Biomedical subjects

S Ono

Publications and source records attributed to S Ono.

At least 199 records · Page 11Linked to original sources

PubMed1999

Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 1. The selection of naphthalene derivatives.

The synthesis and design using molecular modeling techniques for non-peptide, low molecular weight novel fibrinogen receptor (glycoprotein IIb/IIIa: Gp IIb/IIIa) antagonists, is reported. We used a highly potent serine protease inhibitor, Nafamostat, having an amidinonaphthyl unit as the starting compound. The compounds 4-(6-amidino-2-naphthylaminocarbonyl)phenoxyacetic acid (5a) and 4-(6-amidino-2-naphthalenecarboxamido)phenoxyacetic acid (5b) inhibited adenosin-5'-diphospate (ADP)-induced aggregation of human platelet-rich plasma (PRP) with IC50 values of 0.05 and 0.07 microM, respectively, and had lost their ability to inhibit a variety of serine proteases, including thrombin, factor Xa, plasmin and trypsin.

Adenosine Diphosphate↗

PubMed1999

Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 2. Condensed heterocyclic derivatives.

A novel series of platelet receptor glycoprotein (Gp) IIb/IIIa antagonists with condensed heterocycles as their basic core was synthesized. In an in vitro assay, trans-4-(5-amidinobenzofuran-2-carboxamido)cyclohexyloxyacetic+ ++ acid 17e and trans-3-[4-(5-amidinobenzofuran-2- carboxamido)cyclohexyl]propionic acid 17f produced marked inhibitions with IC50 values of 0.018 and 0.006 microM, respectively in a human platelet adenosin-5'-diphospate (ADP)-induced aggregation assay; they also exhibited a wide spectrum of inhibition toward major aggregation agonists (ADP, collagen, thrombin, PMA (tumor promoter) and arachidonic acid). These compounds were > 2-3 orders of magnitude more effective in inhibiting platelet aggregation than human umbilical vein endothelial cell (HUVEC) binding. The oral administration of 10 mg/kg of either 17e and 17f to guinea pig, resulted in a 60% inhibition of ex vivo platelet aggregation after 5 h. Oral administration of ethyl trans-4-(5-amidinoben-zofuran-2- carboxamido)cyclohexyloxyacetate 18e (10 mg/kg) resulted in 80% inhibition of platelet aggregation in dogs for 6 h after oral administration with a return to baseline by 24 h. Ethyl trans-3-[4-(5-amidinobenzofuran-2-carboxamido)cyclohexyl]propionat e 18f (AR0598) produced 80% inhibition for 5 h after oral administration. Prodrug 18e showed a good profile in dogs with a long duration of action. 18e (AR0510) was selected as suitable clinical candidate for development as an orally active antithrombotic agent.

Adenosine Diphosphate↗

PubMed1999

Pulmonary neutrophil accumulation following human endotoxemia.

OBJECTIVE: To elucidate the role of pulmonary neutrophil accumulation in the pathogenesis of human acute lung injury (ALI) following endotoxemia. DESIGN: Retrospective study. SETTING: Surgical unit in a tertiary-care university hospital. PATIENTS: Thirty-three patients who died of intra-abdominal sepsis and received an autopsy. MEASUREMENTS: Just before each patient's death, (1) plasma endotoxin was determined by the limulus gelation test, and (2) the severity of ALI was estimated by the Murray lung injury score. (3) Neutrophil accumulation in the pulmonary microcirculation was evaluated in the autopsy specimens using a computerized picture analysis method. RESULTS: (1) Endotoxin-positive patients were more likely to fall into the severe lung injury group (endotoxin-positive patients, 38% vs endotoxin-negative patients, 0%; p < 0.01). (2) The endotoxin-positive patients exhibited significantly higher neutrophil accumulation in the pulmonary microcirculation than endotoxin-negative patients (8,349 +/- 984/mm(2) vs 4,047 +/- 447/mm(2), respectively; p < 0.01). (3) Severe lung injury patients with endotoxemia had almost the same degree of neutrophil accumulation in the pulmonary microcirculation as mild-to-moderate lung injury patients with endotoxemia (8,338 +/- 1,622/mm(2) vs 8, 359 +/- 1,290/mm(2), respectively), showing a significant higher neutrophil accumulation compared to no lung injury patients without endotoxemia (5,102 +/- 410/mm(2); p < 0.01). CONCLUSION: Endotoxemia might cause ALI and pulmonary neutrophil accumulation. Pulmonary neutrophil accumulation might not be enough to cause severe lung injury (ARDS), although it is necessary to cause ALI, because the degree of pulmonary neutrophil accumulation did not correlate with the severity of ALI.

Adult↗

PubMed1999

Stimulated neutrophils evoke signal transduction to increase vascular permeability in rat lungs.

