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Biomedical subjects

S Yasuda

Publications and source records attributed to S Yasuda.

At least 199 records · Page 11Linked to original sources
PubMed1996

Synthesis of [[(benzenesulfonamido)alkyl]phenyl]alkanoic acid derivatives containing pyridyl or imidazolyl groups and their thromboxane A2 receptor antagonistic and thromboxane A2 synthase inhibitory activities.

As part of our search for a dual inhibitor possessing both thromboxane A2 (TXA2) receptor antagonistic and TXA2 synthase inhibitory activities, some [[(benzenesulfonamido)alkyl]phenyl]alkanoic acid derivatives possessing a pyridyl or imidazolyl group were synthesized. Their TXA2 receptor antagonistic and TXA2 synthase inhibitory activities were evaluated in terms of the inhibitory effects on U-46619-induced guinea-pig platelet aggregation and on thromboxane B2 (TXB2) production in human platelets, respectively. It was found that 3-[4-[2-(1-imidazolyl)-1-(4-chlorobenzenesulfonamido)ethyl]phenyl] propionic acid (22a), containing an imidazolyl group, is a well-balanced dual inhibitor having both TXA2 receptor antagonistic activity (IC50 = 0.31 microM) and TXA2 synthase inhibitory activity (IC50 = 0.39 microM).

Animals↗
PubMed1996

Synthesis and thromboxane A2 antagonistic activity of [[1-aryl(or benzyl)-1-(benzenesulfonamido)methyl]phenyl]alkanoic acid derivatives.

In order to find new antiasthmatic and antithrombotic agents, various [[1-aryl(or benzyl)-1-(benzenesulfonamido)methyl]phenyl]alkanoic acid derivatives were synthesized. Evaluation of these compounds for thromboxane A2 (TXA2) antagonistic activities indicated that 4-[4-[(4-chlorobenzenesulfonamido)phenylmethyl]phenyl]butyric acid (6h) ,4-[4-[1-(4-chlorobenzenesulfonamido)-2-phenylethyl]phenyl]butyric acid (6y) and many other compounds have potent inhibitory effects on U-46619-induced guinea-pig platelet aggregation. No significant difference in the inhibitory effect between (+)-6h and its antipode could be detected, although (+)-6h and its antipode could be detected, although (+)-6y was about 10 times more potent than (-)6y. The pKb values of 6h and 6y were estimated to be 8.9 and 10, respectively on U-46619-induced contraction of guinea-pig trachea as a pharmacological measure of TXA2 antagonistic activity. These compounds also showed potent inhibitory effects on U-46619-induced bronchoconstriction in guinea-pig after oral administration in vivo. They were also evaluated for other related pharmacological effects involving the arachidonic acid cascade. It was found that these compounds possess TXA2 synthase inhibitory activity together with TXA2 antagonistic activity, and 6h also possesses weak leukotriene D4 (LTD4) antagonistic activity. Structure-activity relationships for TXA2 antagonistic activity of these derivatives are discussed.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

ME3221, a surmountable angiotensin AT1-receptor antagonist, prevents hypertensive complications in aged stroke-prone spontaneously hypertensive rats.

The protective effects of ME3221, 3-methoxy-2,6-dimethyl-4-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-y l]methoxy] pyridine, on aged (32-week-old) stroke-prone spontaneously hypertensive rats (SHRSP) were studied following long-term (for 8 months) oral administration. At a dose of 10 mg/kg/day, ME3221 suppressed the mortality and the hypertensive complications observed in control SHRSP: cerebral apoplexy (hemorrhage, and spongeform and malacia in the cerebral cortex), increased proteinuria, and total N-acetyl-beta-D-glucosaminidase activity, and cardiac hypertrophy and pleural effusion. The protective activity of ME3221, a surmountable angiotensin AT1-receptor antagonist, was comparable to losartan, an insurmountable AT1-antagonist, and also to enalapril, an angiotensin-converting enzyme inhibitor. In addition, ME3221 reduced the systolic blood pressure more effectively than the two reference drugs.

Angiotensin Receptor Antagonists↗
PubMed1996

[A case of nonresectable advanced gastric cancer responding to combined chemotherapy with 5'-DFUR, CDDP, and MMC].

