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Biomedical subjects

K Tsubaki

Publications and source records attributed to K Tsubaki.

At least 55 records · Page 3Linked to original sources

Randomized trials between behenoyl cytarabine and cytarabine in combination induction and consolidation therapy, and with or without ubenimex after maintenance/intensification therapy in adult acute myeloid leukemia. The Japan Leukemia Study Group.

PURPOSE: We analyzed complete remission (CR), disease-free survival (DFS), and event-free survival (EFS) rates in two groups of patients treated with either N4-behenoyl-1-beta-D-arabinosylcytosine (BHAC) or cytarabine, and analyzed DFS with or without ubenimex, a biologic response modifier. PATIENTS AND METHODS: Newly diagnosed patients with acute myeloid leukemia (AML) were randomized to receive either BHAC or cytarabine as remission-induction combination chemotherapy and two courses of consolidation therapy. After maintenance/intensification therapy, patients in CR were randomized to receive either ubenimex and no drug. RESULTS: Of 341 patients registered, 326 were assessable. The age of assessable patients ranged from 15 to 82 years (median, 48). The overall CR rate was 77%: 72% in the BHAC group and 81% in the cytarabine group, and there was a significant difference between the two groups (P = .035, chi 2 test). The predicted 55-month EFS rate of all patients was 30%: 23% in the BHAC group and 35% in the cytarabine group, with a significant difference between groups (P = .0253). The predicted 55-month DFS rate of all CR patients was 38% and that of CR patients less than 50 years of age was 47%. There was no significant difference in DFS between the ubenimex group and the group that did not receive ubenimex. CONCLUSION: Analyses of our clinical trial showed that the use of BHAC in remission-induction therapy and in consolidation therapy resulted in poorer CR and EFS rates in adult AML patients compared with the use of cytarabine at the doses and schedules tested. Immunotherapy with ubenimex after the end of all chemotherapy did not improve DFS.

Acute Disease↗

Agents for the treatment of overactive detrusor. IX. Synthesis and pharmacological properties of metabolites of N-tert-Butyl-4,4-diphenyl-2-cyclopentenylamine (FK584) in human urine.

We synthesized the racemates of the five presumed metabolites (1b-f) of (S)-(--)-N-tert-butyl-4,4-diphenyl-2-cyclopentenylamine hydrochloride (FK584, S(--)-1a), a novel agent for the treatment of overactive detrusor syndrome, in order to confirm the structures of the metabolites and also to evaluate their inhibitory activity against detrusor contraction. (+/-)-N-tert-Butyl-4-(4-hydroxyphenyl)- and 4-(4-hydroxyphenyl)- and 4-phenyl-2-cyclopentenylamines (1b--e) were synthesized via 5-(4-methoxyphenyl)- and 5-(4-benzyloxy-3-methoxyphenyl)-5-phenyl-2-cyclopenten-1-one (9g, h), respectively. Compounds 1b-f prepared in this study were identical with the metabolites in human urine in gas chromatography-mass spectrometry and analytical HPLC. The inhibitory activity of compounds 1b-f against detrusor contraction in vitro induced by electrical field stimulation in guinea-pigs was less potent than that of FK584.

Amines↗

Agents for the treatment of overactive detrusor. V. Synthesis and inhibitory activity on detrusor contraction of N-tert-butyl-4,4-diphenyl-2-cyclopentenylamine.

N-tert-Butyl-4,4-diphenyl-2-cyclopentenylamine ((+/-)-3) was designed to restrict the conformation of terodiline 1 and was synthesized in a 6-step approach starting with diphenylacetaldehyde (10) or in a 4-step approach starting with 2,2-diphenyl-4-pentenoic acid (17). Using di-p-toluoyltartaric acid as a resolving agent, the synthetic (+/-)-3 was resolved into its optically pure forms, (-)- and (+)-3. The (-)-enantiomer (-)-3.HCl (FK584) showed about ten times more potent inhibitory activity on urinary bladder rhythmic contraction in rats (ED30 = 0.18 mg/kg, i.v.) than terodiline (ED30 = 1.9 mg/kg, i.v.), while the (+)-enantiomer (+)-3.HCl showed no inhibitory activity at 1.0 mg/kg i.v. Compound (-)-3.HCl (FK584) has pharmacological properties similar to those of terodiline, as evaluated by in vitro assay and is currently in clinical development for the treatment of overactive detrusor.

