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H Mitsuhashi

Publications and source records attributed to H Mitsuhashi.

At least 19 recordsLinked to original sources
PubMed1999

Pharmacological activities of TEI-8362, a novel inhibitor of human neutrophil elastase.

1. TEI-8362, 4-(N-(3-((3-carboxypropyl)amino)-8-methyl-1-oxo-4-azaisochromen-6- yl)carbamoyl)-4-((phenylmethoxy)carbonylamino)butanoic acid (C26H28N4O9) is a novel inhibitor of human neutrophil elastase (HNE). We evaluated its pharmacological profile in vitro and in vivo. 2. TEI-8362 demonstrated potent inhibition of HNE with a Ki value of 1.38 x 10(-9) M. Its selectivity for HNE among a variety of proteases ranged from 163 fold to 68,000 fold in favour of HNE. 3. The pulmonary haemorrhage that occurred after i.t. instillation of HNE to hamsters was inhibited by either i.t., i.v., or inhalant administration of TEI-8362. 4. Intratracheal administration of lipopolysaccharide induced pulmonary neutrophilia. Twenty-four hours after lipopolysaccharide administration, the additional treatment with formyl-methionyl-leucyl-phenylalanine resulted in a specific neutrophil-dependent acute lung injury. In this model, lung injury was significantly attenuated by i.t., i.v., or inhalant administration of TEI-8362. 5. These pharmacological actions of TEI-8362 suggest that this drug has therapeutic value in the treatment of destructive lung diseases due to neutrophils.

Animals↗
PubMed1999

Spontaneous splenic rupture in a patient with large hepatocellular carcinoma.

We report a 61-yr-old woman with acute circulatory failure from spontaneous splenic rupture with decompensated liver cirrhosis complicating large hepatocellular carcinoma exposed on the right liver surface. On admission, the patient was tentatively diagnosed as having rupture of the hepatocellular carcinoma, and she died 15 hours after admission despite blood transfusion. Autopsy revealed that the origin of the intraperitoneal hemorrhage was a ruptured spleen. According to a MEDLINE search of the English-language literature published between 1966 and March 1998, this is the first reported case of spontaneous splenic rupture in a patient with hepatocellular carcinoma without splenic metastasis.

Carcinoma, Hepatocellular↗
PubMed1998

Sulfite is released by human neutrophils in response to stimulation with lipopolysaccharide.

Exposure to sulfite, a well-known air pollutant, induces inflammatory reactions characterized by neutrophil infiltration into the airways. Using a simple and sensitive assay for sulfite concentration in biological fluids, we demonstrate herein that human neutrophils released significant amounts of sulfite (1.0 nmol/h/10(7) cells) in response to lipopolysaccharide (LPS), a major component of bacterial endotoxin. A large proportion of the sulfite release by neutrophils was dependent on inorganic sulfate contained in culture media, suggesting production via the sulfate reducing pathway in this response. We also show that glucocorticoids and FK506 completely inhibit LPS-mediated sulfite release by neutrophils. Given the well-known antimicrobial activities of sulfite, our results suggest that sulfite acts as a neutrophil mediator of host defense. A putative role of sulfite as an endogenous biological mediator is further underscored by the observation that in vivo administration of LPS is associated with a marked increase in the serum concentration of sulfite in Wistar rats. Inhibition of sulfite release by immunosuppressive agents may contribute to increased susceptibility to bacterial infection commonly associated with the administration of these drugs.

Animals↗
PubMed1998

Case report: a patient who developed an amoebic liver abscess during treatment with interferon.

A 65-year-old female received recombinant interferon (IFN) alpha-2b daily for the treatment of chronic hepatitis C. Fever (39 degrees C or higher) developed 14 days after the start of administration. Abdominal computed tomography suggested multiple liver abscesses, which had not been detected before IFN administration. An autopsy revealed an amoebic liver abscess. A subclinical infection of Entamoeba histolytica in this case developed into amoebic liver abscess during IFN administration.

Aged↗
PubMed1998

Relationship between endothelial function and fibrinolysis in early hypertension.

