CN116077490A - 用于抑制术后眼睛炎性病况的抗炎和散瞳前房溶液 - Google Patents
用于抑制术后眼睛炎性病况的抗炎和散瞳前房溶液 Download PDFInfo
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Abstract
本发明提供用于通过在眼外科手术程序期间眼内给予包含非甾类抗炎剂和α‑1肾上腺素能散瞳剂的溶液,例如,酮咯酸和苯肾上腺素的液体冲洗液抑制眼外科手术程序之后的术后炎性病况的方法。
Description
I.发明领域
本发明涉及使用包含非甾类抗炎剂和α-肾上腺素能散瞳剂的用于在眼外科手术程序期间眼内给予的液体药物组合物抑制术后炎性病况的方法。
II.发明背景
眼外科手术必然导致细微眼内结构的创伤,其引起前列腺素合成和炎性级联。产生的炎症可导致出现过度炎症和相关的术后炎性病况,特别是在具有将他们置于提高的术后炎性病况风险中的术前病况或可能经历提高的外科创伤水平的受试者中。
眼睛外科手术通常需要使用生理冲洗液以便于手术程序并且保护和维持眼内组织的生理学完整性。通常需要冲洗液的眼外科手术程序的实例包括白内障摘除和晶状体置换及屈光性晶状体交换程序、角膜移植程序和玻璃体视网膜手术及用于青光眼的小梁切除术程序。在整个眼内外科手术中,患者的瞳孔必须充分扩大以提供清晰的手术视野和限制与程序可能相关的创伤。瞳孔扩大(散瞳)通常通过术前局部给予散瞳剂扩大眼睛来实现。
在外科手术期间,随着外科手术工具的尖端插入到眼睛前房并且引起外科手术创伤,虹膜括约肌趋向收缩(缩瞳),减小瞳孔所界定的窗口。如果瞳孔直径在整个程序中没有充分维持,损伤眼内结构的风险增加并且所需的手术时间通常被延长。临床上瞳孔直径的显著减小与程序相关并发症(包括后囊膜撕裂、残留晶状体碎片和玻璃体渗漏)的增加有关。
许多眼外科医生会将肾上腺素掺入眼内冲洗液中以帮助维持瞳孔扩大。虽然肾上腺素为一种α-和β-肾上腺素能激动剂,苯肾上腺素为一种有时在外科手术前局部给予以促进散瞳的α-1激动剂,但是用于眼内给予的无防腐剂和无亚硫酸氢盐形式的苯肾上腺素在美国未被批准。
为了患者的舒适度,减少术后疼痛和刺激也是合乎需要的。为此,可在术前和/或术后用非甾类抗炎药物(NSAID)治疗患者。酮咯酸为一种可以以可保存的形式市售获得的眼用NSAID。来自Allergan的为包含0.01%苯扎氯铵作为防腐剂的酮咯酸氨丁三醇溶液,可以以3-mL和6-mL滴瓶获得。Bedford Laboratories也提供浓缩形式(1mL中15mg或30mg或10mL中60mg或300mg)的用于血管内或肌内注射给予的酮咯酸氨丁三醇。Allergan提供一种无防腐剂的0.45%酮咯酸氨丁三醇眼用溶液,其用羧甲基纤维素钠、氯化钠、无水柠檬酸钠配制在个体使用的小瓶中,商标名为一些眼科医生还在术前使用局部NSAID试图预先阻止术中缩瞳。这种缩瞳预防方法并非最佳的,因为术中冲洗液冲洗出术前递送的来自被冲洗液浸洗的眼睛内区域的试剂。
2014年FDA批准的OMIDRIATM(苯肾上腺素和酮咯酸注射剂)(1%/0.3%),OmerosCorporation,为标明用于通过防止术中缩瞳维持瞳孔大小的和用于减轻术后疼痛的α1-肾上腺素能受体激动剂和非选择性环氧合酶抑制剂。OMIDRIATM被列入用于白内障手术或眼内晶状体置换期间所使用的标准冲洗液中。目前OMIDRIATM并未被标明用于减轻术后炎症。
III.发明概述
本发明提供用于抑制眼外科手术程序之后的术后炎性病况的方法。所述方法包括鉴定具有提高的患术后炎性病况风险的受试者,所述鉴定可基于先前存在的生理学病况或特征、既往治疗史或用药史术前作出,和在眼外科手术程序期间眼内给予所述受试者在眼内冲洗载体中包含非甾类抗炎药物(NSAID)和α-1肾上腺素能受体激动剂散瞳剂的溶液。所述NSAID和散瞳剂以足以通过促进散瞳和抑制缩瞳维持术中瞳孔直径例如程序期间维持至少6.0mm的术中瞳孔直径的量包含在溶液中,并且给予充足量的溶液以使在眼组织内摄入足以在术后至少六个小时的时期内抑制环氧合酶的量的NSAID,从而抑制术后炎性病况。在本发明的其它实施方案中,对提高的术后炎症风险的鉴定可在程序期间基于程序期间遭受的创伤性质发生。在又其它的实施方案中,对提高的术后炎性病况风险的鉴定可在术中和/或术前作出。
用于根据本发明给予的溶液的合适的NSAID包括氟比洛芬、舒洛芬、双氯酚酸、酮洛芬、酮咯酸、吲哚美辛、奈帕芬胺和溴芬酸,并且合适的α-1肾上腺素能受体激动剂包括苯肾上腺素、肾上腺素、羟甲唑啉和萘甲唑啉。在本发明优选的实施方案中,NSAID为酮咯酸并且散瞳剂为苯肾上腺素。在另一个实施方案中,所述溶液包含浓度为240-720μM的苯肾上腺素和浓度为44-134μM的酮咯酸。苯肾上腺素和酮咯酸可适当地以3:1-10:1的苯肾上腺素与酮咯酸摩尔比率包含在内。
在本发明的一个实施方案中,所述溶液的给予导致在术后至少六个小时的时期内对眼组织中基线环氧合酶-1(COX-1)和环氧合酶-2(COX-2)活性至少85%,优选至少90%的抑制。在本发明的另一个实施方案中,所述溶液的给予导致在术后至少七个小时的时期内对眼组织中基线COX-1和COX-2活性至少85%,优选至少90%的抑制。在本发明的另一个实施方案中,所述溶液的给予导致在术后至少八个小时的时期内对眼组织中基线COX-1和COX-2活性至少85%的抑制。在本发明的另一个实施方案中,所述溶液的给予导致在术后至少八个小时的时期内对眼组织中基线COX-1和COX-2活性至少90%的抑制。在又一个实施方案中,所述溶液的给予导致在术后至少十个小时的时期内对眼组织中基线COX-1和COX-2活性至少85%的抑制。
