著者

渡辺 俊明 田中 正彦 渡邉 和俊 高松 康雄 戸部 昭広

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.124, no.3, pp.99-111, 2004-03-01 (Released:2004-02-25)

参考文献数

51

被引用文献数

84 86

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Increasing data suggest that oxygen free radical species play detrimental roles in ischemic diseases. A free radical scavenger capable of inhibiting oxidative injury is expected to become a new drug for the treatment of ischemic diseases such as cerebral ischemia. Edaravon (3-methyl-1-phenyl-2-pyrazolin-5-one), which has been developed as an neuroprotective agent for more than 15 years since its discovery, is approved for the treatment of acute cerebral infarction. In this paper, the pharmacologic characteristics and clinical effects of edaravone are reviewed. In early stage of investigation, edaravone was found to have promising activities as an antioxidative radical scavenger, quenching hydroxyl radical (•OH) and inhibiting both •OH-dependent and •OH-independent lipid peroxidation. Edaravone showed inhibitory effects on both water-soluble and lipid-soluble peroxyl radical-induced peroxidation systems, which are different from the inhibitory effects of vitamins C and E in each system, respectively. Oxidative injury to cultured endothelial cells caused by arachidonate (AA) peroxides is prevented in the existence of edaravone. To clarify the characteristics of this free radical scavenger, further investigation was carried out. Edaravone ameliorated exacerbation of cortical edema induced by a focal ischemia-reperfusion model in rats, suggesting inhibitory effects on oxidative injury to the blood-brain barrier (BBB). Additionally, edaravone also prevented rat cortical edema caused by intracortical AA infusion in which free radical production and subsequent oxidative injury to the BBB are involved. With advances in in vivo measurement technology of oxygen radicals, edaravone was shown to inhibit postischemic increases in •OH production and tissue injury in the penumbral or recirculated area in rat cerebral ischemia models. In clinical studies, edaravone improved the core neurologic deficits, activities of daily living, and functional outcome of stroke patients. Furthermore, a study using proton magnetic resonance spectroscopic techniques showed that edaravone preserved N-acetyl-aspartate in stroke patients, a promising neuronal marker in the brain. Further investigation is essential for a better understanding of free radical-mediated cerebral injury during ischemia followed by recirculation. We hope that edaravone represents a promising neuroprotectant for drug therapy in acute cerebral ischemia.

著者

小松 貞子 中井 弘司 高松 康雄 盛中 泰洋 渡辺 和俊 篠田 真樹 飯田 成宇

出版者

The Japanese Society for the Study of Xenobiotics

雑誌

薬物動態 (ISSN:09161139)

巻号頁・発行日

vol.11, no.5, pp.451-462, 1996-10-31 (Released:2007-03-29)

参考文献数

14

被引用文献数

6 6

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MCI-186の代謝物および代謝の種差を明らかにするため,代謝物の検索,構造推定,尿中への未変化体および代謝物の排泄率,in vitro代謝について検討を行った.以下にその要約を示す. 1.MCI-86の主代謝物はいずれの動物およびヒトにおいてもMCI-186のsulfateおよびglucuronideであった.ラット,イヌの尿中ではMCI-186 sulfateが多く,ヒト尿中ではMCI-186 glucuronideが多く,種差が認められた. 2.いずれの種においても尿中排泄が主排泄経路であった.未変化体の尿中排泄率は投与量の3%以下とわずかであった.イヌやヒトでは尿中排泄量のほとんどが未変化体およびMCI-186のsulfate,glucuronideで説明できるのに対し,ラットでは未知の代謝物が尿中放射能量の20~27%と多く存在した.ラットの尿中排泄において大きな性差は認められなかった. 3.ラットおよびイヌの肝S9を用いたMCI-186のin vitro代謝においては,ラット,イヌともMCI-186 sulfate生成活性のほうがglucuronide生成活性よりも高く,またラットにおいてはいずれの生成活性も雄性ラットのほうが雌性ラットよりも高値であった.