A 39-year-old man was referred for epigastric fullness and a mass in the umbilical region. A giant mass was palpated in the epigastric region, while a mass 1 cm in diameter with a hemorrhagic tendency was felt in the umbilical region. Fluoroscopy of the upper gastrointestinal tract and gastroscopy revealed a Borrmann 3 tumor in the upper part of the gastric corpus. The tumor was found by CT scanning to be growing clearly across the wall of the stomach, and the invasion to the transverse colon was suspected by the enema. The tumor was unresectable because of the extensive tumor invasion of the abdominal wall. Therefore, the patient received 2 courses of combined chemotherapy with 5'-DFUR, CDDP, and MMC. As a result, the tumor in the epigastric region was reduced dramatically, and it became unpalpable 6 months after treatment. At the same time, the tumor in the umbilical region disappeared. Both CT scanning and upper gastrointestinal radiography disclosed tumor reduction, and sufficient oral ingestion became possible. The administration of 5'-DFUR has since been continued as maintenance therapy. Aside from transient anorexia and slight leukopenia, the patient developed no symptoms during the treatment period. At present. 2 years and 9 months after starting chemotherapy, the patient is in good health.

Adult↗
PubMed1996

[Cancer detection with whole-body FDG PET images without attenuation correction].

Whole-body positron emission tomography (PET) using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) has been applied successfully for the detection of cancer. In PET studies, transmission scans for attenuation correction are usually performed. In whole-body PET studies, however, the transmission scans lengthen the acquisition time and are not practical for routine clinical use. Thirty-two patients underwent whole-body PET studies with transmission scans. A total of 106 lesions were true positive on corrected images. At the same time that the corrected images were being reconstructed, uncorrected images were also reconstructed and visually inspected. In a patient with a large breast cancer (11 cm in diameter), the parasternal metastatic lymph node was not identified on the uncorrected image because of image artifacts produced by high FDG accumulation in the breast cancer. In a patient with recurrent colonic cancer, paraaortic metastatic lymph nodes were not well visualized because of attenuation effects. However, 104 out of 106 (98.1%) lesions were recognizable on uncorrected images as well as corrected images. This suggests that uncorrected images can be used for the detection of cancers.

Adult↗
PubMed1996

[Cancer screening with whole-body FDG PET].

We are using whole-body positron emission tomography (PET) for cancer screening. A total of 1,105 healthy subjects have undergone PET studies 1,138 times in fifteen months. Emission scans were performed from the pelvis to the maxilla 45 to 60 minutes after intravenous administration of 260 to 370 MBq 2-deoxy-2-[18F]fluoro-D-glucose (FDG). Malignant tumors were detected with PET in nine patients (0.81%): 2 lung cancers, 2 colonic cancers, 1 breast cancer, 1 thyroid cancer, 1 gastric cancer, 1 renal cancer, and 1 lymphoma. Eight of these patients underwent surgery (excepting the lymphoma patient). Lymph node metastasis was not observed in any of the eight cases and surgery was curative. PET scan results were negative in the cases of three prostatic cancers, one bladder cancer, and two colonic mucosal cancers. High FDG accumulations were noticed in benign lesions such as sarcoidosis, chronic thyroiditis, pulmonary tuberculoma, Warthin's tumor of the parotid gland, and chronic sinusitis. In some cases, image artifacts caused by intense myocardial FDG accumulations resulted in incomplete examinations of the lung. Occasionally, high FDG accumulations were observed in the bowel. Our study results suggest the possibility of using whole-body PET for detecting wide varieties of cancers in resectable stages.

Adult↗
PubMed1995

Pharmacological profile of ME3221, a novel angiotensin II receptor antagonist.

The pharmacological profile of a new surmountable angiotensin AT1 receptor antagonist, ME3221, 3-methoxy-2,6-dimethyl-4-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4- yl]methoxy]pyridine, was studied in several animal models, and was compared with that of losartan. EF2831, 3-hydroxy-2,6-dimethyl-4-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4- yl]methoxy]pyridine, a metabolite of ME3221, is also a surmountable angiotensin AT1 receptor antagonist, whose potency was 1/30 that of ME3221 in vitro, but equal to or 1/3 of that of ME3221 in in vivo experiments. In rats and marmosets, ME3221 antagonized angiotensin II-induced pressor responses, but did not affect bradykinin-induced depressor responses. ME3221 lowered the blood pressure in renal hypertensive rats and spontaneously hypertensive rats (SHR), and its ED25 value was 3 times that of losartan. Repeated administration of ME3221 to SHR had a stable and long-lasting antihypertensive effect without influencing heart rate. Thus ME3221, like losartan, may be useful in the treatment of renal and essential hypertension.

