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Biomedical subjects

K Yasunaga

Publications and source records attributed to K Yasunaga.

At least 37 records · Page 2Linked to original sources
PubMed1993

Treatment of adult T-cell leukemia/lymphoma with MST-16, a new oral antitumor drug and a derivative of bis(2,6-dioxopiperazine). The MST-16 Study Group.

BACKGROUND: MST-16, a new orally administered bis(2,6-dioxopiperazine) analogue and an inhibitor of topoisomerase II, was given to 24 patients with adult T-cell leukemia-lymphoma (ATLL) in a Phase I-II multi-institutional cooperative study. METHODS: MST-16 was administered orally daily for 7 days, with courses repeated at intervals of 2-3 weeks in 24 patients. RESULTS: Two complete remissions (CR) and eight partial remissions (PR) were obtained in 23 evaluable patients who received 1200-2800 mg/day of MST-16. Among 13 acute-type ATLL, one CR and five PR were obtained. Among eight lymphoma-type ATLL, two PR were detected. Among two chronic-type ATLL, one CR and one PR occurred. Remissions were obtained at 7-232 days (median, 23 days) and lasted 43-374 days (median, 68 days). The major toxic effects were leukopenia (68%), anemia (52%), thrombocytopenia (35%), and gastrointestinal disorders (22%). CONCLUSIONS: MST-16 was shown to be effective in ATLL, which has no standard therapy. This drug deserves further clinical trials because it shows little cross resistance to currently available antitumor drugs.

Administration, Oral↗
PubMed1993

Addition of serum from patients with collagen diseases increases to cultured human endothelial cells production and release of von Willebrand factor.

The addition of sera from patients with collagen diseases, particularly those with vascular complications, to the supernatant of cultured vascular endothelial cells (EC) in vitro significantly increased the surface and intracellular amounts of von Willebrand factor antigen (vWF:Ag) compared with results obtained with sera from normal healthy subjects. Peak levels of vWF:Ag occurred after 24 h of in vitro culture. Moreover, the amounts of vWF:Ag secreted into the EC supernatant with patient serum added were significantly higher than the amounts secreted into EC supernatant with control serum added, even after 48 h of in vitro culture. Levels of large and intermediate multimers (LIM) of von Willebrand factor (vWF) increased in EC supernatant exposed to serum from patients with collagen diseases as compared with levels in supernatant exposed to serum from normal controls, whereas no significant differences were detected overall between adding the plasma of patients and of normal subjects. In addition, C-reactive protein (CRP) induced a time- and dose-related release of vWF:Ag from EC, while glucocorticoid did not effect the release of vWF:Ag from EC. These results suggest that the sera of patients with collagen diseases, particularly those with vascular complications, stimulate the production and release of LIM of vWF from EC.

C-Reactive Protein↗
PubMed1993

Flow cytometric analysis of changes in cytoskeletal proteins during platelet destruction and activation using a monoclonal antibody against platelet myosin.

We developed a new monoclonal antibody directed against platelet myosin (NNKY6-19). Using this antibody, we analyzed platelet cytoskeletal changes related to stimulation with thrombin and to long-term storage. Immunoelectron microscopy showed increased binding of NNKY6-19 to pseudopods and the open canalicular system during treatment with thrombin (0.1 U/ml) and during storage for 7 days. Flow cytometry also showed increased binding to platelets by NNKY6-19 and an antiactin monoclonal antibody during storage. The binding of NNKY6-19 showed an increase greater than that with the antiactin antibody after storage of platelets for 7 days and after thrombin treatment. These findings indicated that the increased binding of NNKY6-19 had some relationship to changes in intracellular myosin and platelet morphology. Thus use of NNKY6-19 allowed analysis of subtle changes related to platelet activation, which differed from those detected by antibodies against platelet glycoproteins or by the antiactin antibody. This antibody appears to provide a simple method for studying changes in platelet cytoskeletal and surface proteins.

