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碳酸酐抑制劑由於系統性使用時，常伴隨倦怠感、尿路結石、體重減輕、白血球減
少等問題，故用於治療青光眼時，常作為第二線用藥，或用於急性青光眼之治療．到
了1980年代許多學者嚐試合成局部點用之碳酸酐抑制劑，如美國Iowa大學之研究小
組Schoenwald等所發展之Ethoxyzolamide衍生物，Aminozolamide及6-Hydroxyethoxy
-2-benzothiazole Sulfonamide ( 6-HS)經動物或臨床試驗已被証實局部點用後具降
眼壓效果．為眼解局部點用碳酸酐抑制劑特性，在本論文中，以Alpha-chymotryps
in誘發之青光眼兔子為動物模式，對6-HS進行以下之研究，包括：6-HS水溶液之安定
性、藥物對角膜與鞏膜之穿透力、血中與眼部組織之孳物動力學及比較系統性給藥與
局部點眼給藥對眼壓之影響．
在論文中所發展以螢光檢測器之HPLC方法使用Reversephase Pheny1 Column，移動相
為60:40 Methanol :1 % Acetic Acid，流速為 1 mL/min，生物檢品經萃取後，所測
得血漿、紅血球及眼球組織中所含6-HS之最低濃度分別為0.03 μ/mL，0.03 μg/mL
與0.013 μg．
6-HS 之水溶液於PH值4至7之間最安定，應用Arrhenius公式推算25℃ PH為7之半衰期
為483年．其主要分解物為原化合物之－so2nh2由-OH所取代．
以自製之Lu''s Apparatus檢測Alpha-chymotrypsin誘發之青光眼兔子可以發現此種動
物模式具有前房體積增加與房水排除不良之特徵．以靜脈注射或局部點眼給予6-HS時
，藥物於正常眼與青光眼之分佈與排除不同，在兩種之給藥途徑，青光眼睫狀體之藥
物濃度皆先達到最高濃度，但排除速度亦較快．
以角膜擴散裝置測得6-HS對兔子正常角膜之穿透係數為3×10-6 cm/sec, 而對去上皮
層角膜、去內皮層角膜與青光眼誘發時間較長之角膜之穿透係數分別為19.39×10-6
cm/sec, 3.86×10-6 cm/sec及5.47×10-6 cm/sec．另外，6-HS之鞏膜穿透係數（
31.50×10-6 cm/sec）遠大於角膜穿透係數．
6-HS以 6mg/kg 與 20mg/kg之劑量靜脈注射於高眼壓兔子後，眼壓之最大降幅分別為
23.3% 及55.3%，而局部點用50μL 6-HS 凝膠則最大降幅為 24.4%，但局部點用二次
50μL 3% 6-HS 懸液劑並無明顯降眼壓之效果．
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Carbonic anhydrase inhibitors are very effective in treating glaucoma, but
their clinical usefulness was limited by variety of systemic side effects.
Recently, several investigators anhydrase inhibitor with some success
reported. Among them aminozolamide and 6-hydroxyethoxy-2-benzothiazole
sulfonamide (6-hs), developed by Schoenwald et al. ( University of Iowa,
Iowa City, USA) were reported to have effect in reducing intraocular
pressure (IOP) in both animal study and clinical trials. In this
dissertation, alpha-chymotrypsin induced glaucoma rabbits were used as
animal model to study the ocular pharmacokinetics and pharmacodynamics of
6-hs, which included: the stability of the aqueous solution, the corneal
and scleral penetration, blood and ocular pharmacokinetics and the IOP
lowering effect after various routes of administration.
In this dissertation, a high performance liqui chromatography (HPLC)
method was developed to determine the concentration of 6-HS in various
biological samples. THe operating conditions for the HPLC methodlogy
included: reverser phase pheny1 column; mobile phase : methanol/1 % acetic
acid solution(60/40); flow rate 1 mL/min and a fluorometric detector. The
detection limits of 6-HS plasma, RBC and ocular tissue were 0.03 mcg/mL,
0.03 mcg/mL and 0.013 mcg respectively.
The aqueous sloution of 6-HS was more stable in the ph range between 4 to
7. At ph 7, 25℃ the calcuated half-life for 6-HS was 483 years.
The alpha-chymotrypsin induced glaucoma rabbits were found to have the
characteristics of increased volume of anterior chamber and obstructed
outflow of aqueous humor by using a home-made Lu''s apparatus. The ocular
pharmacokinetics of 6-HS in normal and glaucoma rabbits were different. In
glaucoma eye, the iris-ciliary body reached its highest drug concentration
earlier and eliminated faster than that of normal eye.
The permeability coefficient of cornea in normal , deepithelium,
de-endothelium and long duration glaucoma eye were 3.0 x 10-6 cm/sec,
19.39 x 10-5 cm/sec, 3.86 x 10-06 cm/sec and 5.47 x 10-6 cm/sec
respectively. The permeability coefficient of sclera was 31.5 x 10-6
cm/sec, which was much larger than that of cornea.
After intravenous administration of 6 mg/kg or 20 mg/kg of 6-HS, the
maximal IOP lowering effects were 23.3 % and 55.3 % respectively. Single
topical instillation of 50μ L of 3 % 6-HS gel caused a maximal IOP
lowering effect of 24.4 % but no effect was observed by using two drops of
3 % 6-HS suspension.
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