Angiotensin II↗
PubMed1995

Amphoteric drugs. 3. Synthesis and antiallergic activity of 3-[(5,11-dihydro[1]benzoxepino[4,3-b]pyridin-11- ylidene)piperidino]propionic acid derivatives and related compounds.

An important approach to the design of antiallergic agents with reduced penetration into the central nervous system (CNS) is described. A series of 3-[(5,11- dihydro[1]benzoxepino[4,3-b]-pyridin-11-ylidene)piperidino]propion ic acid derivatives (31-47) and related compounds (48-54) were synthesized and evaluated for antiallergic activity and penetration of a compound into the CNS in comparison with the corresponding 6H-dibenz[b,e]oxepin derivative (3). Combination of zwitterionization and introduction of a pyridine component resulted in an increase in antiallergic activity and a great reduction of penetration into the CNS, which was evaluated by the selectivity (B/A) of antihistaminic activities in the central system [ID50 value (B) for ex vivo H1 binding to mouse brain membranes] and in the peripheral system [ED50 value (A) for inhibitory effect on histamine-induced increase in vascular permeability in mice]. This surprising reduction of penetration into the CNS could be considered on the basis of an increase in hydrophilicity caused by both of the zwitterionization and the introduction of a pyridine component. 3-[4-(8-Fluoro-5,11-dihydro[1]benzoxepino[4,3- b]pyridin-11-ylidene)piperidino]propionic acid (33) exhibited a strong antiallergic effect in various experimental models and very low penetration into the CNS. Compound 33 (HSR-609) is now under clinical trial as a promising antiallergic agent with greatly reduced penetration into the CNS.

Animals↗
PubMed1995

Application of whole-body positron emission tomography in the imaging of esophageal cancer: report of a case.

We describe herein a case of esophageal cancer in which both primary and metastatic lymph node foci were successfully imaged with whole-body positron emission tomography (PET) scanning. A 75-year-old woman with biopsy-proven squamous cell carcinoma of the esophagus underwent whole-body PET scanning for staging evaluation. The patient was injected with 373.7 MBq [18F]-2-fluoro-2-D-deoxyglucose (FDG), and 60 min later, scanning was performed from the neck to the pelvis. The whole-body images showed intense FDG uptake in the primary lesion and multiple focal areas of increased FDG uptake in the mediastinum and abdomen, which corresponded to the lymph node foci confirmed by computed tomography (CT) scan. To our knowledge, this is the first report of whole-body PET scanning being applied in the imaging of esophageal cancer.

Aged↗
PubMed1995

Brain tissue identification based on myosin heavy chain isoforms.

Non-muscle tissues contain 3 myosin heavy chain (MHC) isoforms; MIIA, MIIB1 and MIIB2. MIIA is a non-muscle type isoform distributed in all non-muscle tissues and smooth-muscle, while MIIB1 and MIIB2 are brain-type isoforms distributed mainly in neuronal tissues. The ratio of MIIA and MIIB (A/B ratio) differs between tissues, suggesting that this ratio may be a useful marker for tissue identification. To apply the A/B ratio for tissue identification in forensic practice, we developed a highly sensitive ELISA for quantification of each MHC isoform. At least 100 pg of both MHC isoforms could be detected by the present method. Analysis of the A/B ratio of the cerebrum, cerebellum, liver, kidney, spleen and andrenal gland by the present method indicated that the A/B ratio of the brain tissue (< 0.5) was quite different from other tissues (> 3.0). The A/B ratio could be determined from at least 8 micrograms of fresh tissue sample and 0.1 mg of dried tissue sample stored for 1 month at room temperature. Therefore, the A/B ratio seems to be an excellent marker for identification of the brain tissue.

Adrenal Glands↗
PubMed1995

Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4'-hydroxylation status.

