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T Okazaki

Publications and source records attributed to T Okazaki.

At least 127 records · Page 7Linked to original sources
PubMed1998

Studies on nonpeptide angiotensin II receptor antagonists. I. Synthesis and biological evaluation of pyrazolo[1,5-b][1,2,4]triazole derivatives with alkyl substituents.

Alkyl-substituted pyrazolo[1,5-b][1,2,4]triazole derivatives were synthesized and evaluated for activity as angiotensin II receptor antagonists. Molecules with the (methylbiphenylyl)tetrazole moiety and N-5 were the preferred compounds. Ethyl substitutions at both C-2 and C-7 resulted in the optimal compound, 2,7-diethyl-5-[[2"-(1H -tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]tria zole (5n), with a pA2 value of 8.774 in rabbit aorta. In the in vivo tests, 5n inhibited the angiotensin II-induced pressor response in rats after oral administration. This compound also produced a dose-dependent decrease in blood pressure when administered orally to conscious furosemide-treated dogs, having a longer duration of action as compared to DuP753. These data suggest that 5a may be a useful agent for the treatment of angiotensin II-dependent disease, such as hypertension.

Administration, Oral↗
PubMed1998

Studies on nonpeptide angiotensin II receptor antagonists. III. Synthesis and biological evaluation of 5-alkylidene-3,5-dihydro-4H-imidazol-4-one derivatives.

5-Alkylidene-3,5-dihydro-4H-imidazol-4-one derivatives were synthesized and evaluated for activity as angiotensin II receptor antagonists. Substitutions at C-2 and C-5, respectively, with a propyl group and a 1-methylethylidene group resulted in the optimal compound, 3,5-dihydro-5-(1-methylethylidene)-2-propyl-3-[[2'-(1H-tetrazol - 5-yl)biphenyl-4-yl]methyl]-4H-imidazol-4-one (2b), with a pA2 value of 8.85 in rabbit aorta. When administered orally to rats, 2b showed a greater inhibitory effect on angiotensin II-induced pressor response than DuP 753. Compound 2b also showed a good antihypertensive effect when administered orally to conscious sodium-depleted spontaneously hypertensive rats, with a duration of action of 24 h. These data suggest that 2b may be a useful agent for the treatment of angiotensin II-dependent diseases such as hypertension.

Angiotensin II↗
PubMed1998

Studies on nonpeptide angiotensin II receptor antagonists. IV. Synthesis and biological evaluation of 4-acrylamide-1H-imidazole derivatives.

A novel series of nonpeptide angiotensin II antagonists containing the acrylamide group at the 4-position of the imidazole ring was synthesized and their antagonistic activity was examined by functional assay in rabbit aorta. The acrylamide group was selected as a large lipophilic surrogate for the chloro group of EXP3174. A structure-activity relationship study of the acrylamide moiety has shown that substitution at the 4-position with the N-methyl-3,3-dimethylacrylamide group resulted in the optimal compound, 2-butyl-4-[(3,3-dimethylacryloyl)methyl-amino]-1-[[2'-(1H-tetra zol-5- yl)biphenyl-4-yl]methyl]-1H-imidazole-5-carboxylic acid (1), which was superior to EXP3174 in vitro. Since 1 showed only poor activity against angiotensin II-induced pressor response in rats after oral administration, the carboxylic acid function of 1 was converted into prodrug esters (13). Among these, the 1-[(ethoxycarbonyl)oxy]ethyl ester (13a) showed the most potent and longest-lasting activity when given orally to rats. When administered orally to conscious furosemide-treated dogs, 13a showed an approximately 3-fold increased hypotensive activity in comparison with DuP 753. These data suggest that 13a may be an useful agent for the treatment of angiotensin II-dependent diseases, such as hypertension.

Acrylamides↗
PubMed1998

Isolation and characterization of a new pyrano[4',3':6,7]naphtho[1,2-b]xanthene antibiotic FD-594.

During our screening of microbial metabolites for effective drugs against tumor cell lines, we discovered a new pyrano[4',3':6,7]naphtho[1,2-b]xanthene derivative, FD-594 from the fermentation broth of Streptomyces sp. TA-0256. FD-594 shows moderate activity against tumor cell lines, comparative to that of adriamycin, as well as antibacterial activity against some Gram-positive bacteria.

Animals↗
PubMed1998

A novel bone resorption inhibitor, A-75943 isolated from Streptomyces sp. SANK 61296.

