CN1224420C - 视细胞功能紊乱治疗剂 - Google Patents
视细胞功能紊乱治疗剂 Download PDFInfo
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- CN1224420C CN1224420C CNB998162760A CN99816276A CN1224420C CN 1224420 C CN1224420 C CN 1224420C CN B998162760 A CNB998162760 A CN B998162760A CN 99816276 A CN99816276 A CN 99816276A CN 1224420 C CN1224420 C CN 1224420C
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Abstract
本发明提供治疗视细胞功能紊乱的药剂，其包括白细胞介素抑制剂，如大环内酯化合物，尤其是FK506。
Description
技术领域
本发明涉及视细胞功能紊乱的治疗剂。
发明背景
在眼部结构中，视网膜存在于眼底，通过视网膜的视细胞层的存在，控制眼睛识别物体存在与否和物体形状的功能。近年来，眼部疾病患者通过进行测定视网膜电图(以下有时简称为ERG)进行视网膜功能的物镜试验(objective test)，并利用该测定诊断病症。ERG由a-波、b-波、c-波等组成，认为a-波主要反映视细胞功能，b-波反映双极细胞层(主要为米勒细胞)功能，c-波反映视网膜色素上皮细胞功能。当某些原因使视网膜功能损伤时，在每种波的峰的延迟(latency)和振幅中出现变化。例如，在糖尿病性视网膜病病例中，已知各波的峰的延迟从早期扩展，而振幅减弱；在视网膜退化性疾病中，如色素性视网膜退化，所有的波减弱并消失；在视网膜脉络膜病中，如中枢视网膜动脉梗塞、中枢视网膜静脉血栓、眼底高渗、视网膜剥离等，根据疾病所处的阶段，各种波变弱。由于b-波等的产生源比产生a-波的视细胞更接近于视网膜的中心侧(central side)，所以当光线到达视网膜时，首先激发视细胞，当该激发传递到该中心侧面上的视网膜细胞时，首先产生b-波等。因此，即使当产生源不是视细胞时，这些波也在视细胞功能的强烈影响下。换言之，当视细胞功能损伤时，即使b-波等的产生源正常，ERG元素也变得异常。因此，在ERG中a-波是最重要的元素，如果由于视细胞功能损伤而引起波的峰的延迟和振幅产生变化，该变化可被抑制或复原，那么视细胞功能紊乱可望被有效地治疗。
发明概述
本发明者进行深入细致的研究，惊奇地发现白细胞介素2(以下有时简单称之为IL-2)抑制剂对视细胞功能紊乱具有优越的改善作用，并且对视细胞功能紊乱有关的疾病呈现优越的治疗作用，从而实现了本发明。
因此，本发明提供如下内容。
(1)治疗视细胞功能紊乱的药剂(agent)，其包括作为活性组分的白细胞介素2抑制剂。
(2)(1)的药剂，其中白细胞介素2抑制剂是大环内酯化合物或环孢菌素。
(3)(2)的药剂，其中大环内酯化合物是下式的三环化合物(I)或其药学上可接受的盐：
其中相邻的各对R1和R2、R3和R4以及R5和R6独立
a)由2个相邻的氢原子组成，其中R2任选是烷基，或
b)任选在与所述对的成员连接的碳原子之间形成另一个键；
R7是氢原子、羟基、被保护的羟基或烷氧基，或者可与R1形成氧代；
R8和R9彼此独立为氢原子或羟基；
R10是氢原子、烷基、被一或多个羟基取代的烷基、链烯基、被一或多个羟基取代的链烯基或者是被氧代取代的烷基；
X是氧代、(氢原子、羟基)、(氢原子、氢原子)或式-CH2O-基团；
Y是氧代、(氢原子、羟基)、(氢原子、氢原子)或式N-NR11R12或N-OR13基团；
R11和R12彼此独立为氢原子、烷基、芳基、甲苯磺酰基；
R13、R14、R15、R16、R17、R18、R19、R22和R23彼此独立为氢原子或烷基；
R24是任选取代的环，该环可含有一或多个杂原子；以及
n是1或2。
除以上说明的意义外，Y、R10和R23可与其结合的碳原子一起为含有氮原子、硫原子和/或氧原子的饱和或不饱和5或6元杂环基，该杂环基任选被一或多个选自以下的基团取代：烷基、羟基、烷氧基、苄基、式-CH2Se(C6H5)基团及被一个或多个羟基取代的烷基。
