Biomedical subjects

H Mizoguchi

Publications and source records attributed to H Mizoguchi.

At least 163 records · Page 9Linked to original sources

PubMed1997

Pharmacokinetics of recombinant human interleukin-11 (rhIL-11) in healthy male subjects.

AIMS: To study the pharmacokinetics of recombinant human interleukin-11 (rhIL-11) in healthy male volunteers following subcutaneous (s.c.) and intravenous (i.v.) administration. METHODS: RhIL-11 was infused intravenously at 10-50 micrograms kg-1 for 1 or 3 h, or administered subcutaneously at 3-50 micrograms kg-1 to volunteers. RhIL-11 was also administered at 3 micrograms kg-1 s.c. once daily for 7 days. Plasma and urinary concentrations were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: RhIL-11 showed linear pharmacokinetics after both intravenous infusion and s.c. administration. Comparison of t1/2 and MRT values after i.v. administration with those after s.c. administration indicated that rhIL-11 pharmacokinetics after s.c. administration were absorption rate-limited. Bioavailability after s.c. administration was about 65%. Since RhIL-11 was not detected in urine after a single 50 micrograms kg-1 s.c. dose, rhIL-11 was considered to be eliminated by metabolism. There was no significant change in the pharmacokinetic profile of rhIL-11 following repeated s.c. administration. CONCLUSIONS: RhIL-11 demonstrated linear pharmacokinetics at these dose ranges after single and repeated s.c. administration or constant-rate i.v. infusion in healthy volunteers.

Adolescent↗

PubMed1997

Cyclophosphamide therapy for pure red cell aplasia associated with granular lymphocyte-proliferative disorders.

Granular lymphocytes have been characterized as cells with azurophilic granules in the cytoplasm. Patients with increased numbers of granular lymphocytes are designated as granular lymphocyte-proliferative disorders (GLPDs). A variety of haematological abnormalities are associated with T-cell-lineage GLPD. Among these, pure red cell aplasia is frequent, and adequate therapy is required. Seven patients with pure red cell aplasia, or a related condition complicating T-cell-lineage GLPD, were entered into this study. Cyclophosphamide was initiated at a daily oral dose of 100 mg. After 2 weeks the dose was reduced to 50 mg/d, and maintained at that dose. Cyclophosphamide was administered until the lymphocyte count was <1 x 10(9)/l and T-cell receptor-beta gene analysis was used to monitor the response to treatment. All the patients were successfully treated, irrespective of their former treatment. Clinical remission was associated with the disappearance of the abnormal granular lymphocyte clone, as detected by Southern blot hybridization analysis. Therapeutic responses began after 8 weeks, and clinical complete remissions were obtained after 6 months. Oral cyclophosphamide monotherapy can successfully treat the pure red cell aplasia associated with T-cell-lineage GLPD.

Adult↗

PubMed1997

Mechanism of action of antithymocyte globulin in the treatment of aplastic anaemia: in vitro evidence for the presence of immunosuppressive mechanism.

Antithymocyte globulin (ATG) is one of the effective drugs used in the treatment of aplastic anaemia (AA). Although it has been speculated that the mechanism of action of ATG is mediated by its immunosuppressive effect on lymphocytes which might have an inhibitory effect on haemopoietic stem and progenitor cells, no definite evidence of the presence of such a mechanism has been demonstrated. In this study we investigated whether such a mechanism is truly operating in ATG therapy for AA. In five patients who responded to ATG, bone marrow cells were obtained after haematological recovery and CD34-positive cells were separated by immunobeads. Autologous CD34-positive cells were mixed with autologous peripheral CD4- or CD8-positive cells obtained before ATG therapy and after haematological recovery, liquid-cultured for 12h, and then cultured in methylcellulose for 14d in the presence of haemopoietic growth factors. In all five cases studied, only the CD8 cells obtained before ATG therapy suppressed the colony forming unit-granulocyte-macrophage (CFU-GM)- and burst forming unit-erythroid (BFU-E)-derived colony formation. This result is definite evidence that one of the mechanisms of action of ATG in AA is an inhibitory effect on CD8-positive cells which have suppressive activity for the growth of haemopoietic progenitor cells.

