Nissei Bilis Co.

Shiga, Japan

Nissei Bilis Co.

Shiga, Japan
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Tawa M.,Shiga University of Medical Science | Shimosato T.,NISSEI BILIS Co. | Sakonjo H.,NISSEI BILIS Co. | Okamura T.,Shiga University of Medical Science
Pharmacology | Year: 2017

Background/Aims: Nitroglycerin is widely used as a coronary vasodilator in the treatment of ischemic heart diseases. This study investigated the influence of hypoxia on nitroglycerin-induced relaxation in endothelium-intact and -denuded rabbit, monkey, and porcine coronary arteries. Methods: Helically cut strips of coronary arteries were suspended in organ chambers, and isometric tension was recorded. Results: Nitroglycerin concentration dependently relaxed endothelium-intact rabbit coronary arteries, which were not different under normoxic and hypoxic conditions. On the other hand, nitroglycerin-induced relaxation of endothelium-denuded arteries was significantly attenuated by hypoxia. Similarly, the relaxant response of endothelium-intact monkey coronary arteries to nitroglycerin was not affected by hypoxia, whereas that of endothelium-denuded arteries was impaired. As is the case with rabbit and monkey coronary arteries, exposure to hypoxia resulted in impaired relaxation by nitroglycerin in endothelium-denuded but not endothelium-intact porcine coronary arteries. Conclusion: These findings suggest that coronary endothelium plays a pivotal role in preventing the hypoxia-induced impairment of nitroglycerin responsiveness, regardless of the animal species. © 2017 S. Karger AG, Basel.

Hayashi T.,RIKEN | Hayashi T.,Japan National Cardiovascular Center Research Institute | Hayashi T.,Human Brain Research Center | Hayashi T.,Kyoto University | And 15 more authors.
Journal of Clinical Investigation | Year: 2013

A cell-based therapy for the replacement of dopaminergic neurons has been a long-term goal in Parkinson's disease research. Here, we show that autologous engraftment of A9 dopaminergic neuron-like cells induced from mesenchymal stem cells (MSCs) leads to long-term survival of the cells and restoration of motor function in hemiparkinsonian macaques. Differentiated MSCs expressed markers of A9 dopaminergic neurons and released dopamine after depolarization in vitro. The differentiated autologous cells were engrafted in the affected portion of the striatum. Animals that received transplants showed modest and gradual improvements in motor behaviors. Positron emission tomography (PET) using [ 11C]-CFT, a ligand for the dopamine transporter (DAT), revealed a dramatic increase in DAT expression, with a subsequent exponential decline over a period of 7 months. Kinetic analysis of the PET findings revealed that DAT expression remained above baseline levels for over 7 months. Immunohistochemical evaluations at 9 months consistently demonstrated the existence of cells positive for DAT and other A9 dopaminergic neuron markers in the engrafted striatum. These data suggest that transplantation of differentiated autologous MSCs may represent a safe and effective cell therapy for Parkinson's disease.

Nakagami H.,Osaka University | Nishikawa T.,Osaka University | Tamura N.,Anges MG Inc. | Maeda A.,Osaka University | And 8 more authors.
Journal of Cellular and Molecular Medicine | Year: 2012

