Biomedical subjects

K Miyata

Publications and source records attributed to K Miyata.

At least 127 records · Page 7Linked to original sources

PubMed1998

Intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent suppresses the restenotic changes of the coronary artery in pigs in vivo.

OBJECTIVES: This study was designed to examine whether or not intramural delivery of ST638 (a specific tyrosine kinase inhibitor) with biodegradable stent can suppress the restenotic changes of the coronary artery in vivo. BACKGROUND: Clinical and animal studies demonstrated that restenosis after coronary intervention results from a combined effect of neointimal formation and geometric remodeling (decrease in total cross-sectional area). Thus, the most effective strategy to prevent the restenosis appears to inhibit both the neointimal formation and geometric remodeling by antiproliferative agent and stent, respectively. We have previously shown that ST638 markedly suppresses the restenotic changes of the porcine coronary artery when applied from the adventitial site. METHODS: A poly-L-lactic acid biodegradable stent was coated with either ST638 (0.8 mg) or equimolar of its inactive metabolite, ST494. A pair of these stents were implanted alternatively in the left anterior descending or circumflex coronary artery in pigs (n=6). Three weeks after the procedure, coronary stenosis was assessed by angiography followed by histological examination. RESULTS: Coronary stenosis was significantly less at the ST638 stent site than at the ST494 stent site (47+/-5% vs. 25+/-4%, p < 0.01). Histological examination also showed that the extent of neointimal formation and that of geometric remodeling were significantly less at the ST638 stent site than at the ST494 stent site (p < 0.05). CONCLUSIONS: These results indicate that intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent overcomes the proliferative stimuli caused by balloon injury, the stent itself, and the drug coating on the stent, resulting in the suppression of the restenotic changes of the coronary artery in vivo. This strategy might also be useful in the clinical setting in humans.

Animals↗

PubMed1998

Difference in incidence and transmission mode of methicillin-resistant Staphylococcus aureus among surgery, orthopedics, and pediatrics wards: a prospective study at a university hospital.

The incidence and circumstances of colonization by methicillin-resistant Staphylococcus aureus were prospectively investigated. Among 404 patients, 15 (3.7%) were carriers on admission, and 43 (10.6%) became colonized, mainly after surgical operation. A different mode of transmission was suggested in each ward.

Adult↗

PubMed1998

Involvement of the 5-HT3 receptor in CRH-induce defecation in rats.

We evaluated the possibility that serotonin (5-HT) mediates defecation induced by corticotropin-releasing hormone (CRH) exogenously administered or released from the central nervous system by stress via the 5-HT3 receptor in rats. Intracerebroventricular (i.c.v.) injection of CRH (1, 3, and 10 micrograms/rat) dose dependently increased the number of stools excreted in rats, whereas intravenous (i.v.) injection of up to 100 micrograms/kg CRH did not affect defecation. alpha-Helical CRH-(9-41) and 5-HT3 receptor antagonists ramosetron and azasetron inhibited CRH (10 micrograms i.c.v.)-induced defecation in a dose-dependent manner with ED50 values of 4.3 micrograms/kg i.v., 3.8 micrograms/kg p.o., and 70.4 micrograms/kg p.o., respectively. alpha-Helical CRH-(9-41) also inhibited CRH-induced defecation by i.c.v. injection with an ED50 value of 0.078 microgram/rat. In contrast, ramosetron and azasetron injected i.c.v. had no effect on CRH-induced defecation. alpha-Helical CRH-(9-41), ramosetron, and azasetron reduced defecation caused by restraint stress with ED50 values of 0.32, 3.6, and 19.7 micrograms/kg i.v., respectively. These results indicate that CRH exogenously administered or released from the central nervous system by stress peripherally promotes the release of 5-HT, which in turn stimulates defecation through the 5-HT3 receptor.

Animals↗

PubMed1998

Inhibition of ileal Na+/bile acid cotransporter by S-8921 reduces serum cholesterol and prevents atherosclerosis in rabbits.