(4)(2)或(3)的药剂，其中大环内酯化合物是FK506。
(5)(1)-(4)中任一项的药剂，其可用于治疗视网膜病。
(6)(5)的药剂，其中视网膜病是局部缺血性视网膜病。
(7)(6)的药剂，其中局部缺血性视网膜病是糖尿病性视网膜病。
(8)(1)-(7)中任一项的药剂，它是眼部局部用药的形式。
(9)一种治疗视细胞功能紊乱的方法，其包括给予需要治疗视细胞功能紊乱的患者有效量的白细胞介素2抑制剂。
(10)白细胞介素2抑制剂在制备用于治疗视细胞功能紊乱的药用组合物中的用途。
发明详述
本发明中所用的IL-2抑制剂并不特别限定，只要其具有IL-2抑制活性即可。其一个实例是IL-2产生抑制剂。另一个实例是IL-2信号传导抑制剂。优选其实例包括大环内酯化合物，如FK506、子囊霉素衍生物、纳巴霉素衍生物等以及环孢菌素等。
大环内酯化合物的特别实例包括下式的三环化合物(I)及其药学上可接受的盐。
其中相邻的各对R1和R2、R3和R4以及R5和R6独立
a)由2个相邻的氢原子组成，其中R2任选是烷基，或
b)任选在与所述对的成员连接的碳原子之间形成另一个键；
R7是氢原子、羟基、被保护的羟基或烷氧基，或可与R1形成氧代；
R8和R9彼此独立为氢原子或羟基；
R10是氢原子、烷基、被一或多个羟基取代的烷基、链烯基、被一或多个羟基取代的链烯基或者是被氧代取代的烷基；
X是氧代、(氢原子、羟基)、(氢原子、氢原子)或式-CH2O-基团；
Y是氧代、(氢原子、羟基)、(氢原子、氢原子)或式N-NR11R12或N-OR13基团；
R11和R12彼此独立为氢原子、烷基、芳基、甲苯磺酰基；
R13、R14、R15、R16、R17、R18、R19、R22和R23彼此独立为氢原子或烷基；
R24是任选取代的环，并可任选含有一或多个杂原子；以及
n是1或2。
除以上说明的意义外，Y、R10和R23可与其结合的碳原子一起为含有氮原子、硫原子和/或氧原子的饱和或不饱和5或6元杂环基，其中该杂环基可被一或多个选自以下的基团取代：烷基、羟基、烷氧基、苄基、式-CH2Se(C6H5)基团及被一或多个羟基取代的烷基。
R24优选是，如，任选具有如下适当取代基的环(C5-C7)烷基，例如
(a)3，4-二氧代环己基，
(b)3-R20-4-R21环己基，
其中R20是羟基、烷氧基或-OCH2OCH2CH2OCH3，R21是羟基、-OCN、烷氧基、带有适当取代基的杂芳氧基、-OCH2OCH2CH2OCH3、被保护的羟基、氯、溴、碘、氨基草酰氧基、叠氮化物、对甲苯磺酰氧基硫代羰氧基或R25R26CHCOO-(其中R25是在需要时任选被保护的羟基或者被保护的氨基，R26是氢原子或甲基，
或者R20和R21组合形成环氧化物环的氧原子)；或
(c)环戊基，其中环戊基被甲氧基甲基、在要求时任选被保护的羟基甲基、酰氧基甲基(其中酰基部分是任选被季铵化的二甲氨基或任选被酯化的羧基)、一个或多个任选被保护的氨基和/或羟基或者氨基草酰氧基甲基取代。优选的实例包括2-甲酰基-环戊基。
以下详细解释式(I)中使用的各符号的定义、其特定实例及其优选的实施方案。
“低级”，除非另有说明，指基团具有1-6个碳原子。
“烷基”和“烷氧基”的烷基部分的优选实例包括直或支链的脂肪烃残基，如低级烷基(例如，甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、新戊基、己基等)。
“链烯基”的优选实例包括具有一个双键的直或支链的脂肪烃残基，如低级链烯基(例如，乙烯基、丙烯基(如烯丙基等)、丁烯基、甲基丙烯基、戊烯基、己烯基等)。
“芳基”的优选实例包括苯基、甲苯基、二甲苯基、异丙基苯基、2，4，6-三甲苯基、萘基等。
“被保护的羟基”和“被保护的氨基”的保护基的优选实例包括1-(低级烷硫基)(低级)烷基，如低级烷硫基甲基(如甲硫基甲基、乙硫基甲基、丙硫基甲基、异丙硫基甲基、丁硫基甲基、异丁硫基甲基、己硫基甲基等)，更优选给出C1-C4烷硫基甲基，最优选甲硫基甲基；
三取代的甲硅烷基，如三(低级)烷基甲硅烷基(如三甲基甲硅烷基、三乙基甲硅烷基、三丁基甲硅烷基、叔丁基二甲基甲硅烷基、三叔丁基甲硅烷基等)和低级烷基二芳基甲硅烷基(如甲基二苯基甲硅烷基、乙基二苯基甲硅烷基、丙基二苯基甲硅烷基、叔丁基二苯基甲硅烷基等)，更优选三(C1-C4)烷基甲硅烷基和C1-C4烷基二苯基甲硅烷基，最优选叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基；