本发明方法可用于任何与术后炎症风险相关的眼外科手术程序,包括需要瞳孔扩大和与术后炎症相关的程序,例如白内障摘除和晶状体置换、屈光性晶状体交换、玻璃体切除术、视网膜光凝固、视网膜脱离修复、黄斑孔修复、虹膜后(retroiris)肿瘤或肿块切除、后巩膜切开术和视神经切开术,或者与玻璃体内注射引起的炎性病况的抑制有关的程序。在一些实施方案中,本发明溶液在程序期间,例如,在整个程序中连续地给予以冲洗眼内组织。在其它实施方案中,本发明溶液作为程序的部分通过眼内注射给予。在又其它的实施方案中,本发明溶液通过在程序期间冲洗眼内组织,随后在程序结束时眼内注射一针溶液给予。在又一个实施方案中,本发明溶液通过在程序结束时,例如在鉴定由于术中遭受的创伤而处于术后炎性病况风险中的患者后,术后注射一针溶液给予。在又一个实施方案中,所述溶液在术前、术中和/或术后通过眼内注射给予。
在本发明的另一个方面,所述方法用于选自玻璃体切除、视网膜光凝固、视网膜脱离修复、黄斑孔修复、虹膜后肿瘤或肿块切除、后巩膜切开术和视神经切开术,或与玻璃体内注射引起的炎性病况的抑制有关的程序中。
被本发明方法抑制的术后炎性病况包括,例如,毒性眼前段综合征、黄斑囊样水肿(包括非人工晶状体黄斑囊样水肿和人工晶状体(Irvine-Gass)黄斑囊样水肿)、急性眼内炎、后囊膜浑浊、前囊膜收缩、白内障手术后单纯疱疹病毒性角膜炎、术后低眼压、尼龙缝线毒性、白内障手术后长期角膜内皮细胞丢失、角膜水肿、虹膜发炎、角膜-视网膜炎性综合征、巩膜炎、巩膜外层炎、玻璃体束综合征、术后急性虹膜睫状体炎、葡萄膜炎、白内障摘除后视网膜外层沉积、伴随巨细胞沉积的反复膜增殖、毒性玻璃体炎、虹膜后粘连、术后眼内纤维蛋白形成、切口纤维化、黄斑裂孔手术并发症、脉络膜渗漏和眼前房积脓。
在其它实施方案中,由于包括小瞳孔直径(例如,小于6mm的术前扩大的瞳孔直径)、虹膜松弛综合征、葡萄膜炎、视网膜静脉阻塞、视网膜前膜、高龄(例如,超过65岁、年长者或老年人)、糖尿病、糖尿病黄斑水肿、糖尿病视网膜病变、黄斑变性或全身性高血压在内的术前生理学病况或特征,包括先前的眼外科手术或使用α-1-肾上腺素能受体拮抗剂或拉坦前列素的药物治疗在内的术前治疗史,包括后囊膜破裂、二次晶状体囊切开术、虹膜嵌顿、残留的晶状体物质或玻璃体脱出在内的外科手术创伤,和尼龙缝线、虹膜固定型人工晶状体或前房型人工晶状体的外科手术安置,受试者被鉴定为具有提高的术后炎性病况的风险。
在本发明进一步的方面,由于选自小瞳孔直径(例如,小于6mm的术前扩大的瞳孔直径)、虹膜松弛综合征、葡萄膜炎、视网膜静脉阻塞、视网膜前膜、糖尿病黄斑水肿、糖尿病视网膜病变、黄斑变性或全身性高血压的术前生理学病况或特征,包括先前的眼外科手术或使用α-1-肾上腺素能受体拮抗剂或拉坦前列素的药物治疗在内的术前治疗史;包括后囊膜破裂、二次晶状体囊切开术、虹膜嵌顿、残留的晶状体物质或玻璃体脱出在内的外科创伤,和尼龙缝线、虹膜固定型人工晶状体或前房型人工晶状体的外科手术安置,受试者被鉴定为具有提高的术后炎性病况的风险。
本发明还提供用于通过鉴定具有患术后炎性病况的生理学风险的受试者和在眼外科手术程序期间眼内给予所述受试者在眼内冲洗载体中包含非甾类抗炎药物(NSAID)和α-1肾上腺素能受体激动剂散瞳剂的溶液抑制眼外科手术程序之后的术后炎性病况的方法,其中所述NSAID和散瞳剂以足以由于散瞳剂术中促进散瞳和NSAID术中抑制缩瞳维持术中瞳孔直径从而减少术中创伤和足以通过NSAID的术中和术后抗炎作用抑制术后炎性病况的量包含在溶液中。
本发明提供用于通过在眼外科手术程序期间眼内给予处于术后炎性病况风险中的受试者在眼内冲洗载体中包含非甾类抗炎药物(NSAID)和α-1肾上腺素能受体激动剂散瞳剂的溶液抑制眼外科手术程序之后的术后炎性病况的方法。所述NSAID和散瞳剂以足以通过促进散瞳和抑制缩瞳维持术中瞳孔直径的量包含在溶液中,并且给予充足量的溶液以使在眼组织内摄入足以在术后至少六个小时的时期内抑制环氧合酶的量的NSAID,从而抑制术后炎性病况。
IV.附图简述
本发明现将通过举例的方式,参考附图进行更加详细的描述,在附图中:
图1-3提供实施例1的临床研究的结果。图1说明平均瞳孔直径(PD)随时间从基线至外科手术结束的平均(±SEM)变化。瞳孔直径从基线到程序结束以及在皮层清洗结束时从受试者的外科手术视频记录以1分钟的间隔测量。图2说明研究所得到的外科手术期间任何时间时的最大术中瞳孔收缩。图3说明术后早期期间的平均眼睛疼痛视觉模拟量表(VAS)得分(全分析集人群)。
图4-7提供实施例2的狗前房研究的结果,并且说明前房给予平衡盐溶液中的1.0%苯肾上腺素/0.3%酮咯酸注射剂后指定时间点时雌性狗眼睛组织中酮咯酸的平均浓度。图4显示角膜、晶状体囊膜、虹膜-睫状体(ICB)、眼房水和前部巩膜中的酮咯酸浓度。图5显示球结膜和眼睑结膜中的酮咯酸浓度。图6显示玻璃体液、视网膜、脉络膜-RPE(外周)、脉络膜-RPE(反光色素层)和后部巩膜中的酮咯酸浓度。图7显示t=0到t=10小时时视网膜组织中COX-1和COX-2的平均百分比抑制。