The ileal Na+/bile acid cotransporter (IBAT) plays an important role in the enterohepatic circulation of bile acids. We investigated the effects of IBAT inhibition on the maintenance of serum cholesterol level by using a novel IBAT inhibitor, S-8921, in rabbits. Administration of S-8921 by its incorporation into the diet (0.01% to 0.1%) for 1 to 2 weeks in heterozygous Watanabe heritable hyperlipidemic rabbits decreased serum cholesterol by 29% to 37% and increased fecal excretion of measured bile acids by 60% to 180% compared with control rabbits. Liver microsomal cholesterol 7alpha-hydroxylase and 3-hydroxy-3-methylglutaryl coenzyme A reductase activities were increased by 75% to 84% and 84% to 89%, respectively, with S-8921 treatment. S-8921 administration (0.1% in the diet) to normal New Zealand White rabbits for 2 weeks resulted in increased hepatic low density lipoprotein receptor expression, which was assessed by Northern blot analysis. In cholesterol-fed New Zealand White rabbits, S-8921 treatment (0.003% to 0.1% in the diet) for 10 weeks dose-dependently inhibited the development of hypercholesterolemia. It also inhibited the accumulation of cholesterol in the aortic arch and reduced the severity of coronary atherosclerosis. These results indicate that IBAT inhibition by S-8921 affects serum cholesterol, liver enzymes, low density lipoprotein receptor activity, and atherosclerosis in the same manner as bile acid sequestrants. We suggest that an IBAT inhibitor such as S-8921 could be useful in the treatment of hypercholesterolemia.

Animals↗

PubMed1998

Increased serum levels of vascular endothelial growth factor in Kawasaki disease.

Vascular endothelial growth factor (VEGF) is an angiogenic mitogen that specifically targets vascular endothelial cells. The objective of this study was to evaluate the role of VEGF in Kawasaki disease (KD), the most common cause of systemic vasculitis in childhood. Serum VEGF levels were measured by ELISA in 22 patients with KD, 22 febrile children with infection, and 19 healthy children. Samples from KD patients were divided into three groups: acute stage (n = 20), subacute stage (n = 13), and convalescent stage (n = 15). The results showed that KD patients in the acute and subacute stages had significantly higher levels of VEGF than did patients with infectious diseases and the healthy control subjects. When compared with the VEGF levels of patients with and without coronary artery lesions (CAL), significantly higher levels of VEGF were observed in the subacute stage in patients with CAL and in patients without CAL in the acute stage. Serial examination revealed that the serum VEGF levels in KD patients with CAL increased from a relatively low level in the acute stage to an extremely high level in the subacute stage. In contrast, patients without CAL were found to have extremely high levels of VEGF only in the acute stage of KD. In KD patients, the serum VEGF levels did not correlate with the inflammatory markers and clinical symptoms. Our results raise the possibility that VEGF is involved in the pathogenesis of KD, especially in the development of CAL. Further study is needed to clarify the biologic effect of VEGF on coronary arteries in KD.

Acute Disease↗

PubMed1998

Novel 5-hydroxytryptamine 4 (5-HT4) receptor agonists. Synthesis and gastroprokinetic activity of 4-amino-N-[2-(1-aminocycloalkan-1-yl)ethyl]-5-chloro-2-methoxybenzamide s.

A novel series of 4-amino-N-[2-(1-aminocycloalkan-1-yl)ethyl]-5-chloro-2-methoxyb enzamides. derivatives (1), which had amines conformationally restricted due to the effect of repulsion by neighboring substituents, were prepared and evaluated for 5-hydroxytryptamine 4 (5-HT4) agonistic activities by using the contraction of longitudinal muscle myenteric plexus (LMMP) of guinea pig ileum. One of the most potent compounds in this series was 4-amino-5-chloro-N-[2-(1-dimethylamino-1-cyclohexyl)ethyl]-2-methoxybenz amide (1c, YM-47813) with an EC50 value of 1.0 microM on LMMP. This compound effectively enhanced gastric motility and gastric emptying in conscious dogs by oral administration (1-3 mg/kg).

