Biomedical subjects

T Morikawa

Publications and source records attributed to T Morikawa.

At least 19 recordsLinked to original sources

PubMed1995

Augmentation of transport for cisplatin-glutathione adduct in cisplatin-resistant cancer cells.

We studied the outward transport of cisplatin (CDDP)-glutathione (GSH) adduct (DDP-GSH) in CDDP-resistant cancer cells. Incubating the cells in the presence of CDDP resulted in the formation of an adduct with GSH and subsequent transport outside the cells. We used human colonic cancer cells sensitive (HCT8) and resistant (HCT8DDP) to CDDP and human ovarian cancer cells sensitive (A2780) and resistant (A2780DDP) to CDDP as materials. The concentration of intracellular GSH was higher in the resistant cells (118.7 +/- 5.9 nmol/10(6) HCT8DDP versus 19.0 +/- 1.0 nmol/10(6) HCT8 and 24.1 +/- 1.2 nmol/10(6) A2780DDP versus 9.4 +/- 0.5 nmol/10(6) A2780, respectively). The activity of the GSH-synthesizing enzyme, gamma-glutamylcysteine synthetase (gamma-GCS) was higher in the CDDP-resistant cells (7.1 +/- 0.2 milliunits/10(6) HCT8DDP versus 2.2 +/- 0.1 milliunits/10(6) HCT8 and 2.9 +/- 0.1 milliunits/10(6) A2780DDP versus 1.4 +/- 0.1 milliunits/10(6) A2780, respectively). Furthermore, immunological levels of gamma-GCS and the expression of gamma-GCS mRNA were higher in these CDDP-resistant cells than those in the control cells, in accordance with the change in the concentration of GSH. DDP-GSH transport increased in the CDDP-resistant colonic cancer cells by 219% (324 +/- 12 fmol/10(6) HCT8DDP cells/min versus 148 +/- 11 fmol/10(6) HCT8 cells/min) and the CDDP-resistant ovarian cancer cells by 126% (127 +/- 7 fmol/10(6) A2780DDP cells/min versus 101 +/- 8 fmol/10(6) A2780 cells/min). DDP-GSH transport was also estimated using inside-out vesicles from these cells. The active transport of DDP-GSH was 243% of HCT8 in HCT8DDP and 121% of A2780 in A2780DDP. These data suggest that the acquisition of CDDP resistance in cancer cells is due partly to the increase in the transport of DDP-GSH outside the cells as well as the increase in the concentration of GSH. Immunological estimation of the membrane proteins against human erythrocyte glutathione S-conjugate-stimulated Mg(2+)-ATPase sera resulted in no apparent cross-reactivity, suggesting that there are several transport systems for DDP-GSH.

Antineoplastic Agents↗

PubMed1995

A useful testing strategy in phase III trials: combined test of superiority and test of equivalence.

A useful testing strategy is proposed for a confirmatory phase III clinical trial. It consists of a combined test of superiority and test of equivalence, and it is easy to apply. By introducing the strategy, we can perform a post hoc analysis in a confirmatory experiment. Thus a more flexible decision will be possible than the usual single testing method provides. It is shown that the procedure needs no adjustment for multiplicity from the point of view of the closed testing procedure. The relationship between this strategy and a confidence interval is also discussed.

Clinical Trials, Phase III as Topic↗

PubMed1995

Calcium-induced platelet aggregation in washed platelets from guinea pigs.

The present study investigated the effects of extracellular calcium on washed platelets of guinea pigs, rabbits, rats and humans. CaCl2 without agonists induced platelet aggregation in guinea pigs and rabbits, but not in rats or humans. CaCl2 increased platelet [Ca2+]i in Fura-2-loaded guinea pig platelets. Calcium-induced platelet aggregation was inhibited by W-7 (a calmodulin antagonist), aspirin, indomethacin, TMB-8 (an inhibitor of intracellular Ca2+ release) and also nicardipine (a calcium antagonist). These data suggest that CaCl2-induced platelet aggregation is mediated by calmodulin, cyclooxygenase and other, as yet unknown, mechanisms.

Animals↗

PubMed1995

Effect of roxithromycin on peripheral neutrophil adhesion molecules in patients with chronic lower respiratory tract disease.

