Shin yamanote Hospital

Tokyo, Japan

Shin yamanote Hospital

Tokyo, Japan
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Ito T.,Musashino University | Ito T.,Shin Yamanote Hospital | Koyama Y.,Shin Yamanote Hospital | Koyama Y.,Otsuma Women's University | Otsuka M.,Musashino University
Journal of Pharmaceutical Sciences | Year: 2014

Our plasmid delivery systems comprising deoxyribonucleic acid (DNA), polyethyleneimine (PEI), and hyaluronic acid (HA) have already achieved the high-extragene expression in tumor tissues. Repeated transfection with certain cytokine genes effectively induced tumor regression and complete disappearance of the tumor in some cases. Frequent injection is sometimes difficult depending on the tumor site. However, single injection often leads to an unsatisfactory efficacy owing to the short duration of the gene expression. In this study, we prepared calcium phosphate (CaP) nanocapsule including plasmid DNA complexes as a durable gene transfection system, which would be slowly degraded, and release DNA complex in the body. CaP nanocupsule including DNA complexes with a diameter of approximately 200 nm was prepared by immersing HA-coated DNA-PEI complex in simulated body fluid. It showed gene expression in cultured cells with duration longer than 2 weeks. By this slow-releasing system, significant tumor-growth suppression and, finally, complete tumor disappearance were observed after single injection into the tumor. Capsulated DNA complex with Ca thus seems promising as a sustained gene expression device. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:179-184, 2014 © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.


Ito T.,Musashino University | Ito T.,Shin Yamanote Hospital | Takemasa M.,Tokyo University of Science | Makino K.,Tokyo University of Science | Otsuka M.,Musashino University
Journal of Pharmacy and Pharmacology | Year: 2013

Objectives Simvastatin has recently been demonstrated to serve as a therapeutic agent for osteoporosis. However, it is hard to dissolve in water and has side effects such as rhabdomyolysis. Solubilization of the drug by deoxycholate was attempted, and the resulting simvastatin/deoxycholate assembly (DeCA/Sim) was coated by calcium phosphate (CaP) to reduce the side effects of simvastatin. The aim of this study was to examine the therapeutic effects of the CaP-coated deoxycholate micelle containing simvastatin in osteoporosis model mice. Methods Deoxycholate micelle containing simvastatin coated by CaP (CaP-DeCA/Sim) was prepared by immersion of deoxycholate/simvastatin assembly in simulated body fluid (SBF). The therapeutic effect of CaP-DeCA/Sim on osteoporosis model mice was evaluated by X-ray computed tomography, and also its effect on other body conditions. Key findings The CaP coating remarkably reduced cytotoxicity in cultured cells. When CaP-DeCA/Sim was injected into ovariectomized mice, inflammation was suppressed, and led to a whole-body therapeutic effect (body weight, bone mineral content and bone mechanical strength). The deoxycholic acid/simvastatin assembly coated by CaP is thus useful for the treatment of osteoporosis. Conclusions Such biocompatible CaP nanocapsules including deoxycholate micelles is expected to be a novel strategy to construct an effective device for delivery of hydrophobic drugs. © 2012 The Authors. JPP © 2012. Royal Pharmaceutical Society.


Ito T.,Musashino University | Ito T.,Shin Yamanote Hospital | Otsuka M.,Musashino University
Biological and Pharmaceutical Bulletin | Year: 2013

Calcium phosphate (CaP)-based compounds are biocompatible and have been accepted as promising candidates for novel drug-releasing devices. CaP is biodegradable and can be utilized as a durable drug release reservoir. We developed an injectable self-setting apatite cement. When a plasmid DNA complex containing CaP was injected into tumor-bearing mice, it solidified in the body and slowly released the DNA complex, inducing durable gene expression and high therapeutic effect on solid tumors. Encapsulation of a drug by CaP acts as a protective capsule for the unstable contents and improves biocompatibility. CaP nanocapsules encapsulating a plasmid DNA complex or drug-involved micelle were prepared, and they showed high stability against enzyme and protein degradation. CaP also showed high potential as a durable acid pH buffer. Aqueous alginate solution was found to form a soft gel in the body and was investigated as a drug-releasing device. However, degradation of the alginate gel is sometimes too rapid in an acidic environment such as the area around osteoporotic bones. We found that amorphous CaP powder added to the alginate gel could control the dissociation rate, buffering the pH inside the gel. Alginate gel including CaP powder and a drug for osteoporosis allowed sustained release of the drug under acidic conditions, and a good therapeutic effect was achieved in osteoporosis model rats. CaP could thus be a valuable material for drug-delivery systems as a slow-releasing drug reservoir, a protective coating, or a pH buffer. © 2013 The Pharmaceutical Society of Japan.


