhibitory effect of Y-24180 ((+/-)-4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6, 9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine) on platelet-activating factor (PAF)- or antigen-induced airway microvascular leakage was studied in guinea pigs by oral administration. The tissue content of extravasated Evans blue dye was used as an index of plasma exudation in the trachea, main bronchi, central intrapulmonary airways and peripheral intrapulmonary airways. In all of these tissues, Y-24180 potently inhibited the leakage induced by PAF. The ED50 value of Y-24180 determined in each of the tissues was approximately 0.02 mg/kg, demonstrating that the inhibitory potency of Y-24180 is 4-6 times that of WEB 2086, another PAF antagonist. Even at a dose of 10 mg/kg, however, Y-24180 showed no inhibitory effect on the leakage induced by leukotriene (LT) D4, histamine or bradykinin. In the antigen-induced model of guinea pigs sensitized with aerosolized ovalbumin, Y-24180 (0.1-10 mg/kg) and WEB 2086 (1-100 mg/kg) potently inhibited the microvascular leakage in all of the examined airway tissues except for the trachea. At 1-100 mg/kg, however, both ONO-1078, an LT-receptor antagonist, and OKY-046, a thromboxane A2 synthetase inhibitor, prevented partially but not significantly the antigen-induced leakage. These results provide evidence that endogenous PAF partially mediates the antigen-induced airway microvascular leakage in guinea pigs.

Animals↗
PubMed1995

Hepatocyte growth factor as a potent survival factor for rat pheochromocytoma PC12 cells.

Hepatocyte growth factor (HGF), a natural ligand for the c-met protooncogene product, is a multipotent polypeptide which elicits mitogenic, motogenic, and morphogenic activities for various types of cells. To better understand the biological activity of HGF, as related to neuroectodermal-derived cells, we investigated the effects of HGF on rat pheochromocytoma PC12 cells. HGF increased the number of PC12 cells during long culture, but elicited no direct mitogenic activity, as determined by DNA synthesis. When the cells were cultured in medium containing lower concentrations of fetal calf serum, HGF prolonged the survival of PC12 cells; the number of cells did not decrease during 13 days when the cells were cultured in the presence of HGF, but the cells were completely withdrawn when cultured in the absence of HGF. Nerve growth factor but not HGF induced the differentiation of PC12 cells. High affinity receptor for HGF with Kd values of 20-40 pM was expressed in PC12 cells and other types of cells derived from the central nervous tissue: T98G cells (human glioblastoma), GOTO, and SCCH-26 cells (human neuroblastoma). HGF stimulated motility of T98G cells, while it induced weak mitogenic response in GOTO cells. We suggest that HGF is a potent survival factor for PC12 cells, without exerting any direct mitogenic activity and inducing the cell differentiation, and that this factor may have a distinct biological activity for neuroectoderm-derived cells.

Animals↗
PubMed1995

Localization and functional coupling of HGF and c-Met/HGF receptor in rat brain: implication as neurotrophic factor.

Hepatocyte growth factor (HGF), a natural ligand for the c-met protooncogene product, has mitogenic, motogenic and morphogenic activities for various cell types and functions as a organotrophic factor for regeneration of the liver, kidney and lung. We obtained evidence that HGF may function as a novel neurotrophic factor in the central nervous system. Northern blot analysis showed that 6 kb HGF mRNA and 9 kb c-Met/HGF receptor mRNA are expressed in various regions of the adult rat brain. In situ hybridization analysis revealed that intense hybridization signals for HGF mRNA were localized in cerebral cortex, hippocampus and amygdala. Consistently, specific localization of HGF protein in neurons of these regions was detected by immunohistochemical analysis and non-neuronal glial cells in cingulum, cerebellum, pons and medulla were also specifically stained. Specific intense hybridization signals for c-Met/HGF receptor mRNA were also widely distributed in the brain, including neurons of olfactory bulb, cerebral cortex, primary olfactory cortex, hippocampus and cerebellum. On the basis of the co-expression of HGF and c-Met/HGF receptor in hippocampal neurons, we found that HGF prolonged survival of embryonic hippocampal neurons in primary culture: HGF elicited maximal surviving effect at 0.5-1 ng/ml and the potency was comparable to that of nerve growth factor. More importantly, expression of both HGF and c-Met/HGF receptor mRNAs was markedly induced in response to cerebral ischemic injury. We propose that HGF functions as a neurotrophic factor in the central nervous system and that this neurotrophic function may have a role in the survival and reconstruction of specific neurons in response to cerebral injury.