Abnormalities in fibrinolysis, endothelial function, and glucose and lipid metabolism have been reported in hypertension. This study was conducted to examine the interrelationships between fibrinolytic factors, glucose and lipid metabolism, and endothelial function in hypertension. The effects of administering an angiotensin converting enzyme inhibitor, benazepril, were also examined. Blood levels of the following substances were measured in patients with borderline and mild hypertension (n=50, 51+/-19 years) and in age-matched controls (n=10): total cholesterol, triglycerides, tissue plasminogen activator activity and antigen, and plasminogen activator inhibitor type 1 activity and antigen. Insulin sensitivity was assessed by oral glucose tolerance test, and endothelial function was assessed by evaluating changes in diameter of the brachial artery during reactive hyperemia as observed by ultrasonography. Activities of tissue plasminogen activator and plasminogen activator inhibitor type 1 were both elevated in the hypertensive patients. Stepwise multiple regression analysis showed that plasminogen activator inhibitor type 1 antigen correlated with insulin sensitivity, total cholesterol levels, and triglycerides levels (P<.01). Endothelial function was negatively correlated with tissue plasminogen activator activity and antigen (P<.01). The chronic administration of benazepril (5-10 mg/d) for 20 weeks improved insulin sensitivity, endothelial function (6.6+/-3.4-->9.0+/-2.5%, P<.01), and tissue plasminogen activator activity and antigen. These results indicate that abnormalities in fibrinolysis are associated with endothelial dysfunction as well as disorders of glucose and lipid metabolism in patients with borderline and mild hypertension. The treatment of such patients with benazepril appeared to improve the impairment in fibrinolysis and endothelial dysfunction.

Adult↗
PubMed1998

Levels of serum glycosaminoglycans in renal failure.

We measured the concentration of serum glycosaminoglycans (GAGs) in patients with glomerulonephritis, renal failure and on hemodialysis using the dye binding method. In glomerulonephritis, concentration of serum GAGs did not increase, and there was no correlation between serum and urinary GAGs. In patients with renal failure and hemodialysis, concentration of serum GAGs was significantly lower than in controls. Concentration of serum GAGs was correlated with concentration of serum albumin, which is an indicator of malnutrition in patients on hemodialysis. One month of hemodialysis did not affect the concentration of serum GAGs in patients with renal failure, but six months of hemodialysis increased the concentration of serum GAGs. These results suggest that matrix production is suppressed in renal failure with malnutrition.

Adult↗
PubMed1997

Serum secretory leukoprotease inhibitor levels in chronic bronchitis and Sjögren's syndrome.

Serum secretory leukoprotease inhibitor (SLPI) is synthesized and secreted by serous cells in airway glands, and the serum level is speculated to reflect airway gland hyperplasia. To test this hypothesis, we measured the serum SLPI in 38 clinically stable patients with chronic bronchitis (3F and 35M; 58 +/- 2 years, mean +/- S.E.M.) (group CB), 24 patients with Sjögren's syndrome (24F; 52 +/- 3 years) (group SG), and compared it with 12 healthy control subjects (6F and 6M; 54 +/- 3 years) (group CN) using an enzyme-linked immunosorbent assay (ELISA). The serum SLPI from group CB (105 +/- 8 ng/ml) was significantly higher than that from group CN (60 +/- 2 ng/ml) and further, it significantly correlated with sputum volume per day. Although the mean value of serum SLPI from group SG (64 +/- 5 ng/ml) was not different from that from group CN, serum SLPI significantly correlated with the duration of respiratory symptoms (cough and/or sputum) in group SG. In conclusion, serum SPLI level reflects airway gland hyperplasia, suggesting that SLPI measurement is a possible laboratory method to estimate airway glandular hyperplasia.

Bronchitis↗
PubMed1997

[What has been done for international harmonization and what remains to be solved?].