A novel bone resorption inhibitor, A-75943, was isolated from Streptomyces sp. SANK 61296. Its structure was determined to be (1"S,2'R,3"S,4S',5"S)-2-[(3",5"- dimethyl-2"-oxocyclohexan-1"-yl)-6'-oxotetrahydropyran-4'-yl ]acetamide by spectral analyses and chemical conversion of cycloheximide. A-75943 inhibited bone resorption in vitro in a concentration-dependent manner with an IC50 of 0.35 microM, and also displayed an inhibitory effect on bone resorption in thyroid and parathyroid-extracted rats.

Animals↗
PubMed1998

A-53930A and B, novel N-type Ca2+ channel blockers.

A-53930A, B and C, which inhibit N-type Ca2+ channels, were isolated from the culture broth of Streptomyces vinaceusdrappus SANK 62394. A-53930A and B were new compounds which contained a carbamoyl group on the 6-hydroxyl group of the D-gulosamine part of streptothricin. A-53930C was identical to streptothricin B. A-53930A, B and C inhibited [125I]omega-conotoxin MVIIA binding to N-type Ca2+ channels (IC50= 0.17, 0.091 and 0.071 microM), but did not inhibit [3H]PN200-110 binding to L-type Ca2+ channels (IC50 > 50 microM). These compounds also inhibited [3H]norepinephrine release from chick cerebral cortex synaptosomes (IC50=91.0, 20.6 and 39.5 microM), indicating these compounds selectively block N-type Ca2+ channels which are important for neurotransmitter release. It was also revealed that although A-53930C had antimicrobial activity against gram-negative and -positive bacteria and fungi, A-53930A and B showed weak activity only against gram-negative bacteria.

Animals↗
PubMed1998

[Limited operation for stage I lung cancer: a retrospective study].

Although lobectomy is standard therapy for Stage I non-small cell lung cancer, it often cannot be performed in poor-risk patients. In this report, we describe the results of a retrospective study to assess the usefulness of limited operation for stage I lung cancer. Over a 21-year period, 1,286 lung cancers were resected at our center. Among the 497 patients with stage I lung cancer, 36 sublobar resections were performed. There was only one surgery-related death, and the 5-year survival rate was 46% for all patients. At 5 years, survival was 69.2% for patients with squamous cell carcinoma and 33.7% for patients with adenocarcinoma. Survival rates were higher in patients who underwent mediastinoscopy than those who did not, and depended on histological findings and accurate pathological staging.

Adenocarcinoma↗
PubMed1998

[Pathophysiological background of transient hyperphosphatasemia].

We studied the relationship between 23 cases with transient hyperphosphatasemia (TH) and viral infection. Many of the patients appeared to be suffering from viral infection. Measurement of antibody in the titer revealed increases in antibody to Echo 22, Entero 71 and Coxsackie B5 in 20.0%, 11.1% and 11.1% of patients, respectively.

Alkaline Phosphatase↗
PubMed1998

[Sex and age distribution of patients with macroamylasemia found in the daily isoenzyme analysis].

We studied distributions of sex and age for 102 patients with macroamylasemia found in routine isoenzyme analysis. This study was based on a questionnaire to promote understanding of the clinical significance of macroamylase. More than half of the physicians received our report evaluated the information on macroamylase in the questionnaire. Macroamylasemia found in this study consisted of IgA type immunoglobulin in 92% and mostly had high activities in the serum. The back-ground of these patients with macroamylasemia were 10 cases of hepato-biliary disease, 9 cases of diabetes mellitus, 8 cases of autoimmune disease and so on. The frequency of macroamylasemia in males was double than in females and age distribution was not significant in statistic analysis.

Adolescent↗
PubMed1998

[A pulmonary tumorlet with caseous granuloma associated with atypical mycobacterium].

We encountered a case of pulmonary tumorlet with caseous granuloma associated with atypical mycobacterium. A 73-year-old woman was admitted to the hospital because a chest x-ray film showed enlargement of an abnormal shadow in the middle lobe of the right lung. Primary lung cancer was suspected and right middle lobectomy was performed. Acid-fast bacilli (Gaffky 1) were found in a caseous lesion and examination of intraoperatively obtained frozen specimens showed caseous granulomas. The bacilli were later identified as Mycobacterium avium complex. The permanent specimen showed a minute lesion consisting of small clusters of epithelial cells resembling carcinoid tumor in contact with granulomatous tissue. Histopathological examination revealed argyrophilia on Grimelius stain and immunoreactivity to chromogranin-A in the clusters of epithelial cells. Although these results are consistent with small cell carcinoma or peripheral carcinoid tumor, pulmonary tumorlet was diagnosed because of the lesion's small and minimal cytologic atypia, and because of chronic pulmonary damage around the lesion. Pulmonary tumorlets are minute, usually microscopic, tumor-like lesions mostly found in damaged lung tissue obtained at autopsy or during surgery. Morphological diagnosis is sometimes very difficult, but recently these lesions have been regarded as hyperplastic lesions arising in pulmonary neuroendocrine cells (Kultschitzky cells) and caused by chronic pulmonary damage, such as hypoxia and inflammation. Pulmonary tumorlets must be considered in the differential diagnosis of minute lesions suspected to be small cell carcinoma or peripheral carcinoid tumor.