Adult↗

PubMed1997

Nucleotide sequence and transcriptional analysis of the flanking region of the gene (spb) for the trans-acting factor that controls light-mediated expression of the puf operon in Rhodobacter sphaeroides.

We recently reported the existence of a trans-acting factor (SPB) in Rhodobacter sphaeroides that repressed the expression of the puf operon during illumination. SPB was somewhat homologous to HvrA of Rhodobacter capsulatus, but these proteins appear to have functionally different properties. We now report an analysis of the flanking region of spb in the genome of R.sphaeroides, and we show that spb is a positional counterpart of hvrA of R. capsulatus. The region directly downstream of spb was found to contain three genes, two of which were highly homologous to orf5 and ahcY in R. capsulatus. However, a gene corresponding to hvrB, which controls the expression of orf5 and ahcY in R. capsulatus, was absent in R. sphaeroides. The level of the transcript of ahcY did not change in cells grown under photosynthetic and by respiratory conditions. By contrast, orf5 was transcribed at a higher rate in photosynthetically grown cells under high-intensity light than under low-intensity light, indicating features of transcription different from those in R. capsulatus. A third gene, orf318, which was absent in the corresponding region of R. capsulatus, encoded an amino acid sequence that was significantly homologous to the consensus sequence of RfaI and RfaJ of E.coli, which are glycosyl transferases involved in the synthesis of lipopolysaccharide. orf318 was transcribed in the opposite direction to ahcY, and at only a low level, under all conditions tested.

Amino Acid Sequence↗

PubMed1997

Three approaches for laparoscopic unroofing of simple and complicated renal cysts.

We report 2 cases of simple renal cysts which were marsupialized with 2 laparoscopic approaches involving either transperitoneal, with reflection of the colon medially or dissection through the mesocolon, and a case of a multilocular renal cyst which was treated by the retroperitoneal approach. Although laparoscopic unroofing of a renal cyst is a safe and effective alternative to open surgical techniques, the transperitoneal approach should only be used for simple renal cysts. The retroperitoneal approach for complicated renal cysts may be indicated if preoperative examinations exclude the possibility of malignancy.

Aged↗

PubMed1997

Recovery of drug sensitivity by MS-209, a new multidrug resistance-reversing agent, on acute myelogenous leukaemic blasts and K562 cells resistant to adriamycin cell line.

The efficacy of MS-209, a quinoline derivative synthesized as a new multidrug resistance (MDR)-reversing agent, was studied on blast cells from 33 acute myelogenous leukaemia (AML) patients and on the human myelogenous leukaemia K562 cell line resistant to adriamycin (K562/ADM). By the addition of MS-209, the intracellular daunorubicin (DNR) contents which had been found to be low in P-gp-positive AML blasts and in K562/ADM were significantly enhanced to the level of P-gp-negative blasts and that of sensitive K562. The intracellular rhodamine (Rh123) contents also increased in P-gp-positive blasts and K562/ADM cells with MS-209. A leukaemic blast colony assay also demonstrated the effect of MS-209, i.e. a high D10 value for DNR of P-gp-positive blasts was reduced to the D10 level similar to that observed in P-gp-negative blasts by the addition of MS-209. The greater DNR sensitivity reversing effect of MS-209 was observed in blasts with higher P-gp positivity. These findings suggest the potential usefulness of MS-209 in overcoming MDR in AML patients, especially those with high P-gp expression. This study clarified the relationship between the clinical outcome of the patients and the P-gp positivity, intracellular DNR content and DNR drug sensitivity of leukaemic progenitors.

Adult↗

PubMed1997

Treatment of the anemia of aplastic anemia patients with recombinant human erythropoietin in combination with granulocyte colony-stimulating factor: a multicenter randomized controlled study. Multicenter Study Group.