To evaluate the effects of roxithromycin in patients with chronic lower respiratory tract disease including diffuse panbronchiolitis, we studied lymphocyte function-associated antigen-1 (LFA-1) and Mac-1, neutrophil adhesion molecules, using peripheral neutrophils from healthy volunteers and from patients with chronic lower respiratory tract disease. The number of Mac-1 expressed on neutrophils of the patients was significantly greater (0.68 +/- 0.16) than in the healthy subjects (0.45 +/- 0.14), while the number of LFA-1 expressed on neutrophils of the patients was nearly similar to that in the healthy volunteers (0.95 +/- 0.10 vs 0.89 +/- 0.11). The neutrophil numbers in bronchoalveolar lavage fluid and the number of Mac-1 expressed on peripheral neutrophils significantly decreased in all patients who responded clinically to a low dose of roxithromycin for a long period of time (56.0 +/- 25.2 vs. 22.7 +/- 19.7%, p < 0.05 and 0.70 +/- 0.16 vs. 0.59 +/- 0.08, p < 0.05, respectively), whereas roxithromycin had no effect on the quantitative expression of LFA-1 (0.96 +/- 0.14 to 1.00 +/- 0.09, not significant) in all responders.

Adult↗

PubMed1995

Increase in activated CD8+ cells in bronchoalveolar lavage fluid in patients with diffuse panbronchiolitis.

To study the role of T cells in diffuse panbronchiolitis (DPB), we investigated T-cell subsets in bronchoalveolar lavage fluid (BALF) or 33 patients with DPB, nine patients with bronchiectasis, and 20 healthy volunteers. BALF from DPB patients contained a higher percentage of neutrophils than that from patients with bronchiectasis or healthy volunteers, whereas the percentage of lymphocytes was similar in the three groups. DPB patients, however, had a higher number of lymphocytes and a reduced CD4/CD8 ratio compared with the other subjects. A two-color analysis of T-cell subsets in peripheral blood and BALF revealed a significant increase in the percentage and number of CD8+HLA-DR+ cells and in the number of CD4+HLA-DR+ cells in BALF of DPB patients. The expression of the adhesion molecules CD 11a and CD18 on lung CD3+ cells was enhanced over that on blood CD3+ cells in DPB patients. However, there was no significant difference in the expression of these antigens in peripheral blood or BALF among the groups. There was no significant relationship between BALF interleukin (IL)-8 and lymphocyte accumulation in the lungs of the DPB patients, whereas a significant correlation between the percentage of neutrophils and IL-8 levels in BALF of DPB patients was observed. After treatment with macrolide antibiotics, a significant reduction in the number of lymphocytes and activated CD8+ cells and an elevation in the CD4/CD8 ratio in BALF of DPB patients was observed. Our findings suggest an activation of CD8+ cells in the airway lumen of DPB patients, supporting the hypothesis that lymphocytes are important cellular components of bronchial inflammation in DPB.

Anti-Bacterial Agents↗

PubMed1995

Idiopathic chronic eosinophilic pneumonia associated with noncaseating epithelioid granulomas.

A 34 year old Japanese woman was referred to our university hospital due to pulmonary opacities and bilateral hilar lymphadenopathy on chest X-ray. She also had uveitis, erythematous skin nodules, and oral and genital ulcers. Laboratory data showed eosinophilia in the circulation and bronchoalveolar lavage fluid. Histological study revealed massive eosinophilic infiltration and noncaseating epithelioid granulomas in the lung and mediastinal lymph node, without evidence of vasculitis. Pulmonary opacities, lymphadenopathy, and blood eosinophilia promptly improved with corticosteroid therapy. In this patient, idiopathic chronic eosinophilic pneumonia overlapped with features of sarcoidosis and Behçet's disease.

Adult↗

PubMed1995

Lactam-conformationally restricted analogs of N alpha-arylsulfonyl arginine amide: design, synthesis and inhibitory activity toward thrombin and related enzymes.