Actins↗
PubMed1993

Platelet activation induced by an antiplatelet autoantibody against CD9 antigen and its inhibition by another autoantibody in immune thrombocytopenic purpura.

In a patient with immune thrombocytopenic purpura (ITP), we found a novel platelet-activating IgG (act-IgG) and an inhibitory IgG (inhi-IgG) that prevented activation induced by both CD9 monoclonal antibody (mAb) and the act-IgG. Purified IgG from the patient plasma caused a rise in [Ca2+]i and the aggregation of normal platelets, and bound to a 24 kD membrane protein. This aggregation was inhibited by aspirin, staurosporine, an inhibitor of protein kinase C, and F(ab')2 fragments of MALL13, a CD9 mAb. When the platelet count of this patient rose to normal range, the act-IgG disappeared. About 2 weeks later, the relapse of thrombocytopenia was observed. The purified IgG obtained in this period did not activate platelets but inhibited both the rise in [Ca2+]i and platelet aggregation stimulated by NNKY 1-19, a CD9 mAb, as well as the act-IgG, and bound to a 40 kD membrane protein. The inhi-IgG prevented the binding of IV-3, a mAb against Fc gamma receptor II (Fc gamma RII), but did not prevent the binding of NNKY 1-19 to its antigen. We suggest that the activating autoantibody recognized CD9 antigen and activated both the thromboxane- and phospholipase C-dependent pathways, while the inhibitory autoantibody recognized the Fc gamma RII and inhibited CD9 antibody-induced platelet activation mediated via this receptor.

Adult↗
PubMed1993

Detection of platelet antigen for antiplatelet antibodies in idiopathic thrombocytopenic purpura by flow cytometry, antigen-capture ELISA, and immunoblotting: a comparative study.

We compared three methods of detecting platelet antigens for antiplatelet antibodies in patients with idiopathic thrombocytopenic purpura (ITP), i.e., a microtiter well antigen-capture enzyme-linked immunosorbent assay (AC-ELISA), a platelet suspension immunofluorescence test using flow cytometry (PSIFT-FCM), and Western blotting. Using PSIFT-FCM, the reactivity of NNKY1-32, an anti-glycoprotein (GP) IIb/IIIa antibody, and of NNKY5-5 (anti-GPIb) to platelets from 60 ITP patients were examined. By PSIFT-FCM, both the peak channel and the relative fluorescence value were below the mean-2SD for healthy control platelets in 15 patients when NNKY1-32 was used and in 2 patients when NNKY5-5 was used. Western blotting gave an apparent molecular weight for GPIb of 160,000, while GPIIb was 135,000 and GPIIIa was 88,000. By the AC-ELISA, 12 patients were positive for NNKY1-32 and 4 for NNKY5-5. Although NNKY1-32 binding was detected by PSIFT-FCM in 15 of the ITP patients using platelets, only 3 were positive using plasma. By AC-ELISA and Western blotting of plasma, 12 and 10 of the patients were positive for NNKY1-32 and NNKY5-5, respectively. Our results suggest that none of the three methods is good enough to stand alone and that they should be used together in the analysis of platelet antigens for antiplatelet antibodies in ITP.

Autoantibodies↗
PubMed1993

Effects of kami-kihi-to (jia-wei-gui-pi-tang) on autoantibodies in patients with chronic immune thrombocytopenic purpura.

We studied the effect of Kami-kihi-to (Jia-Wei-Gui-Pi-Tang) on the production of autoantibodies in ten patients with chronic immune thrombocytopenic purpura. After administration of Kami-kihi-to, platelet count was increased in seven of the ten patients (p < 0.05). Using Western blotting, we demonstrated the disappearance of autoantibody reaction with antigen in one patient. However, platelet-associated IgG was decreased in eight of ten patients (p < 0.05). Kami-kihi-to appears to promote the suppression of autoantibodies in patients with chronic immune thrombocytopenic purpura. No side effects were observed in any patient. Thus, Kami-kihi-to may be a useful and safe drug in the management of chronic immune thrombocytopenia purpura.