酰基，如由羧酸、磺酸和氨基甲酸衍生的脂族酰基、芳族酰基和芳基取代的脂族酰基等。
脂族酰基的示例为任选具有1或多个适当取代基(如羧基)的低级链烷酰基，如甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、己酰基、羧基乙酰、羧基丙酰基、羧基丁酰基、羧基己酰基等；
任选具有1或多个适当取代基(如低级烷基)的环(低级)烷氧基(低级)链烷酰基，如环丙氧基乙酰基、环丁氧基丙酰基、环庚氧基丁酰基、孟(mentyl)氧基乙酰基、孟氧基丙酰基、孟氧基丁酰基、孟氧基戊酰基、孟氧基己酰基等；
樟脑磺酰基；
具有1或多个适当取代基(如羧基或被保护的羧基等)的低级烷基氨基甲酰基，如羧基(低级)烷基氨基甲酰基(如羧甲基氨基甲酰基、羧乙基氨基甲酰基、羧丙基氨基甲酰基、羧丁基氨基甲酰基、羧戊基氨基甲酰基、羧己基氨基甲酰基)和
三(低级)烷基甲硅烷基(低级)烷氧基羰基(低级)烷基氨基甲酰基(如，
三甲基甲硅烷基甲氧羰基乙基氨基甲酰基、
三甲基甲硅烷基乙氧羰基丙基氨基甲酰基、
三乙基甲硅烷基乙氧羰基丙基氨基甲酰基、
叔丁基二甲基甲硅烷基乙氧羰基丙基氨基甲酰基、
三甲基甲硅烷基丙氧羰基丁基氨基甲酰基)
芳族酰基的示例为任选具有适当取代基(如硝基)的芳酰基，如苯甲酰基、甲苯酰基、二甲苯酰基、萘酰基、硝基苯甲酰基、二硝基苯甲酰基、硝基萘酰基等；以及
任选具有一或多个适当取代基(如卤素)的芳烃磺酰基，如苯磺酰基、甲苯磺酰基、二甲苯磺酰基、萘磺酰基、氟苯磺酰基、氯苯磺酰基、溴苯磺酰基、碘苯磺酰基等。
被芳基取代的脂族酰基可以是，如，任选具有一或多个适当取代基(如低级烷氧基或三卤代(低级)烷基等)的芳(低级)烷酰基，其中特定实例为苯乙酰基、苯丙酰基、苯丁酰基、2-三氟甲基-2-甲氧基-2-苯乙酰基、2-乙基-2-三氟甲基-2-苯乙酰基、2-三氟甲基-2-丙氧基-2-苯乙酰基等。
在以上提到的酰基中，更优选酰基包括任选具有羧基的C1-C4链烷酰基、在环烷基部分具有2个(C1-C4)烷基的环(C5-C6)烷氧基(C1-C4)链烷酰基、樟脑磺酰基、羧基(C1-C4)烷基氨基甲酰基、三(C1-C4)烷基甲硅烷基(C1-C4)烷氧基羰基(C1-C4)烷基氨基甲酰基、任选带有1或2个硝基的苯甲酰基、任选具有卤素的苯磺酰基、具有C1-C4烷氧基和三卤代(C1-C4)烷基的苯基(C1-C4)链烷酰基。其中，最优选乙酰基、羧基丙酰基、孟氧基乙酰基、樟脑磺酰基、苯甲酰基、硝基苯甲酰基、二硝基苯甲酰基、碘代苯磺酰基、2-三氟甲基-2-甲氧基-2-苯乙酰基等。
“由含有氮原子、硫原子和/或氧原子的饱和或不饱和5或6元环组成的杂环基”的优选实例是吡咯基、四氢呋喃基等。
“任选具有适当取代基的杂芳氧基”的“任选具有适当取代基部分的杂芳基”的示例为EP-A-532,088的式I化合物的R1，优选给出1-羟乙基吲哚-5-基。该公开内容结合到本发明中作为参考。
本发明中使用的三环化合物(I)及其药学上可接受的盐具有优越的IL-2抑制作用、免疫抑制作用、抗菌作用和其它药理活性，因此，它们可用于预防和治疗器官和组织移植中的排斥反应、移植产生的宿主反应、自动免疫疾病、感染性疾病等，其作用及制备方法可见注释，如，EP-A-184162、EP-A-323042、EP-A-423714、EP-A-427680、EP-A-465426、EP-A-480623、EP-A-532088、EP-A-532089、EP-A-569337、EP-A-626385、WO89/05303、WO93/05058、WO96/31514、WO91/13889、WO91/19459、WO93/5059等，所有这些文献结合到本发明中作为参考。