Animals↗

PubMed1998

[The effects of YM26818: 1-(2-dimethylaminoethyl)-1-(3,4,5-trimethoxyphenyl)urea and derivatives on pulmonary surfactant secretion and lung compliance].

To discover a novel compound which has an effect on pulmonary surfactant (PS) secretion, we studied the effects of various compounds on PS secretion by measuring the contents of PS in the bronchoalveolar lavage (BAL) fluid in guinea pigs. In the chemical modification study of ambroxol, which is known as a PS secretagogue, and a compound we discovered from our compounds library, 1-(2-dimethylaminoethyl)-1-(3,4,5-trimethoxyphenyl)urea: YM-26818 (the increasing effect on PS in BALF, 34.7% at 50 mg/kg, i.p.). In the surfactant deficient model induced by BAL in guinea pigs, YM-26818 (5 and 10 mg/kg, p.o.) significantly increased the contents of PS in the BAL fluid compared with that of control animals (5 mg/kg: 60.3 +/- 8.0, 10 mg/kg: 59.4 +/- 4.3% increase). Concomitantly by these effects, the recovery of lung compliance was observed in this model (AUC of lung volume, control: 560 +/- 15, YM-26818 5 mg/kg: 898 +/- 51, YM-2681 10 mg/kg: 956 +/- 11 ml.min). These results may indicate that YM-26818 is useful for the therapy of adult respiratory distress syndrome (ARDS) and obstructive pulmonary diseases.

Animals↗

PubMed1998

Pancreatic enzyme-induced pancreatitis and systemic complications in rats.

Effects of retrograde injection into the pancreatic duct and intravenous infusion of pancreatic enzymes and bile salt on the pancreas and other vital organs such as the liver and the lung were investigated in rats. Intraductal injection (1 ml/kg) of alpha-chymotrypsin (50-100 mg/ml), trypsin (10-100 mg/ml), pancreatic elastase (10 mg/ml), lipase (100-300 mg/ml), pancreatic kallikrein (25 mg/ml) and sodium taurocholate (50 mg/ml) solutions significantly increased pancreatic water content. Alpha-chymotrypsin, pancreatic elastase, taurocholate and trypsin elicited gross pancreatic hemorrhage. In contrast, lipase and kallikrein elicited gross pancreatic edema, but not hemorrhage. Intravenous infusion of trypsin (1 mg/kg/hr) and pancreatic elastase (10 mg/kg/hr) significantly increased pulmonary vascular permeability in rats, whereas infusion of neutrophil elastase (0.3 mg/kg/hr) did not elicit these effects. Only trypsin slightly reduced arterial oxygen pressure. These results show pancreatic enzymes and bile salts induce pancreatic inflammation after retrograde injection into the pancreatic duct in rats. Furthermore, trypsin and pancreatic elastase extravasation into the vascular system can lead to pulmonary dysfunction in rats.

Animals↗

PubMed1998

Protective effect of a pancreatic elastase inhibitor against a variety of acute pancreatitis in rats.

Protective effect of trifluoroacetyl-L-lysyl-L-alaninanilide hydrochloride (compound 1), a pancreatic elastase inhibitor, on three types of acute pancreatitis models was examined in rats. Mild, moderate and severe acute pancreatitis were induced by cerulein, the closed duodenal loop method and retrograde injection of a taurocholate plus trypsin solution into the pancreatic duct, respectively. Intravenous infusion of compound 1 at a dose of 30 mg/kg/hr resulted in lower increases in serum amylase, lipase, blood urea nitrogen (BUN) and creatinine levels in rats with mild cerulein-induced edematous pancreatitis. Compound 1 had no beneficial effect on pancreatitis in rats with moderate pancreatitis. In rats with severe pancreatitis, prophylactic treatment of compound 1 (30 mg/kg/hr) reduced both elevated serum BUN level and ascitic volume, and it histologically inhibited the extent of pancreatic edema and hemorrhage. These results suggest that pancreatic elastase is partially responsible for pancreatic edema and hemorrhage exhibited by rats with severe acute pancreatitis.

