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Biomedical subjects

K Miyata

Publications and source records attributed to K Miyata.

At least 199 records · Page 11Linked to original sources
PubMed1995

Intra-arterial administration of the angiogenesis inhibitor TNP-470 blocks liver metastasis in a rabbit model.

We evaluated the best route of administration of TNP-470, an angiogenesis inhibitor, by comparing the anti-tumour effects and toxicity following injection via the hepatic artery, the portal vein, or the jugular vein in a rabbit model of liver metastases. Following the injections of 1 x 10(6) VX2 carcinoma cells into the portal vein of rabbits, 50 mg of TNP-470 was injected continuously into the hepatic artery, portal vein, or jugular vein for 7 days. The number of tumours on the surface of the liver was counted 14 days following the start of the infusion, and the serum glutamic-oxaloacetic transamine (GOT), glutamic-pyruvic transaminase (GPT) and total bilirubin concentrations were examined. In addition, a coloured silicon rubber was injected into the vessels of the liver to visualise the capillary networks around the tumours and assess the degree of suppression of angiogenesis by TNP-470. The mean number of tumours following intra-arterial injection (17.5 +/- 2.9) was significantly less than the control (237.0 +/- 34.0) (P < 0.05). The mean numbers of the tumours following intraportal (89.1 +/- 16.0) and intravenous (140.6 +/- 31.2) injection were both less than the controls (215.3 +/- 45.5, 284.8 +/- 55.4 respectively), but the differences were not significant. We conclude that intra-arterial injection of TNP-470 is the most effective method for preventing liver metastases in this model.

Animals↗
PubMed1995

Overcoming the metastasis-enhancing potential of human tumor necrosis factor alpha by introducing the cell-adhesive Arg-Gly-Asp sequence.

A mutein, F4168, of human tumor necrosis factor alpha (hTNF-alpha) containing the cell-adhesive Arg-Gly-Asp (RGD) sequence near the N terminus was constructed. In contrast to hTNF-alpha, the mutein had binding activity to B16F10/L5 melanoma cells similar to that of fibronectin or laminin, indicating that the adhesive nature of the RGD sequence is conferred upon hTNF-alpha. Introduction of the RGD sequence did not alter the antitumor potential of hTNF-alpha. Simultaneous injection of F4168 and B16F10/L5 melanoma cells into mice did not enhance metastasis formation in lungs, whereas hTNF-alpha significantly promoted it. Enhancement of spontaneous lymph node metastasis of B16F10/L5 cells was also evident in TNF-alpha- but not in F4168-treated mice. In the spontaneous lymph node metastasis model of MethA fibrosarcoma, F4168 injection inhibited metastasis formation more effectively than hTNF-alpha. B16F10/L5 melanoma cells treated with hTNF-alpha enhanced not only their binding activity to laminin but also their invasive potential into Matrigel, whereas F4168 showed no such enhancement. These results suggest that F4168 is a low-toxicity mutein of hTNF-alpha.

Amino Acid Sequence↗
PubMed1995

Novel mutein of tumor necrosis factor alpha (F4614) with reduced hypotensive effect.

To eliminate systemic toxicity, including the hypotension associated with human tumor necrosis factor alpha (TNF-alpha), we constructed mutant proteins (muteins) by mean of genetic engineering. A novel mutein, F4614, containing mutations of 5Thr-->Gly and 6Pro-->Asp, which resulted in the introduction of cell-adhesive Arg-Gly-Asp and 29Arg-->Val, had remarkably reduced hypotensive effects and lower lethality. We present evidence that the Arg-->Val mutation at position 29 is largely responsible for the reduced hypotensive effect. This effect of F4614 was thought to be closely correlated with its low inducibility of nitric oxide and prostaglandin E2 in vivo. In addition, the therapeutically effective dose of F4614 to MethA fibrosarcoma-transplanted mice was increased compared with that of TNF-alpha, indicating a wide therapeutic index. These results indicated that F4614 has several advantages as a systemic therapeutic drug in the treatment of cancer.

Amino Acid Sequence↗
PubMed1995

Serratia marcescens lung abscess in a child with autoimmune neutropenia.

Though Serratia marcescens is widely known to be the cause of serious infections in immunocompromised hosts, a lung abscess caused by S. marcescens is very rare. A 5 year old boy who had previously been diagnosed with autoimmune neutropenia was admitted because of fever and cough. In spite of treatment with some antibiotics, he developed a lung abscess. Aspiration of the pleural fluid revealed that S. marcescens was the pathogen of the disease. In the present case, there were feasible risk factors for the development of Serratia lung abscess namely neutropenia, chronic gingivitis at the time, and treatment with cyclosporin A. There are no reported cases of autoimmune neutropenia which developed into S. marcescens lung abscess in the literature as far as we can determine.