Amines↗

A randomized trial comparing interferon-alpha with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase.

A multicenter randomized study was conducted to compare the effect of interferon-alpha (IFN-alpha) with that of busulfan in newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase. From October 1988 to October 1991, 170 patients were randomized to receive either IFN-alpha or busulfan. Of 159 eligible patients, 31 (38.8%) of 80 patients in the IFN-alpha group and 43 (54.4%) of 79 patients in the busulfan group achieved complete hematologic remission, and 38.8% in the IFN-alpha group and 43.0% in the busulfan group achieved partial hematologic remission. A complete cytogenetic response was induced in seven (8.8%) of 80 patients treated with IFN-alpha and two (2.5%) of 79 patients treated with busulfan, and a partial cytogenetic response was 7.5% (6/80) and 2.5% (2/79), respectively. The difference in major (complete and partial) cytogenetic response between the two groups was significant (P = .046). At a median follow-up of 50 months, the predicted 5-year survival rate was 54% in the IFN-alpha group and 32% in the busulfan group (P = .0290), and the predicted 5-year rate of remaining in chronic phase was 41% in the IFN-alpha group and 29% in the busulfan group (P = .1165). As compared with the patients with no cytogenetic response, the patients with any cytogenetic response (complete, partial or minor) after the IFN-alpha or busulfan treatment were significantly superior in the duration of chronic phase (IFN-alpha group; P = .0017, busulfan group; P = .0010) even after correction for the time to response using the landmark analysis. However, there was no significant difference in survival rate in the IFN-alpha group (P = .1065). There was no significant difference in survival rate (P = .3923) and the duration of chronic phase (P = .6258) between the IFN-alpha and the busulfan group in the patients with a cytogenetic response (complete, partial or minor). These results demonstrate that IFN-alpha treatment produces a significantly superior cytogenetic response and survival rate as compared with the busulfan treatment, and unexpectedly, that busulfan can also eliminate Philadelphia chromosome positive clone in a few patients who showed prolonged survival rate and duration of chronic phase.

Adult↗

All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Japan Adult Leukemia Study Group.

We conducted a multicenter trial of treatment with all-trans retinoic acid (ATRA) for newly diagnosed acute promyelocytic leukemia (APL) in the AML-92 study and compared it with our previous study with standard intensive chemotherapy, the AML-89 study, in the view of complete remission (CR) rate, incidence of early death, and event-free survival (EFS). Patients were scheduled to receive oral ATRA 45 mg/m2 daily until CR. If patients had leukocyte counts above 3 x 10(9)/L at the start of therapy, they received daunorubicine (DNR) 40 mg/m2 for 3 days and behenoyl cytosine arabinoside (BHAC) 200 mg/m2 for 5 days in addition to ATRA. During the ATRA therapy, if patients showed myeloblast plus promyelocyte counts higher than 1 x 10(9)/L in the peripheral blood, they received additional DNR and BHAC in the same schedule, as well. A total of 110 patients were entered into the study. Median age was 43 years (range, 16 to 74). Twenty-eight (26%) of 109 patients (one died before the start of therapy) received ATRA alone. Ninety-seven patients (89%) achieved CR; 48 of 49 (98%) aged less than 40 years, 44 of 52 (84%) aged between 40 and 69, and 5 of 8 (63%) aged above 70 achieved CR, respectively; 25 of 28 (89%) with ATRA alone, 46 of 51 (90%) with ATRA plus initial chemotherapy and 26 of 30 (87%) with ATRA plus later chemotherapy attained CR, respectively. Nine (8%) patients died within 28 days after the start of therapy. In contrast, 44 of 62 patients (71%) attained CR, and 13 (21%) died within 28 days in the AML-89 study with the combination of DNR, BHAC, 6-mercaptopurine and prednisolone. Seven developed retinoic acid syndrome and one died of it in the present study. Other toxicities associated with this drug included cheilitis, desquamation, muscle pain, and hypertriglyceridemia. Predicted 23 months EFS for all ATRA-treated patients and disease-free survival (DFS) in the CR cases were 75% and 81%, respectively, in a median follow-up period of 21 months. Compared to the AML-89 study, there was a highly significant difference in remission rate (P = .004), EFS (P = .0007), and also early mortality rate (P = .02). Present results demonstrated that ATRA with or without chemotherapy gives a statistical improvement in CR rate and early mortality rate, as well as superior survival in newly diagnosed APL.