V发明详述
本发明提供用于通过在眼外科手术程序期间眼内给予处于术后炎性病况风险的受试者在眼内冲洗载体中包含非甾类抗炎药物(NSAID)和α-1肾上腺素能受体激动剂散瞳剂的溶液抑制眼外科手术程序之后的术后炎性病况的方法。所述NSAID和散瞳剂以足以通过促进散瞳和抑制缩瞳维持术中瞳孔直径的量包含在溶液中,从而减少炎症引起的对眼内结构创伤的可能性。给予充足量的溶液以使在眼组织内摄入足以在术后至少六个小时的时期内抑制环氧合酶的量的NSAID,从而抑制或减小术后炎性病况的可能性或严重性。
眼外科手术程序
本发明可用于各种与术后炎性病况的发生相关的眼外科手术程序,包括在眼睛前房或后房实施的眼前段程序和在眼后段实施的程序,例如视网膜程序。在许多情况下,所述程序为前房程序。合适地,期间使用本发明方法的眼外科手术程序为需要瞳孔扩大或散大的程序,通过扩大的瞳孔为外科医生提供扩大的手术视野和可视化的眼内结构。根据本发明,所述溶液通过在程序中冲洗和/或注射眼内给予以通过促进散瞳和抑制缩瞳维持瞳孔直径,从而减少对虹膜和通过虹膜操作的眼内结构的外科创伤。本发明溶液可给予眼前段内,特别是眼前房或眼后房内,或眼后段内。
需要瞳孔扩大和与术后炎症相关的适合实践本发明的程序的实例包括白内障摘除和晶状体置换(CELR)、屈光性晶状体交换(RLE)、玻璃体切除术、视网膜光凝固、视网膜脱离修复、黄斑孔修复、虹膜后肿瘤或肿块切除、后巩膜切开术和视神经切开术。CELR和RLE可涉及用于晶状体摘除和人工晶状体(IOL)置换的飞秒或手术刀切割、晶状体乳化。本发明还可通过与一种或多种其它治疗剂,例如抗血管内皮细胞生长因子(抗-VEGF)如雷珠单抗的注射一起或同时,或紧接其注射之前或之后注射本发明溶液与玻璃体内注射引起的炎性病况的抑制结合使用。
眼外科医生通常在外科手术前使用术前散瞳药物处理以扩大瞳孔。Behndig,A.等,“Intracameral mydriatics in cataract surgery(白内障手术中的前房散瞳剂)”,Cataract Surgery,Zaidi F.(编辑),Rijeka,Croatia:InTech 2013:149-172。用一种或多种散瞳剂使瞳孔保持扩大越大和越久,程序就越容易并且风险越小。外科手术期间瞳孔收缩使程序更加困难,并且增加额外并发症的风险。(Behndig 2013)
术后炎症
大部分白内障程序是常规的并且不复杂。Patalano,V.J.,“The risks andbenefits of cataract surgery(白内障手术的风险和益处)”,Digital Journal ofOphthalmology,2014年6月26日可访问http://www.djo.harvard.edu/site.php?url=/patients/pi/408;A.D.A.M.,Inc.,“Cataracts In-depth report(白内障深度报道)”,TheNew York Times,2014年6月26日可访问http://www.nytimes.com/health/guides/disease/cataract/print.html。但术中并发症的发生常常是不可预知的,并且据估计在美国与3.8%的白内障程序有关。(Patalano 2014);Greenberg,P.B.等,“Prevalence andpredictors of ocular complications associated with cataract surgery in UnitedStates veterans(美国退伍军人中与白内障手术相关的眼并发症的流行及预测因子)”,Ophthalmology118(3):507-514(2011)。
术中缩瞳通过缩小外科医生的视野和工作区使白内障外科手术程序更加困难。(Behndig 2013)外科手术期间小的瞳孔与增加的术中并发症风险有关,包括后囊膜破裂和玻璃体脱出。Artzen,D.等,“Capsule complication during Cataract surgery:Case-control study of preoperative and intraoperative risk factors:Swedish CapsuleRupture Study Group report 2(白内障手术期间囊膜并发症:术前和术中风险因素的病例对照研究:瑞典囊膜破裂研究组报告2)”,J Cataract Refract Surg35(10):1688-1693(2009);Zare,M.等,“Risk factors for posterior capsule rupture and vitreousloss during phacoemulsification(玻璃体乳化期间后囊膜破裂和玻璃体脱出的风险因素)”,J Ophthalmic Vis Res.4(4):208-212(2009)。外科手术操作的可见度和空间的减小也可导致增加的部分晶状体或整个晶状体核丢失入玻璃体腔(滴落核)的机会或引起虹膜损伤。(Behndig 2013)