Autoimmune Diseases↗
PubMed1995

Acute rheumatic fever and poststreptococcal acute glomerulonephritis caused by T serotype 12 Streptococcus.

We present a rare case of a 10 year old Japanese boy with acute rheumatic fever accompanied with poststreptococcal acute glomerulonephritis. We isolated group A Streptococcus serotype T 12, a strain that was thought to be nephritogenic but not rheumatogenic, from throat culture. Although rare, physicians should be aware that acute renal disease may accompany rheumatic fever.

Acute Disease↗
PubMed1995

[A clinical study of gastrointestinal flora in patients with, or without MRSA colonization in the upper-respiratory tract after introduction of preventive measures of hospital infection].

In early 1980's methicillin-resistant Staphylococcus aureus (MRSA) was reported as a major pathogenic organism of geriatric hospital infection in Japan. At the same time in the A geriatric hospital MRSA infection was prevalent. To decrease nosocomial infections some active preventive measures against hospital infection were taken since Oct. 1991. After introduction of preventive measures of hospital infection in geriatric ward (190 beds) nosocomial bacteremia and pneumonia were markedly decreased in comparison to the episode number before introduction of prevention. However several patients with MRSA colonization were observed every month. The aim of this clinical study was to clear how frequent MRSA was isolated from the gastric juice and stool. Any MRSA was not observed in 63 cultured stool, but just one MRSA was isolated in patients with MRSA colonization. On the other hand gram-negative organisms, which were E. coli, P. aeruginosa, P. mirabilis etc., were frequently observed in cultured stool. In conclusion, we considered frequency of MRSA colonization in gastrointestinal space was not so high but rather very low.

Adult↗
PubMed1995

New 1,4-benzodiazepin-2-one derivatives as gastrin/cholecystokinin-B antagonists.

A novel series of 1-aroylmethyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one derivatives was prepared and evaluated for activity as gastrin/cholecystokinin (CCK)-B receptor antagonists. In vitro binding studies showed that some derivatives exhibited potent affinity for gastrin CCK-B receptor and high selectivity over peripheral CCK(CCK-A) receptor. Furthermore these compounds potently inhibited pentagastrin-induced gastric acid secretion upon intravenous administration in an in vivo model in rats. Structure-activity relationship studies of this series suggested that 1-[(R)-2,3-dihydro-1-(2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phe nyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (35b, YM022) was the optimal compound with IC50 values of 0.17, 0.11 and 150 nM for gastrin, CCK-B and CCK-A receptors, respectively, and an ED50 value of 9.5 nmol/kg (i.v.) in rats. The absolute configuration of the precursor of YM022, an (R)-3-amino-1,3-dihydro-2H-1,4-benzodiazepin-2-one derivative ((R)-25), was determined by X-ray crystallographic analysis of its (S) mandelate. It would be expected that YM022, a potent and selective gastrin CCK-B receptor antagonist, inhibits gastric acid secretion without inducing gastrin-mediated side effects such as hypergastrinemia and hyperplasia of oxyntic mucosa.

Anesthetics↗
PubMed1995

Correction of the QT interval in children.

We evaluated the usefulness of 11 formulas for correcting the QT interval in children, including the square root, cubic root, logarithmic, linear, exponential, and inverse formulas using the Mean-squared residual (MSR) values and Akaike Information Criterion (AIC) in 8,086 first-graders, 9,989 seventh-graders, and 5,786 tenth-graders. The subjects were divided into six groups according to age and sex. MSR and AIC values were lowest in all of the groups for the exponential formula (eQTc) and Fridericia's formula (fQTc). We then evaluated the relative usefulness of these two formulas by determining the optimal value for parameter k using the following exponential model: eQTc = (QT interval)/(RR interval)k. The best-fit value for k was different for each group. However, the tentative abnormal eQTc and fQTc values, determined by statistical analysis, were equivalent in all groups when 0.31 was used as the exponential parameter k. These results suggest that the exponential formula and Fridericia's formula are equally useful for screening for QT prolongation.

Adolescent↗
PubMed1995

[Gastrin/CCK-B receptor antagonists for a novel antiulcer agent].