Three new lactam-conformationally restricted arginine derivatives, 1-butyl-3-(6,7-dimethoxy-2-naphthylsulfonyl)-3-(3-guanidinoprop yl)-substituted gamma-, delta-, and epsilon-lactams (2-4), were synthesized on the basis of backbone modification of the lead structure, 6,7-dimethoxy-2-naphthylsulfonylarginine n-butylmethylamide (1). We tested these compounds for inhibitory activity toward thrombin and other trypsin-like enzymes (trypsin, factor Xa, plasmin, and kallikrein). All the compounds synthesized (1-4) potently inhibited thrombin with IC50 values of 0.75, 0.70, 0.92, and 3.2 microM, respectively; they inhibited thrombin over 40-fold more effectively than the other enzymes tested. The gamma-lactam (2) with the most profound inhibitory activity toward thrombin was a reversible inhibitor with a Ki of 0.26 microM. Compound 2 also showed better thrombin selectivity than the lead compound (1). The lactam-conformational restriction of arylsulfonylarginine amides, especially gamma-lactam, has thus proved to be a useful device for the improvement of antithrombotic activity.

Arginine↗

PubMed1995

[Effect of anticancer drugs on invasive capacity of human small-cell lung cancer cells in vitro].

The effect of anticancer drugs on invasive capacity of Lu 135 human small-cell lung cancer cells was studied in vitro. the invasive capacity decreased in a dose-dependent manner when tumor cells were treated with the anticancer drugs cisplatin and etopside. The inhibition of tumor cell invasion was almost parallel with the inhibition of tumor cell growth. The anticancer drugs also suppressed tumor cell migration and the activity of the matrix-degrading protease, type IV collagenase, activity. But they did not suppress adhesion to basement membrane protein such as laminin, fibronectin, or type IV collagen. Because tumor cells express adhesion molecules on the cell surface, the effect of the anticancer drugs on the expression of one such molecule, integrin, was also studied. Lu 135 cells expressed alpha 4/beta 1 integrin on the cell surface, and the pattern of integrin expression did not change with exposure with the anticancer drugs. These data suggest that the anticancer drugs inhibit the invasive capacity by suppression of migration and type IV collagenase activity of tumor cells, and that they do not modulate adhesion to the extracellular matrix or cell surface adhesion molecules such as integrin. Furthermore, these findings indicate that anticancer drugs may be useful for anti-metastatic therapy in patients with small-cell lung cancer.

Antineoplastic Agents↗

PubMed1995

Usual interstitial pneumonia associated with primary Sjögren's syndrome.

We describe the first case, to our knowledge, of usual interstitial pneumonia (UIP) as the pulmonary manifestation in primary Sjögren's syndrome (SjS). A 45-year-old woman was admitted to our hospital because of a dry cough and an interstitial shadow on a chest roentgenogram. Labial biopsy and sialogram confirmed a diagnosis of SjS. BAL fluid analysis revealed lymphocytosis with a decreased CD4/CD8 ratio compatible with bronchiolitis obliterans organizing pneumonia or lymphoid interstitial pneumonia. Open-lung biopsy specimen, however, showed evidence of UIP. Open-lung biopsy was a useful and necessary examination to determine the nature of the pulmonary complication in primary SjS. Conservative treatment without corticosteroids maintained a stable condition for a follow-up period of 3 years.

Female↗

PubMed1995

[Antibodies of IgM type against small cell lung carcinoma and 29 kD neuronal antigen of rat in a patient with paraneoplastic sensory neuropathy].

62-year old man who had small cell lung carcinoma (SCLC) with subacute sensory neuropathy had an antibody (IgM) recognizing the antigen on peripheral nerves. The antibody in the serum recognized cell surface antigen on small cell carcinoma cell lines and also reacted with peripheral nerves simultaneously, but not with central nervous system. Two months before admission, he felt difficulty in walking because of paresthesias in the extremities. He was found to have a tumor shadow in chest X-ray, and was diagnosed as SCLC by biopsy of right supraclavicular lymph node. Western blot analysis demonstrated that auto-antibody (IgM) in the serum recognizing the antigen on the neuronal axon with single band at 29 kD. Pathogenesis of carcinomatous neuropathy is still unexplained, but the findings presented here have given rise to the possibility that anti-SCLC antibody may cross-react with neuronal antigen, primarily resulting in neuronal disorder.

Animals↗

PubMed1995

Inhibition of corneal ulceration by tetrapeptidyl hydroxamic acid.

