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Biomedical subjects

K Miyata

Publications and source records attributed to K Miyata.

At least 181 records · Page 10Linked to original sources
PubMed1996

Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. I. Synthesis and structure-activity relationships of conformationally restricted fused imidazole derivatives.

We prepared a novel series of conformationally restricted fused imidazole derivatives 4b, 4c and 4d (possessing 4,5,6,7-tetrahydroimidazo[4,5-c] pyridine and substituted 4,5,6,7-tetrahydro-1H-benzimidazole for 4b, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine for 4c and 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine for 4d as a basic amine part and (2-methoxyphenyl)aminocarbonyl group as an aromatic-carbonyl part). Their activities were then evaluated as an 5-hydroxytryptamine (5-HT3) receptor antagonist which may be useful for the treatment of irritable bowel syndrome (IBS) as well as for nausea and vomiting associated with cancer chemotherapy. The most potent compound was N-(2-methoxyphenyl)-4,5,6, 7-tetrahydro-1H-benzimidazole-5-carboxamide 14 in this series with an ID50 value of 0.32 microgram/kg on the von Bezold-Jarisch reflex in rats and an IC50 value of 0.43 microM on the isolated colonic contraction in guinea pig, approximately ten and two times more potent than ondansetron 1, respectively. The structure activity relationships (SAR) study suggested that the high potency of 14 may be attributed to the suitable position and direction of the N-C-N centroid in the conformationally restricted imidazole ring against the planar (2-methoxyphenyl)aminocarbonyl part in the binding of 14 to the receptor.

Animals↗
PubMed1996

Comparative evaluation of the role of endogenous gastrin in basal acid secretion in conscious rats provided with chronic fistula and pylorus ligation.

We determined the relative contributions of endogenous gastrin, histamine and cholinergic tone to basal acid secretion in chronic fistula rats. Results were compared with those for acid secretion in pylorus-ligated rats. In chronic fistula rats, YM022 ¿(R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1 H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea¿ dose-dependently inhibited pentagastrin-stimulated acid secretion and abolished this secretion at 1 mumol/kg, s.c., but did not affect histamine- and carbachol-induced acid secretion even at 10 mumol/kg. In contrast, famotidine at 1 mumol/kg completely inhibited not only the acid secretion induced by histamine but also those by pentagastrin and carbachol. Furthermore, atropine abolished carbachol- and pentagastrin-stimulated acid secretion and significantly suppressed histamine-stimulated acid secretion at 0.1 mumol/kg. YM022 dose-dependently inhibited basal acid secretion. The YM022 dosage required to inhibit basal acid secretion is consistent with that required to suppress pentagastrin-induced acid secretion. Famotidine (1 mumol/kg) and atropine (0.1 mumol/kg) also abolished basal acid secretion. In pylorus-ligated rats, YM022 inhibited acid secretion in a dose-dependent manner; the inhibition at 1 mumol/kg, i.v. was 65%. No additional effect was observed when rats were dosed at 30 mumol/kg. Famotidine partially inhibited acid secretion in these rats, whereas atropine abolished this secretion. These results indicate that the major part of basal acid secretion in rats is attributable to endogenous gastrin via histamine- and cholinergic tone-dependent pathways. Moreover, pylorus ligation reduces the relative contribution of gastrin to acid secretion due to the activation of cholinergic tone.

Animals↗
PubMed1996

[Corneal distortion induced by speculum--studies with computer-assisted corneal topography].

The corneal distortion induced by the presence of an eyelid speculum was analysed by the Videokeratoscope-Eyesys Corneal Analysis System (EYESYS), with a Barraquer type speculum (B group) in 22 normal eyes and with a Kratz-Barraquer type speculum in 38 normal eyes (KB group). The following differences were evaluated in the 2 groups: intraocular pressure (IOP), refractive power, change in astigmatism of the Cravy method, and corneal refractive power before and after the specula were put in the interpalpebral fissure. Significant differences were found in the IOP in the KB group, in spherical equivalent in the B and KB groups, and in corneal refractive power in the B groups. Then the 38 eyes of the KB group were divided into two groups by the average level of proptosis and the average difference of IOP, and the corneal refractive power of the two groups was compared by statistical analysis. Significant difference was found in the direction of 0 degree/ 180 degrees in the group with higher than average proptosis and in the direction of 90 degrees/ 270 degrees in the group with higher than average difference in IOP. Multiple regression analysis suggested that higher grades of proptosis were related with steeper vertical meridians and that wider palpebral fissures were associated with steeper horizontal meridians. Multiple regression also showed that the speculum did not cause corneal distortion with the proper relation between level of proptosis and width of the palpebral fissure.