A multicenter randomized controlled study was undertaken in order to determine whether epoetin beta (EPO) ameliorates the anemia in aplastic anemia (AA) patients treated with granulocyte colony-stimulating factor (G-CSF). Enrolled patients were randomized into 3 groups: group C receiving G-CSF alone as the control; group L receiving G-CSF and 200 IU/kg of EPO; group H receiving G-CSF and 400 IU/kg of EPO. Throughout the study, the dose and the administration interval of G-CSF were adjusted to maintain neutrophil counts between 1000 and 5000 microliters EPO was administered subcutaneously for 12 wk as the first step in treatment and when favorable effects were observed over this period, treatment was continued for another 12 wk as the second step in treatment. Significant erythroid responses were defined as increases in untransfused hemoglobin values > 1.0 g/dl or > 50% decreases in RBC transfusion requirements over the treatment period. Of 131 patients enrolled, 88 patients allocated to groups L and H were evaluated for toxicity to EPO and 110 were evaluated for erythroid responses. Four of the 31 patients (12.9%) in group C, 6 of the 41 patients (14.6%) of group L, and 14 of the 38 patients (36.8%) of group H showed erythroid responses in the first step in treatment. The erythroid responses of group H were significantly higher than those of the other 2 groups (p < 0.05). The significant effects of EPO were due to erythroid responses in non-severe AA. Responding patients were significantly different from non-responders with regard to disease severity, hemoglobin concentration, reticulocyte count, serum endogenous erythropoietin levels and serum transferrin receptors; non-severe AA patients were more likely to respond to EPO, and responding patients had lower serum EPO and higher hemoglobin concentration, reticulocyte count and serum transferrin receptors than non-responders. The response rate increased in the second step in treatment, suggesting that long-term treatment improved the efficacy of EPO. No serious side-effects were observed. From these results, we conclude that EPO given in combination with G-CSF is a safe and effective alternative for the treatment of anemia of a subset of AA patients.

Adult↗

PubMed1997

Delta-1 opioid receptor-mediated antinociceptive properties of a nonpeptidic delta opioid receptor agonist, (-)TAN-67, in the mouse spinal cord.

The effects of enantiomorphs of TAN-67 (2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a alpha-octahydro-quinolino[2,3,3-g]isoquinoline), (-)TAN-67 and (+)TAN-67, given intrathecally (i.t.) on antinociceptive response with the tail-flick test were studied in male ICR mice. (-)TAN-67 at doses from 17.9 to 89.4 nmol given i.t. produced a dose- and time-dependent inhibition of the tail-flick response, whereas its enantiomer (+)TAN-67 even at smaller doses (1.8, 4.5 and 8.9 nmol) given i.t. decreased the latencies of the tail-flick response. In addition, (+)TAN-67 at higher doses (17.9-89.4 nmol) given i.t. produced scratching and biting pain-like responses. The antinociceptive response induced by i.t.-administered (-)TAN-67 was mediated by the stimulation of delta-1 but not by delta-2, mu or kappa opioid receptors, because the effect was blocked by the i.t. pretreatment with BNTX, but not by naltriben, [D-Phe-Cys-Tyr-[D-Try-Orn-Thr-Pen-Thr-NH2 or nor-binaltorphimine dihydrochloride. Pretreatment with (-)TAN-67 given i.t. 3 hr earlier attenuated the tail-flick inhibition induced by subsequent i.t. administration of (-)TAN-67 and by [D-Pen2,5]enkephalin (DPDPE). However, the tail-flick inhibition induced by [D-Ala2]deltorphin II, [D-Ala2,NMePhe4,Gly5-ol]enkephalin and U50,488H were not affected by (-)TAN-67 pretreatment. Conversely, pretreatment with DPDPE given i.t. 3 hr earlier attenuated the tail-flick inhibition induced by subsequent i.t. administration of (-)TAN-67 and by DPDPE. However, the tail-flick inhibition induced by [D-Ala2]deltorphin II was not affected by i.t. DPDPE pretreatment. It is concluded that (-)TAN-67 given i.t. produces delta-1 opioid receptor-mediated antinociception; on the other hand, its enantiomer (+)TAN-67 produces hyperalgesia. Present studies provide other evidence that delta-1 opioid receptors exist separated from delta-2 opioid receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1997

[Progress in the treatment of multiple myeloma].