The inhibitory activity of a new peptidyl collagenase inhibitor, FN-439 or tetrapeptidyl hydroxamic acid (H2N-C6H4-CO-Gly-L-Pro-D-Leu-D-Ala-NHOH), was determined against vertebrate collagenases derived from human fibroblast, human polymorphonuclear leukocyte (PMN) and tadpole skin. In addition, the effect of FN-439 in inhibiting corneal ulceration was also investigated with alkali-burned rabbit corneas. FN-439 can block the active site of collagenase, and hydroxamic acid can chelate Zn2+ which is essential for collagenase activity. Furthermore, this compound contains D-amino acids to resist nonspecific host-derived degradative enzymes. In our experiments, corneal ulceration occurred in 5 of the 9 control eyes, but in none of the 9 eyes treated with FN-439 (P < 0.01). The only cellular elements observed at the ulcerated area were PMNs and monocytes. FN-439 appeared to act against PMN collagenase. In addition, we compared the change in the concentration of FN-439 (D-peptide) and the L-form of FN-439 (L-peptide) in aqueous humor aspirated from the rabbit eyes burned with alkali. After incubation for 3 hours, the concentration of the D-peptide was decreased by 3%, while that of the L-peptide was decreased by 60%. FN-439 may be useful for treating noninfectious corneal ulcers because of its potent activity (IC50 = 1 microM) and chemical and biological stabilities.

Animals↗

PubMed1995

[Stereotactic radiosurgery with the gamma knife for brain metastases in patients with lung cancer].

Between February 1992 and April 1993, six patients with lung cancer were treated with gamma knife radiosurgery for brain metastases. Five patients had adenocarcinoma, and one patient had small cell carcinoma. Two patients had solitary metastases, and four patients had multiple metastases. Twelve metastases were treated with the gamma knife (peripheral dose between 12 Gy and 25 Gy). After radiosurgery, three complete and eight partial responses were achieved, which resulted in an overall response rate of 92%. In two patients, histological studies showed that few viable cells were surrounded by necrosis. Neurological status improved in all patients, and none died of complications. However, four of six patients later developed new intracranial metastases outside the treatment field. These data suggest that radiosurgery with the gamma knife is effective against brain metastases in patients with lung cancer, especially when the lesions are deep in the brain.

Adenocarcinoma↗

PubMed1995

[Pulmonary malignant fibrous histiocytoma treated with cisplatin plus etoposide followed by surgery].

A 47-year-old woman was admitted to our hospital with a mass shadow in the upper lobe of the right lung. Undifferentiated carcinoma was diagnosed after transbronchial biopsy. Combination chemotherapy consisting of cisplatin and etoposide was given. After two cycles of chemotherapy, partial response was obtained, and surgery was done because there was no evidence of lymph node metastasis or distant metastasis. After successful surgery, malignant fibrous histiocytoma was diagnosed because histological examination revealed the typical storiform pattern and most tumor cells showed positive cytoplasmic staining for alpha 1-antitrypsin, alpha 1-antichymotrypsin, and CD68. No evidence of another primary lesion was found, so this tumor was thought to be a pulmonary malignant fibrous histiocytoma. Cisplatin and etoposide have synergistic effect in vivo, and this combination is widely used as a standard regimen for small cell lung cancer and other malignancies. It might also be effective against pulmonary malignant fibrous histiocytoma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1994

Enzymic O-sulfation of tyrosine residues in hirudins by sulfotransferase from Eubacterium A-44.

The enzymic O-sulfation of Tyr residues in a recombinant hirudin variant-1 (rHV-1) and its analog in which Glu61 and Glu62 were replaced by Tyr, [E61Y, E62Y]rHV-1, was carried out by use of sulfotransferase isolated from an anaerobic bacterium from the human intestine, Eubacterium A-44. Although rHV-1 was not sulfated by this enzyme, the sulfation of [E61Y, E62Y]rHV-1 was observed, and three kinds of sulfated analog, whose C-terminal six amino acid residues were -PYY(SO3H)YLQ, -PYYY(SO3H)LQ, and -PYY(SO3H)Y(SO3H)LQ, were obtained. Among the sulfated hirudin analogs tested here, the Tyr62 and Tyr63 bisulfated [E61Y, E62Y]rHV-1 showed the strongest thrombin inhibition with the inhibition constant (Ki) of 0.0430 pM, followed by the Tyr63 monosulfated analog (Ki = 0.0593 pM) and the Tyr62 monosulfated one (Ki = 0.158 pM). The Tyr63 monosulfated analog and Tyr62 and Tyr63 bisulfated one were more potent inhibitors of thrombin than unsulfated rHV-1. The increase in affinity caused by sulfation was predominantly due to an increase in the association-rate constant.