Aged↗
PubMed1998

Increase of mast cells in the liver and lung may be associated with but not a cause of fibrosis: demonstration using mast cell-deficient Ws/Ws rats.

Tissue fibrosis is frequently associated with an increase of mast cells, and mast cells are regarded as playing a role in the induction of tissue fibrosis. We attempted to examine whether mast cells influenced the induction of fibrosis using Ws/Ws mast cell-deficient rats. The mast cell deficiency of Ws/Ws rats is due to a 12-base pair deletion of the c-kit gene. The activity of c-kit receptor tyrosine kinase is remarkably reduced in Ws/Ws rats. Liver fibrosis was induced by the repeated injections of pig serum, and lung fibrosis was induced by the instillation of bleomycin. Marked fibrosis in the liver and lung did occur in the Ws/Ws rats, and the magnitude of fibrosis was more severe in Ws/Ws rats than in control normal (+/+) rats. The mast cell increase was observed in the liver of +/+ and Ws/Ws rats and in the lung of +/+ rats. However, the number of mast cells in the liver of treated Ws/Ws rats with marked fibrosis was comparable to that observed in the liver of nontreated +/+ rats without fibrosis. Histamine content increased in the liver and lung of +/+ rats after the treatment, but it remained in low levels even after the treatment in Ws/Ws rats. Mast cells and histamine did not appear to play important roles in the induction of fibrosis. Thus, an increase in mast cell number and histamine content may be associated with but not a cause of fibrosis.

Animals↗
PubMed1998

[Diagnosis for human parvovirus B19-polyarthritis: usefulness of empty particle B19.ELISA and B19-DNA.PCR].

OBJECTIVE: To evaluate the usefulness of new ELISA for human parvovirus B19 (B19) antibodies and PCR for the diagnosis of acute onset of B19 polyarthritis. METHODS: We evaluated the reproducibility and sensitivity on the detection of anti-B19 antibody by ELISA using recombinant VP-1 and VP-2 (empty particle), and then studied for the prevalence of IgM and IgG B19 antibody in 125 samples for anti-B19 tests. The random study on anti-B19 antibody assay as well as PCR for B19-DNA was also performed in 130 cases with acute onset of arthritis excluding those with known origins, 224 with rheumatoid arthritis and 149 with other categories. RESULTS: The results by using B19-empty particle ELISA were reproducible and showed the assay was a sensitive way for clinical use. IgM anti-B19 antibodies were positive not only in all samples from erythema infectiosum, but also often in those from hemolytic anemia, pure red cell aplasia, fetal hydrops, hepatic injury, fever of unknown origin. Among 130 with acute onset of arthritis, 21 showed positive tests for IgM anti-B19 antibody and/or B19 DNA. On the other hand, 4 among 224 patients with rheumatoid arthritis were positive for IgM anti-B19 antibody, but all of 149 in control group were negative for IgM anti-B19 antibodies and for B19 DNA. CONCLUSION AND DISCUSSION: Anti-B19 ELISA using B19-empty particle which has been introduced as a routine test system, is a useful tool for the diagnosis of acute onset of B19 arthritis. An additional examination using PCR for B19 DNA may contribute for understanding persistent B19 polyarthritis or reactivation of B19 infection.

Adolescent↗
PubMed1998

[Surgical treatment of an aortic arch aneurysm: reports of 2 cases with lesion of the arch vessels].

A 48-year old woman underwent surgery for an aortic arch aneurysm with stenosis or dilatation of three arch vessels caused by aortitis syndrome. Total arch replacement and reconstruction of three arch vessels were performed with hypothermic selective cerebral perfusion (SCP). To avoid atheroembolism and malperfusion to the brain, the rt. common carotid artery was perfused via the rt. subclavian artery through the dacron vascular graft and the lt. subclavian artery was cannulated and perfused distally to stenosis. A 65-year-old man who had an atherosclerotic aortic arch aneurysm with severe stenosis of the brachiocephalic artery underwent operation. In the operation, extracorporeal circulation was instituted with the arterial return through the lt. subclavian artery. Same as case 1, total arch replacement and reconstruction of three arch vessels were performed under hypthermic SCP. In this case, the left common carotid artery was transected and cannulated directly into the vessel, instead of cannulation through the aortic lumen because of atheromatous plaques in the orifice of the left common carotid artery. The patients recovered uneventfully and doing well now.

