New Drug Development Research Center Inc.

Eniwa, Japan

New Drug Development Research Center Inc.

Eniwa, Japan
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Hayashi N.,Matsutani Chemical Industry Co. | Iida T.,Matsutani Chemical Industry Co. | Yamada T.,Matsutani Chemical Industry Co. | Okuma K.,Matsutani Chemical Industry Co. | And 4 more authors.
Bioscience, Biotechnology and Biochemistry | Year: 2010

This clinical study was conducted to investigate the safety and effect of D-psicose on postprandial blood glucose levels in adult men and women, including borderline diabetes patients. A randomized doubleblind placebo-controlled crossover experiment of single ingestion was conducted on 26 subjects who consumed zero or 5 g of D-psicose in tea with a standard meal. The blood glucose levels at fasting and 30, 60, 90, and 120 min after the meal were compared. The blood glucose level was significantly lower 30 and 60 min after the meal with D-psicose (p < 0:01, p < 0:05), and a significant decrease was also shown in the area under the curve (p < 0:01). The results suggest that D-psicose had an effect to suppress the postprandial blood glucose elevation mainly in borderline diabetes cases. A randomized double-blind placebo-controlled parallelgroup experiment of long-term ingestion was conducted on 17 normal subjects who took 5 g of D-psicose or D-glucose with meals three times a day for 12 continuous weeks. Neither any abnormal effects nor clinical problems caused by the continuous ingestion of D-psicose were found.

PubMed | Koga General Hospital, The Cancer Institute Hospital, University of Tokyo, Kirishima Medical Center and 3 more.
Type: Journal Article | Journal: Molecular and clinical oncology | Year: 2015

A number of previous studies have reported that 30-50% of patients with colorectal cancer (CRC) harbor Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, which is a major predictive biomarker of resistance to epidermal growth factor (EGFR)-targeted therapy. Treatment with an anti-EGFR inhibitor is recommended for patients with KRAS wild-type metastatic colorectal cancer (mCRC). A recent retrospective study of cetuximab reported that patients with KRAS p.G13D mutations had better outcomes compared with those with other mutations. The aim of this retrospective study was to assess the prevalence of KRAS p.G13D mutations and evaluate the effectiveness of cetuximab in mCRC patients with KRAS p.G13D or other KRAS mutations. We reviewed the clinical records of 98 mCRC patients with KRAS mutations who were treated between August, 2004 and January, 2011 in four hospitals located in Tokyo and Kyushu Island. We also investigated KRAS mutation subtypes and patient characteristics. In the patients who received cetuximab, univariate and multivariate analyses were performed to assess the effect of KRAS p.G13D mutations on progression-free survival (PFS) and overall survival (OS). Of the 98 patients, 23 (23.5%) had KRAS p.G13D-mutated tumors, whereas 75 (76.5%) had tumors harboring other mutations. Of the 31 patients who received cetuximab, 9 (29.0%) had KRAS p.G13D mutations and 22 (71.0%) had other mutations. There were no significant differences in age, gender, primary site, pathological type, history of chemotherapy, or the combined use of irinotecan between either of the patient subgroups. The univariate analysis revealed no significant difference in PFS or OS between the patients with KRAS p.G13D mutations and those with other mutations (median PFS, 4.5 vs. 2.8 months, respectively; P=0.65; and median OS, 15.3 vs. 8.9 months, respectively; P=0.51). However, the multivariate analysis revealed a trend toward better PFS among patients harboring p.G13D mutations (PFS: HR=0.29; 95% CI: 0.08-1.10; P=0.07; OS: HR=0.23; 95% CI: 0.04-1.54; P=0.13). In conclusion, treatment with cetuximab may be more clinically beneficial in mCRC patients with a KRAS p.G13D mutation, compared with those harboring other mutations. However, further investigation is required to clearly determine the benefits of cetuximab treatment in patients with KRAS p.G13D mutation-positive mCRC.