术中缩瞳往往与术中虹膜松弛综合征(IFIS)有关。患IFIS的眼睛具有松弛、鼓起的虹膜组织,伴随着增加的在外科手术期间脱垂和瞳孔收缩的风险。Chang,D.F.,Campbell,J.R.,“Intraoperative floppy iris syndrome associated with tamsulosin(与坦索罗辛相关的术中虹膜松弛综合征)”,J Cataract Refract Surg31(4):664-673.22(2005);Chang,D.F.等,“Prospective multicenter evaluation of cataract surgeryin patients taking tamsulosin(Flomax)(服用坦索罗辛(Flomax)的患者中白内障手术的前瞻性多中心评价)”,Ophthalmology114(5):957-964(2007)。已知IFIS病例的数目在接受α-1-肾上腺素能受体拮抗剂,例如坦索罗辛(Flomax)治疗的患者中特别高。(Chang2005);Haridas,A.等,“Intraoperative floppy iris syndrome(IFIS)in patientsreceiving tamsulosin or doxazosin-a UK-based comparison of incidence andcomplication rates(接受坦索罗辛或多沙唑嗪治疗的患者中的术中虹膜松弛综合征(IFIS)-基于英国的发病率和并发症率的比较)”,Graefes Arch Clin Exp Ophthalmol251(6):1541-1545(2013)。坦索罗辛被用于治疗良性前列腺增生(非癌性前列腺肿大)的患者。显著的术中缩瞳已显示发生在超过70%的这些高风险患者中,甚至当外科手术由有丰富经验的白内障外科医生实施时。(Chang 2007)。
即使程序是常规的并且不复杂,外科手术创伤也引起眼内炎症。Lobo,C.,“Pseudophakic cystoid macular edema(人工晶状体眼黄斑囊样水肿)”,Ophthalmologica 227(2):61-67(2012);Miyake,K.,Ibaraki,N.,“Prostaglandins andcystoid macular edema(前列腺素与黄斑囊样水肿)”,Surv Ophthalmol2(47 suppl 1):S203-S18(2002)。炎症通常开始于前房,在外科手术切口处或者由于眼内结构例如虹膜或睫状体直接的机械刺激导致。早期炎症途径是自我延续的,这意味着炎症最初在强度方面增长,并且从前房扩展到玻璃体和视网膜。(Lobo 2012);(Miyake 2002)。
炎症与血管扩大和血管渗漏相关。当眼睛在外科手术后发炎时,视网膜血管渗漏和过量液体积聚引起视网膜肿胀或水肿。(Lobo 2012);(Miyake 2002)。肿胀可包括黄斑,提供如阅读或驾驶等任务中使用的灵敏、精细的视觉的特定中心视网膜的区域。涉及黄斑的视网膜肿胀称为黄斑水肿。黄斑囊样水肿(CME)由出现解剖学上明显的液囊或囊肿定义。Ismail,R.,Sallam,A.,“Complications associated with cataract surgery(与白内障手术相关的并发症)”,Cataract Surgery,Zaidi F.(编辑),Rijeka,Croatia:InTech2013:221-244。白内障手术后炎症和增加的眼内前列腺素水平已鉴定为CME的原因,并且严重的前眼部炎症与术后CME之间存在关联。Rossetti,L.,Autelitano,A.,“Cystoidmacular edema following cataract surgery(白内障手术之后的黄斑囊样水肿)”,OpinOphthalmol11:65-72(2000)。
黄斑囊样水肿(CME)为白内障和成功的玻璃体视网膜外科手术之后视力减退的主要原因。Loewenstein,A.,Zur,D.,“Postsurgical Cystoid Macular Edema(术后黄斑囊样水肿)”,MacularEdema,Dev Ophthalmol.,Coscas,G.(编辑),Basel,Karger 2010:148-159。CME还依然是晶状体囊切开术、穿透性角膜植入术、巩膜扣带术、滤过程序和全视网膜光凝术之后的问题。(Loewenstein 2010);Shimura,M.等,“Panretinal photocoagulationinduces pro-inflammatory cytokines and macular thickening in high-riskproliferative diabetic retinopathy(在高风险增殖性糖尿病视网膜病变中全视网膜光凝术引起促炎性细胞因子和黄斑增厚)”,Graefes Arch Clin Exp Ophthalmol 11:65-72(2000)。术后CME发病率的评估取决于检测的定义与方法。研究估计白内障手术后CME的流行在4%和20%之间。Wielders,L.等,“Prevention of CME after cataract surgery(白内障手术后的CME预防)”,CataractRefract Surg Today Eur.53-55(2013)。在每种情况下CME均不导致视力下降,或视力下降是微小的且不易为患者察觉到。临床上显著的黄斑水肿与视觉损伤相关,并且估计在高达5.8%的白内障手术后的眼睛中发生。(Lobo 2012);(Wielders 2013)