We studied the kinetic disposition and metabolism of E3810 [(+/-)-sodium 2-[[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl ]-1H- benzimidazole], a new proton pump inhibitor, and omeprazole in 15 Japanese male volunteers, six of whom were poor metabolizers and nine of whom were extensive metabolizers of S-mephenytoin. All received once-daily 20 mg doses of E3810 or omeprazole for 7 days in a randomized crossover manner, with a 3-week washout period between the two trial phases. The parent drugs and their principal metabolites in plasma and urine were measured on days 1 and 7 after drug administration. The mean values for area under the plasma concentration-time curve (AUC) of omeprazole were 6.3- and 4.4-fold greater, whereas those of E3810 were 1.8- and 1.9-fold greater in poor metabolizers than in extensive metabolizers after the first and final doses, respectively. Although the mean AUC values for both drugs were significantly (p < 0.01 or p < 0.05) greater in poor metabolizers than in extensive metabolizers, the difference in the AUC between the two groups was smaller after E3810 than after omeprazole administration. The AUC of omeprazole tended to increase with the repeated doses in extensive metabolizers, whereas no such change was observed for E3810. The urinary excretions of the principal metabolite(s) of two proton pump inhibitors also reflected the data derived from plasma samples in relation to S-mephenytoin 4'-hydroxylation status. We conclude that the metabolism of two proton pump inhibitors is under coregulatory control of S-mephenytoin 4'-hydroxylase (CYP2C19), but that the magnitude of CYP2C19-mediated metabolism appears to differ between the two drugs. In contrast to omeprazole, the metabolism of E3810 is less saturable in extensive metabolizers during the repetitive dosings.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1995

Comparison of the interaction potential of a new proton pump inhibitor, E3810, versus omeprazole with diazepam in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation.

OBJECTIVE: To compare the interaction potential of E3810, [(+/-)-sodium 2-[[4-(3-methoxpropoxy)-3-methylpyridin-2-yl]methylsulfinyl] -1H-benzimidazole] a new proton pump inhibitor, and omeprazole with diazepam in relation to S-mephenytoin 4'-hydroxylation status. STUDY DESIGN: Fifteen healthy male volunteers consisting of six poor metabolizers and nine extensive metabolizers of S-mephenytoin 4'-hydroxylation participated in the study, where two poor and three extensive metabolizers each as a group were randomly allocated to one of the three different treatment sequences with a 3-week washout period among the three trial phases. Each volunteer received an oral once-daily dose of E3810 (20 mg), omeprazole (20 mg), or placebo for 23 days and an intravenous dose (0.1 mg/kg) of diazepam on posttreatment day 8. Plasma concentrations of diazepam and demethyldiazepam were measured up to 16 days after the administration of diazepam. RESULTS: Diazepam was more slowly metabolized in the poor metabolizers than in the extensive metabolizers. No significant effects of E3810 and omeprazole on any kinetic parameters of diazepam were observed in the poor metabolizers. In the extensive metabolizers, omeprazole significantly decreased the mean clearance of diazepam and increased its half-life, area under the plasma concentration-time curve, and mean residence time compared with E3810 and placebo (p < 0.05 or 0.01), whereas no changes in these kinetic parameters were observed during the treatment with E3810. Omeprazole significantly increased the mean area under the plasma concentration-time curve (0-16 days) of demethyldiazepam in the extensive metabolizers compared with placebo (p < 0.01), whereas E3810 significantly increased it in the poor metabolizers compared with omeprazole or placebo (p < 0.05). CONCLUSION: The results indicate that E3810 as a substrate goes less toward S-mephenytoin 4'-hydroxylase (CYP2C19) and has a much weaker, if any, potential to interact with diazepam compared with omeprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1995

Prognostic significance of an interface pattern of central fibrosis and tumor cells in peripheral adenocarcinoma of the lung.