Melphalan and prednisolone (MP) have been the standard therapy for multiple myeloma for more than 25 years. Although they produce an objective response in 50-60% of patients, complete remission (CR) is rare and the median survival period is generally 24 to 30 months. Many combination chemotherapeutic agents have been used and resulted in approximately 70% objective response, but the median duration of survival has not significantly been improved. VAD regimen is effective for many patients with myeloma resistant to MP therapy. Furthermore, VAD-cyclosporin combination induces responses in approximately 40% of patients with VAD-resistant myeloma, with increased expression of the multi-drug resistant gene (MDR). Intravenous administration of high dose-melphalan also produces responses in approximately 30% of patients with myeloma resistant to VAD. Interferon-alpha therapy with an alkylating agent-glucocorticoid regimen, shows a higher response rate but similar survival time, compared with those obtained with the MP therapy alone. High-dose therapy with transplantation is promising. High-dose therapy combined with autologous bone marrow transplantation improves the response rate, event-free survival (EFS), and overall survival (OS) in patients with myeloma, demonstrated in the prospective, randomized trial by Attal et al. Total therapy by Barlogie et al. consisted of non-cross-resistant induction regimens, followed by a double autotransplantation (AT) procedure. Compared with the outcome of patients receiving standard therapy, dose intensification with double AT produces not only higher CR rates but also significantly extends EFS and OS in previously untreated patients with myeloma. The reduced mortality rate associated with transplantation, and development of new chemotherapeutic agents will lead to future improvements of the therapy for multiple myeloma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Up-regulation of telomerase activity in human lymphocytes.

We detected telomerase activity in human lymphocytes obtained from normal donors. Telomerase was up-regulated within 24 h when peripheral blood mononuclear cells were cultured in the presence of phytohemagglutinin. The activity increased gradually over 72 h, then remained stable for 96 h. During this period, cell number and the length of telomeric DNA remained constant. Anti-CD3 monoclonal antibody and Pansolbin also induced telomerase activity. These results demonstrate that telomerase is regulated during lymphocyte activation as cells progress from G0 to S phase. This system is useful for the study of telomerase during carcinogenesis, and in the testing of telomerase-inhibitory drugs.

Cell Division↗

PubMed1996

[Basic and clinical aspects of thrombopoietin].

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Animals↗

PubMed1996

Phorbol ester blocks the increase of a high affinity GTPase activity induced by delta 2-opioid receptor agonist in the mouse spinal cord.

The high affinity GTPase activity in the mouse spinal cord was increased in a concentration-dependent manner by a selective delta 2-opioid receptor agonist, [D-Ala2]deltorphin II (0.1-1 microM). This increase of GTPase activity induced by [D-Ala2]deltorphin II was completely blocked by co-incubation with a selective delta 2-opioid receptor antagonist, naltriben (0.1 microM). A protein kinase C activator, phorbol 12,13-dibutyrate (PDB; 0.1-10 microM), which given alone had no effect on basal GTPase activity, blocked dose-dependently the increase of GTPase activity induced by [D-Ala2]deltorphin II (1 microM). Our results indicate the possibility that activation of protein kinase C by phorbol ester uncouples the delta 2-opioid receptor from G-proteins in the spinal cord.

Animals↗

PubMed1996

Pretreatment with pertussis toxin spinally, but not supraspinally, blocks the cold water swimming-induced antinociception in the mouse.

Mice exposed to cold water swimming (4 degrees C) for 3 min produced a marked antinociception. Experiments were designed to determine whether pretreatment with pertussis toxin given intrathecally (i.t.) or intracerebroventricularly (i.c.v.) attenuates cold water swimming-induced antinociception in male ICR mice. Antinociception was measured by the tail-flick test 7 min after cold water swimming. I.t. pretreatment with pertussis toxin at a dose of 0.5 microgram for 24-96 h caused a time-dependent attenuation of cold water swimming-induced antinociception. Moreover, i.t. pretreatment with pertussis toxin at doses from 0.125 to 0.5 microgram for 96 h attenuated cold water swimming-induced antinociception in a dose-dependent manner. However, i.c.v. pretreatment with pertussis toxin at doses from 0.125 to 0.5 microgram for 24-96 h did not affect the cold water swimming-induced antinociception. The present results suggest that pertussis toxin-sensitive Gi/G(o) proteins in spinal cord, but not at the supraspinal sites, are involved in cold water swimming-induced antinociception.