一项体内研究评估了作为眼外科创伤模型的兔子中穿刺术之后眼房水中前列腺素的累积。眼房水中PGE2的浓度伴在穿刺之后一个小时时达到峰值,并且在穿刺术后七小时内保持显著提高,在外科手术损伤后48小时接近基线水平。Graff,G.等,“Transientloss ofprostaglandin synthetic capacity in rabbit iris-ciliary body followinganterior chamber paracentesis(前房穿刺之后兔虹膜睫状体中前列腺素合成能力的瞬时损耗)”,Ocular Immunology and Inflammation6(4):227-238(1998)。该研究说明一旦炎症级联在眼外科创伤期间开始,前列腺素水平将长期维持提高,潜在地导致不期需的与过度炎症相关的术后病况。
术后炎性病况
眼外科手术诱导的过度炎症可导致许多不期需的术后病况,可使用本发明的方法和组合物抑制或减小这些病况的严重性或发病率。眼前段毒性综合征(TASS)为其中非传染性物质进入眼前段并诱导对眼内组织的毒性损害的急性术后炎症反应。几乎所有的病例均发生在安全无事的白内障外科手术之后,并且,最近已有报道在有晶状体眼的人工晶状体植入术后。先前这种综合征定义为其它名称,例如无菌性眼内炎或不知原因的术后葡萄膜炎。此外,称为毒性内皮细胞破坏(TECD)综合征的病症已有描述,并且被认为是TASS的变体。已经显示非甾类抗炎滴剂在若干TASS病例中为一种有益的辅助剂,支持了TASS由炎症介导。Al-Ghouri,A.R.,M.D.,“Toxic Anterior Segment Syndrome(眼前段毒性综合征)”,2014年11月23日可访问http://emedicine.medscape.com/article/1190343-overview。
黄斑囊样水肿(CME)为其中肿胀或增厚发生在中心视网膜(黄斑)上的无痛病况,并且通常与中心视力模糊或扭曲有关。不太常见的病况包括视物变形症、视物显小症、盲点和畏光。CME为一种相对常见的病况,并且往往与各种眼睛病况相关,例如年龄相关性黄斑退化(AMD)、葡萄膜炎、视网膜前膜、玻璃体黄斑牵引、糖尿病、视网膜静脉阻塞、与药物相关的或眼外科手术之后的。当CME在白内障手术之后发展并且其原因被认为与外科手术直接相关时,其被称为Irvine-Gass综合征或人工晶状体CME。Irvine-Gass综合征的药物治疗包括NSAID、皮质甾类和碳酸酐酶抑制剂。白内障外科手术的近期进展,例如晶状体乳化、小切口手术和折叠型人工晶状体中的进展,已经导致与白内障外科手术相关的物理创伤下降。物理外科手术创伤的下降减少了在术后眼睛炎症中起主要作用的前列腺素的释放。然而,术后炎症依然是患者不适、延迟恢复和在一些情况下,次优视觉结果的原因。如果不进行治疗,这种炎症可干扰患者恢复和/或促成其它并发症,例如黄斑囊样水肿的发展。局部施用NSAID通常用于非传染性眼睛炎症和白内障外科手术之后的黄斑囊样水肿的处理和预防。Colin,J.,“The Role of NSAIDs in the Management of Postoperative OphthalmicInflammation(NSAID在术后眼睛炎症处理中的作用)”,Drugs67(9):1291-308(2007)。
虽然最常见的黄斑囊样水肿(CME)的原因是由于白内障摘除或其他眼内外科手术后CME Irvine-Gass综合征,即人工晶状体眼黄斑囊样水肿,许多其它病况也与黄斑区域充满液体的囊区的临床表现相关,即非人工晶状体眼黄斑囊样水肿。CME为许多眼内疾病最终的共同路径,通常涉及视网膜脉管系统。表现可有所不同,取决于致病原;然而,CME可表现为非特异性的临床发现。如果CME的原因不明显,详细的检眼镜检查和偶尔地辅助检验可对鉴定原因是必需的。用于治疗CME的最常见药物包括甾类、非甾类抗炎药物(NSAID)和乙酰唑胺。Roth,D.B.,M.D.,“Nonpseudophakic Cystoid Macular Edema(非人工晶状体眼黄斑囊样水肿)”,2014年11月23日可访问http://emedicine.medscape.com/article/1225735-overview#showall。
炎症还似乎在急性术后眼内炎中发挥作用,并且发明人相信本发明可适合用于改善这种病况。玻璃体腔内地塞米松在急性术后眼内炎治疗中的使用依旧存在争议。临床医生已使用这种短效皮质甾类抑制细菌内毒素、宿主因素和抗生素的炎症效应。在恶性传染性眼内炎的兔模型中,地塞米松显示通过小梁网状结构减少眼内万古霉素的消除,提示甾类给予的一个新的潜在益处。Clark,W.L.,M.D.,“Postoperative EndophthalmitisTreatment&Management(术后眼内炎治疗&处理)”,2014年11月23日可访问http://emedicine.medscape.com/article/1201260-treatment。非甾类抗炎药物可提供等价的抗炎功效(对术后炎症和黄斑囊样水肿二者),而无通常皮质甾类相关的不良事件。Rowen,S.,“Preoperative and Postoperative Medications Used for Cataract Surgery(用于白内障外科手术的术前和术后药物治疗)”,Curr Opin Ophthalmol.10(1):29-35(1999)。