Gastrin plays an important role in gastrointestinal functions such as gastric secretion and mucosal growth. The hypergastrinemia that results from long-term treatment with proton pump inhibitors and histamine H2-receptor antagonists induces hyperplasia of enterochromaffin-like (ECL) cells and increases the secretory response to pentagastrin (acid rebound). Recently, potent and selective gastrin/CCK-B-receptor antagonists, L-365,260, PD136450 and YM022, have been developed. These compounds inhibit basal and meal-stimulated acid secretion as well as pentagastrin-stimulated acid secretion in rats and dogs. Long-term treatment with gastrin/CCK-B-receptor antagonists does not cause hyperplasia of ECL cells and acid rebound at all. Moreover, they prevent hyperplasia and acid rebound induced by proton pump inhibitors and histamine H2-receptor antagonists. Therefore, gastrin/CCK-B-receptor antagonists are suggested to be novel antiulcer and antisecretory agents without potential for acid rebound, hyperplasia and carcinoid.

Animals↗
PubMed1995

Studies on serotonin (5-HT)3-receptor antagonist effects of enantiomers of 4,5,6,7-tetrahydro-1H-benzimidazole derivatives.

We assessed the 5-HT3-receptor antagonist effects of 4,5,6,7-1H-benzimidazole compounds which are derivatives of YM060, a potent and selective 5-HT3-receptor antagonist, in isolated guinea pig colon. YM114 (KAE-393), YM-26103-2, YM-26308-2 (3 x 10(-9) to 3 x 10(-8) M) produced concentration-dependent shifts to the right of the dose-response curves for both 5-HT and 2-methyl-5-HT (2-Me-5-HT). YM114 (pA2 = 9.08 against 5-HT, pA2 = 8.88 against 2-Me-5-HT), YM-26103-2 (pA2 = 8.27 against 5-HT, pA2 = 8.19 against 2-Me-5-HT), and YM-26308-2 (pA2 = 8.58 against 5-HT, pA2 = 8.4 against 2-Me-5-HT) showed similar pA2 values irrespective of the agonist used, suggesting that they have 5-HT3-receptor blocking activity irrespective of the N-position at the aromatic ring. Since these compounds have an asymmetric center, their enantiomers exist. The S-isomers were one to three orders of magnitude less potent than the respective R-isomer compounds, indicating that the stereochemical configuration of 4,5,6,7-tetrahydro-1H-benzimidazoles is an important determinant of their affinity for 5-HT3 receptors. These results suggest that the highly potent 5-HT3 receptor antagonism and high selectivity for 5-HT3 receptors of 4,5,6,7-tetrahydro-1H-benzimidazole derivatives are conserved irrespective of the position of the nitrogen atom in the aromatic ring and that 5-HT3 receptors favor the R-isometric conformation of these compounds.

Adrenergic alpha-Antagonists↗
PubMed1995

Antisecretory and antiulcer effects of YM020, a new H+,K(+)-ATPase inhibitor, in rats and dogs.

We examined the effects of YM020 (3-cyanomethyl-2-methyl-8-[(3-methyl-2-butenyl)oxy]-imidazo[1,2- a]pyridine), a novel H+,K(+)-ATPase inhibitor, on gastric acid secretion and experimental gastroduodenal lesions in rats and dogs. Intraduodenal, subcutaneous and oral YM020 inhibited basal gastric acid secretion in pylorus-ligated rats with ED50 values of 9.1, 9.1 and 9.5 mg/kg, respectively. Oral pretreatment with YM020 5 hr before ligation still suppressed acid secretion, with a potency a little less than that of omeprazole. In anesthetized dogs, intravenous YM020 inhibited histamine-, methacholine- and pentagastrin-induced gastric acid secretion with ED50 values of 0.05, 0.01 and 0.08 mg/kg, respectively. In Heidenhain pouch dogs, although oral YM020 (3 mg/kg) inhibited histamine-induced acid secretion, acid output returned to control levels faster than in dogs treated with omeprazole. Oral YM020 inhibited the formation of water-immersion restraint stress-, indomethacin-, absolute ethanol-, 0.7 N hydrochloric acid- and cysteamine-induced gastric or duodenal lesions with ED50 values of 2.9, 4.3, 2.0, 11.7 and 8.4 mg/kg, respectively. Moreover, subcutaneous YM020 also suppressed the formation of ethanol- and HCl-induced gastric lesions. These results suggest that YM020 has an antisecretory effect almost the same as or 2 to 3 times weaker than those of omeprazole and that its duration is not as long as that of omeprazole in rats and dogs. Furthermore, YM020 possesses a cytoprotective effect and the mechanism of YM020 may be different to that of omeprazole.

Administration, Oral↗
PubMed1995

Effect of serotonin (5-HT)3-receptor antagonists YM060, YM114 (KAE-393), ondansetron and granisetron on 5-HT4 receptors and gastric emptying in rodents.