We previously identified a novel angiogenic peptide, AG30, with antibacterial effects that could serve as a foundation molecule for the design of wound-healing drugs. Toward clinical application, in this study we have developed a modified version of the AG30 peptide characterized by improved antibacterial and angiogenic action, thus establishing a lead compound for a feasibility study. Because AG30 has an α-helix structure with a number of hydrophobic and cationic amino acids, we designed a modified AG30 peptide by replacing several of the amino acids. The replacement of cationic amino acids (yielding a new molecule, AG30/5C), but not hydrophobic amino acids, increased both the angiogenic and the antimicrobial properties of the peptide. AG30/5C was also effective against methicillin-resistant Staphylococcus aureus (MRSA) and antibiotic-resistant Pseudomonas aeruginosa. In a diabetic mouse wound-healing model, the topical application of AG30/5C accelerated wound healing with increased angiogenesis and attenuated MRSA infection. To facilitate the eventual clinical investigation/application of these compounds, we developed a large-scale procedure for the synthesis of AG30/5C that employed the conventional solution method and met Good Manufacturing Practice guidelines. In the evaluation of stability of this peptide in saline solution, RP-HPLC analysis revealed that AG30/5C was fairly stable under 5°C for 12 months. Therefore, we propose the use of AG30/5C as a wound-healing drug with antibacterial and angiogenic actions. © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Abe H.,Nissei Bilis Co. | Okajima T.,Nissei Bilis Co. | Sakonjo H.,Nissei Bilis Co. | Kimura I.,Nissei Bilis Co. | And 2 more authors.
Japanese Pharmacology and Therapeutics | Year: 2012

Donepezil hydrochloride OD Tablets 5 mg ⌈Nichi-Iko⌋ (Nichi-Iko Pharmaceutical Co., Ltd.; Donepezil OD) and Donepezil hydrochloride F. G. 0.5% ⌈Nichi-Iko⌋ (Nichi-Iko Pharmaceutical Co., Ltd.; Donepezil FG) are developed by Nichi-Iko Pharmaceutical Co., Ltd. as generic drugs of Aricept® D Tablets 5 mg (Eisai Co., Ltd.; Aricept D) and Aricept® Fine Granules 0.5% (Eisai Co., Ltd.; Aricept FG), respectively, which are used for treatment of Alzheimer's dementia. The improving effects for learning and memory deficit of these preparations on scopolamine-induced amnesia model in rats were studied in comparison with original drugs using an eight-arm radial maze task. The improving effects were evaluated with four endpoints, the number of working memory error, the running distance and time, and the rate of true choice. Scopolamine injection exhibited a significant increase in the number of working memory error, a significant prolongation of the running time and distance, and a significant decrease in the rate of true choice to confirm the induction of amnesia. Donepezil OD or Aricept D administration showed significant improving effects for learning and memory deficit on the scopolamine-induced amnesia model in all endpoints, and its efficacy of both drugs are comparable. Donepezil FG or Aricept FG administration also showed significant improving effects for learning and memory deficit on the scopolamine-induced amnesia model in all endpoints, and its efficacy of both drugs are comparable. These results suggest that Donepezil OD and Donepezil FG improved learning and memory deficit of the scopolamine-induced amnesia model and its efficacy is equal to Aricept D and Aricept FG, respectively.

Nakagami H.,Osaka University | Shimamura M.,Osaka University | Miyake T.,Osaka University | Shimosato T.,Nissei Bilis Co. | And 9 more authors.
Molecular Medicine Reports | Year: 2012

Recent reports have shown that nifedipine, a calcium channel blocker, increases peroxisome proliferator-activated receptor-γ (PPARγ) activity. Since PPARγ agonists, such as pioglitazone and rosiglitazone, are effective in reducing non-alcoholic steatohepatitis (NASH) and cirrhosis in animal models, we examined the protective effects of nifedipine, as compared with bezafibrate, a PPARα agonist, in a NASH model induced by an L-methionine- and choline-deficient (MCD) diet. An MCD diet for 20 weeks changed the color of the rat liver to yellow with an irregular surface, whereas the color of the liver in both the bezafibrate and nifedipine treatment groups was markedly changed to yellow-brown with a smooth surface. Furthermore, nifedipine, as well as bezafibrate, significantly prevented liver fibrosis induced by an MCD diet, as assessed by Masson's trichrome staining, accompanied by a significant decrease in serum AST. Overall, nifedipine treatment resulted in an improvement in NASH, similar to bezafibrate, in a rat model. In hypertensive patients with metabolic syndrome, nifedipine may provide additional benefits, beyond its blood pressure-lowering effects, to prevent NASH and fatty liver disease.