本发明还可合适地用于抑制术后后囊膜浑浊或前囊膜收缩。在约20%的患者中,白内障手术恢复期间或甚至几个月之囊膜后部分有时变得模糊,引起后囊膜浑浊。后囊膜浑浊发生是因为白内障手术后残存的晶状体上皮细胞在囊膜上生长。Knobbe,C.A.,M.D.,“Cataract Surgery Complications(白内障外科手术并发症)”,2014年11月23日可访问http://www.allaboutvision.com/conditions/cataract-complications.htm。已经显示从孵育的丙烯酸型人工晶状体持续释放塞来昔布(一种NSAID)在后囊膜浑浊的体外模型中抑制晶状体上皮细胞生长。Davis,J.L.等,“Sustained-release Celecoxib FromIncubated Acrylic Intraocular Lenses Suppresses Lens Epithelial Cell Growthin an Ex Vivo Model ofPosterior Capsule Opacity(从孵育的丙烯酸型人工晶状体持续释放塞来昔布在后囊膜浑浊的体外模型中抑制晶状体上皮细胞生长)”,JOculPharmacolTher.28(4):359-68(2012)。
本发明还可适合地用于抑制白内障外科手术后的单纯疱疹病毒性角膜炎。眼单纯疱疹病毒(HSV)感染导致致盲的免疫炎性基质性角膜炎(SK)损伤。早期临床前事件包括角膜基质中多形核白细胞(PMN)浸润和新血管形成。已经证明角膜的HSV感染导致环氧合酶2(COX-2)酶类的上调。HSV感染对COX-2的诱导是关键性的事件,因为已经显示用选择性抑制剂抑制COX-2减少角膜血管生成和SK严重性。已经显示COX-2抑制剂的给予导致减少PMN渗透进入角膜和减小角膜血管内皮细胞生长因子水平,很可能导致减少血管生成反应。Biswas,P.S.等,“Role of Inflammatory Cytokine-induced Cyclooxygenase 2in theOcular Immunopathologic Disease Herpetic Stromal Keratitis(炎性细胞因子诱导的环氧合酶2在眼内免疫病理学疾病疱疹性基质角膜炎中的作用)”,JVirol79(16):10589-600(2005)。
非甾类抗炎药物酮咯酸可预防由于白内障手术和其他程序期间释放的环氧合酶产物引起的术后低眼压,指示本发明进一步的功用。评估处于晶状体乳化治疗中的患者中酮咯酸、溴芬酸和奈帕芬胺对PGE2产生的抑制作用的研究证实相比0.1%奈帕芬胺和0.09%溴芬酸,0.45%酮咯酸达到PGE2的最大抑制。Bucci,F.A.,Jr.等,“ProstaglandinE2Inhibition of Ketorolac 0.45%,Bromfenac 0.09%,and Nepafenac 0.1%inpatients Undergoing Phacoemulsification(经受晶状体乳化治疗的患者中0.45%酮咯酸、0.1%奈帕芬胺和0.09%溴芬酸的前列腺素E2抑制)”,Adv Ther28(12):1089-95(2011)。激光虹膜切开术之后眼内压力(IOP)急性增高的可能性是众所周知的。研究已经显示激光照射虹膜本身也可引起低眼压,所以这种现象可成为周边虹膜成形术后IOP响应的另一种解释。Kim,Y.Y.等,“Biphasic Intraocular Pressure Response to LaserIrradiation ofthe Iris in Rabbits(兔中激光照射虹膜的两相眼内压力响应)”,OphthalmicRes27(4):243-8(1995)。
尼龙缝线毒性也可导致术后炎症,并且通过使用本发明合适地抑制。已有报道105名接受简单、有计划的白内障囊外摘除(ECCE)和后房人工晶状体(PC IOL)植入的连续患者中的10名(9.5%)中所发展的一串症状与体征似乎与伤口缝合有关系。这些体征和症状包括异物感、结膜充血和可能因局部巩膜水肿导致的局限于巩膜伤口及运行10-0尼龙缝线的基础的巩膜陷凹的浸润。临床表现的时间从1周到6周。在一些情况下结膜染色证明了嗜酸性粒细胞和多形核白细胞。革兰氏染色、结膜培养和缝线毒物学研究的结果为阴性的。Balyeat,H.D.等,“Nylon Suture Toxicity After Cataract Surgery(白内障手术后的尼龙缝线毒性)”,Ophthalmology95(11):1509-14(1988)。