Adolescent↗

Agents for the treatment of overactive detrusor. VIII. Synthesis and pharmacological properties of 4,4-diphenyl-2-cycloalkenylamines including FK584 and 3,3- or 4,4-diphenylcycloalkylamines.

This article describes the synthesis of 4,4-diphenyl-2-cycloalkenylamines (3, 5a) including FK584 (S(-)-3a) and 3,3- or 4,4-diphenylcycloalkylamines (2, 4, 5b) and their inhibitory activities against detrusor contraction. The order of inhibitory activity (i.v.) of the N-tert-butylamine derivatives against urinary bladder rhythmic contraction in rats was as follows: S(-)-4,4-diphenyl-2-cyclopentenylamine (FK584, S(-)-3a) > 4,4-diphenylcyclohexylamine (5b) = R(-)-3,3-diphenylcyclopentylamine (R(-)-4) > or = 3,3-diphenylcyclobutylamine (2) > or = terodiline hydrochloride (HCl) (1) = RS(+/-)-4,4-diphenyl-2-cyclohexenylamine (5a) > R(+)-4,4-diphenyl-2-cyclopentenylamine (R(+)-3a) > or = S(+)-3,3-diphenylcyclopentylamine (S(+)-4). Although the inhibitory activity of FK584 and compounds R(-)-4 and 5b against detrusor contraction in vitro induced with KCl in guinea-pigs was less potent than that of terodiline HCl, their inhibitory activities against detrusor contractions in vitro induced by electrical field stimulation and carbachol were more potent than those of terodiline HCl.

Amines↗

[Preferential proliferation of natural killer cells with bone marrow mononuclear cells in multiple myeloma].

We examined proliferation of natural killer (NK) cells in 10 day mixed culture of peripheral blood mononuclear cells (PBMC) from healthy subjects with irradiated bone marrow mononuclear cells (BMMC) with multiple myeloma. In culture, NK cells increased with 9.5-fold. However, no increase was observed in T cells. The NK cell proliferating activity of PBMC stimulated with BMMC was higher than that of IL-2. NK cells at a purity of 90% or higher purity were collected from 10 day culture. Proliferation of these NK cells was stimulated by the addition of IL-2 but was suppressed by the addition of antibody coated erythrocyte (EA). IFN-gamma production was negligible in cultures of these NK cells alone but was marked in cultures with EA stimulate IFN-gamma production. Next, the NK cell obtained as above showed marked NK activity against K 562 cells, and this activity was further enhanced by the addition of IL-2. Also, while NK cells, these NK cells had some activity against Daudi cells and it was enhanced by the addition of IL-2. These results also suggest the presence of unknown cytokines with NK cell proliferating activities in the bone marrow of patients with multiple myeloma.

Bone Marrow Cells↗

[Detection of IgE antibodies to salt-insoluble wheat proteins in sera of patients with atopic dermatitis by ELISA and immunoblotting techniques].

Specific IgE antibodies against salt-insoluble wheat proteins were investigated in sera from 60 patients with atopic dermatitis (AD) positive to wheat specific CAP-RAST. The salt-insoluble wheat protein fraction was prepared from whole protein fraction of wheat flour, which was extracted by PBS containing 6 M urea. IgE antibodies to salt-insoluble proteins were detected in 15 of the sera. IgE-ELISA was applied to these 15 sera, with whole wheat proteins, salt-soluble proteins, and salt-insoluble proteins used as antigens. Wheat specific CAP-RAST values correlated well with the IgE-ELISA titers against salt-soluble proteins (r = 0.918 p < 0.001). On the other hand, IgE-ELISA titers against both the salt-insoluble proteins and the whole wheat proteins correlated least with CAP-RAST values (r = 0.161 and r = 0.113). The inhibition tests indicated that IgE antibodies against salt-insoluble proteins were different from those against salt-soluble ones. Thus, IgE antibodies to salt-insoluble proteins were another antigen target of IgE-mediated allergy manifestation. To determine the molecular weight of antigens reacting with IgE, IgE-immunoblotting was performed. Several polypeptides with molecular weights of 33-45, 84, 90 and 98 KD were detected. However, the antigen patterns of the blots varied depending on the sera used. These findings suggest that salt-insoluble wheat proteins are the major antigens in some wheat-dependent AD, and that IgE detection against salt-insoluble wheat proteins is important for the diagnosis of wheat allergy.