The mechanisms by which stimulated neutrophils (PMNs) damage pulmonary vascular endothelium were investigated using twenty-four perfused lung preparations isolated from rats. We tested the ability of unstimulated and mechanically stimulated PMNs to adhere to pulmonary endothelial cells and, thereby, alter pulmonary vascular permeability (measured as the pulmonary filtration coefficient) and hemodynamics. To stimulate PMNs, they were gently agitated in a glass vial for 10 seconds. Perfusing lungs with the stimulated PMNs (stimulated group) elicited a 3-fold increase in the filtration coefficient as compared to lungs perfused with unstimulated cells (unstimulated group). This increase in filtration was completely blocked by preincubation of stimulated PMNs with CD18 monoclonal antibody (MoAb group). This increase in filtration coefficient was also completely blocked by GF109203X, a protein kinase C inhibitor (GF group). Pulmonary vascular resistance increased when the stimulated PMNs were injected to the isolated lungs. Although, preincubation of stimulated PMNs with CD18 MoAb successfully blocked and GF109203X partly blocked this increase in pulmonary vascular resistance. The accumulation of stimulated PMNs within the lungs, as assessed by myeloperoxidase (MPO) levels, was blocked by preincubation of stimulated PMNs with CD18 MoAb. However, GF109203X did not decrease MPO levels. These findings suggest that stimulated PMN-induced increases in pulmonary vascular filtration, resulted from endothelial cell injury caused by adhesion to the endothelial cells, evoke intracellular signaling within the endothelial cells.

Animals↗

PubMed1999

Toxic shock-like syndrome resembling phlegmasia cerulea dolens.

A case of a 71-year-old Japanese woman with toxic shock-like syndrome is reported. She was admitted to the hospital because of swelling of the right leg. On admission, right lower leg was erythematous and swollen with an erosive lesion. On the second day, she rapidly fell into shock. Phlegmasia cerulea dolens caused by massive iliofemoral venous thrombosis was suspected because she had a history of deep venous thrombosis. But deep venous thrombus was not detected by venography at emergent surgery for thromboembolectomy. She died 38 hours after admission despite maximal supportive therapy. Group A beta-hemolytic streptococci were isolated from blood culture and soft tissue after the patient died.

Aged↗

PubMed1999

Parametric mapping of cerebral blood flow deficits in Alzheimer's disease: a SPECT study using HMPAO and image standardization technique.

UNLABELLED: This study assessed the accuracy and reliability of Automated Image Registration (AIR) for standardization of brain SPECT images of patients with Alzheimer's disease (AD). Standardized cerebral blood flow (CBF) images of patients with AD and control subjects were then used for group comparison and covariance analyses. METHODS: Thirteen patients with AD at an early stage (age 69.8+/-7.1 y, Clinical Dementia Rating Score 0.5-1.0, Mini-Mental State Examination score 19-23) and 20 age-matched normal subjects (age 69.5+/-8.3 y) participated in this study. 99mTc-hexamethyl propylenamine oxime (HMPAO) brain SPECT and CT scans were acquired for each subject. SPECT images were transformed to a standard size and shape with the help of AIR. Accuracy of AIR for spatial normalization was evaluated by an index calculated on SPECT images. Anatomical variability of standardized target images was evaluated by measurements on corresponding CT scans, spatially normalized using transformations established by the SPECT images. Realigned brain SPECT images of patients and controls were used for group comparison with the help of statistical parameter mapping. Significant differences were displayed on the respective voxel to generate three-dimensional Z maps. CT scans of individual subjects were evaluated by a computer program for brain atrophy. Voxel-based covariance analysis was performed on standardized images with ages and atrophy indices as independent variables. RESULTS: Inaccuracy assessed by functional data was 2.3%. The maximum anatomical variability was 4.9 mm after standardization. Z maps showed significantly decreased regional CBF (rCBF) in the frontal, parietal and temporal regions in the patient group (P < 0.001). Covariance analysis revealed that the effects of aging on rCBF were more pronounced compared with atrophy, especially in intact cortical areas at an early stage of AD. Decrease in rCBF was partly due to senility and atrophy, however these two factors cannot explain all the deficits. CONCLUSION: AIR can transform SPECT images of AD patients with acceptable accuracy without any need for corresponding structural images. The frontal regions of the brain, in addition to parietal and temporal lobes, may show reduced CBF in patients with AD even at an early stage of dementia. The reduced rCBF in the cortical regions cannot be explained entirely by advanced atrophy and fast aging process.

Aged↗

PubMed1999

[Evaluation of the liver uptake rate measured by 99mTc-GSA SPECT to assess liver function].

Whether the global liver uptake rate of 99mTc-GSA directly measured by SPECT is useful as a new index of liver function was evaluated in comparison with biochemical test results (PT%, ChE, Alb, ICG R15, KICG) and Child classification. 99mTc-GSA SPECT was performed in 157 patients with diffuse hepatic disease or hepatobiliary tumor, and two indices, namely the global liver uptake rate measured by SPECT 15 minutes after intravenous injection of 99mTc-GSA (LUS 15) and liver uptake per volume (liver uptake density) were examined. Both LUS 15 and liver uptake density were significantly correlated with biochemical test results and Child classification. In particular, close relationships between LUS 15 and ICGR15 (r = -0.720, p < 0.0001), LUS 15 and KICG (r = -0.750, p < 0.0001), and between LUS 15 and ChE (r = 0.720, p < 0.0001), indicate that LUS 15 is a useful index to evaluate liver function. Moreover, the local liver uptake rate measured by SPECT represented regional liver function and was considered a useful index to predict the function of the remnant liver after invasive treatment such as surgery.