白内障手术在一些情况下可导致长期角膜内皮细胞丢失,而玻璃体切除术可导致角膜水肿,两种病况均可通过本发明抑制。已经显示三日或一日剂量的酮咯酸减少外科手术时间、晶状体乳化时间及能量和内皮细胞丢失并且与一小时前剂量或安慰剂的使用相比,改善术后早期的视敏度。Donnenfeld,E.D.等,“Preoperative KetorolacTromethamine 0.4%in Phacoemulsification Outcomes:Pharmacokinetic-responseCurve”(术前0.4%酮咯酸氨丁三醇在晶状体乳化的结果中:药物代谢动力学响应曲线),JCataractRefract Surg.32(9):1474-82(2006);Hiraoka,M.等,“Factors Contributingto Corneal Complications after Vitrectomy in Diabetic Patients(糖尿病患者中玻璃体切除术后有助于角膜并发症的因素)”,Jpn J Ophthalmol.45(5):492-5(2001)。已经显示0.5%酮咯酸氨丁三醇眼用溶液在控制术后炎症中有效和耐受良好。Simone,J.N.,“Comparison of the Efficacy and Safety of Ketorolac Tromethamine 0.5%andPrednisolone Acetate 1%after Cataract Surgery(0.5%酮咯酸氨丁三醇与1%醋酸泼尼松龙在白内障手术后的功效与安全性的比较)”,J Cataract Refract Surg.25(5):699-704(1999)。
人工晶状体植入可与引起角膜失代偿和黄斑囊样水肿的角膜-视网膜炎性综合征相关。炎性方面常常不显著出现,而是表现为轻微睫状充血、轻微耀斑、前房中等细胞和中度玻璃体炎。在足以维持未发炎眼睛中角膜清晰度的内皮细胞计数的存在下角膜将失代偿。金属环晶状体和抛光不良的晶状体引起虹膜擦伤和毛细管渗漏,这增加该综合征的严重性。假定眼内外科手术起始被人工晶状体的某些组分增强的炎症反应。用于这种增加的炎症反应的介导可被甾类和非甾类抗炎剂抑制。白血细胞及其产物,例如溶酶体酶类的存在可足以保持炎症反应,并引起对异常和正常细胞的损伤。蛋白质与其免疫组分以及补体的存在可牵涉在这种综合征中。Obstbaum,S.A.等,“Cystoid Macular Oedema and OcularInflammation.The Corneo-Retinal Inflammatory Syndrome(黄斑囊样水肿和眼睛炎症。角膜-视网膜炎症综合征)”,Trans Ophthalmol Soc UK.99(1):187-91(1979)。
术后巩膜炎和巩膜外层炎也可通过使用本发明抑制。一些眼外科手术之后坏死巩膜角膜炎的病例已在最近出版的文献中报道。该病况可能由外科手术炎症触发和由局部闭塞血管炎引起:在一个病例中,血管壁中免疫复合物的沉积已被证实。临床检验显示感染巩膜中的血管消失,以及组织坏死。Gregersen,E.等,“Necrotizing SclerokeratitisFollowing Cataract Extraction(白内障摘除之后的坏死巩膜角膜炎)”,KlinMonblAugenheilkd.193(6):642-4(1988)。在一个总体682名白内障患者中21个伴随人工晶状体插入的有计划的囊外白内障摘除之后外科手术诱导性弥散性巩膜炎(SIDS)病例的报道中,发现当与非-巩膜炎组(平均年龄73.6岁;SD 10.2;Mann-Whitney U-检验,p=0.0003)相比时SIDS患者的平均年龄显著较低(平均年龄62.5岁;SD 13.68)。SIDS与普通麻醉存在相关性(卡方检验,p=0.0008)。21名SIDS患者中的20名响应口服非甾类抗炎剂,具有良好的视觉结果。Scott,J.A.等,“Surgically Induced Diffuse Scleritis Following CataractSurgery(白内障手术之后的手术引起的诱导性弥散性巩膜炎)”,Eye(Lond).8(Pt 3):292-7(1994)。
玻璃体束综合征在眼外科手术后发生,并且由微小的伤口破裂构成,接着为发展为玻璃体束的玻璃体脱出,并且也可合适地通过实施本发明抑制。玻璃体束综合征在医源性或非医源性创伤的情况下发展。医源性来源的玻璃体束综合征通常在前段外科手术之后,虽然其也可在眼筋膜囊下注射和肌肉外科手术之后。已有记录角膜创伤愈合在内皮细胞一侧(内层)比较慢。不良的缝合技术是影响伤口破裂的主要因素。将角膜伤口边缘紧紧压在一起可证明会起皱,并且也可导致缝合道变大,促使缝合圈内组织坏死。一旦后部伤口裂缝与前部伤口缺陷之间的通讯发生(紧密缝合的组织坏死之后),前部水溶液可流出;玻璃体嵌顿也可发生,产生玻璃体束。偶尔,可发生缝合圈内绞窄组织完全脱落。Rogue,M.R.,M.D.,M.B.A.,F.P.A.O,“Vitreous Wick Syndrome(玻璃体束综合征)”,2014年11月23日可访问http://emedicine.medscape.com/article/1230457-overview#a0101。比较局部施用非甾类抗炎药物或皮质甾类后分离角膜伤口所需力度的研究发现甾类治疗引起比NSAID治疗弱的角膜伤口疤痕。McCarey,B.E.等,“Corneal Wound Healing Strength withTopical Antiinflammatory Drugs(使用局部抗炎药物的角膜伤口愈合能力)”,Cornea14(3):290-4(1995)。