Koyama Y.,Shin Yamanote Hospital | Koyama Y.,Osaka Prefecture University | Yoshihara C.,Chiyoda Corporation | Ito T.,Shin Yamanote Hospital | Ito T.,Osaka Prefecture University
Pharmaceutics | Year: 2015

Immune escape of tumor cells is one of the main obstacles hindering the effectiveness of cancer immunotherapy. We developed a novel strategy to block immune escape by transfecting tumor cells in vivo with genes of pathogenic antigens from Mycobacterium tuberculosis (TB). This induces presentation of the TB antigen on tumor cell surfaces, which can be recognized by antigen presenting cells (APCs) as a “danger signal” to stimulate antitumor immune response. This strategy is also expected to amplify the immune response against tumor-associated antigens, and block immune escape of the tumor. DNA/PEI/chondroitin sulfate ternary complex is a highly effective non-viral gene vector system for in vivo transfection. A therapeutic complex was prepared using a plasmid encoding the TB antigen, early secretory antigenic target-6 (ESAT-6). This was injected intratumorally into syngeneic tumor-bearing mice, and induced significant tumor growth suppression comparable to or higher than similar complexes expressing cytokines such as interleukin-2 (IL-2) and interleukin-12 (IL-12). Co-transfection of the cytokine-genes and the ESAT-6-gene enhanced the antitumor efficacy of either treatment alone. In addition, complete tumor regression was achieved with the combination of ESAT-6 and IL-2 genes. © 2015 by the authors; licensee MDPI, Basel, Switzerland.


Namikawa K.,Sapporo Medical University | Ouchi K.,Kawasaki Medical School | Kimura M.,Shin Yamanote Hospital
Journal of Travel Medicine | Year: 2010

Background. There is concern that Japanese travelers are poorly protected against travel-associated infectious diseases including vaccine-preventable infections. This prompted us to study Japanese travelers for measures taken to reduce their risk of acquiring an infectious disease and their immunization uptake. Methods. During April 2007 to May 2008, a questionnaire study was conducted using the European Travel Health Advisory Board (ETHAB) protocol and targeting Japanese group tour clients as well as individual travelers to developing countries. Results. A total of 302 returned questionnaires were analyzed. While the majority (87.4%) sought general information on their destination, few (38.7%) sought the travel health information. Very few (2.0%) got the health information from travel medicine specialists. More than half were either unaware of the risks or thought there was no risk of hepatitis A, hepatitis B, and typhoid fever in their destination. Only half (50.7%) thought vaccines provided sufficient protection and very few (13.6%) believed that vaccines were safe. For most of the vaccine-preventable diseases, only fewer than 10% had received the vaccines. Conclusions. There is a need for specialized travel health services in Japan and health professionals should be encouraged to expand these services. Japanese travelers should be made aware of the importance of seeking pre-travel health advice and information on the health risks at their destination. Travel health professionals should provide a balanced view of the risks and benefits of immunization, and misperceptions about immunization should be addressed. © 2010 International Society of Travel Medicine.


Teramoto T.,Teikyo University | Kawamori R.,Juntendo University | Miyazaki S.,Shin yamanote Hospital | Teramukai S.,Kyoto Prefectural University of Medicine | And 3 more authors.
Journal of Atherosclerosis and Thrombosis | Year: 2015

Aim: The aim of this analysis was to investigate the relationships between dyslipidemia, achieved blood pressure (BP) values and the lipid levels, as well as the control of four cardiovascular risk factors (BP, low-density lipoprotein: LDL cholesterol, hemoglobin A1c: HbA1c and smoking) and the incidence of cardiovascular disease (CVD), in Japanese patients receiving antihypertensive therapy. Methods: A total of 13,052 patients with no history of CVD were included in this subanalysis of the prospective observational OMEGA study in Japanese hypertensive patients treated with olmesartan. Multivariable Cox regression models were used to evaluate the relationship with the risk of CVD. Results: The incidence of CVD during the 36-month study period was 5.59/1,000 patient-years among the patients with dyslipidemia (n=6,297) and 5.57/1,000 patient-years among the patients without dyslipidemia (n= 6,755), with no significant differences between the two groups. Higher achieved BP values tended to be associated with an increased CVD risk in both the patients with and without dyslipidemia. In addition, the risk of CVD tended to be higher in the patients with an achieved LDL cholesterol level of ≥120 mg/dL than in those with an LDL level of ≥120 mg/dL (trend p=0.0005) and in the patients with an achieved high-density lipoprotein cholesterol level of≥60 mg/dL than in those with an HDL level of ≥60 mg/dL (trend p=0.0017). Furthermore, the risk of CVD was higher among the patients with fewer controlled risk factors than among those with control of all four risk factors (trend p<0.0001). Conclusions: In order to prevent CVD in olmesartan-treated hypertensive patients with no history of CVD, it is important to control both the lipid and BP levels and aim for comprehensive risk factor control. © Journal of Atherosclerosis and Thrombosis. All right received.