Nakagami H.,Osaka University | Osako M.K.,Osaka University | Nakagami F.,Osaka University | Shimosato T.,Nissei Bilis Co. | And 7 more authors.
International Journal of Molecular Medicine | Year: 2010

The favorable metabolic effects of telmisartan have been attributed to its angiotensin II receptor blockade and action as a partial agonist of peroxisome proliferator-activated receptor (PPAR)-γ. We previously reported that administration of telmisartan markedly inhibited lipid accumulation in the liver in mice fed a high-fat diet. In the present study, we further examined the protective effect of telmisartan in a non-alcoholic steatohepatitis (NASH) model induced by feeding Wistar rats an L-methionine- and choline-deficient (MCA) diet. In the first experiment, rats were fed an MCA diet for 8 weeks with or without telmisartan (3 mg/kg/day). Liver fibrosis was observed by Masson trichrome staining, and co-treatment was shown to attenuate liver fibrosis. In the second experiment, Wistar rats were fed an MCA diet for 20 weeks, and telmisartan (3 mg/kg/day) was administered during weeks 0-20 as a preventive model or weeks 8-20 as a therapeutic model. As a result, telmisartan administration in both models significantly attenuated liver fibrosis and an increase in serum AST. Of importance, the HGF concentration in the liver was significantly increased in the telmisartan-treated group. Overall, telmisartan showed a potential action to improve NASH induced by an MCA diet, possibly due to increased HGF production through partial agonist of PPAR-γ. These favorable characteristics of telmisartan as a partial agonist of PPAR-γ may provide a benefit in the treatment of metabolic syndrome beyond its blood pressure-lowering effect.

Nakagami H.,Hamamatsu University School of Medicine | Shimosato T.,NISSEI BILIS Co. | Shimamura M.,Hamamatsu University School of Medicine | Morishita R.,Osaka University
Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry | Year: 2013

Obesity and metabolic syndrome are major risk factors for the development of atherosclerosis or chronic kidney disease. In this paper, we investigated the effect of rosuvastatin and atorvastatin on endothelial function, and liver and kidney function in obese fa/fa Zucker diabetic fatty (ZDF) rats. ZDF rats were administered rosuvastatin (10 mg/kg/day p.o.) or atorvastatin (10 mg/kg/day p.o.) for 12 weeks. Rosuvastatin treatment decreased body weight and fat weight. Neither statin affected the blood sugar and total cholesterol levels, whereas they led to a significant decrease in triglyceride and liver markers (AST and ALT). Rosuvastatin, but not atorvastatin, markedly reduced elevated urinary protein excretion after 12 weeks of treatment. Endothelial function, which was evaluated by EC50 values for acetylcholine-induced relaxation of mesenteric artery rings, was altered after 12 weeks of treatment with rosuvastatin, but not atorvastatin. Our findings suggest that rosuvastatin treatment may improve obesity, proteinuria and endothelial function compared with treatment with atorvastatin. © 2013 Bentham Science Publishers.

Nakagami H.,Hamamatsu University | Pang Z.,Osaka University | Shimosato T.,NISSEI BILIS Co. | Moritani T.,NISSEI BILIS Co. | And 5 more authors.
Hypertension Research | Year: 2014