Adult↗
PubMed1996

Serum levels of hyaluronic acid indicate the severity of joint symptoms in patients with systemic and polyarticular juvenile rheumatoid arthritis.

OBJECTIVE: Elevated serum levels of hyaluronic acid (HA) correlate with joint inflammation in adult rheumatoid arthritis (RA). There are no laboratory indices for specifically assessing joint inflammation. Therefore, serial measurements of HA were assessed as a possible tool for measuring the severity of arthritic symptoms in children with juvenile rheumatoid arthritis (JRA). METHODS: Serum levels of HA, measured by a sandwich assay method using HA binding protein, were correlated with the severity of joint symptoms and with laboratory test values in 71 patients with JRA, 30 children with other rheumatic diseases, and 138 children without rheumatic disease. RESULTS: Serum levels of HA showed significant correlation with the severity of joint symptoms, but not with systemic symptoms, in patients with systemic and polyarticular JRA. No other laboratory tests, including C-reactive protein and erythrocyte sedimentation rate, reflected the severity of joint symptoms. This correlation of serum levels of HA with joint symptoms was observed in patients with systemic and polyarticular JRA, but not in pauciarticular JRA, other rheumatic diseases, or nonrheumatic diseases, even when signs of arthritis were present in the latter 3 groups. CONCLUSION: Serum levels of HA are useful in objectively evaluating arthritic symptoms in patients with systemic and polyarticular JRA, and may have diagnostic value in this disease.

Adolescent↗
PubMed1995

RP67580, a neurokinin1 receptor antagonist, decreased restraint stress-induced defecation in rat.

We investigated the possibility that substance P would mediate defecation in rats subjected to restraint-stress. The increases in fecal pellet output caused by restraint-stress were inhibited by a neurokinin (NK)1 receptor antagonist, RP67580 with an ED50 (95% confidence limits) value of 0.59 (0.54-0.65) mg/kg i.p. RP68651, the enantiomer of RP67580 devoid of affinity for NK1 receptors, had little effect on it. In contrast, (+/-)SR48968, an NK2 receptor antagonist, was without effect. Furthermore, capsaicin treatment (125 mg/kg i.p.) was inactive in this model. These results suggest that the activation of NK1 receptors and substance P released from intrinsic neurons of the colon would be involved in stress-induced defecation in rats.

Analgesics↗
PubMed1995

Novel muteins of human tumor necrosis factor with potent antitumor activity and less lethal toxicity in mice.

Eight muteins of recombinant human tumor necrosis factor-alpha (rhTNF; 1SSSRTP...29RR...155L), in which 29Arg was replaced by another amino acid, were prepared and their anti-tumor effects in BALB/c mice bearing Meth A fibrosarcoma were evaluated. The therapeutic indices, which mark the extent of the therapeutically effective dose, of V29 (29Arg-->Val) and D29 (-->Asp) were 3.5 and 3.2, respectively, whereas that of rhTNF was 1.4. Clearly, the therapeutically effective range of these muteins was extended along with a decrease in lethal toxicity. V29 did not produce hypotension in the rat system, but D29 did. In addition, V29 showed potent anti-tumor activity (Tumor Volume Inhibition Rate = 81% on day 15 after implantation) in 3 consecutive injection schedules despite the decreases in toxicity compared with rhTNF. The relative receptor binding constant was determined using HEp-2 cells (expressing mainly 55-kDa-TNF receptor; p55R) and HL60 cells (expressing mainly 75-kDa-TNF receptor; p75R), and revealed that the reduced toxicity of V29 in mice was due to the reduced binding to p55R (34% of rhTNF). On the other hand, the ratio of the constants HEp-2/HL60 of V29 was 11 in comparison with the value of 1.0 for rhTNF, suggesting that this mutein binds preferentially to p55R. The biological activities in human cell lines (HEp-2 and HL60 cells) correlated well with the binding activities to each receptor in vitro. Therefore, the much lower toxicity and the potent anti-tumor activity of this mutein suggest that V29 merits further investigation in pre-clinical and clinical trials.