With the idea of expediting drug development and increasing the availability of new medicines to patients, the International Conference on Harmonization (ICH) was organized more than five years ago. Since then, significant progress has been made toward harmonizing preclinical and clinical requirements for the development of medicinal products. For companies whose drug development strategy is global and ongoing in different countries, international harmonization has been an important subject for R&D strategy as well as a critical target that must be achieved. Rhône-Poulenc Rorer, a multi national pharmaceutical company, has globally developed an anti cancer drug, docetaxel, in midstream of international harmonization efforts, and faced various difficulties related to international harmonization. In this paper, based on the author's preclinical experience obtained from the development of docetaxel, various approaches in addressing ICH related difficulties/problems and pending issues are described. In conclusion, the author acknowledges that ICH has made a significant achievement in harmonizing the requirements in certain areas of drug development. However, it seems that even a joint effort of ICH participants, pharmaceutical industry and regulatory agencies may not be enough to address social difficulties associated with drug development rather than scientific discipline. Among many other classes of drugs, the relationship with society appears to be most complicated in anti-cancer drug development, specifically at the clinical level, in which cancer patients are recruited for Phase I study. Finally, as a future target of ICH, harmonization efforts on the way NDA dossiers are appraised and processed across tri-partite regulatory authorities is of great interest for international pharmaceutical enterprises.

Antineoplastic Agents↗
PubMed1997

Macrophage apoptosis in rat crescentic glomerulonephritis.

The fate of macrophages at the site of inflammation is unknown. We investigated this question in a macrophage-mediated model of crescentic glomerulonephritis in which macrophage accumulation is relatively stable despite the presence of high levels of local macrophage proliferation. Accelerated anti-glomerular basement membrane glomerulonephritis was induced in groups of six rats that were killed on day 1, 7, 14, or 21. Macrophage apoptosis was demonstrated in kidney sections by three methods: in situ terminal deoxyribonucleotide transferase (TdT)-mediated dUTP nick end labeling (TUNEL) combined with ED1 antibody immunostaining of macrophages, ED1 immunostaining combined with classical nuclear morphology, and electron microscopy. Substantial macrophage apoptosis became evident on day 14 of the disease, following the appearance of high levels of macrophage proliferation. The parallel relationship between proliferation and apoptosis is the likely explanation for the stabilization of macrophage numbers within the inflamed kidney. A striking feature was that macrophage proliferation and apoptosis was largely restricted to areas of focal damage, such as in the development of glomerular crescents. Increasing levels of macrophage proliferation and apoptosis were evident as crescents developed from a cellular to a fibrocellular phenotype, with a dramatic reduction in both of these processes in the progression to a fibrotic phenotype, suggesting an important role for macrophage apoptosis in the resolution of fibrocellular crescents to an acellular fibrotic structure. In conclusion, this study has identified apoptosis as an important mechanism counterbalancing local proliferation in the regulation of macrophage accumulation at sites of inflammation. Indeed, apoptosis may be a central regulator of the progression and resolution of macrophage-mediated tissue injury.

Animals↗
PubMed1997

Potency of truncated secretory leukoprotease inhibitor assessed in acute lung injury models in hamsters.

We evaluated the potency of truncated secretory leukoprotease inhibitor (truncated SLPI) in a human sputum elastase (HSE)-induced lung injury model and in a specific neutrophil-mediated acute lung injury model in hamsters. Intratracheal administration of HSE induced acute lung hemorrhage that could be measured by determination of the hemoglobin content in the bronchoalveolar lavage fluid. Intratracheal administration of truncated SLPI 1 hr before HSE administration inhibited acute lung hemorrhage in a dose-dependent manner (ED50 = 46.8 microg/kg), as did i.v. injection of the inhibitor given 2 min before HSE administration (ED50 = 14.7 mg/kg). Intratracheal administration of endotoxin (lipopolysaccharide) induced pulmonary neutrophilia. Twenty-four hours after lipopolysaccharide administration, the addition of formyl-methionyl-leucyl-phenylalanine resulted in a neutrophil-dependent acute lung injury that expressed an increase in hemoglobin content and in elastase-like activity in bronchoalveolar lavage fluids. In this model, lung injury was significantly attenuated by i.v. and intratracheal administration of truncated SLPI. These results suggest that truncated SLPI appears to be a good candidate inhibitor for the treatment of destructive lung diseases due to neutrophils.

Animals↗
PubMed1996

Administration of truncated secretory leukoprotease inhibitor ameliorates bleomycin-induced pulmonary fibrosis in hamsters.