Aged↗
PubMed1997

Hyperosmolarity-induced gene stimulation is mediated by the negative calcium responsive element.

The negative calcium responsive elements of the parathyroid hormone gene bind to a specific set of nuclear proteins in an extracellular calcium (Ca2+e)-dependent manner. We have found that one of the negative calcium responsive elements, named oligo B, is found in the 5'-flanking region of such vasoactive genes as the vasopressin and atrial natriuretic polypeptide genes. Furthermore, the oligo B-like sequence in the former gene is conserved throughout evolution. Because expression of some of these vasoactive genes is altered by external stimuli which change cell volume, we examined whether oligo B is involved in gene regulation by hyperosmolarity. Here, we demonstrate that the binding between oligo B and its binding nuclear proteins including a redox factor 1 was reduced by hyperosmolarity generated by sodium chloride but not by urea. Such attenuated binding was reversed by dephosphorylating nuclear proteins by a potato acid phosphatase, suggesting that NaCl treatment elicited phosphorylation of these nuclear proteins to weaken their binding activity to oligo B. Furthermore, these nuclear events led to hyperosmolarity-mediated transcriptional stimulation of the genes bearing this DNA element in the cultured cells.

Calcium↗
PubMed1997

Pharmacological profile of YM358, a novel nonpeptide angiotensin AT1 receptor antagonist.

The pharmacological profile of YM358, 2,7-diethyl-5-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]tri azole potassium salt monohydrate, a novel non-peptide angiotensin AT1 receptor antagonist, was studied in vitro and in vivo. YM358 competed with [125I][Sar1, Ile8]angiotensin II for angiotensin AT1 receptors in rat liver membranes. YM358 displayed competitive kinetics and the pKi value was calculated as 8.79. In contrast, YM358 had little effect on the binding of [125I][Sar1, Ile8]angiotensin II to the angiotensin AT2 receptor in bovine cerebellum. In isolated rabbit aorta, YM358 produced a parallel rightward shift in the concentration-response curve for angiotensin II with a pA2 value of 8.82. YM358 had no effect on the contraction induced by KCl, norepinephrine, serotonin, histamine, prostaglandin F2alpha or endothelin-1 even at 10(-5) M. On the basis of pKi values in the binding assay and pA2 values in the isolated tissues, YM358 was approximately 3-10 times more potent than losartan in antagonizing angiotensin AT1 receptors. In pithed rats, intravenous administration of YM358 inhibited an increase in mean blood pressure induced by intravenous infusion of angiotensin II in a dose-dependent manner. In conscious normotensive rats, YM358 at 3-30 mg/kg p.o. inhibited the angiotensin II-induced pressor response in a dose-dependent manner. YM358 at 30 mg/kg caused maximum and complete inhibition 30 min after dosing, and inhibition lasted more than 24 h. These results demonstrate that YM358 is a potent, AT1-selective and competitive nonpeptide angiotensin receptor antagonist. Moreover, YM358 is both orally active and long-lasting. This pharmacological profile suggests that YM358 would be suitable for the treatment of cardiovascular disorders such as hypertension and chronic heart failure.

Angiotensin II↗
PubMed1997

Antihypertensive activity of a nonpeptide angiotensin II receptor antagonist, YM358, in rats and dogs.

The antihypertensive activity of YM358, 2,7-diethyl-5-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]tri azole potassium salt monohydrate, a new nonpeptide angiotensin II receptor antagonist, was characterized in rats and dogs. In conscious rats, YM358 after a single oral administration (1-30 mg/kg) lowered blood pressure. The rank order of hypotensive potency of YM358 in conscious rats was 2-kidney, 1-clip renal hypertensive rats > spontaneously hypertensive rats > normotensive rats on the basis of maximum hypotension. YM358 also caused decreases in blood pressure in 2-kidney, 1-clip renal hypertensive dogs and furosemide-treated dogs. Repeated administration of YM358 to 2-kidney, 1-clip renal hypertensive rats for 28 days produced a stable and long-lasting antihypertensive effect without influencing circadian blood pressure and heart rate rhythms. No reflex tachycardia was observed in any animals of either species treated with YM358. Therefore, the pharmacological profile of this compound indicates that YM358 has potential as a useful antihypertensive agent.

Angiotensin II↗