Fifty-nine surgically resected pulmonary adenocarcinomas were histologically classified into four types (A, B, C, and D) according to the pattern of invasion, ie, the extent of invasive tumor cell growth in the interface zone between alveoli replaced by cancer cells and the central region of fibrosis (so-called "scar"). In pattern A cancer cells proliferate along the alveolar walls without forming a frankly invasive lesion. In pattern B invasive lesions occupy less than 30% and in pattern C more than 30% of the fibrosing area. Pattern D refers to invasion of the bronchial lumen by cancer cells. The 59 tumors included 14 of pattern A, 12 of pattern B, 16 of pattern C, and 17 of pattern D. The 5-year survival rate for patients with pattern A tumors was 100%, and the rates for patients with pattern B, C, and D tumors were 64.2%, 30.0%, and 11.8%, respectively. Each difference between pairs of survival curves was statistically significant (P < .05). We found a correlation between the pattern of invasion and other prognostic factors. However, even in the cases evaluated as favorable by other prognostic factors (stage I, tumor less than 35 mm in diameter, negative for lymph node metastases, well-differentiated histology, negative for subpleural invasion, negative for vascular invasion) the survival curves became steeper going from pattern A to patterns B, C, and D. We conclude that the pattern of invasion is correlated with the prognosis of surgically treated patients. Our study may provide new histological criteria for the prognostic evaluation of pulmonary adenocarcinoma.

Adenocarcinoma↗
PubMed1995

Association of genetic alterations on chromosome 17 and loss of hormone receptors in breast cancer.

To investigate possible relationships between genetic alterations and hormonal deregulation during breast cancer development and/or progression, we examined 616 primary breast cancers for loss of heterozygosity (LOH) at chromosomal regions 16q24, 17p13.3 and 17q21, and for amplifications of the ERBB2 and c-MYC loci. A comparison of oestrogen receptor (ER) and progesterone receptor (PgR) status in tumour cells with data concerning these genetic alterations revealed that LOH at 17q21 was significantly correlated with absence of oestrogen receptors (ER) (P < 0.0003) or progesterone receptors (PgR) (P < 0.0001), and with the absence of both (P < 0.0001). Similarly, a significant association was observed between amplification of ERBB2 and the absence of either ER or PgR. LOH at 17p13.3 was associated with the absence of PgR (P < 0.01). These data suggest a possible relationship between specific genetic changes on chromosome 17 and hormonal deregulation in the progression of breast cancer.

Breast Neoplasms↗
PubMed1995

Transient expression of a brain/embryonic-type myosin heavy chain isoform (MIIB2) in regenerating rat liver.

The expressions of non-muscle-type (MIIA) and brain/embryonic-type (MIIB2) myosin heavy-chain isoforms in regenerating rat liver were examined. In regenerating liver after partial hepatectomy, the level of MIIA was nearly constant, while that of MIIB2 increased transiently. The level of MIIB2 was very low in normal livers, and increased gradually and then declined with a peak at the 4th day, when the regeneration was almost completed. The level of proliferating cell nuclear antigen was highest at the 2nd day. Serine dehydratase activity in the liver decreased on partial hepatectomy, began to increase at the 5th day, and reached 71% of the control at the 7th day. These results suggest that MIIB2 plays a role in reconstruction or differentiation of the regenerating tissues rather than in proliferation of hepatocytes.

Animals↗
PubMed1995

Effect of chronic treatment with ME3221 on blood pressure and mortality in aged stroke-prone spontaneously hypertensive rats.

1. The protective effect of ME3221, a surmountable AT1 antagonist, on the hypertension and its concomitant complications in aged (32 week old) stroke-prone spontaneously hypertensive rats (SHRSP) was studied following long-term (32 weeks) oral administration, and compared with those of losartan (metabolite EXP3174 is an insurmountable AT1 antagonist) and enalapril. 2. During the treatment period, ME3221, at a dose of 10 mg/kg per day steadily reduced the systolic blood pressure, and no tolerance was developed to the fall in blood pressure. The reference drugs showed similar activity, but the antihypertensive effect of ME3221 was more potent. 3. In the control group, rats began to die from 52 weeks of age and all rats had died by 64 weeks of age. In contrast, no rats treated with ME3221, losartan or enalapril died before 64 weeks of age. 4. ME3221, losartan and enalapril suppressed the hypertensive complications observed in control SHRSP, that is, cerebral apoplexy (stroke and cerebral oedema), renal injury (increased proteinuria, total N-acetyl-beta-D-glucosaminidase activity and ascites) and heart failure (cardiac hypertrophy and pleural effusion). 5. These results indicate that ME3221 has a stable anti-hypertensive effect, prevents hypertensive complications and prolongs survival in aged SHRSP equally as well as losartan and enalapril.

Aging↗