Entity

Time filter

Source Type

Ibaraki, Japan

Gondard E.,Rockefeller University | Anaclet C.,Rockefeller University | Akaoka H.,Rockefeller University | Guo R.-X.,Rockefeller University | And 8 more authors.
Neuropsychopharmacology | Year: 2013

Long-term abolition of a brain arousal system impairs wakefulness (W), but little is known about the consequences of long-term enhancement. The brain histaminergic arousal system is under the negative control of H3-autoreceptors whose deletion results in permanent enhancement of histamine (HA) turnover. In order to determine the consequences of enhancement of the histaminergic system, we compared the cortical EEG and sleep-wake states of H3-receptor knockout (H3R-/-) and wild-type mouse littermates. We found that H3R-/-mice had rich phenotypes. On the one hand, they showed clear signs of enhanced HA neurotransmission and vigilance, i.e., a higher EEG θ power during spontaneous W and a greater extent of W or sleep restriction during behavioral tasks, including environmental change, locomotion, and motivation tests. On the other hand, during the baseline dark period, they displayed deficient W and signs of sleep deterioration, such as pronounced sleep fragmentation and reduced cortical slow activity during slow wave sleep (SWS), most likely due to a desensitization of postsynaptic histaminergic receptors as a result of constant HA release. Ciproxifan (H3-receptor inverse agonist) enhanced W in wild-type mice, but not in H3R-/-mice, indicating a functional deletion of H3-receptors, whereas triprolidine (postsynaptic H1-receptor antagonist) or α-fluoromethylhistidine (HA-synthesis inhibitor) caused a greater SWS increase in H3R-/-than in wild-type mice, consistent with enhanced HA neurotransmission. These sleep-wake characteristics and the obesity phenotypes previously reported in this animal model suggest that chronic enhancement of histaminergic neurotransmission eventually compromises the arousal system, leading to sleep-wake, behavioral, and metabolic disorders similar to those caused by voluntary sleep restriction in humans. © 2013 American College of Neuropsychopharmacology. Source


Patent
Banyu Pharmaceutical Co. | Date: 2011-03-07

The present invention provides the compounds represented by formula (I): or pharmaceutical salts thereof, wherein: wherein X5 represents sulfur atoms and the like, A1 represents carbon atoms and the like, A2 represents nitrogen atoms and the like and A ring represents phenyl group and the like, having mGluR1 inhibiting effect, and being useful for preventing or treating convulsion, acute pain, inflammatory pain, chronic pain, brain disorder such as cerebral infarction or transient ischemick attack, psychotic disorder such as schizophrenia, anxiety, drug dependence, Parkinsons disease, or gastrointestinal disorder.


Iwamoto Y.,Tokyo Womens Medical University | Tajima N.,Jikei University School of Medicine | Kadowaki T.,University of Tokyo | Nonaka K.,Banyu Pharmaceutical Co. | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2010

Objective: To compare the efficacy and safety of sitagliptin (a dipeptidyl peptidase-4 inhibitor) and voglibose (an α-glucosidase inhibitor) monotherapy in Japanese patients with type 2 diabetes who have inadequate glycaemic control (HbA1c ≥6.5% and <10.0%) on diet and exercise. Methods: In a multi-center, randomized, double-blind, parallel-group study, 319 patients were randomized (1:1) to 12-week treatment with sitagliptin 50 mg once daily or voglibose 0.2 mg thrice daily before meals. The primary analysis assessed whether sitagliptin was non-inferior to voglibose in lowering HbA1c. Results: After 12 weeks, sitagliptin was non-inferior to voglibose for HbA1c-lowering efficacy. Furthermore, sitagliptin was superior to voglibose, providing significantly greater reductions in HbA1c from baseline [least squares mean changes in HbA1c [95% confidence intervals (CI)] = -0.7% (-0.8 to -0.6) and -0.3% (-0.4 to -0.2), respectively; between-group difference = -0.4% (-0.5 to -0.3), p < 0.001]. Sitagliptin was also superior to voglibose on other key efficacy endpoints, including change from baseline in 2-h postmeal glucose (-2.8 mmol/l vs. -1.8 mmol/l, p < 0.001) and fasting plasma glucose (-1.1 mmol/l vs. -0.5 mmol/l, p < 0.001). After 12 weeks, the incidences of clinical adverse experiences (AEs), drug-related AEs and gastrointestinal AEs in the sitagliptin group (48.5, 10.4 and 18.4%, respectively) were significantly (p < 0.05) lower than those in the voglibose group (64.7, 26.3 and 34.6%, respectively). The incidences of hypoglycaemia, serious AEs and discontinuations due to AEs were low and similar in both groups. Conclusions: In Japanese patients with type 2 diabetes, once-daily sitagliptin monotherapy showed greater efficacy and better tolerability than thrice-daily voglibose over 12 weeks. © 2010 Blackwell Publishing Ltd. Source