PubMed | Chonnam National University, Catholic University of Daegu, Indiana University, University of Hong Kong and 3 more.
Type: | Journal: Scientific reports | Year: 2015

Vascular calcification, a pathologic response to defective calcium and phosphate homeostasis, is strongly associated with cardiovascular mortality and morbidity. In this study, we have observed that pyruvate dehydrogenase kinase 4 (PDK4) is upregulated and pyruvate dehydrogenase complex phosphorylation is increased in calcifying vascular smooth muscle cells (VSMCs) and in calcified vessels of patients with atherosclerosis, suggesting that PDK4 plays an important role in vascular calcification. Both genetic and pharmacological inhibition of PDK4 ameliorated the calcification in phosphate-treated VSMCs and aortic rings and in vitamin D3-treated mice. PDK4 augmented the osteogenic differentiation of VSMCs by phosphorylating SMAD1/5/8 via direct interaction, which enhances BMP2 signaling. Furthermore, increased expression of PDK4 in phosphate-treated VSMCs induced mitochondrial dysfunction followed by apoptosis. Taken together, our results show that upregulation of PDK4 promotes vascular calcification by increasing osteogenic markers with no adverse effect on bone formation, demonstrating that PDK4 is a therapeutic target for vascular calcification.

Friedman S.R.,New Drug Development Research Center Inc. | Sandoval M.,New Drug Development Research Center Inc. | Mateu-Gelabert P.,New Drug Development Research Center Inc. | Meylakhs P.,Center for Independent Social Research | And 2 more authors.
Substance Use and Misuse | Year: 2011

A positive-deviance control-case life history study of injection drug users (IDUs) in New York City who had injected drugs for 8-15 years compared 21 IDUs who were antibody negative for both HIV and hepatitis C with 3 infected with both viruses and 11 infected with hepatitis C virus but not HIV. Eligible subjects were referred from other research studies and from community organizations that conduct testing for HIV and hepatitis C virus. Data were collected during 2005-2008 and were analyzed using life history and grounded theory approaches. They support grounded hypotheses that IDUs who are able to attain symbiotic goals like avoiding withdrawal and maintaining social support are assisted thereby in remaining uninfected with HIV or hepatitis C. These hypotheses should be tested using cohort studies and prevention trials to see if helping IDUs attain symbiotic goals reduces infection risk. The study's limitations are noted. © 2011 Informa Healthcare USA, Inc.

Tsujiuchi T.,Nagoya University | Natsume A.,Nagoya University | Motomura K.,Nagoya University | Kondo G.,Nagoya University | And 12 more authors.
American Journal of Translational Research | Year: 2014

The main determinant of glioblastoma (GBM) resistance to temozolomide (TMZ) is thought to be O6-methylguanine-DNA methyltransferase (MGMT), which is a DNA-repair enzyme that removes alkyl groups from the O6-position of guanine. Previously, we reported that a MGMT-siRNA/cationic liposome complex exerted a clear synergistic antitumor effect in combination with TMZ. Translation to a clinical setting might be desirable for reinforcing the efficacy of TMZ therapy for GBM. In this study, we aim to evaluate the safety of MGMT-siRNA/cationic liposome complexes and determine whether the convection-enhanced delivery of these complexes is suitable for clinical use by undertaking preclinical testing in laboratory animals. No significant adverse events were observed in rats receiving infusions of MGMT-siRNA/cationic liposome complex directly into the brain with or without TMZ administration. A pig which received the complex administered by CED also showed no evidence of neurological dysfunction or histological abnormalities. However, the complex did not appear to achieve effective distribution by CED in either the rat or the porcine brain tissue. Considering these results together, we concluded that insufficient distribution of cationic liposomes was achieved for tumor treatment by CED.

Des Jarlais D.C.,Beth Israel Deaconess Medical Center | Des Jarlais D.C.,New Drug Development Research Center Inc. | Arasteh K.,Beth Israel Deaconess Medical Center | Friedman S.R.,New Drug Development Research Center Inc.
Substance Use and Misuse | Year: 2011

New York City experienced the first and largest HIV epidemic among injecting drug users (IDUs). Using data collected from IDUs entering the Beth Israel drug detoxification program, we trace the history of this epidemic from the mid-1970s through the early 2000s. The epidemic can best be described in terms of successive stages: (1) introduction and rapid transmission of HIV in the IDU population; (2) stabilization of HIV prevalence at a high level (over 50%); (3) a decline in incidence and prevalence, following large-scale implementation of syringe exchange programs; and (4) a sexual transmission phase, in which HIV prevalence is approximately equal among injecting and noninjecting heroin and cocaine users, and sexual transmission is more important than injecting-related transmission among IDUs. Given the current spread of HIV among IDUs in many places in the world, New York City provides a very strong example for implementation of large-scale comprehensive syringe exchange programs as early as possible in HIV epidemics among IDUs. © 2011 Informa Healthcare USA, Inc.