Adolescent↗

Agents for the treatment of overactive detrusor. VI. Synthesis and pharmacological properties of acetamide derivatives bearing cyclic amines in N-substituents.

With the aim of improving of the efficacy and decreasing the side effects of oxybutynin (1), N-[(tetrahydro-3- or 4-pyridyl)methyl]-, N-(4-piperidyl)-, and N-(3- or 4-piperidylalkyl)-2-hydroxyacetamides (3a-n, 4a-g) and the related carboxamides (3o-r, 4h-k, 13', 17) were synthesized and evaluated for inhibitory activity against urinary bladder rhythmic contraction in rats and for mydriatic activity in rats. Some of these compounds were superior to oxybutynin in both inhibitory activity against bladder contraction and selectivity between inhibitory activity against bladder contraction and mydriatic activity. Among them, N-[(1,2,3,6-tetrahydro-4-pyridyl)methyl]- and N-[(1,2,3,6-tetrahydro-1-methyl-4-pyridyl)methyl]-2-hydroxy-2,2- diphenylacetamide (3e, 3f) exhibited the most potent inhibitory activity against bladder contraction (ED30 = 0.005 and 0.003 mg/kg i.v., respectively). Judging from the effect of 3e on detrusor contraction in vitro in guinea-pigs, it appeared that the inhibitory activity of 3e against bladder contraction in vivo was related mainly to its inhibitory activity against detrusor contraction in vitro induced with carbachol (antimuscarine-like activity). The selectivity (20-fold) of 3e between inhibitory activity against bladder contraction and mydriatic activity was greatly superior to that (0.48-fold) of oxybutynin. Compound 3e was synthesized by debenzylation (method E or F) of the corresponding N-[[1-(4-methoxybenzyl)-tetrahydro-4-pyridyl]methyl] derivative (3k), which was prepared by acylation (method B) of the corresponding (tetrahydro-4-pyridyl)methylamine (7k) or by reduction (method D) of the corresponding pyridinium chloride (14k) with NaBH4.

Acetamides↗

Agents for the treatment of overactive detrusor. VII. Synthesis and pharmacological properties of 2,3- and 3,4-diphenylcyclopentylamines, 2,3-diphenyl-2-cyclopentenylamines, and related compounds.

As part of our search for new agents for the treatment of overactive detrusor, 2,3- and 3,4-diphenylcyclopentylamines (3), 2,3-diphenyl-2-cyclopentenylamines (4), and related compounds (5 and 18) were synthesized and evaluated for inhibitory activity (i.v.) against urinary bladder rhythmic contraction in rats. Among them, some compounds involving N-tert-butyl-2,3-diphenyl-2-cyclopentenylamine (4b) exhibited inhibitory activity against bladder contraction superior to that of terodiline (2). Mydriatic activity (i.v.) of compound 4b in rats, an index of its side effects due to antimuscarinic activity, was found to be relatively weak in comparison with its inhibitory activity against bladder contraction. The pharmacological profile of 4b was examined in comparison with that of terodiline. Most of the objective amines (3, 4, 5) were synthesized by preparation of Schiff bases from the corresponding cyclic ketones (6, 7, 8) and amines in the presence of TiCl4 in CH2Cl2 and subsequent reduction with NaBH4 in the presence of MeOH in one pot (method A).

Amines↗

Change of serum alpha-1 microglobulin and beta-2 microglobulin following allogeneic bone marrow transplantation.