We investigated the effects of YM060 [(R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazol e hydrochloride] and YM114 (KAE-393) [(R)-5-[(2,3-dihydro-1-indolyl)-carbonyl]-4,5,6,7-tetrahydro-1H- benzimidazole hydrochloride] on 5-HT4 receptors and gastric emptying in normal and cisplatin-treated rats and compared results with those for ondansetron and granisetron. YM060, YM114, ondansetron and granisetron dose-dependently inhibited the specific binding of [3H]-GR113808 ([[1-[(2-methylsulphonyl)amino]ethyl]-4-piperidin-yl]methyl 1-methyl-1H-indole-3-carboxylate) in guinea pig striatum, with pKi values of 5.53, 5.13, 5.21 and 5.63, respectively. According to the pKi values reported in 5-HT3-receptor binding of [3H]GR65630 to rat cortical membranes, the affinity of YM060, YM114, ondansetron and granisetron for 5-HT4 receptors was approximately 5, 5, 3.5 and 3.5 log units lower than that for 5-HT3 receptors, respectively. In the guinea pig longitudinal muscle with myenteric plexus and rat esophageal tunica muscularis mucosae, YM060 and YM114 showed neither 5-HT4-agonistic nor antagonistic properties. Although ondansetron produced concentration-dependent increases in the magnitude of the twitch response in longitudinal muscle, it did not possess 5-HT3- and 5-HT4-agonistic activity. Granisetron antagonized 5-HT-induced relaxation of the rat esophagus with an apparent pA2 value of 5.39. Intravenous YM060, YM114, ondansetron and granisetron significantly enhanced gastric emptying of glass beads and improved cisplatin-induced slowing of gastric emptying in rats. These results indicate that the selectivity of YM060 and YM114 for 5-HT3 receptors is higher than that of ondansetron and granisetron and that these 5-HT3 antagonists have gastroprokinetic activity in normal and cisplatin-treated rats without affecting 5-HT4 receptors.

Animals↗
PubMed1995

Characteristics of inhibitory effects of serotonin (5-HT)3-receptor antagonists, YM060 and YM114 (KAE-393), on the von Bezold-Jarisch reflex induced by 2-Methyl-5-HT, veratridine and electrical stimulation of vagus nerves in anesthetized rats.

We evaluated the inhibitory effects of YM060 [(R)-5-[(1-methyl-1H-indol- 3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride] and YM114 (KAE-393) [(R)-5-[(1-indolinyl)carbonyl]-4,5,6,7-tetrahydro-1H- benzimidazole monohydrochloride] on the von Bezold-Jarisch reflex (BJR) induced by 2-methyl-5-HT, a selective serotonin (5-HT)3-receptor agonist; veratridine, which stimulates chemoreceptors and baroreceptors; and electrical stimulation of vagal efferent nerves in anesthetized rats. Results were compared with those of ondansetron and granisetron. 2-Methyl- 5-HT (5-160 micrograms/kg, i.v.) and veratridine (100-200 micrograms/kg, i.v.) dose-dependently decreased the heart rate (BJR). YM060, YM114, ondansetron and granisetron dose-dependently inhibited 2-methyl-5-HT (40 micrograms/kg, i.v.)-induced BJR, with ID50 values of 0.012, 0.060, 0.97 and 0.15 microgram/kg, i.v., respectively. Their 5-HT3 receptor blocking potencies against 2-methyl-5-HT-induced BJR were largely consistent with those against 5-HT-induced BJR. In contrast, higher doses (100 micrograms/kg, i.v.) of YM060, YM114, ondansetron and granisetron did not inhibit veratridine (150 micrograms/kg, i.v.)-induced BJR. Atropine (300 micrograms/kg, i.v.) abolished bradycardia induced by electrical stimulation of vagal efferent nerves, whereas YM060, YM114, ondansetron and granisetron had no effect at a dose of 1000 micrograms/kg, i.v. 5-HT (0.625-5.0 micrograms) injected into the left ventricle also caused a dose-dependent decrease in heart rate, an effect that was abolished by YM060 (0.1 microgram/kg, i.v.), atropine (100 micrograms/kg, i.v.) and vagotomy. These results suggest that YM060 and YM114 are highly potent and selective 5-HT3-receptor antagonists that do not affect veratridine- or electrical stimulation-induced bradycardia in anesthetized rats. They also suggest that 5-HT-induced BJR in anesthetized rats originates from 5-HT3 receptors located on the endings of vagal afferent nerves in the heart.

Animals↗
PubMed1995

Synergistic effects of insulin-like growth factor II (IGF-II) with leukemia inhibiting factor (LIF) on establishment of rat pluripotential cell lines.