Animals↗
PubMed1995

[Effect of FRG-8813, a new histamine H2-receptor antagonist, on gastric mucus production in rats].

We examined the effect of FRG-8813, a new histamine H2-receptor antagonist, on 1% NH3-induced gastric mucosal lesions and basal gastric mucus production in rats. The effect of FRG-8813 (10 mg/kg) given orally was investigated macroscopically and histochemically compared with that of 16,16-dimethyl prostaglandin E2 (dmPGE2, 2 micrograms/kg) or capsaicin (Cap, 10 mg/kg) in the fundic gland area. FRG-8813, dmPGE2 and capsaicin inhibited the NH3-induced mucosal lesions, and stimulated the mucus secretion 5 min after the administration. Chemical deafferentation abolished the gastroprotective effect of FRG-8813 or Cap and attenuated the increase by FRG-8813, dmPGE2 or Cap in mucus secretion seen after 5 min. These results suggest that FRG-8813 exerts its effect on gastric mucus production partially through the capsaicin-sensitive afferent nerves, like the mechanism involved in gastroprotection, and that the increase in mucus production by FRG-8813 is at least in part responsible for the gastroprotection.

16,16-Dimethylprostaglandin E2↗
PubMed1995

[Experimental studies of physiological and pathological effects induced by systemic hypoxia and the hypoxia-reoxygenation model in rats].

We attempted to make a basic model to investigate a series of factors that induce histological changes in systemic hypoxia-reoxygenation injuries. At first, we set the experimental conditions for hypoxia and the hypoxia-reoxygenation models as follows: respiration volume: 1.5 ml/stroke, respiratory frequency: 80 times/min, oxygen concentration: 14%. Next, Male SPF Wistar rats were anesthetized with pentobarbital sodium. For artificial ventilation, a cannula was inserted in the trachea and connected to the rodent ventilator through two flow meters to allow mixing of 100%N2 and 95%O2-5%CO2 gases at a desired ratio. The influence of hypoxia-reoxygenation was studied and evaluated histologically and biochemically. The rats were placed under the hypoxic condition for either 3 or 6 hr. Then, oxygen partial pressure was restored to 21% followed by reoxygenation for either 3 or 6 hr. Then the rats were sacrificed, and the pituitary, adrenals, heart, stomach and kidneys were removed. The results were as follows: 1) GPT activities were increased by a load of hypoxia, but no influence of reoxygenation was detected. 2) Under the condition of experimental hypoxia, the weights of the pituitary and adrenals increased significantly. 3) The histological findings indicated that 6-hr hypoxia followed by 3-hr reoxygenation induced hypoxia-reoxygenation injuries mostly affecting the anterior pituitary and adrenal medulla.

Adrenal Glands↗
PubMed1995

Absorption of indomethacin from nasal cavity in rats.

AIM: To investigate if identical bioavailability, rapid Tmax, and Cmax of indometacin (Ind) could be achieved when Ind is administered in rats via intranasal (ina) route. METHODS: The pharmacokinetics of Ind solution at a dosage of 3 mg.kg-1 was studied after i.v., ina, and po in rats using HPLC. RESULTS: It showed that the time to peak (Tmax) of ina Ind 3 mg.kg-1 solution was 0.08 h, approached that after i.v. route the peak concentration (Cmax) following ina was 20.0 mg.L-1, 2.4 times higher than po dosing. CONCLUSION: It demonstrated that the ina administration of Ind was superior to po in rats, and that Ind absorption through nasal mucosa was a reasonable approach at lower doses.

Absorption↗
PubMed1994

A serosa-searing apparatus for producing gastric ulcer in rats.