Administration, Oral↗
PubMed1993

Early detection of diabetic nephropathy and criteria for the initiation of therapy.

In 86 patients with non-insulin-dependent diabetes mellitus who were negative for proteinuria by a test paper method, the albumin excretion rate was compared to the albumin/creatinine ratio, and a baseline albumin/creatinine ratio value was determined at which therapy to arrest the progression of nephropathy should be initiated. The albumin excretion rate, albumin/creatinine ratio, and urinary creatinine excretion were determined from urine samples obtained at outpatient visits. The reproducibility of time-restricted urine sampling was investigated using the creatinine excretion rate. The mean coefficient of variation was found to be 42%, and inaccurate urine sampling appeared to cause variation in the albumin excretion rate. A significant difference was evident between males and females in creatinine excretion (0.823 +/- 0.152 mg/min for males and 0.577 +/- 0.182 mg/min for females, p < 0.001). The baseline albumin/creatinine ratio value for initiating therapy was established to be 36 mg/g creatinine for males and 51 mg/g creatinine for females. Use of the albumin/creatinine ratio appears to provide a simple and valuable index for determining when to initiate therapy for diabetic nephropathy.

Adult↗
PubMed1993

Periodic production of antiplatelet autoantibody directed against GPIIIa in cyclic thrombocytopenia.

We report here a female patient with cyclic thrombocytopenia associated with antiplatelet autoantibodies. There was an inverse relationship between the level of platelet-associated IgG and platelet count. Bone marrow megakaryocytes were normal in number even during the thrombocytopenia. The binding of monoclonal antibodies (mAbs) against glycoprotein (GP) IIb/IIIa to patient platelets was significantly inhibited in the thrombocytopenic phase, while these mAbs normally bound to patient platelets obtained during the normal platelet count. Western blotting and mAb-specific immobilization of platelet antigens showed that both plasma autoantibody and the eluted IgG from the patient platelets bound to GPIIIa. These results suggest that the periodic production of antiplatelet autoantibody against GPIIIa caused cyclic destruction of platelets in this patient.

Adult↗
PubMed1993

Expression of platelet alpha-granule proteins in a human megakaryocytic leukemia cell line (CMK 11-5).

We investigated the expression of three platelet alpha-granule proteins, thrombospondin (TSP), von Willebrand factor (vWF), and fibrinogen (Fbg), in a human megakaryocytic cell line (CMK 11-5) by immunocytochemical staining, using the alkaline phosphatase anti-alkaline phosphatase (APAAP) complex method and immunoelectron microscopy of ultrathin-frozen sections. CMK 11-5, established from a Down's syndrome patient with acute megakaryoblastic leukemia, has characteristics closely resembling those of normal megakaryocytes. Under basal conditions, TSP expression was observed in the alpha-granules, whereas the other two proteins were not detected. When the cells were cultured with 12-o-tetradecanoylphorbol-13-acetate (TPA), the expression of TSP was enhanced and vWF was also detected, but not Fbg. Cells cultured in the presence of plasma for 24 h took up Fbg and stored it in their alpha-granules. These findings suggest that TSP and vWF are synthesized by CMK 11-5 cells, with the former being produced more rapidly than the latter, whereas Fbg is endocytosed from the plasma.

Cytoplasmic Granules↗
PubMed1993

Flow cytometric analysis of surface membrane proteins on activated platelets and platelet-derived microparticles from healthy and thrombasthenic individuals.