Adult↗

PubMed1999

[Investigation of postoperative death after lung resection for lung cancer caused by interstitial pneumonia].

We investigated interstitial pneumonia, one of the most severe postoperative acute complications of respiratory surgery. In sixteen years, from 1982 through 1997, 2,453 cases underwent thoracotomies caused by lung cancers, in our institute. There were 20 cases (0.79%) who died within 30 days after surgery (operative death). Six out of 20 cases died of interstitial pneumonia, one of the most frequent postoperative complications. We examined these six patients and 2 patients with postoperative interstitial pneumonia who died within 32 days. Preoperative lung function tests, laboratory data, chest CT and/or chest X-ray films cannot predict development of postoperative interstitial pneumonia. Those who acquired postoperative interstitial pneumonia had continuous high fever after surgery following reticular shadows on their chest X-ray and increase in LDH levels. We could not detect any characteristic viral infections. Although, they were treated by steroid, elastase inhibitor and/or immune suppressant, they died within 32 days. In conclusion, development of postoperative of interstitial pneumonia cannot be predicted from preoperative laboratory data and/or lung function tests.

Female↗

PubMed1999

[Factors related to the QT prolongation in chronic renal failure].

QT prolongation, a risk factor for arrhythmia and cardiac death, is observed in uremic patients. Though hypocalcemia, autonomic nerve dysfunction and cardiac hypertrophy are assumed to cause the uremic QT prolongation, the exact mechanism remains unspecified. We therefore examined factors related to the QT interval in chronic renal failure (CRF). Corrected QT interval (QTc) was significantly prolonged in CRF just before the induction of dialysis therapy (group A) compared with nephrotic syndrome with the intact or mildly impaired renal function (group B). QTc was also prolonged in acute renal failure (group C). Cardio-thoracic ratio, serum albumin and Ca correlated with QTc in group A, but not in B or C. A single HD session in group A failed to shorten QTc, despite a significant increase in serum Ca++. Autonomic dysfunction did not appear to be a major determinant of QT prolongation, since QTc was not different between diabetics and non-diabetics in group A and in chronic HD patients (group D). In group D, QTc did not correlate with SV1 + RV5 on ECG or left ventricular wall thickness (LVWT) on echocardiography. In another group of chronic HD patients (group E), there was no significant correlation between QTc and the parameters of left ventricular mass, plasma brain natriuretic peptide (BNP). However, in the patients subjected to repeated echocardiography in group D, QTc and LVWT changed in parallel. In a retrospective analysis of QTc in group D, QTc was maximally prolonged at the time of starting HD therapy, and gradually improved in the following 1-5 years in both diabetics and non-diabetics. In contrast, chronic CAPD patients (group F) revealed no improvement of QTc. Thus, uremic QT prolongation cannot be explained simply by any of the previously assumed factors, but appears to be affected by multiple factors, which are partially correctable by chronic HD therapy.

Autonomic Nervous System Diseases↗

PubMed1999

[A case of myotonic dystrophy showing proximal dominant muscle involvement but not myotonia].

A 45-year-old female had progressive difficulty in climbing stairs and standing from a chair for 10 years. She had binocular cataracts which were operated at the age of 42 years. On examination, she had marked muscle wasting in the proximal limbs, scapular and sternomastoid muscles. She presented as marked muscle weakness in the proximal portion of the lower extremities and moderate in the upper extremities and the legs. Deep tendon reflexes were absent in all limbs. There was no grip myotonia, or percussion myotonia of the thenar muscle and tongue. Myotonia was not elucidated even after the hands were exposed to cold water. Moreover, none of the examined muscles revealed insertion myotonic discharge on electromyography. Serum CK level was normal and IgG value decreased to 546 mg/dl. Muscle biopsy of the left biceps muscle showed the variation in fiber size, increased central nuclei and many fiber with pyknotic nuclear clumps on HE staining. Sarcoplasmic mass and ring fibers were also found on HE staining. There were a few percents of ragged-red fibers on Gomori-trichrome staining, and type 1 fiber atrophy was found on pH 4.5 ATP-ase staining. The expansion of lymphocyte CTG trinucleotide repeats in the myotonin protein kinase gene was about 733, so that she was diagnosed as having myotonic dystrophy (MD). MRI of skeletal muscles exhibited marked atrophy especially in the femoral region and the biceps muscle. This patient had the proximal dominant muscle weakness, and absent myotonia even on electromyographic examination, which are unusual clinical features of adult onset MD.

Atrophy↗

PubMed1999