Diabetes mellitus, hypertension and metabolic syndrome are major risk factors for the occurrence of cardiovascular events. In this study, we used spontaneous hypertensive rat (SHR)/NDmcr-cp (cp/cp) (SHRcp) rats as a model for metabolic syndrome to examine the effects of dipeptidyl peptidase (DPP)-4 inhibition on hypertension, glucose metabolism and endothelial dysfunction. First, we confirmed that SHRcp rats showed very severe obesity, hypertension and endothelial dysfunction phenotypes from 14 to 54 weeks of age. Next, we examined whether the DPP-4 inhibitor teneligliptin (10 mg kg -1 per day per os for 12 weeks) could modify any of these phenotypes. Treatment with teneligliptin significantly improved hyperglycemia and insulin resistance, as evidenced by an oral glucose tolerance test and homeostasis model assessment for insulin resistance, respectively. Teneligliptin showed no effects on systolic blood pressure or heart rate. In regard to endothelial function, the vasodilator response to acetylcholine was significantly impaired in SHRcp rats when compared with WKY rats. Long-term treatment with teneligliptin significantly attenuated endothelial dysfunction through the upregulation of endothelium-derived nitric oxide synthase mRNA. These results demonstrate that long-term treatment with teneligliptin significantly improved endothelial dysfunction and glucose metabolism in a rat model of metabolic syndrome, suggesting that teneligliptin treatment might be beneficial for patients with hypertension and/or diabetes. © 2014 The Japanese Society of Hypertension All rights reserved.

Shimamura M.,Hamamatsu University School of Medicine | Nakagami H.,Hamamatsu University School of Medicine | Shimosato T.,Nissei Bilis Co. | Moritani T.,Nissei Bilis Co. | And 6 more authors.
Experimental and Therapeutic Medicine | Year: 2011

Treatment with angiotensin type 1 receptor blockers (ARBs) is known to improve renal dysfunction and glucose metabolism in obese diabetic animal models and humans. This study examined the effects of irbesartan, a unique ARB with PPARγ activation, on endothelial dysfunction, renal dysfunction, abnormal lipid profile, and liver dysfunction in obese fa/fa Zucker diabetic fatty (ZDF) rats. ZDF rats were administered irbesartan (30 mg/kg/day p.o.) for 12 weeks. Blood pressure, glucose metabolism, lipid profile and renal function were measured every 4 weeks. Response of mesenteric artery rings to acetylcholine was also evaluated as an index of endothelial function after 12 weeks of treatment. Although irbesartan did not affect glucose and insulin levels in both glucose and insulin tolerance tests, decreases in systolic blood pressure, dyslipidemia, and urinary protein excretion were noted from 4 weeks after the start of treatment and continued until 12 weeks. Endothelial and liver dysfunctions were also improved after 12 weeks of treatment. Compared to previous reports showing the effects of irbesartan at later time points such as 6 or 12 months, the present study demonstrated that a low-dose of irbesartan had favorable effects from the early period of treatment, independent of glucose metabolism. Our findings suggest that a low-dose of irbesartan improves diabetic complications quickly after starting treatment, and may support the use of irbesartan for preventing progression of diabetic complications.

Tawa M.,Shiga University of Medical Science | Shimosato T.,Shiga University of Medical Science | Shimosato T.,NISSEI BILIS Co. | Iwasaki H.,Shiga University of Medical Science | And 2 more authors.
Naunyn-Schmiedeberg's Archives of Pharmacology | Year: 2015

Nitrate tolerance is an important problem in the treatment of ischemic heart diseases. The present study investigated whether or not a soluble guanylyl cyclase (sGC) activator can be used as a coronary vasodilator under nitrate-tolerant conditions. Helically cut strips of endothelium-denuded monkey and canine coronary arteries were suspended in organ chambers for isometric tension recording. Nitrate tolerance was induced by a 1-h treatment with nitroglycerin (0.1 mM) followed by 1-h washout of the agent. Control strips were not exposed previously to nitroglycerin, but otherwise were treated identically. The relaxant response to nitroglycerin was dramatically impaired by previous exposure to the drug for 1 h in either monkey or canine coronary arteries, indicating the development of nitrate tolerance. In contrast, development of nitrate tolerance did not affect the relaxant potency and efficacy of the sGC activator BAY 60-2770 in either the monkey or canine coronary arteries. These findings suggest that it may be possible to use sGC activators as substitute drugs for nitroglycerin if tolerance is developed during the treatment of ischemic heart diseases. © 2015 Springer-Verlag Berlin Heidelberg.

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