Chronic ulcer models produced by serosa-searing method are very similar histologically to the ulcer healing process occurring in humans. In an effort to produce a serosa-searing chronic ulcer model in rats, we devised a new balance-type apparatus. This searing apparatus is capable of changing adequately both temperature and duration of time. Furthermore, the pressure which serves to bring the searing iron tip into contact with the stomach serosa surface can also be precisely changed. Optimal conditions for reproducing the serosa-searing ulcer model were at 65 degrees C and in 5 sec. Moreover, in order to evaluate the effects of pressure, various pressure levels (A: 5 g, 17.68 g/cm2; B: 10 g, 35.37 g/cm2; C: 15 g, 53.05 g/cm2; D: 20 g, 70.74 g/cm2; E: 25 g, 88.42 g/cm2; F: 30 g, 106.10 g/cm2; G: 35 g, 123.79 g/cm2 (+/- 1 g, 0.149 g/cm2)) of 5-sec duration at 65 +/- 0.1 degrees C were used. Macroscopically, gastric mucosal lesions were most clearly observed in a pressure-related manner 7 days after the procedure. Histologically, definite deep ulcerations (UI-III or UI-IV) were observed at pressure level C (15 g, 53.05 g/cm2) or more. The highest incidence (87%) of histological gastric ulcers (UI-IV) was observed in pressure level E (25 g, 88.42 g/cm2). The healing process was observed at 40 to 60 days postoperatively. At 100 days after the procedure, recurrences were observed both macroscopically and histologically. In conclusion, this new apparatus is very useful for reproducing a chronic ulcer model for observing the healing and recurrence process.

Animals↗
PubMed1994

[A study on fixatives for the simultaneous histological estimation of the gastric mucous gel layer and mucous cells in rat gastric surface mucosa].

We examined the special characteristics of various kinds of fixatives and tried to find the most suitable method for simultaneous histological estimation of the mucous gel layer and mucous cells in rat gastric paraffin sections stained with Alcian blue (pH2.5)-periodic acid Schiff (AB-PAS). The tested fixatives were (group in parentheses): absolute ethanol at -80 degrees C (A), absolute methanol at -80 degrees C (B), Carnoy's solution (C), formalin-ethanol (D) and formalin-Tyrode (E). The thickness of the mucous gel layer (ML) and the numbers of AB- and PAS-positive cells (AB cells, PAS cells) of both the fundic gland area (F. area) and pyloric gland area (P. area) were measured microscopically (x 200). ML in the F. area was found in the order of (A) > (B) > (C) > (D) = (E). AB cells were in the order of (A) > (E) > (B) > (C) > (D); and PAS cells were in the order of (B) > (A) > (E) > (C) > (D). Effects of various fixatives in the P. area showed the same trend as the F. area. Apart from above mentioned procedures, we observed the effects of ethanol at various temperatures: -80 degrees C, -25 degrees C, -4 degrees C and 20 degrees C. ML, AB and PAS cells showed the highest level at -80 degrees C. Moreover, to confirm that these fixatives retain the mucus, we evaluated the hexose and hexosamine contents contained in the fixative solution after fixation. As a result of various fixations, the hexose and hexosamine values in the fixative solution were the smallest for ethanol at -80 degrees C. In conclusion, ethanol at -80 degrees C was the most suitable fixative for histological estimation of mucous gel and mucous cells in rat gastric surface mucosa.

Animals↗
PubMed1994

[Effects of FRG-8813, a new histamine H2-receptor antagonist, on gastric mucus in rats].

We examined the effects of FRG-8813, a new histamine H2-receptor antagonist with potent antisecretory activity, on gastric mucus in male SD rats (7w). In this study, the effects of FRG-8813 (1, 3, 10 mg/kg), given orally twice a day for 7 days, were investigated by histochemical and biochemical methods in comparison with those of cimetidine (CM, 30 mg/kg) and famotidine (FM, 1 mg/kg) in the fundic gland area (F. area) and pyloric gland area (P. area). In the histochemical study by alcian blue (pH 2.5)-PAS (AB-PAS) or high iron diamine-alcian blue (HID-AB) staining, the CM group showed a significant decrease in PAS and tended to show decreases in HID-AB positive mucus and mucous gel layer in the F. area; the FM group also showed a decrease in AB positive mucus in the P. area. On the other hand, the AB-PAS and HID-AB positive mucus of the FRG-8813 group were not affected. In the biochemical study, FRG-8813 increased the gastric mucosal hexose, hexosamine and sialic acid composing the mucus in a dose-dependent manner in the F. area. These results suggest that FRG-8813 does not cause a decrease in gastric mucus, unlike CM or FM, and it may be able to promote mucus secretion through increasing the mucous component in the F. area.

Acetamides↗
PubMed1994

Fever of unknown origin: a review of 80 patients from the Shin'etsu area of Japan from 1986-1992.