Animals↗

PubMed1996

Comparative allelotype of early and advanced stage non-small cell lung carcinomas.

To identify chromosomal loci of tumor suppressor genes involved in the genesis and progression of non-small cell lung carcinoma (NSCLC), comparative allelotype analysis was performed in 23 stage I primary lung tumors and in 22 metastatic lung tumors to the brain. In total, 84 loci on all 22 autosomal chromosomes were examined for loss of heterozygosity (LOH) by restriction fragment length polymorphism (RFLP) analysis with 40 polymorphic DNA probes and polymerase chain reaction (PCR)-LOH analysis of 44 polymorphic loci. LOH on chromosome arms 3p, 13q, and 17p was detected frequently (> 60%) in both stage I primary lung tumors and brain metastases, whereas the incidence of LOH on chromosome arms 2q, 5q, 9p, 12q, 18q, and 22q was more than 60% only in brain metastases. In particular, the incidence of LOH on chromosome arms 2q, 9p, 18q, and 22q in brain metastases was significantly higher than that in stage I primary lung tumors (P < 0.05). These results indicate that tumor suppressor genes on chromosome arms 3p, 13q, and 17p are involved in the genesis of NSCLC, whereas those on several chromosome arms, especially on 2q, 9p, 18q and 22q, play an important role in the progression of NSCLC.

Brain Neoplasms↗

PubMed1996

Effect of interleukin 11 on normal and pathological thrombopoiesis.

Interleukin 11 (IL-11) is a stromal cell-derived cytokine that has multiple effects on hematopoietic and nonhematopoietic systems. In vitro, it enhances the growth of early progenitors and promotes megakaryocytopoiesis and erythropoiesis. In healthy animals, IL-11 administration stimulates megakaryocyte maturation and increases peripheral platelet counts. IL-11 accelerates the recovery of peripheral neutrophil, erythrocyte, and platelet counts in mice that have undergone cytoablative treatment. Therefore, IL-11 may be useful clinically as an agent promoting recovery from hematopoiesis. However, its clinical use in patients with hematological malignancies may be restricted because IL-11 has been reported to stimulate some leukemia and myeloma cells. In the United States, phase I trials have shown that IL-11 accelerates recovery from chemotherapy-induced or bone-marrow transplantation (BMT)-induced thrombocytopenia. In Japan, phase II trials studying the thrombopoietic effect of IL-11 in patients with solid tumors postchemotherapy, in patients undergoing BMT, and in patients with aplastic or refractory anemia are now under way. Recently, thrombopoietin (TPO) has been cloned, and its thrombopoietic effect and accelerating effect on platelet count recovery in thrombopoietic states have been demonstrated in animal models. The physiological effect of TPO is restricted to hematopoiesis; therefore, it may have fewer side effects than IL-11. However, in addition to its hematopoietic effect, IL-11 administration to mice that have undergone cytoablative therapy significantly decreases morbidity and mortality due to chemotherapy-related endogenous infections caused by gut microorganisms. Therefore, IL-11 can be used in patients postchemotherapy and post-BMT not only to promote platelet recovery but also to prevent life-threatening infections. The use of in-vitro-expanded hematopoietic stem cells for BMT or as target cells for gene therapy is one of the most exciting areas in the field of medicine. Since IL-11 can expand hematopoietic progenitor-cell populations when used in combination with other cytokines, it may be useful as an ex vivo hematopoietic progenitor-cell-amplifying agent.

Anemia, Aplastic↗

PubMed1996

Diazepam pretreatment suppresses morphine withdrawal signs in the mouse.