The purposes of this study were to investigate the effect of our recently developed truncated secretory leukoprotease inhibitor (SLPI) on bleomycin (BLM)-induced lung injury and fibrosis in hamsters, which is widely used as a model of interstitial pulmonary fibrosis, and to assess the possible involvement of neutrophil elastase in the pathogenesis of pulmonary fibrosis. The fibrosis model was prepared by administration of BLM (10 mg/kg) intratracheally to hamsters. The truncated SLPI was administered at a dose 5 or 15 mg/kg intraperitoneally twice a day only for 10 d starting from the time of BLM administration. BLM administration resulted in decreases in body weight and survival rate. Elastase activity in the supernatant of bronchoalveolar lavage (BAL) fluids was increased at 3 and 7 d after BLM administration in parallel with the increase in the number of neutrophils in the fluids. Histopathologically, at 14 and 28 d after BLM administration, diffuse thickening and fibrosis of alveolar walls with marked cell infiltration and severe distortion of alveolar structure, including honeycomb lung, were observed to have occurred. In this model, the decreases in body weight and survival rate and the increase in elastase activity were inhibited by the truncated SLPI dose-dependently, and pulmonary fibrosis was significantly ameliorated by the administration of this shortened form of SLPI. These results suggest that neutrophil elastase may be implicated in the pathogenesis of BLM-induced pulmonary fibrosis and that the truncated SLPI might be a promising therapeutic in the treatment of interstitial pulmonary fibrosis.

Animals↗
PubMed1996

Aerosolized human neutrophil elastase induces airway constriction and hyperresponsiveness with protection by intravenous pretreatment with half-length secretory leukoprotease inhibitor.

This study was designed to determine the effects of inhaled human neutrophil elastase (HNE) on airway constriction and airway responsiveness, and to examine the protection by an intravenous recombinant half-length secretory leukoprotease inhibitor, r1/2SLPI in guinea pigs. Aerosol inhalation of HNE (250 microgram/ml, for 3 min) caused a transient but significant airway constriction, in which lung resistance (RL) increased from 194 +/- 18 (mean +/- SEM) to 461 +/- 42 cm H2O/L/s (p < 0.001). Thirty minutes after the end of HNE inhalation, airway responsiveness to intravenous 5-hydroxytryptamine (5-HT) was significantly increased. The provocative dose causing a 200% increase in RL (PD200) was significantly decreased from 10.0 +/- 1.2 to 6.5 +/- 0.8 microgram/kg (p < 0.001). Forty-five minutes after the end of HNE inhalation, total cells in bronchoalveolar lavage fluid (BALF) were significantly increased (p < 0.05). Histologic study of intrapulmonary bronchi demonstrated an acute inflammatory response characterized by damage to the epithelium, airway obstruction by mucus plugs, and recruitment of mononuclear and polymorphonuclear cells to the bronchial epithelium. r1/2SLPI (30 mg/kg) injected 5 min before the initiation of HNE inhalation significantly inhibited the airway constriction (p < 0.05), the airway hyperresponsiveness (p < 0.01), and the increase of cells in BALF (p < 0.05). The present data suggest that HNE plays a role in the induction of airway constriction and airway hyperresponsiveness in various inflammatory lung diseases with pulmonary neutrophil infiltration, such as chronic obstructive pulmonary diseases (COPD) and possibly bronchial asthma. r1/2SLPI may be useful as an antiprotease treatment.

Aerosols↗
PubMed1994

A rare portosystemic shunt detected by MRI and diagnosed by dynamic liver scintigraphy with Tc-99m phytate.

Although various types of portosystemic shunts with portal hypertension have been widely reported, a collateral circulation near the pancreas head is rare. The authors report a case of a rare portosystemic shunt surrounding the pancreatic head, which was diagnosed by dynamic liver scintigraphy using Ikoma's scintigraphic criteria for the presence of portosystemic shunts. According to these criteria, abnormal accumulation of radioactivity at various abdominal sites (not identified on static images after the dynamic study) on 6 or more continuous frames of 5-second intervals (i.e., for 30 seconds or more after the arterial phase) indicates the presence of a portosystemic shunt. If liver scintigraphy is performed on a patient with portal hypertension, the dynamic study is valuable in the detection and diagnosis of a portosystemic shunt.

Aged↗
PubMed1994

Increased excretion of urinary transforming growth factor beta in patients with focal glomerular sclerosis.