To examine effects of IGF-II on establishment of pluripotential diploid cells from rat embryos, we cultured blastocysts in medium containing mouse LIF with or without IGF-II. Combination of mouse LIF (5,000 units/ml) and rat IGF-II (100 ng/ml) promoted growth of inner cell mass (ICM) and was effective for establishment of pluripotential cell lines derived from the ICM. The cell lines indicated colony forms different from the rat ES cell lines. However, they showed morphological alteration to adult-like tissue cells, formed embryoid body in suspension culture, and thus, seemed to retain a pluripotent characteristics. The rat IGF-II is useful for establishing of pluripotential cells efficiently.

Animals↗
PubMed1995

[Effects of angiogenesis inhibitor TNP-470 to suppress the recurrence in the liver remnant after partial hepatectomy for liver metastases in rabbits].

We investigated the effects of an angiogenesis inhibitor, TNP-470, in suppressing the recurrence in the liver remnant after partial hepatectomy for VX2 liver metastases model of rabbits. After inoculation of 1 x 10(6) VX2 tumor cells via the portal vein, the medial lobe of the liver was resected. Then, TNP-470 (7 mg/body/day) was infused (Group 1), or distilled water (Group 2), continuously via the mesenteric vein for a week. The control group received only infused distilled water via the mesenteric vein. Fourteen days after the tumor inoculation, there were 66.0 +/- 20.2 (mean +/- SD) metastatic colonies on the liver surface of control group, against 23.3 +/- 24.0 and 123.7 +/- 47.9 colonies in Group 1 and Group 2, respectively. There were significant differences between control group and Group 2, and between Group 1 and Group 2. We consider that the liver regeneration following hepatectomy might provoke tumor growth of occult metastases in the liver remnants. TNP-470 suppressed these growth by its anti-neovascular activity. And this effect reduced the number of metastatic colonies. Fourteen days after hepatectomy, the weights of the liver were no different among 3 groups. The BrdU Labeling Index was also no different between Group 1 and Group 2. TNP-470 did not suppress the regeneration of the liver remnant. We consider that the systemic side effects of TNP-470 might be made minimal, because this agent affects only on endothelial cells. These results suggest that the angiogenesis inhibitor TNP-470 is beneficial to suppress hepatic recurrence after partial hepatectomy for liver metastases without suppression of liver regeneration.

Animals↗
PubMed1995

[Hepatic arterial infusion therapy for gastric liver metastasis using implanted reservoir].

Gastric liver metastasis is a fatal disease, and there is no golden standard as to its therapeutic mode. We experienced 58 such cases. Liver resections were performed in six cases (Group 1). Hepatic arterial infusion (HAI) chemotherapy, with 500 mg 5-FU and 100 mg of carboplatin as one shot weekly, was performed in fifteen cases (Group 2). The 50% survival was 656 days for Group 1, and 565 days for Group 2. Another nine cases, implanted with arterial catheter and reservoir did not qualify for HAI due to subsequent extra-hepatic spread of the disease (Group 3). For the rest of the patients (Group 4, n = 28), HAI could not be applied, due to existing extrahepatic spread of gastric cancer, which exhausted these patients. The 50% survival was 104 days and 93 days for Group 3 and Group 4, respectively. HAI therapy showed considerably improved survival for gastric liver metastasis. However, its indication needs to be clarified further.

Adenocarcinoma↗
PubMed1995

Molecular typing of the methicillin resistance determinant (mec) of clinical strains of Staphylococcus based on mec hypervariable region length polymorphisms.

We used a method for molecular typing the methicillin resistance determinant (mec) based on the size of the mec-associated hypervariable region amplified by the polymerase chain reaction (PCR) to examine 61 methicillin-resistant Staphylococcus aureus (MRSA), 15 methicillin-resistant (Mcr) S. epidermidis, and 11 Mcr S. haemolyticus clinical isolates. In the 61 MRSA isolates, five sizes of PCR products were observed. The MRSA isolates were grouped into five hypervariable region (HVR) genotypes on the basis of the size of the PCR product. Three different sizes were detected among 15 isolates of Mcr S. epidermidis and two sizes among 11 isolates of Mcr S. haemolyticus. The PCR products amplified from 14 of 15 Mcr S. epidermidis isolates were the same as products amplified from MRSA isolates, which was confirmed by the PCR-SSCP (single-strand conformation polymorphism) method. In methicillin-susceptible isolates, the target gene was not amplified. This method is thought to be useful in epidemiologic investigations of nosocomial infections caused by MRSA. This is the first typing method capable of comparing the mec determinants of MRSA isolates and Mcr coagulase-negative staphylococcal isolates to establish the origin of the mec determinant.

Base Sequence↗