In this survey involving 10 hospitals, we analyzed data on 80 Japanese patients from the Shin'etsu area (Nagano-ken and Niigata-ken) who were observed for fever of unknown origin (FUO). Our objectives were to identify the underlying causes and the relevant diagnostic methods. Fourteen of the patients died of the underlying illness. The cause of the FUO was infection in 43 patients, allergic or autoimmune disease in 13, neoplasm in 7, miscellaneous causes in 3, and undetermined in 14. FUO was self-limited in 13 patients and persistent in one patient. Methods successfully used to establish the final diagnosis in 66 patients were: evaluation of the clinical course or response to treatment in 16, serologic tests in 12, bacteriologic studies in 10, biopsy in 9, cytologic examination in 6, conventional radiology in 6, necropsy in 3, endoscopy in 2, and biochemical testing in 2.

Adolescent↗
PubMed1994

[Image analysis of optic disk swelling in diabetic retinopathy].

Optic disc swelling was measured by computerized image analysis in diabetic patients. The subjects were divided into four groups. Group 1 contained 13 eyes without diabetic retinopathy, group 2, 14 eyes with a mild stage of simple diabetic retinopathy, group 3, 14 eyes with a severe stage of simple diabetic retinopathy and group 4, 14 eyes with preproliferative diabetic retinopathy. There were statistically significant differences in the optic disc swelling between group 1 and group 4, and between group 2 and group 4 (p < 0.05). The optic disc swelling increased as the stage of diabetic retinopathy progressed.

Diabetic Retinopathy↗
PubMed1993

Molecular analysis of the Duchenne muscular dystrophy gene in patients with Becker muscular dystrophy presenting with dilated cardiomyopathy.

Molecular analysis of the Duchenne muscular dystrophy (DMD) gene was performed on 4 unrelated patients with Becker muscular dystrophy (BMD) presenting with dilated cardiomyopathy. Two patients with a deletion involving exon 1 were quite unique in that they developed fatal myocardial involvement in their teens, despite the absence of significant muscular weakness. The deletion found in these patients comprised the 3'-end of exon 1 and the greater part of intron 1. Two other patients with a deletion of exon 47 showed progressive muscular atrophy and weakness; they were considered to be typical BMD in both clinical features and the type of gene deletion. We speculate that a deletion around exon 1 may severely damage the expression and/or the function of dystrophin selectively in cardiac muscle, but not in skeletal muscle.

Adolescent↗
PubMed1992

Developmental changes in hepatocyte growth factor mRNA and its receptor in rat liver, kidney and lung.

Hepatocyte growth factor (HGF) is a mesenchymal-derived factor which induces mitosis, cell movement and morphogenesis of tissue-like structure. We analyzed changes in HGF mRNA and its receptor, the c-met proto-oncogene product, in the liver, kidney and lung during late fetal and postnatal development in rats. In the liver, the HGF-mRNA level was very low during late gestation and in neonates, it increased remarkably and reached a maximum two weeks postnatally, to be followed by a decrease to 33% of the maximum. HGF mRNA in the kidney and lung was either undetectable or very low during late gestation and the neonatal period and increased markedly to reach a maximum, respectively, 3-4 weeks postnatally. HGF-mRNA level in the adult rat lung was fivefold higher than that in the liver and kidney. The number of HGF receptors on plasma membranes of these tissues was low in neonates but there was a rapid increase after birth and a maximum was reached within three weeks. The number of HGF receptors/ng plasma membrane protein at the maximal level was highest in the liver and lowest in the lung. c-met/HGF-receptor mRNA in the liver was also low during late-gestation or in early neonatal periods and increased postnatally. Since HGF-mRNA and HGF-receptor levels changed differently in liver, kidney and lung, the expression of HGF and its receptor may be independently regulated in each organ. However, in these organs, HGF mRNA and the HGF receptor increased within a few weeks of birth, HGF may play roles in organ growth, organ maturation and the maintenance of tissue homeostasis during the postnatal period, presumably through its potential to act as mitogen, motogen and morphogen.

Aging↗
PubMed1992

Absorption of acetylsalicylic acid from the rat nasal cavity.

The fate of salicylate in the plasma of rats was followed after nasal, intravenous, and oral administration of 2.0-mg doses of aspirin. Aspirin was well absorbed following nasal administration of a neutralized, nonirritating solution containing triethanolamine. The rate of absorption was slower than that of other nasally administered drugs, such as propranolol or progesterone. The bioavailability of aspirin following nasal administration was 100%, whereas the oral bioavailability was only 58.8% at the dose studied.

Absorption↗