Acute Disease↗

PubMed1998

[Anterior ischemic optic neuropathy in a case of polyarteritis nodosa].

A 68-year-old male admitted to our hospital because of fever, body weight loss and multiple mononeuropathy. He developed visual loss in his right eye due to anterior ischemic optic neuropathy (AION). Surgical treatment of jejunal perforation was performed and histological examination of jejunal ulcer confirmed the diagnosis of polyarteritis nodosa (PN). Combination therapy of steroid (prednisolone 50 mg/day) and cyclophosphamide (50 mg/day) was started, which saved him from any other ischemic change including that of his left eye. As long as we know, AION occurring in PN is very rare, that is, only 4 cases have been reported in Japan.

Aged↗

PubMed1998

Mechanism of hypocholesterolemic action of S-8921 in rats: S-8921 inhibits ileal bile acid absorption.

The mechanism of the hypocholesterolemic action of S-8921, methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)- 4-hydroxy-6,7,8-trimethoxy-2-naphthoate, was examined in rats. In diet-induced hypercholesterolemic rats, 2 weeks oral administration of S-8921 dose- and time-dependently decreased plasma cholesterol level in the daily dose range of 0.1 to 10 mg/kg. Results with the dual-isotope plasma ratio method indicated that S-8921 inhibits cholesterol absorption from the intestine and enhances its elimination from the body. The in situ loop method showed that S-8921 does not inhibit the absorption of cholesterol from rat jejunum, clearly inhibits active absorption of taurocholic acid (TCA) and glycocholic acid (GCA) from rat ileum and does not inhibit passive absorption of cholic acid (CA) from the rat jejunum. In rat ileal brush-border membrane vesicles, S-8921 inhibited the sodium-dependent uptake of TCA in a concentration-dependent manner with IC50 of 2.1 microM, not the Na(+)-dependent D-glucose and L-alanine uptake. These results suggest that S-8921 is a potent, selective inhibitor of the Na(+)-dependent bile acid transport system in the ileal mucosal cell brush-border membrane, and this inhibition is the mechanism by which this drug decreases intestinal bile acid reabsorption to result in a significant decrease of plasma cholesterol.

Animals↗

PubMed1998

Effects of YF476, a potent and selective gastrin/cholecystokinin-B receptor antagonist, on gastric acid secretion in beagle dogs with gastric fistula.

The antisecretory effects of the gastrin/cholecystokinin-B (CCK-B) receptor antagonist YF476 ((R)-1-[2,3-dihydro-2-oxo-1-pivaloylmethyl-5-(2'-pyridyl) 1H-1,4-benzodiazepin-3-yl]-3-(3-methylaminophenyl)-urea, CAS 155488-25-8) on secretagogue- and peptone-induced gastric acid secretion in beagle dogs with chronic gastric fistula were examined. Plasma gastrin concentrations were evaluated following introduction of peptone into the stomach. Intravenous administration of YF476 dose-dependently inhibited pentagastrin (1 microgram/kg/h)-induced gastric acid secretion, with an ED50 value of 0.0023 mumol/kg. In contrast, intravenous administration of YF476 (0.3 mumol/kg) did not affect histamine (15 micrograms/kg/ h)-induced gastric acid secretion. Oral administration of YF476, famotidine and omeprazole dose-dependently inhibited peptone (8%, 200 ml)-induced gastric acid secretion with ED50 values of 0.11, 0.76 and 4.28 mumol/kg, respectively. The antisecretory effect of YF476 was about 7 and 40 times more potent than that of famotidine and omeprazole, respectively. Plasma gastrin concentrations were increased by introduction of peptone. These results suggest that YF476 is an extremely potent and selective antisecretory drug and the endogenous gastrin plays an important role in peptone-induced gastric acid secretion in dogs.

Animals↗

PubMed1998

Extracellular matrix production regulation by TGF-beta in corneal endothelial cells.