Mizuarai S.,Banyu Pharmaceutical Co. | Kotani H.,Banyu Pharmaceutical Co. | Kotani H.,Chiyoda Corporation
Human Genetics | Year: 2010

Synthetic lethal interaction is defined as a combination of two mutations that is lethal when present in the same cell; each individual mutation is non-lethal. Synthetic lethal interactions attract attention in cancer research fields since the discovery of synthetic lethal genes with either oncogenes or tumor suppressor genes (TSGs) provides novel cancer therapeutic targets. Due to the selective lethal effect on cancer cells harboring specific genetic alterations, it is expected that targeting synthetic lethal genes would provide wider therapeutic windows compared with cytotoxic chemotherapeutics. Here, we review the current status of the application of synthetic lethal screening in cancer research fields from biological and methodological viewpoints. Very recent studies seeking to identify synthetic lethal genes with K-RAS and p53, which are known to be the most frequently occurring oncogenes and TSGs, respectively, are introduced. Among the accumulating amount of research on synthetic lethal interactions, the synthetic lethality between BRCA1/2 and PARP1 inhibition has been clinically proven. Thus, both preclinical and clinical data showing a preferential anti-tumor effect on BRCA1/2 deficient tumors by a PARP1 inhibitor are the best examples of the synthetic lethal approach of cancer therapeutics. Finally, methodological progress regarding synthetic lethal screening, including barcode shRNA screening and in vivo synthetic lethal screening, is described. Given the fact that an increasing number of synthetic lethal genes for major cancerous genes have been validated in preclinical studies, this intriguing approach awaits clinical verification of preferential benefits for cancer patients with specific genetic alterations as a clear predictive factor for tumor response. © 2010 Springer-Verlag. Source


Mizuarai S.,Banyu Pharmaceutical Co. | Irie H.,Banyu Pharmaceutical Co. | Kotani H.,Banyu Pharmaceutical Co. | Kotani H.,Chiyoda Corporation
Current Molecular Medicine | Year: 2010

Pharmacodynamic (PD) biomarkers play a pivotal role in anti-tumor drug development as a biochemical measurement to estimate the level of drug interaction with the target, or to assess the downstream impact of its interaction with the target. Although immunohistochemistry (IHC)-based protein biomarkers have been conventionally used as PD biomarkers, gene expression-based PD biomarkers have recently emerged as quantitative biomarkers. This review introduces examples of gene expression-based mRNA biomarkers that have been validated in preclinical or clinical studies of several anti-tumor agents including HDAC, mTOR, and B-RAF inhibitors. The measurement of PD biomarker levels in tumors has proven to be ideal; however, in clinical studies, easily accessible surrogate tissues have been used for analysis. In the present review, we also discuss the advantages and disadvantages in using surrogate tissues, such as peripheral blood mononuclear cells (PBMCs), skin tissue, and circulating tumor cells, in the assessment of PD biomarkers. PD biomarkers are generally classified into two categories: 1) target engagement biomarkers and 2) early efficacy biomarkers. This classification depends on their respective distance from target intervention. The strategies used to identify and distinguish between these two types of PD biomarkers via expression profiling are also discussed. Finally, we propose two novel approaches for PD marker identification. One approach utilizes mRNA expression profiling of tumors prior to drug treatment rather than post-treatment samples. The second method involves the application of microRNA expression profiles to determine PD effects. In conclusion, the recent advances in mRNA and microRNA profiling and the identification of gene expression-based PD biomarkers may aid investigators to drive drug development through the establishment of quantitative PD effects. © 2010 Bentham Science Publishers Ltd. Source

Discover hidden collaborations