Amino Acid Sequence↗

PubMed1994

Inhibition of matrix metalloproteinases by peptidyl hydroxamic acids.

Synthetic inhibitors of interstitial collagenase, tri- and tetrapeptidyl hydroxamic acids, have been developed and tested for their inhibitory activities against human matrix metalloproteinases. A water soluble inhibitor, p-NH2-Bz-Gly-Pro-D-Leu-D-Ala-NHOH (FN-439) inhibited interstitial and granulocyte collagenases, granulocyte gelatinase and skin fibroblast stromelysin with IC50 of 1 x 10(-6) M, 3.0 x 10(-5) M and 1.5 x 10(-4), respectively, but not thermolysin and serine proteinases. FN-439 was found to retain its inhibitory activity against matrix metalloproteinases even after prolonged incubation with pronase or human granulocyte elastase, indicating a favorite candidate of the inhibitor to modulate metalloproteinase activities in vivo.

Amino Acid Sequence↗

PubMed1994

Cluster a personality disorder: a marker of worse treatment outcome of major depression?

This study attempted to identify a specific personality disorder (PD) cluster associated with poor outcome after a 4-month course of antidepressant therapy. Subjects were 96 consecutive outpatients with major depression. The Structured Clinical Interview for DSM-III-R (SCID) was used to make Axis I and Axis II diagnoses. To evaluate the net effect of each PD cluster on the outcome of depression, a log-linear model was applied. The analysis showed that the presence of a PD from cluster A was significantly correlated with the 4-month outcome of depression.

Adult↗

PubMed1994

Constitutive production of multiple colony-stimulating factors in patients with lung cancer associated with neutrophilia.

Production of colony-stimulating factor (CSF) was examined in three patients with lung cancer associated with neutrophilia. All three patients presented a marked increase in neutrophil count (26,000-39,000 microliters-1) that continued at least for 3 weeks and rapidly disappeared after surgical removal of the tumours. Culture media (CM) incubated with the excised tumour tissues stimulated the colony formation of bone marrow myeloid progenitor cells in vitro. Northern blot analysis of poly(A)+ RNA from the tumour tissues revealed a constitutive expression of granulocyte (G), macrophage (M), and granulocyte-macrophage (GM) CSF genes in all tumours. Immunoassay specific for these CSFs revealed that G- and M-CSF immunoreactivity was detected in all CM and GM-CSF protein in two out of three CM. The plasma CSF levels also increased before operation and decreased to normal or near-normal range after operation. In contrast, tumour cell CM obtained from two lung cancer patients without leucocytosis neither stimulated haematopoietic colony formation nor contained immunoreactive CSFs. These results indicated that the neutrophilia found in the three patients was probably caused by constitutive production of multiple CSFs by lung cancer cells.

Aged↗

PubMed1994

[Roxithromycin treatment in patients with chronic lower respiratory tract disease--its clinical efficacy and effect on cytokine].

We demonstrated the efficacy of "long term" roxithromycin (RXM) treatment in 15 patients with chronic lower respiratory tract disease (11 with diffuse panbronchiolitis and 4 with sinobronchial syndrome). (1) Fourteen (93.3%) of the 15 patients showed improvement when assessed by the comprehensive improvement score, and they showed significant improvements in PaO2 (74.2 +/- 10.4 Torr to 84.3 +/- 10.9 Torr, p < 0.01), %VC (86.9 +/- 20.2% to 96.0 +/- 21.9%, p < 0.001) and FEV1 (1.81 +/- 0.87 L to 2.14 +/- 1.08 L, p < 0.01) after RXM treatment. (2) Neutrophils accumulated in the pre-RXM treatment bronchoalveolar lavage (BAL) fluid and decreased in BAL fluid of patients responding to RXM treatment (49.8 +/- 28.3% to 17.1 +/- 15.7%, p < 0.01). Additionally, the levels of interleukin 1 beta and interleukin 8 were significantly higher in BAL fluid of these patients than those in the healthy volunteers (p < 0.025, p < 0.01 respectively), and correlated with the neutrophil accumulation (r = 0.619, p < 0.05). These cytokines showed a decrease after RXM treatment. These results indicated that RXM acts by reducing pulmonary inflammation through reduction of neutrophil migration to inflammatory sites, and is effective on chronic lower respiratory tract disease.

Adult↗