臺灣博碩士論文加值系統

本論文以厚朴酚為研究藥物，進行其物化性質測定及對眼內壓影響之測試；並建立NMDA (N-methyl-D-aspartate)誘發神經視網膜炎動物模式及螢光素於玻璃體之藥物動力學模式。厚朴酚經由NMDA誘發前給藥之方式，再由螢光素玻璃體和血液視網膜障壁藥動學參數，評估厚朴酚對視神經保護之功效。
由本研究所建立厚朴酚的HPLC分析方法，應用於厚朴酚溶解度及分佈係數檢品的濃度測定，於pH 7.4之磷酸緩衝液下所測得之溶解度為16.2 μg/mL，Log P值為4.44 ± 0.01。以眼壓恢復法動物模式，進行厚朴酚懸液劑對眼內壓影響之評估，結果顯示厚朴酚沒有顯著影響眼內壓。
過量的NMDA會破壞視網膜神經細胞，本研究利用NMDA進行玻璃體內注射，誘發神經視網膜炎，以建立NMDA誘發神經視網膜炎動物模式；再利用HPLC及眼部螢光儀測定動物經靜脈瞬時注射螢光素鈉後，血漿及玻璃體之螢光素濃度，並根據螢光素濃度之經時變化，經玻璃體藥物動力學模式套合，求得下列藥動學參數：kin (螢光素進入玻璃體的速率常數)、kout (螢光素回到血液循環的速率常數)、MRT (螢光素於玻璃體之平均滯留時間)、Permeability coefficient (血液視網膜障壁之滲透係數)。
由厚朴酚於NMDA誘發神經視網膜炎模式的實驗結果可以發現，事先給予厚朴酚，所得之kin、MRT及Permeability coefficient皆較不給藥之誘發組之結果低，代表厚朴酚能夠防止或減少視神經細胞被過量之NMDA破壞，所以螢光素穿過血液視網膜障壁的能力減低了；若以kout作比較，事先給予厚朴酚所得之kout值比不給藥誘發組之結果高，顯示厚朴酚能夠維持血液視網膜障壁向外主動運輸之機能。所以厚朴酚具有視神經保護的能力，且能夠維持血液視網膜障壁的完整性及正常功能。

Magnolol was investigated in this study. Its physico-chemical properties and intraocular pressure (IOP) lowering effect were measured. This study established an animal model of NMDA (N-methyl-D- aspartate)-induced neuroretinities, and a vitreous pharmacokinetic model of fluorescein. For further assessing the neuroprotection effect of magnolol, we compared the pharmacokinetic parameters of vitreous and blood-retina-barrier (BRB) with or without pre-administration of magnolol.
An HPLC analytical method was established to determine the solubility and distribution coefficient of magnolol in pH 7.4 phosphate buffer. The solubility and distribution coefficient were 16.2 μg/mL and 4.44 ± 0.01 (Log P), respectively. The IOP effect of magnolol was determined by topical administration of magnolol suspension (50 μL, 0.5%) into the eyes of New Zealand rabbits using IOP recovery method. As the result, there was no significant effect on IOP for the topical use of magnolol.
Excess NMDA damages the ganglion cell of retina. According to this mechanism, by intra-vitreous injection of NMDA, we established the animal model of NMDA-induced neuroretinities. The fluorescein levels in plasma and vitreous after IV bolus injection of sodium fluorescein (25 mg/kg body weight) were measured by HPLC method and Fluorotron Master®, respectively. The time courses of fluorescein in plasma and vitreous were fit the established pharmacokinetic models to obtain pharmacokinetic parameters, including kin (the rate constant of fluorescein from blood to vitreous), kout (the rate constant of fluorescein from vitreous to blood), MRT (the mean resident time of fluorescein in vitreous), and permeability coefficient of BRB.
The kin, MRT, and permeability coefficient of fluorescein in pre-administration magnolol group were markedly lower than that of the group without dosing magnolol. Thus, the results might suggest that magnolol protects the ganglion cell of retina from the damage of excess NMDA, and reduces the penetration ability of fluorescein across the BRB. In conclusion, the higher kout was obtained in pre-administration magnolol. It revealed that magnolol could maintain the function of the outward active transport of BRB. Overall of the study, magnolol had a neuroprotection effect on retina ganglion cell, and maintained the integrity and function of BRB.

正文目錄………………………………………………………………..Ⅰ
表目錄…………………………………………………………………. Ⅴ
圖目錄…………………………………………………………………..Ⅵ
附錄目錄………………………………………………………………..Ⅷ
中文摘要………………………………………………………..………Ⅸ
英文摘要……………………………………………………………….ⅩⅠ
第一章、緒論
壹、研究背景………………………………………………………1
貳、眼球構造及青光眼的簡介
一、眼球的構造…………………………………………………2
二、青光眼的簡介………………………………………………7
參、視神經細胞的損害
一、視網膜缺血…………………………………………………11
二、興奮性胺基酸之作用………………………………………14
肆、視神經保護治療劑
一、視神經保護治療劑之研究…………………………………17
二、厚朴酚之簡介………………………………………………21
伍、非侵犯性眼部螢光技術
一、螢光素鈉之簡介……………………………………………23
二、眼部螢光儀…………………………………………………26
陸、螢光素之玻璃體藥物動力學…………………………………30
柒、研究目的………………………………………………………38
第二章、材料與方法
壹、材料
一、藥品與試劑………………………………………………….39
二、儀器………………………………………………………….41
貳、方法
一、厚朴酚物化之性質測定
(一) 溶解度………………………………………………….42
(二) 分配係數……………………………………………….42
(三) 分析方法……………………………………………….43
二、厚朴酚對眼內壓之影響
(一) 厚朴酚懸液劑之製備………………………………….44
(二) 眼壓恢復法動物模式……………………………….....45
三、螢光素血中濃度之測定
(一) 動物實驗……………………………………………….46
(二) 螢光素分析方法……………………………………….47
四、視神經保護實驗
(一)、NMDA誘發動物神經視網膜炎模式…….…………..48
(二)、眼部螢光素濃度之測定………………………………49
(三)、厚朴酚之視神經保護實驗……………………………50
(四)、計算藥物動力學參數...……………………………….50
第三章、結果
壹、HPLC圖譜及校正曲線………………….….……………..….52
貳、厚朴酚之物化性質
一、溶解度………………………………………..………...……56
二、分佈係數…………………………………………….………56
參、眼壓恢復法動物模式試驗……………………………….…….58
肆、血漿中螢光素濃度經時變化
一、HPLC圖譜及校正曲線……………………………………...60
二、血漿中濃度經時變化……………………………………….60
三、藥物動力學……………………………………………….….65
伍、玻璃體中螢光素濃度經時變化
一、玻璃體中濃度經時變化……………………………….…….67
二、藥物動力學……………………………………………….….71
第四章、討論
壹、厚朴酚之物化性質…………………………………………….77
貳、厚朴酚懸液劑對眼內壓之影響………………………………..78
參、螢光素之藥物動力學
一、血漿藥動學…………………………………………………..79
二、玻璃體藥動學……………………………………………….80
肆、NMDA誘發動物神經視網膜炎模式…………………………81
伍、厚朴酚對視神經保護之評估……………………………..……82
第五章、結論…………………………………………………………....84
第六章、參考文獻………………………………………………………85
附錄…………………………………………………………………..…92

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