By serially measuring serum levels of alpha-1 microglobulin and beta-2 microglobulin following allogeneic bone marrow transplantation (BMT), we tried to define their relationship to renal dysfunction, acute graft-versus-host disease (GVHD) and infection as complications of the transplantation. The study involved a total of 25 patients with leukemia, myelodysplastic syndrome and aplastic anemia who received BMT in this department; one patient received re-transplantation, thus bringing the total number of transplants to 26. Twenty-four patients received BMT from HLA-identical siblings while two others received BMT from unrelated donors. Alpha-1 microglobulin was within normal limits in all patients before BMT; among various complications such as nephrotoxicity, acute GVHD and infection which took place after transplantation, a raised alpha-1 microglobulin level was found only in nephrotoxicity; however, the increase was not significant compared with the pre-transplantation level. The pre-transplantation beta-2 microglobulin level was higher than normal in some patients; it was significantly increased in all of the above complications compared with the pretransplantation level (1.57 +/- 0.57 mg/l). A significant correlation was found between the serum creatinine level and the beta-2 microglobulin level (r = 0.849) in patients with renal dysfunction. In some patients, however, the beta-2 microglobulin level increased earlier than the serum creatinine level, and this finding was considered useful for the early diagnosis of renal dysfunction following allogeneic BMT.

Adolescent↗

[Effect of hypoallergenic wheat (HAW-A1) on atopic dermatitis (AD) with wheat allergy, and its antigenic analysis using sera from patients with AD].

Wheat allergy has been suggested to be played an important role in the development and exacerbation of the severe type of atopic dermatitis (AD) in some cases. In this paper, we fractionated wheat antigenic proteins to salt-soluble and salt-insoluble fractions and assayed the IgE antibody titers against each fraction using AD patients' sera, indicating that the salt-soluble fraction has potential of major allergenicity. Then we prepared a hypoallergenic wheat flour (HAW-A1) by decomposition of the salt-soluble fraction using the salt solution washing procedure, and examined the hypoallergenicity of HAW-A1 in IgE-ELISA and IgE-immunoblotting with wheat-RAST positive AD's sera. The results were confirmed that most components of the salt-soluble proteins containing allergenic protein bands are decomposed from HAW-A1, and no IgE antibody titer could be detected in AD patients' sera. The next, the clinical usefulness of this hypoallergenic wheat (HAW-A1) was evaluated in 18 subjects with recalcitrant AD, who were suspected of having wheat allergy. In 15 of the 18 AD subjects tested, HAWN is very useful as a substitute of wheat foods, and in 11 of these patients has higher titers of IgE antibodies against the salt-soluble than salt-insoluble fractions which were extracted from regular wheat flour, and in 4 of these patients also have undetectable levels of IgE antibodies against either fraction. On the other hand, in 3 of 18 AD subjects who revealed positive reaction to HAWN ingestion as same as to regular wheat ingestion, and IgE antibodies to salt-insoluble proteins remaining in HAW-A1, were found. These results indicate that HAW-A1 is very useful as a substitute for wheat food, least in AD patients with wheat allergy who have high titers of IgE antibodies against the salt-soluble than salt-insoluble fractions, and who also have undetectable levels of IgE antibodies against the both fractions.

Adolescent↗

Randomized study of individualized induction therapy with or without vincristine, and of maintenance-intensification therapy between 4 or 12 courses in adult acute myeloid leukemia. AML-87 Study of the Japan Adult Leukemia Study Group.

BACKGROUND: It was assessed whether addition of vincristine (VCR) to remission induction therapy would increase the complete remission (CR) rate, and, secondarily, whether 12 courses of maintenance-intensification therapy would produce longer survival than 4 courses in adult acute myeloid leukemia (AML). METHODS: A randomized comparison of individualized induction therapy was conducted between daunorubicin, behenoyl cytarabine, 6-mercaptopurine, and prednisolone with or without VCR. After 3 courses of intensive consolidation therapy, maintenance-intensification therapy was randomized to 4 or 12 courses given every 6 weeks. RESULTS: Of 265 patients registered, 252 were evaluable. CR was obtained in 78%; 80% in 205 patients of age younger than 60 years, and 65% in 47 of age 60 years or older. Addition of VCR reduced the CR rate significantly (84% to 70%, P = 0.007). Predicted 4-year survival, continuing CR, and disease-free survival (DFS) rates of 196 CR patients are 45%, 41%, and 35%, respectively. Patients receiving 12 courses of maintenance-intensification showed better DFS. By multivariate analyses, significant factors for achievement of CR were performance status 0 to 2, age younger than 60 years, and no VCR; and those for longer DFS were achievement of CR by one course, age younger than 50 years, and French-American-British (FAB) classification M3 or M5. Among 131 patients randomized to the maintenance, the administration of 12 courses was the most important factor (P = 0.0040) for longer DFS, followed by FAB M3 or M5, and by achievement of CR by one course. CONCLUSIONS: Addition of VCR in remission induction therapy was harmful, and longer intensive maintenance therapy prolonged DFS in adult AML.