Amino Acid Sequence↗
PubMed1995

Retinoic acid directly stimulates osteoclastic bone resorption and gene expression of cathepsin K/OC-2.

Vitamin A metabolites such as all-trans-retinoic acid (all-trans-RA) affect several steps of metabolic processes in vertebrates. In the last few years, several studies have shown the effect of RA on bone formation and metabolism. However, mechanisms of its action still remain unclear, especially with respect to the regulation of bone cells. Therefore, this study was carried out to clarify how RA regulates the activity of osteoclasts. Using a pit assay involving unfractionated bone cells, including osteoclasts obtained from rabbits, we found that RA stimulated an increase in the bone-resorbing activity in a dose- and time-dependent manner. Furthermore, this effect occurred more rapidly than that of treatments with 1 alpha,25-dihydroxyvitamin D3. However, this effect of RA may be partly related to cross-talk between osteoclasts and other types of cells. Therefore we studied the effect of RA on isolated osteoclasts. We found that all-trans-RA regulates the gene expression of cathepsin K/OC-2, a dominant cysteine proteinase, at the transcriptional level in mature osteoclasts isolated from rabbits. Moreover, retinoic acid-receptor alpha mRNA and retinoid X-receptor beta mRNA were expressed in these mature osteoclasts. Our results indicate that osteoclasts are target cells for RA and that RA might regulate a part of bone formation and metabolism through osteoclasts.

Animals↗
PubMed1995

Characterization of [3H]YM060, a potent and selective 5-HT3 receptor radioligand, in the cerebral cortex of rats.

The binding properties of a new radioligand, [methyl-3H]-(-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7- tetrahydro-1H-benzimidazole monohydrochloride ([3H]YM060), were studied in membranes of the rat cerebral cortex. [3H]YM060 rapidly associated with its binding sites in membranes and reversibly dissociated. Saturation analysis revealed that the specific binding of [3H]YM060 was saturable and non-specific binding was low. Scatchard analysis yielded a linear plot, suggesting a single population of binding sites with a dissociation constant (Kd) of 8.4 +/- 0.2 pM (n = 3) and the kinetic Kd determined from the association constant (K+1) and the dissociation rate constant (K-1) was similar. The maximum number of binding sites (Bmax) was 37.0 +/- 0.8 fmol/mg protein (n = 3). [3H]YM060 binding was potently and stereospecifically inhibited by serotonin (5-HT)3 receptor agonists and antagonists. Other 5-HT receptor ligands such as 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), methysergide and ketanserin were inactive to inhibit specific binding at 10(-4) M. These results suggest that [3H]YM060 is a highly potent and selective 5-HT3 receptor radioligand and will be useful in the further analysis of 5-HT3 receptors.

Animals↗
PubMed1995

Gastric mucosal protection by YM638, a novel leukotriene D4 receptor antagonist, in rats.