We used flow cytometry to investigate surface membrane protein expression by platelets and platelet-derived microparticles from normal individuals and a patient with Glanzmann's thrombasthenia. Microparticles were detected by both forward scatter and side scatter using FACScan. The binding of coagulation factors on microparticles was investigated by using monoclonal anti-Factor IX (IXa) and anti-Factor X (Xa) antibodies. Furthermore, the procoagulant activity of microparticles was measured with a chromogenic substrate (S-2222) using a microtiter enzyme-linked immunosorbent assay. Both types of platelets showed similar release of microparticles. Microparticles released from platelets after activation with the calcium ionophore A23187 did not bind factors IXa and Xa, but when purified factors Va and Xa were added to the incubation buffer, factor Xa binding increased markedly in both normal and thrombasthenic platelets. Both normal and thrombasthenic platelets showed a similar time-dependent release of microparticles when activated with A23187. However, the binding of an antibody to granule membrane protein-140 also increased time-dependently in normal microparticles, but was little increased in thrombasthenic microparticles. These findings suggest that glycoprotein IIb/IIIa does not participate in the expression of prothrombinase activity on the surface of activated platelets and microparticles, whereas this glycoprotein appears to have an important role in the movement of granule membrane protein-140 from platelets to microparticles.

Adult↗
PubMed1993

[Measurement of platelet thromboxane A2/prostaglandin H2 receptor in asthmatic patients].

To evaluate the characteristics of platelet TXA2/PGH2 receptors in patients with bronchial asthma, we performed radiobinding assay of gel-filtrated washed platelets obtained from 15 asthmatic patients and 8 normal adults using [3H]-labeled S-145, a TXA2/PGH2 receptor antagonist, as a radiolinged. Data were evaluated by Schatchard's analysis, and the dissociation constant (Kd), an index of the binding characteristic of receptors, and the maximum number of binding sites (Bmax) were calculated. Venous blood was simultaneously collected and was centrifuged, and platelet-rich plasma was prepared. The platelet aggregation rates induced by various concentrations of U-46619, a TXA2 analogue, were measured by Born's method (nephelometry), and the concentration that induced 50% of the maximum platelet aggregation (EC50) was calculated using a concentration-response curve. The Kd value did not differ between the asthmatic patients and normal controls. Some of the asthmatic patients showed a low EC50 and a high Bmax. EC50 was inversely correlated with Bmax. The number of platelet TXA2/PGH2 receptors was shown to be increased in some asthmatic patients.

Adult↗
PubMed1993

[Study on the inhibitory effect of AA-2414 on platelet aggregation and its clinical effect in asthmatic patients].

We previously reported that AA-2414, an eicosanoid receptor antagonist, inhibits platelet aggregation mediated by TXA2/PGH2 receptors in patients with bronchial asthma, but that the inhibitory effects differ among individuals. In this study, we measured the in vitro inhibition rate of platelet aggregation by AA-2414 using U-46619 as an aggregating agent in 22 asthmatic patients and classified them into Group A (showing an inhibition rate of 60% or more) and Group B (showing a rate of less than 60%). Subsequently, AA-2414 tablets (40 mg/day) were orally administered to both groups for 6 weeks, and the clinical effects were compared. A positive correlation was observed between the in vitro U-46619-induced platelet aggregation rate and the inhibition rate of aggregation by AA-2414. At the end of administration, marked inhibition of U-46619-induced platelet aggregation was observed in all patients. However, Group A showed a higher improvement rate of symptoms than Group B. Asthmatic patients can be classified into the groups showing good or poor platelet responses. The response may reflect reactivity to TXA2 in the local airway.

Adult↗
PubMed1993

Ultrastructural analysis of a human megakaryocytic leukemia cell line (CMK11-5) in response to platelet agonists.

To further characterize the ultrastructure of the human megakaryocytic leukemia cell line, CMK, and its subclone CMK11-5, was observed. Stimulation with platelet agonists, ADP, thrombin, and collagen caused enlargement of vacuoles, projections of the cell surface, appearance of fibrous material in the enlarged vacuoles, and loss of alpha granules. We also found that horseradish peroxidase (HRP) incorporated into the granular structures of the cell could be transported out of the cell. The activation of CMK cells by platelet agonists indicates that human megakaryocytes may be activated in thrombotic states. CMK with particular megakaryocytic properties is a useful cell model for studying megakaryocytic function.

Blood Platelets↗