PURPOSE: Production of extracellular matrix (ECM) by corneal endothelial cells is related to physiologic functions and pathologic conditions and is regulated by many cytokines, including transforming growth factor-beta (TGF-beta). In this study, the molecular mechanism of ECM production regulation by TGF-beta was investigated in cultured corneal endothelial cells. METHODS: The production of ECM components (laminin and fibronectin) was detected in cultured corneal endothelial cells by western blot analysis. To determine the signal transduction pathways, mutant TGF-beta type I receptor (TbetaR-I) and/or Smad protein family members (intracellular signal transducers in TGF-beta signaling) were overexpressed by transfecting their cDNA into the cultured cells, and the effects on ECM production were observed. RESULTS: The production of laminin and fibronectin was stimulated by treatment with TGF-beta1 or TGF-beta2. After transient transfection of cDNA of the constitutively active (CA) mutant of TbetaR-I, the production of laminin and fibronectin was stimulated even in the absence of TGF-beta. The transfection of the dominant negative mutant of TbetaR-I counteracted the effects of TGF-beta. These results confirm that TGF-beta directly stimulates ECM production from corneal endothelial cells through TbetaR-I. The ECM production stimulation by TGF-beta or CA TbetaR-I was accelerated by the overexpression of Smad2, Smad3, and/or Smad4 and inhibited by that of Smad7. These results show that TGF-beta signals connected to ECM production are regulated by Smad family members, located downstream of TbetaR-I. CONCLUSIONS: The results of this study show that TGF-beta stimulates ECM production from corneal endothelial cells through TbetaR-I and Smad family transducers.

Animals↗

PubMed1998

In vitro pharmacologic profile of YM158, a new dual antagonist for LTD4 and TXA2 receptors.

YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl ) propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate) antagonizes leukotriene (LT) D4 and thromboxane (TX) A2 receptors. Functional assays in vitro showed that YM158 exhibits competitive dual antagonism of LTD4 and TXA2 receptor-mediated contraction of isolated guinea pig tracheae, with pA2 values of about 8.87 and 8.81, respectively. Its antagonistic activity for the LTD4 receptor was approximately 6.5 times less potent than that of montelukast, and that for the TXA2 receptor was 2.5 times more potent than that of seratrodast. YM158 also inhibited PGD2- and PGF2alpha-induced tracheal contractions. YM158 showed no antagonism against LTC4-, histamine- or carbachol-induced contractions of guinea pig tracheae. Furthermore, YM158 antagonized the stable TXA2 analog U46619-induced aggregation of both guinea pig and human platelets and inhibited the LTD4-induced contraction of guinea pig ileum. From these results, YM158 appears to be a novel, selective dual antagonist for both LTD4 and TXA2 receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1997

Effect of a selective 5-HT3 receptor agonist on gastric motility in fasted and fed dogs.

The effect of m-chlorophenylbiguanide, a selective 5-HT3 receptor agonist, on gastric antral motility was investigated in conscious dogs with a force transducer implanted chronically. m-Chlorophenylbiguanide (0.1-1 mg/kg i.v.) dose dependently enhanced antral motility in the fasted state, and the amplitude of m-chlorophenylbiguanide (1 mg/kg i.v.)-induced antral contractions reached the level of natural phase III contractions. In contrast, m-chlorophenylbiguanide reduced the amplitude of antral contractions in the fed state. A selective 5-HT3 receptor antagonist, ramosetron (0.0003-0.03 mg/kg i.v.), inhibited both effects of m-chlorophenylbiguanide. m-Chlorophenylbiguanide (1 mg/kg i.v.)-induced contractions were inhibited by atropine (0.03 or 0.1 mg/kg i.v.). These results indicate that pharmacological activation of 5-HT3 receptors has opposite effects on canine gastric antral motility in the fasted and in the fed state, being stimulatory and inhibitory, respectively. The stimulatory effect seems to be mediated mainly via the release of acetylcholine.

Animals↗

PubMed1997

Gastrointestinal motor activity in conscious ferrets.