YM638 ([[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl] thio]-1,3,4-thiadiazol-2-yl]thio] acetic acid) is a novel leukotriene D4 receptor antagonist. We investigated the involvement of the leukotriene D4 receptor blocking activity of YM638 in the gastric mucosal protection of this drug in rats. YM638 significantly prevented gastric lesion formation induced by water-immersion restraint stress, indomethacin, absolute ethanol, 0.7 N HCl and the combination of 0.2 N HCl and hemorrhagic shock, with ED50 values of 26.4, 4.1, 4.7, 35.4 and 8.0 mg/kg p.o., respectively. Cetraxate and sofalcone showed inhibitory effects on most of these gastric lesions, but the inhibitory effects of these compounds were much weaker than those of YM638. In contrast, YM638 had no effect on gastric acid secretion and gastric lesion formation in pylorus-ligated rats, or on duodenal lesion formation in cysteamine-administered rats. YM638 competitively antagonized leukotriene D4-induced contraction of the isolated stomach, with a pA2 value of 7.63 +/- 0.18. In anesthetized rats, intravenous YM638 inhibited leukotriene D4-induced aggravation of gastric lesions caused by HCl, and leukotriene D4 and HCl-induced reduction of the potential difference. In addition, oral YM638 significantly increased gastric mucosal blood flow and prevented ethanol-induced increase in gastric vascular permeability. Endogenous prostaglandins, sulfhydryls and nitric oxides were not involved in this inhibitory effect on absolute ethanol-induced gastric lesion. YM638 did not react with the stable free radical 1,1-diphenyl-2-picrylhydrazyl in vitro, indicating that YM638 does not have potential as free radical scavenger. These results suggest that the preventive effect of YM638 on gastric lesions is attributable not only to its leukotriene D4 receptor blocking activity but also to the activation of gastric mucosal defensive mechanisms such as mucosal blood flow and vascular permeability.

Animals↗
PubMed1995

Evaluation of an antisense RNA transgene for inhibiting growth hormone gene expression in transgenic rats.

We compared the levels of growth hormone (GH) mRNA in the pituitary, plasma GH concentration, and altered phenotype in rats heterozygous and homozygous for an antisense RNA transgene targeted to the rat GH gene, with those in nontransgenic rats. We initially investigated whether the transgene promoter, which is connected to four copies of a thyroid hormone response element (TRE) that increases promoter activity, affected in vivo transgene expression in the pituitary of the transgenic rats. Plasma GH concentration correlated negatively with T3 injection in surgically thyroidectomized heterozygous transgenic rats. There was a reduction of about approximately 35-40% in GH mRNA levels in the pituitary of homozygous animals compared with those in non-transgenic rats. Plasma GH concentration was significantly approximately 25-32 and approximately 29-41% lower in heterozygous and homozygous transgenic rats, respectively, compared with that in nontransgenic animals. Furthermore, the growth rates in homozygous transgenic rats were reduced by approximately 72-81 and approximately 51-70% compared with those of their heterozygous and nontransgenic littermates, respectively. The results of these studies suggested that the biological effect of GH in vivo is modulated dose-dependently by the antisense RNA transgene. The rat GH gene can therefore be targeted by antisense RNA produced from a transgene, as reflected in the protein and RNA levels.

Animals↗
PubMed1995

Spongy degeneration in the zitter rat: ultrastructural and immunohistochemical studies.

Pathological changes in the grey matter of the zitter rat were examined by electron microscopy and immunohistochemistry to investigate the pathogenesis of spongy degeneration. Vacuole formation was first detected in the pons and the outer thalamus at 2 weeks of age. The vacuoles arose from the periaxonal or inter-myelinic spaces as well as the cytoplasm of some oligodendrocytes or astrocytes. With increasing age, some dendrites and the cytoplasm of neurons developed an electron lucent area with sparse organelles and the vacuoles occasionally fused together. Although spongy degeneration gradually extended to the entire CNS, no inflammatory or phagocytotic cell infiltration and no viral particles were detected. Glial fibrillary acidic protein immunoreactivity increased transiently in the vacuolated areas from 2 to 15 weeks of age (maximal at 7 weeks of age). Although zitter rats older than 65 weeks showed some reactive astrocytes in vacuolated areas, their numbers and the intensity of immunostaining decreased with advanced vacuolation suggesting astrocytic hypofunction in response to tissue damage. Immunoreactivity for synaptophysin was weaker in the zitter rats than in the control rats throughout the observation period, which suggested that synapse formation was disturbed in the zitter rats, probably due to a combination of hypomyelination and vacuole formation in the grey matter. These findings suggest that an unknown genetic abnormality, probably related to cell membrane biosynthesis or cell-to-cell interactions, produces both hypomyelination and spongy degeneration in the zitter rat.