The urinary transforming growth factor beta (TGF-beta) excretion was measured in 33 patients including 10 with systemic lupus erythematosus (SLE), 8 with focal glomerular sclerosis (FGS), 9 with IgA nephropathy (IgAN), and 6 with membranous nephropathy (MN), and in 7 healthy subjects by enzyme-linked immunosorbent assay using a monoclonal antibody specific for TGF-beta 1 + 2 + 3. A significantly increased urinary TGF-beta excretion was observed in FGS patients (555.5 +/- 458.4 ng/mg Cr) as compared with normal controls (46.9 +/- 43.9 ng/mg Cr) (p < 0.05) and a relative increase in SLE patients (96.4 +/- 58.2 ng/mg Cr) and a decrease in MN patients (24.8 +/- 13.3 ng/mg Cr). In contrast, there was no difference in TGF-beta excretion between IgAN patients (54.1 +/- 37.4 ng/mg Cr) and normal controls. A correlation between the amount of proteinuria and TGF-beta was not found. As has been previously demonstrated in experimental studies, TGF-beta may play a similar role in human glomerular diseases. The results obtained in this study raised the possibility that extracellular matrix might be produced by glomerular cells in vivo under the control of TGF-beta and that TGF-beta might act as a stimulator for the development of glomerulosclerosis.

Adolescent↗
PubMed1994

Combined treatment with cyclophosphamide and prednisolone can induce remission of nephrotic syndrome in a patient with renal amyloidosis, associated with rheumatoid arthritis.

A 67-year-old woman, who had been diagnosed with classical rheumatoid arthritis (RA), was admitted to our hospital because of massive proteinuria. Biopsy of the kidney revealed deposition of amyloid fibrils in the subepithelial and subendothelial spaces of the glomerular capillary walls. Though the treatment with prednisolone and dipyridamole against nephrotic syndrome and amyloidosis due to RA was not effective, cyclophosphamide, which was added after tapering of prednisolone, was able to induce remission of nephrotic syndrome after two years. The levels of CRP and serum amyloid A protein (SAA) returned to within the normal limits. As the impairment of renal function is thought to be due to deposition of amyloid supplied from the precursors of amyloid fibrils filtered from the general circulation in RA patients, remission of nephrotic syndrome might result from the suppression of production of SAA or removal of amyloid fibrils. Cyclophosphamide, which has the potential both to suppress disease activity in RA and to produce degradation of amyloid fibrils in glomeruli, may be useful against renal or systemic amyloidosis complicated by RA.

Aged↗
PubMed1994

Henoch-Schönlein purpura in rheumatoid arthritis.

This is the first report of Henoch-Schönlein purpura associated with permanent joint damage due to rheumatoid arthritis, which was observed in 3 of the 10 adults we treated for Henoch-Schönlein purpura since 1974. Each of 3 women had been admitted with palpable purpura of the lower extremities. The diagnosis was based on various findings including arthralgia, stiffness, and/or swelling of the joints, and on the results of radiographic, immunofluorescence and other studies. Renal biopsy revealed slight mesangial proliferation in 2 of the patients. The nephropathy did not deteriorate following discharge. However, bilateral swelling of the wrists with destructive joint changes was subsequently observed on radiographs in all patients. Since 2 patients showed positivity for human leukocyte antigen DR4, this antigen may have been a genetic factor in the joint disease in these patients.

Adult↗
PubMed1994

[Thrombotic thrombocytopenic purpura (TTP) with a low level of apolipoprotein A-I (Apo A-I) which responded to combination of vincristine and beraprost].

A 51-year-old man was admitted to the psychiatric ward because of increasing confusion and irrational behavior. He was later transferred to our department due to anemia and thrombocytopenia. A diagnosis of thrombotic thrombocytopenic purpura (TTP) was made based on the presence of thrombocytopenic purpura, microangiopathic hemolytic anemia, neurological symptoms and fever. Corticosteroids, plasma exchange (PE), dextrans, dipyridamole and vincristine (VCR) were given without satisfactory response. Beraprost sodium was prescribed followed by a dramatic improvement and complete remission. A number of reports indicated that prostacyclin metabolism was involved in the pathogenesis of TTP. Recently Apo A-I was identified to be a prostacyclin-stabilizing factor, which was initially low in this patient. If patients do not respond to either PE or VCR, consideration should be given to treatment with beraprost, especially when the level of Apo A-I is low.

Apolipoprotein A-I↗