尤其是，名为FR900506(＝FK506)、FR900520(子囊霉素)、FR900523和FR900525的化合物由链霉菌属产生，如Streptomycestsukubaensis，No.9993(保藏单位：National Institute of Bioscience andHuman-Technology of Industrial Science and Technology，the Ministry ofInternational Trade and Industry，1-3，Higashi 1-chome，Tsukuba-shi，Ibaraki-ken，Japan(以前：Fermentation Research Institute，Agency ofIndustrial Science and Technology，the Ministry of International Tradeand Industry)，保藏日期：1984年10月5日，保藏号：FERM BP-927或者吸水链霉菌Yakushimaensis亚种(Streptomyces hygroscopicussubsp.Yakushimaensis)，No.7238(保藏单位：National Institute ofBioscience and Human-Technology Agency of Industrial Science andTechnology，1-3，Higashi 1-chome，Tsukuba-shi，Ibaraki-ken，Japan(以前：Fermentation Research Institute，Agency of Industrial Science andTechnology，the Ministry of International Trade and Industry)，保藏日期：1985年1月12日，保藏号：FERM BP-928(EP-A-0184162)，下式化合物，FK506(通用名：他克莫司)是代表性化合物。
化学名：17-烯丙基-1，14-二羟基-12-[2-(4-羟基-3-甲氧基环己基)-1-甲基乙烯基]-23，25-二甲氧基-13，19，21，27-四甲基-11，28-二氧杂-4-氮杂三环[22.3.1.04，9]二十八-18-烯-2，3，10，16-四酮
在该三环化合物(I)中，更优选的化合物是其中相邻的各对R3和R4以及R5和R6彼此独立任选在与所述对的成员连接的碳原子之间形成另一个键；
R8和R23各自独立为氢原子；
R9是羟基；
R10是甲基、乙基、丙基或烯丙基；
X是(氢原子、氢原子)或氧代；
Y是氧代；
R14、R15、R16、R17、R18、R19和R22各自独立为甲基；
R24是3-R20-4-R21-环己基，
其中R20是羟基、烷氧基或-OCH2OCH2CH2OCH3，
R21是羟基、-OCN、烷氧基、具有适当取代基的杂芳氧基、-OCH2OCH2CH2OCH3、被保护的羟基、氯、溴、碘、氨基草酰氧基、叠氮化物、对甲苯磺酰基氧基硫代羰氧基或R25R26CHCOO-，其中R25是在需要时任选被保护的羟基或被保护的氨基，R26是氢原子或甲基，或者R20和R21结合形成环氧化物环的氧原子；和
n是1或2。
特别优选的三环化合物(I)包括，除FK506外，还有子囊霉素衍生物，如EP-A-427,680的实施例66a中说明的33-表-氯-33-脱氧子囊霉素的卤化衍生物等。
其它优选的IL-2抑制剂(大环内酯化合物)包括MERCK INDEX，12版，No.8288中说明的纳巴霉素及其衍生物。其优选实例包括WO95/16691的第1页中说明的O-取代的衍生物，式A，其中40th羟基是-OR1(其中R1是羟基烷基、氢化烷氧基烷基、酰氨基烷基和氨基烷基)，如40-O-(2-羟基)乙基纳巴霉素、40-O-(3-羟基)丙基纳巴霉素、40-O-[2-(2-羟基)乙氧基]乙基纳巴霉素和40-O-(2-乙酰氨基乙基)-纳巴霉素。可在适当的条件下，通过使纳巴霉素(或二氢或脱氧纳巴霉素)与带有离去基团的有机基团(如，RX其中R是所要求的O-取代基的有机基团，如烷基、烯丙基和苄基部分，X是离去基团，如CCl3C(NH)O和CF3SO3))反应制备这些O-取代的衍生物。这些条件是：当X是CCl3C(NH)O时，为酸性或中性条件，如在三氟甲磺酸、樟脑磺酸、对甲苯磺酸或其对应的吡啶鎓或取代的吡啶鎓盐存在下，当X是CF3SO3时，在碱如吡啶、取代的吡啶、二异丙基乙胺和五甲基吡啶存在下。最优选纳巴霉素衍生物是WO94/09010中说明的40-O-(2-羟基)乙基纳巴霉素，结合到本发明中作为参考。