Aging↗
PubMed1995

Effects of 17 beta-oestradiol and 5 alpha-dihydrotestosterone on the expression of the muscle and heart types of lactate dehydrogenase isozymes in the masseter muscle of developing mice.

17 beta-oestradiol (E2) and/or 5 alpha-dihydrotestosterone (5 alpha-DHT) had no effect on the expression of isozymes of lactate dehydrogenase (LDH) in the masseter muscle of intact male mice. However, treatment with E2 restored the level of the muscle (M) type of LDH isozyme, which had been reduced by testectomy, to that found in intact male mice treated with vehicle only. Moreover, 5 alpha-DHT alone was more effective than E2 in increasing the relative level of this isozyme in testectomized mice. 5 alpha-DHT had a more significant effect on the increase in the relative level of the M-type LDH isozyme when combined with E2. These results suggest that androgens promote, in the presence of oestrogens, the postnatal changes in the characteristics of the masseter muscle of developing male animals.

Animals↗
PubMed1995

Comparative study of the affinities of the 5-HT3 receptor antagonists, YM060, YM114 (KAE-393), granisetron and ondansetron in rat vagus nerve and cerebral cortex.

The 5-HT3 receptor blocking properties of YM060, YM114 (KAE-393), granisetron and ondansetron were examined in the vagus nerve and cerebral cortex of rats. 5-HT and 2-methyl-5-HT induced dose-dependent depolarizations of rat isolated vagus nerve with EC50 values of 2.53 (1.93-3.33) x 10(-6) and 4.03 (2.87-5.66) x 10(-6) M, respectively. YM060, YM114 and granisetron dose-dependently antagonized the depolarization of the rat vagus nerve induced by 5-HT, with decreases in the slope and maximal response at higher concentrations. Apparent pA2 values for these antagonists were 10.27 +/- 0.09, 10.12 +/- 0.16 and 9.44 +/- 0.40, respectively. Ondansetron produced a clear rightward shift of the concentration-response curve to 5-HT. The pA2 value was 8.63 (8.23-9.68). YM060 and YM114 at up to 10(-5) M produced no significant depression of the depolarizing responses to DMPP and GABA. YM060, YM114, granisetron and ondansetron displaced specific binding of [3H]GR65630 to rat cortical membranes with pKi values of 10.48 (10.41-10.57), 10.24 (10.18-10.28), 9.15 (9.02-9.28) and 8.70 (8.64-8.77), respectively. An excellent correlation (r = 0.97) was obtained between pA2 values in the vagus nerve and pKi values in the cerebral cortex. YM060, YM114, granisetron and ondansetron showed low affinities for 5-HT1A, 5-HT2 receptor, adrenergic alpha 1, alpha 2, dopamine D2, muscarinic M2, mu-opioid, benzodiazepine and histamine H1 receptors. These results support the possibility that the same type of 5-HT3 receptor occurs in rat vagus nerve and cerebral cortex.

Animals↗
PubMed1995

Mechanism of enhancement of the immune responses to influenza vaccine with cholera toxin B subunit and a trace amount of holotoxin.

Cholera toxin B subunit (CTB) (1 microgram) and a trace amount of cholera toxin (CT) (0.1-10 ng), when inoculated intranasally into Balb/c mice together with influenza vaccine, induced synergistically a greater delayed-type hypersensitivity (DTH) response to the vaccine than did a trace amount of CT alone. In parallel with the in vivo response, normal peritoneal macrophages that were incubated in vitro with the vaccine and the CT-containing CTB, induced a higher adenylate cyclase activity and a greater ability to transfer DTH response into naive recipient mice than did the macrophages incubated with the vaccine and CT. The treatment of macrophages with the vaccine and CTB failed to induce either adenylate cyclase or DTH response. From these results, the mechanism by which CTB and a trace amount of CT enhance immune responses synergistically could be explained by the enhancement of the CT action on macrophages or by the efficient binding of a trace amount of CT to antigen-presenting cells in the presence of a relatively large amount of CTB, resulting in enhanced cyclic AMP formation followed by enhanced antigen presentation.

Animals↗