Tongu M.,The University of Shimane | Tongu M.,Shin Yamanote Hospital | Harashima N.,The University of Shimane | Tamada K.,Yamaguchi University | And 2 more authors.
Cancer Science | Year: 2015

Immunomodulating monoclonal antibodies (mAb) can evoke antitumor T-cell responses, which are attenuated by regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). Treatment with cyclophosphamide (CP) and gemcitabine (GEM) can mitigate the immunosuppression by Treg and MDSC, respectively. In the current study, we examined the antitumor effects of a combination of local injection with anti-CD137 mAb and intermittent low-dose chemotherapy using CP and GEM in subcutaneously established CT26 colon carcinoma. Although a significant antitumor effect was observed when local anti-CD137 mAb therapy (5 μg) was started early in the tumor-bearing stage (day 10), no therapeutic efficacy was observed when the mAb therapy was started at a later tumor-bearing stage (day 17). Analyses of the tumor-infiltrating immune cells revealed that the number of Gr-1high/low CD11b+ MDSC started to increase 13 days after tumor inoculation, whereas injection with low-dose (50 mg/kg) CP and GEM mitigated this increase. In addition, although intermittent injections with low-dose CP and GEM on days 10 and 18 suppressed tumor growth significantly, additional local injections of anti-CD137 mAb on days 19, 21, and 23 further augmented the therapeutic efficacy. Cytotoxic T lymphocytes reactive to CT26 and a tumor antigen peptide were induced successfully from the spleen cells of tumor-cured or tumor-stable mice. In a bilateral tumor inoculation model, this combination therapy achieved systemic therapeutic effects and suppressed the growth of mAb-untreated tumors. These results suggest that intermittent immunochemotherapy using CP and GEM could retain the therapeutic potential of anti-CD137 mAb that is normally impaired during the late tumor-bearing stage. Intermittent chemotherapy and anti-CD137 antibody therapy. © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.


Mori Y.,Jikei University School of Medicine | Taniguchi Y.,Shin Yamanote Hospital | Matsuura K.,Jikei University School of Medicine | Sezaki K.,The Surgical Center | And 2 more authors.
Diabetes Technology and Therapeutics | Year: 2011

Background: This study was performed to examine the efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes using continuous glucose monitoring (CGM) of 24-h glycemic changes. Subjects and Methods: The study was a prospective open-label pilot study in patients with type 2 diabetes who were admitted to our hospital and treated with sitagliptin alone or concomitantly with another oral hypoglycemic drug. CGM was performed for 2 days before sitagliptin administration and for another 2 days after administration. The average 24-h blood glucose level, SD of the 24-h blood glucose level, 24-h glycemic fluctuation range, mean amplitude of glycemic excursions (MAGE), and hyperglycemic and hypoglycemic time periods were compared before and after administration. Results: Sitagliptin administration alone and with a concomitant drug decreased the average 24-h blood glucose level, SD of the 24-h blood glucose level, 24-h glycemic fluctuation range, MAGE, and hyperglycemic time, compared with these parameters before administration. There were significant correlations between the average 24-h blood glucose level before administration and the decrease in the average 24-h blood glucose level after administration and between MAGE before administration and the decrease in MAGE after administration. Conclusions: Sitagliptin decreased the average glycemic level and also improved 24-h glycemic fluctuation, including postprandial hyperglycemia. © 2011, Mary Ann Liebert, Inc.


Furuta T.,Tokyo Medical University | Kimura M.,Shin Yamanote Hospital | Watanabe N.,Jikei University School of Medicine
American Journal of Tropical Medicine and Hygiene | Year: 2010

In cerebral malaria, the binding of parasitized erythrocytes to the cerebral endothelium and the consequent angiogenic dysregulation play a key role in pathogenesis. Because vascular endothelial growth factor (VEGF) is widely regarded as a potent stimulator of angiogenesis, edema, inflammation, and vascular remodeling, the plasma levels of VEGF and the soluble form of the VEGF receptor (sVEGFR)-1 and -2 in uncomplicated malaria patients and healthy adults were measured by enzyme-linked immunosorbent assay (ELISA) to examine their roles in malaria. The results showed that VEGF and sVEGFR-2 levels were significantly elevated in malaria patients compared with healthy adults. Moreover, it was confirmed that malarial parasite antigens induced VEGF secretion from the human mast cell lines HMC-1 or KU812 cell. This is the first report to suggest that the interaction of VEGF and sVEGFR-2 is involved in the host immune response to malarial infection and that malarial parasites induce VEGF secretion from human mast cells. © 2010 by The American Society of Tropical Medicine and Hygiene.


Ito T.,Shin Yamanote Hospital | Eriguchi M.,Shin Yamanote Hospital | Koyama Y.,Shin Yamanote Hospital
MRS Communications | Year: 2015

Poly(acrylic acid) (PAA) and poly(vinylpyrrolidone) (PVP) are both highly safe synthetic polymers approved as pharmaceutical excipients. When their aqueous solutions are mixed, insoluble rigid complex is precipitated. On the other hand, if the dried PAA film was immersed in aqueous PVP solution, swollen PAA/PVP soft hydrogel was obtained. Heated drying of the gel afforded a transparent water-swellable film. The swellable PAA/PVP complex film exhibited favorable properties in medical use. If the film was put on a bleeding site, it swelled, and stuck to a hemorrhaging spot, and efficiently arrested bleeding. It could also prevent the adhesion formation by injured intestines. Copyright © Materials Research Society 2015.

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