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Ōsaka, Japan

Mabuchi M.,Health Science University | Shimizu T.,Health Science University | Ueda M.,Health Science University | Sasakawa Y.,Health Science University | And 6 more authors.
In Vivo | Year: 2015

Prostate cancer antigen (PCA)-1/AlkB homologue 3 (ALKBH3) has been identified as a clinically significant factor and siRNA of PCA-1 inhibits DU145 proliferation both in vitro and in vivo. HUHS015 (1), a previous reported PCA-1 small-molecule inhibitor, was also effective without any obvious side-effects or toxicity. The potency of HUHS015, however, is not satisfying. We thought the reason is poor solubility of HUHS015 because insoluble material remained at the injection site after subcutaneous administration. To improve this inhibitor's solubility, we prepared various salts of HUHS015 and examined their solubility, which resulted in the selection of HUHS015 sodium salt (2) for further studies in vivo. Next, we compared the pharmacokinetics of 1 and 2 via several administration routes. We observed significant improvements in the pharmacokinetic parameters. For example, subcutaneous administration of 2 increased the area under the curve (AUC)0-24 by 8-fold compared to 1 and increased the suppressive effect on the proliferation of DU145 cells in a xenograft model.

Abe M.,Tokyo Medical University | Abe M.,MG Pharma Inc. | Yuki Y.,Tokyo Medical University | Yuki Y.,Tokyo International University | And 8 more authors.
Journal of Biotechnology | Year: 2014

Tumor necrosis factor alpha (TNF) plays a pivotal role in chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease. Although anti-TNF antibody therapy is now commonly used to treat patients suffering from these inflammatory conditions, the cost of treatment continues to be a concern. Here, we developed a rice transgenic system for the production of a llama variable domain of a heavy-chain antibody fragment (VHH) specific for mouse TNF in rice seeds (MucoRice-mTNF-VHH). MucoRice-mTNF-VHH was produced at high levels in the rice seeds when we used our most recent transgene-overexpression system with RNA interference technology that suppresses the production of major rice endogenous storage proteins while enhancing the expression of the transgene-derived protein. Production levels of mTNF-VHH in rice seeds reached an average of 1.45% (w/w). Further, approximately 91% of mTNF-VHH was released easily when the powder form of MucoRice-mTNF-VHH was mixed with PBS. mTNF-VHH purified by means of single-step gel filtration from rice PBS extract showed high neutralizing activity in an in vitro mTNF cytotoxicity assay using WEHI164 cells. In addition, purified mTNF-VHH suppressed progression of collagen-induced arthritis in mice. These results show that this rice-expression system is useful for the production of neutralizing VHH antibody specific for mTNF. © 2014 Elsevier B.V.

Fukuhama C.,MG Pharma Inc. | Tsuruta R.,MG Pharma Inc. | Maruya R.,SOUKEN Co.
Japanese Pharmacology and Therapeutics | Year: 2011

Globin digest (GD) is a commercially available oligopeptide mixture derived from edible globin proteins that has been developed to effectively lower the serum triglyceride levels and to regulate dietary fat metabolism. Supplement 'napple® GD' containing GD is sold commercially in Japan and China. In this study, we evaluated its safety and effect of ingestion for 12 weeks in children using physiological parameters. Fiftyone healthy children with obesity index more than 5 percent (9-14 years age, mean 11.3±SD 1.5 years age, 32 males and 19 females) were given 3 tablets each twice a day after breakfast and dinner for 12 weeks. The dose of GD was 1200 mg/day. We found that height and body weight have increased significantly at 4 weeks (p<0.05), but obesity index have decreased significantly at 12 weeks (p<0.05). Especially, obesity index of children with more than 20 percent decreased significantly at 4 weeks (p<0.05) and body weight did not increased for ingestion period. On the other hand obesity index of children with less than 20 percent did not change, but body weight increased significantly at 4 weeks (p<0.01). No adverse effects were found in physiological parameters and medical interviews throughout trial. These results suggest that supplement 'napple® GD' containing globin digest does not show any toxic effect in children and may decreases incidence of child obesity.

Yuki Y.,Tokyo Medical University | Yuki Y.,Tokyo International University | Mejima M.,Tokyo Medical University | Kurokawa S.,Tokyo Medical University | And 23 more authors.
Plant Biotechnology Journal | Year: 2013

Plants have been used as expression systems for a number of vaccines. However, the expression of vaccines in plants sometimes results in unexpected modification of the vaccines by N-terminal blocking and sugar-chain attachment. Although MucoRice-CTB was thought to be the first cold-chain-free and unpurified oral vaccine, the molecular heterogeneity of MucoRice-CTB, together with plant-based sugar modifications of the CTB protein, has made it difficult to assess immunological activity of vaccine and yield from rice seed. Using a T-DNA vector driven by a prolamin promoter and a signal peptide added to an overexpression vaccine cassette, we established MucoRice-CTB/Q as a new generation oral cholera vaccine for humans use. We confirmed that MucoRice-CTB/Q produces a single CTB monomer with an Asn to Gln substitution at the 4th glycosylation position. The complete amino acid sequence of MucoRice-CTB/Q was determined by MS/MS analysis and the exact amount of expressed CTB was determined by SDS-PAGE densitometric analysis to be an average of 2.35 mg of CTB/g of seed. To compare the immunogenicity of MucoRice-CTB/Q, which has no plant-based glycosylation modifications, with that of the original MucoRice-CTB/N, which is modified with a plant N-glycan, we orally immunized mice and macaques with the two preparations. Similar levels of CTB-specific systemic IgG and mucosal IgA antibodies with toxin-neutralizing activity were induced in mice and macaques orally immunized with MucoRice-CTB/Q or MucoRice-CTB/N. These results show that the molecular uniformed MucoRice-CTB/Q vaccine without plant N-glycan has potential as a safe and efficacious oral vaccine candidate for human use. © 2013 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

Fukuhama C.,MG Pharma Inc. | Tsuruta R.,MG Pharma Inc. | Fukuhara I.,Fukuhara Clinic
Japanese Pharmacology and Therapeutics | Year: 2016

Globin digest (GD), an oligopeptide mixture derived from edible globin proteins, used as Food for Specified Health Use (FOSHU) in Japan, Health Food in China and Functional Food in Korea. We have reported that the combination of magnesium hydroxide and GD has the antihypertensive effect in spontaneously hypertensive rats and protective effect against stroke in stroke-prone spontaneously hypertensive rats. The present clinical study attempted to evaluate the hypotensive effect and the safety of magnesium hydroxide and GD in a double blind, placebo-controlled, parallel group study. The study was conducted on 42 subjects with mild hypertension (male/female =16/26). These subjects were randomly divided into two groups. The test group ingested the supplements containing magnesium hydroxide 700 mg/day (as Mg 292 mg/day) and GD 1000 mg/day. Control group ingested this active placebo. Each group was given 6 tablets by orally twice a day for 8 weeks. After 8 weeks ingestion, the systolic blood pressure and the diastolic blood pressure of the test group were significantly suppressed 7.6 mmHg (P<0.01) and 3.1 mmHg (P<0.05) compared to 0 week values. Any abnormal changes in clinical findings such as blood test, urinalysis and physical examination were not observed. These results demonstrated that the supplements containing of magnesium hydroxide and globin digest are safety and useful for suppressing blood pressure in the subjects with mild hypertension. (Jpn Pharmacol Ther 2016 ; 44 : 101-11).

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