PubMed | Beth Israel Deaconess Medical Center and New Drug Development Research Center Inc.
Type: Review | Journal: Archives of pharmacal research | Year: 2016

Protein phosphorylation and post-phosphorylation events regulate many cellular signaling pathways. Peptidyl-prolyl isomerase (Pin1) is the only peptidyl-prolyl cis/trans isomerase that interacts with numerous oncogenic or tumor suppressive phosphorylated proteins, causes conformational changes in target proteins, and eventually regulates the activities of such proteins. These alterations in activity play a pivotal role in tumorigenesis. Since Pin1 is overexpressed and/or activated in various types of cancers, and the dysregulation of proline-directed phosphorylation contributes to tumorigenesis, Pin1 represents an attractive target for cancer therapy. This review will describe the role of Pin1 in cancer and the current status of Pin1 inhibitor development.

Ishida Y.,Calpis Co. | Shibata Y.,Calpis Co. | Fukuhara I.,Fukuhara Clinic | Yano Y.,New Drug Development Research Center Inc. | And 2 more authors.
Bioscience, Biotechnology and Biochemistry | Year: 2011

A double-blind, placebo-controlled, randomized clinical trial was conducted to evaluate the effects of ingesting an excess of tablets containing casein hydrolysate, incorporating angiotensin I-converting enzyme (ACE) inhibitory peptides such as Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), in subjects with blood pressure ranging from normal to mild hypertension. A total of 48 subjects were given either 5 times more than the effective amount of casein hydrolysate or a placebo in tablet form for 4 weeks. In the active group, systolic blood pressure (SBP) decreased significantly as compared with the placebo group. In stratified analysis, however, this antihypertensive effect was not found in normotensive subjects. In addition, neither an acute or nor an excessive reduction in blood pressure nor clinically important adverse events were observed in this study. These findings suggest that intake of a 5-fold excess of tablets containing casein hydrolysate can lead to a mild improvement in hypertension without side effects.

Deren S.,New Drug Development Research Center Inc. | Kang S.-Y.,New Drug Development Research Center Inc. | Mino M.,New Drug Development Research Center Inc. | Guarino H.,New Drug Development Research Center Inc.
Journal of Immigrant and Minority Health | Year: 2010

Background Puerto Rican drug users recruited in NY who previously used drugs in Puerto Rico (PR) have been found to have higher HIV injection and sex-related risk behaviors than those who had not used in PR. This study examined predictors of risk among migrant Puerto Rican drug users. (For the purpose of this paper, the term "migrant" was used to designate Puerto Rican drug users who had used drugs in Puerto Rico and were recruited in New York or New Jersey). Methods A total of 290 drug users who had previously used drugs in PR were recruited in NY and New Jersey and interviewed regarding drug use history and HIV risk behaviors. Results Participants engaged in high risk behaviors, e.g., 39% shared injection paraphernalia and 62% reported unprotected sex. Multivariate analyses found that predictors of injection-related risk included being born in PR and purchasing drugs jointly with other drug users; predictors of sex-related risk included younger age and homelessness. Discussion Addressing risk reduction among those drug users who were born in Puerto Rico and are younger or homeless was indicated, and efforts to reach those at highest risk through NEPs was recommended. © Springer Science+Business Media, LLC 2009.

PubMed | New Drug Development Research Center Inc.
Type: Journal Article | Journal: Journal of the American Chemical Society | Year: 2015

The mitochondrial pool of Hsp90 and its mitochondrial paralogue, TRAP1, suppresses cell death and reprograms energy metabolism in cancer cells; therefore, Hsp90 and TRAP1 have been suggested as target proteins for anticancer drug development. Here, we report that the actual target protein in cancer cell mitochondria is TRAP1, and current Hsp90 inhibitors cannot effectively inactivate TRAP1 because of their insufficient accumulation in the mitochondria. To develop mitochondrial TRAP1 inhibitors, we determined the crystal structures of human TRAP1 complexed with Hsp90 inhibitors. The isopropyl amine of the Hsp90 inhibitor PU-H71 was replaced with the mitochondria-targeting moiety triphenylphosphonium to produce SMTIN-P01. SMTIN-P01 showed a different mode of action from the nontargeted PU-H71, as well as much improved cytotoxicity to cancer cells. In addition, we determined the structure of a TRAP1-adenylyl-imidodiphosphate (AMP-PNP) complex. On the basis of comparative analysis of TRAP1 structures, we propose a molecular mechanism of ATP hydrolysis that is crucial for chaperone function.

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