The effect of diazepam on the development of physical dependence on morphine and on the naloxone-precipitated increase in cortical NA turnover were investigated in mice. Co-administration of diazepam (1-4 mg/kg, i.p.) during chronic morphine treatment suppressed the expression of naloxone (3 mg/kg, s.c.)-precipitated withdrawal signs (jumping, exploratory rearing and weight loss). However, a single injection of diazepam (4 mg/kg, i.p.) in morphine-dependent mice did not affect the expression of naloxone-precipitated withdrawal signs. The 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) level and noradrenaline (NA) turnover (MHPG/NA) in the cerebral cortex were increased by naloxone (3 mg/kg) challenge. These increases in the cortical MHPG level and NA turnover were significantly prevented by co-administration of diazepam (4 mg/kg, i.p.) during chronic morphine treatment. These findings suggest that the co-administration of diazepam during chronic morphine treatment may prevent some neurochemical changes in the central noradrenergic system during chronic morphine treatment, and may suppress the development of physical dependence on morphine. Therefore, the inhibitory action of GABA via benzodiazepine binding sites may play an important role in the development of physical dependence on morphine.

Adrenergic alpha-Agonists↗

PubMed1996

Use of antisense oligodeoxynucleotide to determine delta-opioid receptor involvement in [D-Ala2]deltorphin II-induced locomotor hyperactivity.

Intracerebroventricularly (i.c.v.)-administered [D-Ala2]deltorphin II (20 micrograms) produced a marked locomotor hyperactivity in male ICR mice. The locomotor hyperactivity induced in response to i.c.v. [D-Ala2]deltorphin II (20 micrograms) was suppressed by pretreatment with naltriben (NTB, 10 micrograms) but not 7-benzylidene naltrexone (BNTX, 1 microgram) and D-Phe-Cys-Tyr-D-Try-Orn-Thr-Phe-Thr-NH2 (CTOP, 100 ng). The influence of antisense oligodeoxynucleotide to delta-opioid receptor mRNA (delta-AS oligo) or a mismatch oligodeoxynucleotide (MM oligo) on the locomotor hyperactivity induced by [D-Ala2]deltorphin II was determined. Groups of mice pretreated i.c.v. with delta-AS oligo (1 microgram), MM oligo (1 microgram) or saline (4 microliters) once a day for 3 days, were injected i.c.v. [D-Ala2]deltorphin II (10 or 20 micrograms) and the locomotor response to [D-Ala2]deltorphin II was measured. The locomotor hyperactivity of i.c.v. [D-Ala2]deltorphin II (10 or 20 micrograms) were significantly suppressed by i.c.v. pretreatment with delta-AS oligo but not MM oligo. The present results indicate that pretreatment with delta-AS oligo suppresses mouse locomotor hyperactivity produced by stimulation of delta 2-opioid receptors in the brain.

Amino Acid Sequence↗

PubMed1996

A case-control study of myelodysplastic syndromes among Japanese men and women.

To determine the risk factors of the myelodysplastic syndromes (MDS) we conducted a case-control study in Japan. One hundred and sixteen MDS patients were diagnosed from 1 September to 31 October 1992 and from 1 August to 31 October 1993 in the 32 hospitals enrolled in the idiopathic Disorders of Hematopoietic Organs Research Committee. Age, sex, and hospital-matched controls were selected for each case. Information on cigarette smoking and drinking habits, hair dye use, history of keeping pet animals, and occupational exposures to organic solvents, lead and radiation was obtained from self-administered questionnaires. Conditional logistic regression was applied to this individually matched case-control study and odds ratios (ORs) were computed to estimate association between each exposure variable and risk of MDS. Alcohol drinking was associated with increased risk of MDS (OR = 2.15; 95% confidence interval = 1.12-4.16) and there was a significant trend in risk with increasing amounts of ethanol consumed per week (P < 0.05). We also found elevated ORs for cigarette smokers (OR = 1.80), users of hair dye products (OR = 1.77), and workers exposed to organic solvents (OR = 1.50), although these ratios were not statistically significant. Exposure to pet animals was not associated with risk of MDS. The association observed between alcohol drinking and MDS was still eminent even after adjusted with other variables of cigarette smoking, hair dye use and occupational exposure to organic solvents, and the dose-response relationship was also confirmed.

Adult↗