三环化合物(I)、纳巴霉素及其衍生物的药学上可接受的盐是无毒的、药学上可接受的常用盐，其实例为无机或有机碱的盐，如碱金属盐(如，钠盐、钾盐等)、碱土金属盐(如，钙盐、镁盐等)、铵盐和胺盐(如三乙胺盐、N-苄基-N-甲胺盐等)。
在本发明的IL-2抑制剂中，尤其是大环内酯化合物，由于构象异构体或不对称碳原子和双键存在，可包括一对或多对立体异构体，如旋光异构体和几何异构体。这些构象异构体和异构体也包括在本发明之内。另外，大环内酯化合物可形成溶剂化物，这种情况也包括在本发明内。优选的溶剂化物实例为水合物和乙醇化物。
其它IL-2抑制剂可从MERCK INDEX，12th版，No.2821，美国专利Nos.4,,117,118、4,215,199、4,288,431、4,388,307，Helv.Chim.Acta，60，1568(1977)和65，1655(1982)以及Transplant.Proc.17，1362(1985)等得知。更明确地说，它们是环孢菌素，如环孢菌素A、B、C、D、E、F和G及其衍生物。特别优选环孢菌素A。这些都结合到本说明书中作为参考。
三环化合物(I)、其药学上可接受的盐、环孢菌素及其衍生物都可归类为抑制IL-2产生的“IL-2产生抑制剂”。纳巴霉素及其衍生物可归类为抑制IL-2信号传递的“IL-2信号传导抑制剂”。
在本发明中，视细胞功能紊乱是指某些原因引起的视网膜的视细胞受累于功能紊乱的状况，它可通过与正常状态下相比，ERG中a-波的峰的延迟或振幅的变化证实。由于视细胞功能紊乱是由各种视网膜病(如退化性视网膜病、视网膜脉络膜病等)所引起，本发明的视细胞功能紊乱治疗剂可用于治疗视网膜病。特别是在局部缺血性视网膜病模型中，本发明的视细胞功能紊乱治疗剂具有优越的改善视细胞功能紊乱的作用，其可从下述的实验实施例证实，并可用于治疗局部缺血性视网膜病。局部缺血视网膜病由各种原因引起。例如，视网膜血管病由系统性疾病(如糖尿病、高血压和动脉硬化)引起，其示例性实例为糖尿病性视网膜病、眼底高渗、以及视网膜局部血管疾病引起，如中枢视网膜动脉梗塞、中枢视网膜静脉血栓、视网膜外周血管梗塞、早熟性视网膜病(retinopathy of prematurity)等。
本发明中的治疗包括任何处理，如预防、治疗、症状的缓解、症状的减轻、病情发展的抑制等。
可将本发明中所用的白细胞介素2抑制剂用作人和动物的药剂，并可通过口服、静脉给药(包括输液)、皮下给药、直肠或阴道给药、眼部局部给药(包括眼膏剂)全身或局部给药。考虑到系统性影响、明显的副作用等因素，特别优选采用眼部局部给药形式。
白细胞介素2抑制剂的剂量依据给药对象(如人和动物)的种类、年龄、体重、所治疗的疾病、所要求的治疗效果、给药途径、治疗方法、疗程等变化。通常，全身给药时，剂量为大约0.0001-1000mg，优选0.001-500mg，可以单次剂量或每日2-4次剂量或以缓释方式给予。当眼部局部用药时，每只眼以每日数次，优选滴入或每日1-6次给予含有活性成分的制剂，制剂中活性组分的比例为0.001-10.0w/v％，优选0.005-5.0w/v％。
根据本发明，可将活性成分白细胞介素2抑制剂单独或与其它药理活性成分组合的方式给药。当制成制剂后给药时，其可作为经常规方法制备的剂型给予。剂型可以是，如，滴眼剂、眼用软膏剂、粉末剂、颗粒剂、片剂、胶囊剂、注射剂、软膏剂等，特别优选滴眼剂和眼膏剂。这些制剂可根据常规方法制备。在这些制剂中，口服制剂优选固体溶液剂，其根据与EP-A-0240773的制备相同的方法制备。当要求滴眼剂时，优选EP-A-0406791中说明的滴眼剂。当需要时，可加入滴眼剂中常用的添加剂，如等渗剂(如，氯化钠)、缓冲剂(如，硼酸、磷酸-氢化钠、磷酸二氢钠等)、防腐剂(如，苯扎氯铵、苄索氯铵、氯丁醇等)、粘合剂[如，糖(乳糖、甘露糖醇、麦芽糖等)、透明质酸(透明质酸钠、透明质酸钾等)、其盐、粘多糖(硫酸软骨素等)、聚丙烯酸钠、乙烯基羧基聚合物、交联聚丙烯酸酯等]。这些结合到本说明书中作为参考。
以下以实施例形式更详细地解释本发明，这些实施例并不限定本发明。
实施例
实验实施例1 对视网膜局部缺血大鼠ERG变化的影响
通过结扎大鼠视网膜血管及再灌注诱发局部缺血状态，建立大鼠局部缺血性视网膜病模型，采用该模型测定对视网膜潜能(potential)变化的影响。
(1)试验动物