Acute Disease↗

Presence in Kawasaki disease of antibodies to mycobacterial heat-shock protein HSP65 and autoantibodies to epitopes of human HSP65 cognate antigen.

The central features of Kawasaki disease are immune activation and cytokine-mediated generalized vasculitis. To identify the predisposing factors, we examined the antibody response to BCG antigens, since reactivation of a previous BCG inoculation site is an early, specific manifestation of this disease. BCG antigens were separated on SDS-PAGE, transferred to membrane, and incubated with acute- and convalescent-phase sera of 21 patients with Kawasaki disease. Sera were also examined for the presence of antibodies to mycobacterial 65-kDa heat-shock protein (HSP65), and to its human homolog P1 antigen using synthetic peptides of nonhomologous region. To demonstrate the HSP65-sensitized T cells, in vitro proliferation assay was performed. All convalescent, but not acute phase, sera showed a strong antibody reactivity against 65-kDa protein. The reactivity was directed to recombinant HSP65. Non-cross-reactive sequences between rHSP65 and human HSP65 cognate were synthesized. The sera recognized these peptides of rHSP65 and autologous P1 antigen. Peripheral lymphocytes proliferated following the addition of rHSP65 (stimulation indices, 2.16-7.82; mean, 4.54). These findings suggest that HSP65 may be the most potent factor predisposing to Kawasaki disease, and that an autoreactivity to the epitope of the human HSP65 homolog may be related to the susceptibility to the disease.

Amino Acid Sequence↗

Agents for the treatment of overactive detrusor. IV. Synthesis and structure-activity relationships of cyclic analogues of terodiline.

A series of pyrrolidine derivatives were synthesized and examined for inhibitory activity on detrusor contraction in vivo. Among those compounds, 5,5-dimethyl-2-(2,2-diphenylethyl)-3-isopropylidenepyrrolidine+ ++ hydrochloride (41.HCl), 2-(2,2-di(4-fluorophenyl)ethylene)-5,5-dimethyl-3-isopropylidenepyrro lidine hydrochloride (42.HCl), (+)-5,5-dimethyl-2-(N,N-diphenylaminomethyl)-3-isopropylidenepy rrolidine hydrochloride (+)-(43a.HCl), (-)-5,5-dimethyl-2-(N,N-diphenylaminomethyl)-3-isopropylidenepy rrolidine hydrochloride (-)-(43a.HCl), and 2-(N,N-di(4-fluorophenyl)aminomethyl)-5,5-dimethyl-3-isopropylidenepy rrolidine methanesulfonate (43b.MsOH) showed stronger inhibitory activity on detrusor contraction than terodiline.

Animals↗

[Analysis of anti-platelet antibodies using flow cytometry].

We analyzed the production of anti-platelet antibodies by alloimmunization in patients with hematological disorders who receive blood transfusions frequently. HLA antibodies were detected by anti-human globulin lymphocyte cytotoxicity test (AHG-LCT), and anti-platelet antibodies by flow cytometry (FCM). Results from FCM correlated well with those of AHG-LCT. The rate of coincidence was 92.1%. Production of alloantibodies in patients was detected in 32.7% in the without filter group, but decreased to 17.1% (p < 0.05) in the filter group. The avidin-biotin assay and concentration of globulin fraction in patient's serum by affi-gel blue column were useful for increasing sensitivity in detecting anti-platelet antibodies. Anti-platelet specific antibodies were detected in 5 patients (5/226; 2.2%) and these antibodies coexisted with HLA antibodies in all patients. The antibody in 3 of these patients were identified as HPA-2b (Siba), and those in the other 2 patients were combined antibodies on platelet identification panel and immunoblotting. It may be possible that high titer serum of anti-platelet specific antibodies could be identified by its fluorescent intensity. Measures against HPA-2b are considered necessary because platelet specific antibodies were produced in 2.2% of patients who received blood transfusions frequently.

Blood Platelets↗