Effect of a New Immunosuppressant Histon Deacetylase (HDAC) Inhibitor FR276457 in a Rat Cardiac Transplant Model(Pharmacology)
スポンサーリンク
概要
- 論文の詳細を見る
Histone deacetylase (HDAC) is a known modulator of gene transcription, and the immunosuppressive activity of HDAC inhibitors has been demonstrated in recent several reports. In this study, the HDAC inhibitor FR276457, a hydroxamic derivative, was found to have a similar inhibitory effect on all mammalian HDACs tested, but no isozyme selectivity. Both FR276457 and tacrolimus exerted an immunosuppressive effect on in vitro rat splenocyte proliferation stimulated with Concanavalin A. Next, the effect of FR276457 on allograft rejection when administered either as a monotherapy or in combination with tacrolimus was investigated in a rat heterotopic cardiac transplant model. Orally administered FR276457 prolonged the median survival times (MST) of the transplanted grafts in the vehicle group from 6d to 17 or 21d at doses of 20 or 40mg/kg, respectively. Histopathological analysis showed the structures of the myocardium were not affected, but interstitial cellular infiltration could not be suppressed completely. Tacrolimus (0.032mg/kg) prolonged allograft MST to 16d. FR276457, when combined with tacrolimus, prevented allograft rejection at a dose lower than that of the monotherapy. The combination dose prolonged the MST in the groups treated with 10 and 20mg/kg to >28d, and cellular infiltration was suppressed completely. In conclusion, this study demonstrated that the oral administration of HDAC inhibitor FR276457 can prevent allograft rejection as a monotherapy, and has additive or synergistic effects when combined with tacrolimus.
- 社団法人日本薬学会の論文
- 2008-09-01
著者
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Yanagihara Takehiko
Pharmacology Research Laboratories Astellas Pharma Inc.:astellas Research Institute Of America Llc.
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MORI Hiroaki
Fermentation Research Laboratories, Astellas Pharma Inc.
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MUTOH Seitaro
Pharmacology Research Laboratories, Astellas Pharma Inc.
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Noto Takahisa
Department Of Applied Pharmacology 1 Pharmacology Research Labs Astellas Pharma Inc.
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Noto Takahisa
Pharmacology Research Laboratories Astellas Pharma Inc.
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Mutoh Seitaro
Pharmacology Res. Labs Astellas Pharma Inc. Jpn
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Mutoh Seitaro
Pharmacology Research Labs Astellas Pharma Inc.
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Yamada Toshiko
Astellas Research Institute Of America Llc.
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Mori Hiroaki
Fermentation Research Laboratories Astellas Pharma Inc.
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KINUGASA Fumitaka
Department of Immunology, Pharmacology Research Labs, Astellas Pharma, Inc.
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KINUGASA Fumitaka
Pharmacology Research Laboratory, Astellas Pharmaceutical Inc.
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NOTO Takahisa
Applied Pharmacology Research Laboratory, Astellas Pharmaceutical Inc.
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MATSUOKA Hideaki
Astellas Research Institute of America LLC.
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MORI Hiroaki
Pharmacology Research Laboratory, Astellas Pharmaceutical Inc.
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SUDO Yuji
Astellas Research Institute of America LLC.
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Matsuoka Hideaki
Pharmacology Research Laboratories Astellas Pharma Inc.:astellas Research Institute Of America Llc.
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Kinugasa Fumitaka
Department Of Immunology Pharmacology Research Labs Astellas Pharma Inc.
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Mori Hiroaki
Pharmacology Research Laboratories Astellas Pharma Inc.
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