将Long Evans有色大鼠(雄性，接受试验时为7-或8-周龄：体重200-250g)预喂养8日，用在正常条件下(如体重)无异常的动物进行试验。
(2)实验物质和给药方法
采用本发明中作为活性组分的FK506，以下0.1％的滴眼剂(混悬液)用作试验药物。
试验药物
根据EP-A-0406791(实施例6)中说明的相同方法制备的混悬液含有下列组分
FK506 1.0mg
聚乙烯醇 7.0mg
磷酸氢二钠12水合物 0.05mg
磷酸二氢钠2水合物 0.76mg
磷酸 适量
氢氧化钠 适量
氯化钠 8.56mg
苯扎氯铵 0.1mg
注射用水 适量
总量 1ml
采用无活性组分的滴眼剂基质物质作为对照。从实验第1日至第7日，每日三次(8:00，13:00，18:00)，用微量加液器以10μl/只眼，向眼中滴入试验药物。以相同的方式通过滴入给予对照剂。
(1)局部缺血性视网膜病模型的建立
在实验第8日，通过腹膜内给予安定(0.625mg/kg)和戊巴比妥(20mg/kg)，将大鼠麻醉，从侧面取出部分眶骨膜。移出由视神经、眼动脉和眼静脉组成的锥体蒂，将所有的锥体蒂结扎以引起局部缺血。局部缺血继续45分钟，通过释放结扎再灌注。
(2)ERG测定
根据以下所列校准仪器和参数。“Standard for ClinicalElectroretinography”(International Standardization Committee)
仪器：
电生理学专用计算机-2000(LKC技术公司)
ERG测定参数：
放大器
高速滤器：500Hz
低速滤器：0.3Hz
陷波滤波器：关
振幅：50μV/区(最大1500μV)
时间：20ms/区(最大2500ms)
角膜电极
电阻：10-20KΩ
光刺激
单次闪烁：15ms
强度：2.289cd.s.m-2
空视野
滤光片：无
在上述条件下，在局部缺血前后，采用时间推移(lapse of time)测定ERG。
(3)结果
以局部缺血前的ERG作为100％，测定再灌注后a-波峰的延迟的比率。再灌注后立即消失。结果示于表1中。
表1
| 给药组 | (n) | a-波峰的延迟(％平均值±SD) | ||
| 再灌注后60min | 再灌注后90min | 再灌注后120min | ||
| 对照药物 | (8) | 195.6±53.5 | 190.8±55.3 | 191.9±60.4 |
| 试验药物 | (8) | 137.1±47.1* | 141.6±44.8* | 134.4±31.6* |
*P＜0.05(通过ANOVA检测，与对照药物比较)
a-波峰的延迟在再灌注后立即消失，但之后随时间推移，峰的延迟延长。从表1中可见，与对照药物组比较，试验药物给药组可明显抑制a-波峰延迟的延长。
本申请以在美国提交的专利申请No.60/113,939为基础，其内容结合到本发明中作为参考。
Claims (4)
1.FK506在制备通过眼部局部给药用于治疗视细胞功能紊乱的药用组合物中的用途。
2.权利要求1的用途，其中的视细胞功能紊乱是视网膜病。
3.权利要求2的用途，其中的视网膜病是局部缺血性视网膜病。
4.权利要求3的用途，其中的局部缺血性视网膜病是糖尿病视网膜病。
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| US11393998P | 1998-12-24 | 1998-12-24 | |
| US60/113,939 | 1998-12-24 |
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| AU2003209297A1 (en) | 2002-01-18 | 2003-09-02 | Massachusetts Eye And Ear Infirmary | Methods and compositions for preserving the viability of photoreceptor cells |
| WO2004027027A2 (en) * | 2002-09-18 | 2004-04-01 | Trustees Of The University Of Pennsylvania | Method of inhibiting choroidal neovascularization |