Gastrointestinal motility was measured with force transducers in conscious ferrets. The gastrointestinal motility pattern in both the interdigestive and digestive states was similar to that reported for humans. The activity front, phase III contractions of the migrating motor complex, occurred cyclically in the antrum and migrated to the duodenum and ileum in the interdigestive state, and relatively low-amplitude contractions were sustained in the antrum, duodenum and ileum in the digestive state. Colonic motility was characterized by basal relatively low-amplitude contractions and a single high-amplitude contraction preceding defecation. Cisapride (0.3-3 mg/kg s.c.) enhanced antral and colonic motility. This ferret model will help the investigation and evaluation of drug effects on gastrointestinal motility in humans.

Animals↗

PubMed1997

Effect of ramosetron on short-circuit current response in rat colonic mucosa.

We investigated the effects of ramosetron (YM060, (-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1 H-benzimidazole monohydrochloride) on the short-circuit current (Isc) responses to 5-HT receptor agonists in the rat distal colon, and compared its potency to that of other 5-HT3 receptor antagonists. 5-Hydroxytryptamine (5-HT) concentration-dependently increased Isc. The Isc response to 5-HT was partially reduced by tetrodotoxin and ramosetron, and strongly inhibited by GR113808 ([[1-[(2-methyl-sulphonyl) amino]ethyl]-4-piperidin-yl]methyl 1-methyl-1 H-indole-3-carboxylate). 2-Methyl-5-HT and 5-methoxytryptamine also increased Isc. The former response was inhibited by ramosetron, and the latter was abolished by GR113808. Ramosetron, YM114 (KAE-393, (-)-(R)-5-[(1-indolinyl)carbonyl]-4,5,6,7-tetrahydro-1 H-benzimidazole monohydrochloride) and granisetron concentration-dependently antagonized the Isc responses to 2-methyl-5-HT with reduction in the maximal response at higher concentrations. Apparent pA2 values for these antagonists were 10.40, 10.37 and 8.99, respectively. Ondansetron produced clear rightward shifts of the concentration-response curves to 2-methyl-5-HT, with a pA2 value of 8.53. These results suggest that 5-HT increases Isc through the 5-HT3 and 5-HT4 receptors, and that ramosetron is a potent and selective 5-HT3 receptor antagonist in rat colonic mucosa.

Animals↗

PubMed1997

(3R)-N-(1-(tert-butylcarbonylmethyl)-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-(methylamino)phenyl)urea (YF476): a potent and orally active gastrin/CCK-B antagonist.

A number of new 1,4-benzodiazepin-2-one-based gastrin/CCK-B receptor antagonists related to the archetypal analogue L-365,260, and more closely to the recently reported compound YM022, have been synthesized and evaluated for biological activity. The compounds were screened for their ability to inhibit the binding of [125I]CCK-8 to gastrin/CCK-B receptors prepared from rat brains and that of [3H]L-364,718 to CCK-A receptors from rat pancreas, and were shown to be potent and selective ligands for the gastrin/CCK-B receptor. Functional studies in vivo demonstrated the compounds to be antagonists of the receptor as evidenced by their ability to inhibit pentagastrin-induced gastric acid secretion in anesthetized rats. More extensive evaluation in vivo included determination of ED50 values in the rat acid secretion model for selected compounds and an examination of the effect of these compounds on pentagastrin-induced gastric acid secretion in Heidenhain pouch dogs following oral and intravenous administration. Two compounds, i.e. (3R)-N-[1-[(tert-butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5-(2-pyri dyl) -1H-1,4-benzodiazepin-3-yl]-N'-[3-(methylamino)phenyl]urea, 15c (YF476), and (3R)-N-[1-[(tert-Butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5- (2-pyridyl)-1H-1,4-benzodiazepin-3-yl]-N'-[3-(dimethylamino)phenyl ]urea hydrochloride, 15d, showed potent dose-dependent effects in both models with the former showing excellent oral bioavailability and an ED50 of 21nmol/kg po in dogs. 15c is currently under clinical investigation for the treatment of gastro-oesophagal reflux disease (GORD).

Administration, Oral↗