| US20050118344A1 (en) | 2003-12-01 | 2005-06-02 | Pacetti Stephen D. | Temperature controlled crimping |
| US20060258698A1 (en) | 2005-02-09 | 2006-11-16 | Sreenivasu Mudumba | Liquid formulations for treatment of diseases or conditions |
| WO2007019427A2 (en) * | 2005-08-08 | 2007-02-15 | Massachusetts Eye & Ear Infirmary | Methods and compositions for preserving the viability of photoreceptor cells |
| US8492400B2 (en) | 2006-02-09 | 2013-07-23 | Santen Pharmaceutical Co., Ltd. | Stable formulations, and methods of their preparation and use |
| JP5506378B2 (ja) | 2006-03-23 | 2014-05-28 | 参天製薬株式会社 | 血管透過性に関連する疾患または病気のための製剤および方法 |
| EP3868407A4 (en) * | 2018-10-15 | 2022-02-23 | Osaka University | MEDICINE FOR IMPROVING OR PREVENTING RETINA AND/OR PHOTORECEPTION RELATED SYMPTOMS AND METHOD FOR SCREENING SUBSTANCE FOR IMPROVING OR PREVENTING RETINA AND/OR PHOTORECEPTION RELATED SYMPTOMS |
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| IL102414A (en) * | 1991-07-25 | 1996-08-04 | Univ Louisville Res Found | Medicinal preparations for the treatment of ocular inflammation, containing rapamycin |
| US5922773A (en) * | 1992-12-04 | 1999-07-13 | The Children's Medical Center Corp. | Glaucoma treatment |
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| KR20010099928A (ko) | 2001-11-09 |
| AU781049B2 (en) | 2005-05-05 |
| BR9917113A (pt) | 2001-10-23 |
| NZ513111A (en) | 2003-10-31 |
| JP2002542150A (ja) | 2002-12-10 |
| NO20013146L (no) | 2001-08-20 |
| AU1690600A (en) | 2000-07-31 |
| CA2356382A1 (en) | 2000-07-06 |
| EP1140134A1 (en) | 2001-10-10 |
| CN1352565A (zh) | 2002-06-05 |
| MXPA01006449A (es) | 2002-04-24 |
| NO20013146D0 (no) | 2001-06-22 |
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| AR022017A1 (es) | 2002-09-04 |
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