本发明还为术后急性虹膜睫状体炎或术后虹膜及睫状体炎症提供治疗机会。已经报道了对辅助使用非甾类抗炎药物在14名患者中治疗慢性虹膜睫状体炎的评估,其中8名患有幼年型类风湿性关节炎,6名患有特发性虹膜睫状体炎。在所有患者中,将NSAID加入其治疗疗程中改善虹膜睫状体炎的活性,允许减少皮质甾类药物剂量。这些数据提示NSAID治疗在儿童慢性虹膜睫状体炎的治疗中可具有辅助作用。Olson,N.Y.等,“Nonsteroidalanti-inflammatory drug therapy in chronic childhood iridocyclitis(慢性幼年型虹膜睫状体炎的非甾类抗炎药物治疗)”,Am JDis Child 142(12):1289-92(1988)。白内障为幼年型特发性关节炎相关葡萄膜炎的早期并发症。在严格控制葡萄膜炎下,IOL植入是该类患者视觉恢复的重要替代选择。在白内障手术之前、期间或之后用NSAID控制葡萄膜炎呈现本发明进一步的功用。Kotaniemi,K.等,“Intraocular Lens Implantation inPatients with Juvenile Idiopathic Arthritis-Associated Uveitis(幼年型特发性关节炎相关的葡萄膜炎患者中的人工晶状体植入)”,OphthalmicRes.38(6):318-23(2006)。
此外本发明可用于抑制白内障摘除后视网膜外层沉积引起的炎症。在一项被鉴定为患有其中后囊膜屏障被打破的白内障摘除后视网膜外层沉积的2名患者的报告中,发现炎症被限制到后段,并且,对感染原因的研究性检查为阴性的。Behera,U.C.,“EpiretinalDeposits Post Cataract Extraction(白内障摘除后视网膜外层沉积)”,Retin CasesBrief Rep.7(4):359-61(2013)。
伴随巨细胞沉积的反复膜增殖可伴随一些白内障手术病例。一项报告发表了在其眼睛中(在第一个病例中两只眼睛,在第二个病例中左眼)经受AcrySof IOL(SA60AT)植入以治疗白内障和伴随葡萄膜炎的玻璃体混浊的72岁日本女性和67岁日本男性的结果。虽然眼内炎症看起来被成功控制,后囊膜的后表面上巨细胞沉积的数量伴随分别在5和9个月后囊膜浑浊的发展而逐渐增加,并且需要掺钕钇铝石榴石(Nd:YAG)激光晶状体囊切开术。Iwase,T.,“Reiterative Membranous Proliferation With Giant-Cell Deposits onHydrophobic Acrylic Intraocular Lenses After Triple Procedures in Eyes withCataracts and Uveitis(三重程序后白内障和葡萄膜炎眼睛中伴随疏水丙烯酸人工晶状体上巨细胞沉积的反复膜增殖)”,Cutan Ocul Toxicol.29(4):306-11(2010)。
玻璃体腔注射后眼内炎症的11个病例的报告指示了本发明的另一个合适用途。这些病例中仅一个涉及伴随视网膜脓肿传染性眼内炎,所有其他涉及毒性玻璃体炎。七只眼显示眼前房积脓,五只弥散性视网膜出血。毒性反应在注射后48小时内发生,然而在眼内炎病例中,其在72小时后发生。报告的作者认为这种反应的原因为所使用特定注射器商标。改变为另一注射器商标后,在接下来的6个月期间无进一步的毒性玻璃体炎病例发生。Ness,T.等,“Toxic Vitreitis Outbreak After Intravitreal Injection(玻璃体腔注射后毒性玻璃体炎爆发)”Retina.30(2):332-8(2010)。
粘连为其中虹膜附着到角膜(即,前膜粘连)或晶状体(即,后膜粘连)上的眼睛病况,外科手术程序之后这种病况的实例可通过本发明抑制。粘连可由眼睛创伤、虹膜炎或虹膜睫状体炎引起并且可导致某些类型的青光眼。局部皮质甾类已常规地用于抑制炎症。维基百科编著者,"Synechia(eye)(粘连(眼))"Wikipedia,The Free Encyclopedia,2014年11月23日可访问http://en.wikipedia.org/wiki/Synechia_(eye)。
本发明还可用于抑制术后眼内纤维蛋白形成。0.1%双氯芬酸钠对白内障外科手术后前部炎症的抗炎作用已有报道。当双氯芬酸钠眼用溶液与局部皮质甾类组合使用时,无全身性或眼睛疾病的患者中术后纤维蛋白沉淀明显较少。在其他患者,尤其是患有糖尿病、原发性闭角型青光眼和剥脱综合征的那些患者中纤维蛋白沉淀也减少。Matsuo,K.等,“Clinical Efficacy of Diclofenac Sodium on Postsurgical Inflammation AfterIntraocular Lens Implantation(人工晶状体植入后双氯芬酸钠在术后炎症方面的临床功效)”,Refract Surg.21(3):309-12(1995)。
平坦部玻璃体切除术之后切口并发症的四个病例说明了本发明用于抑制切口纤维化的功用。正如所报道的,在每个例子中伤口部位均发生过度纤维化。在一名患者中,病症是轻微的,并且在其一生中不引起临床困难;然而,在三个严重病例中,眼睛继发性损失至眼内组织(纤维化变化)和眼球萎缩。可能起作用的因素包括糖尿病、过度创伤及伤口部位坏死、术后炎症和伤口中玻璃体的牵涉。Kreiger,A.E.,“Incisional Complications inPars Plana Vitrectomy(平坦部玻璃体切除术中的切口并发症)”,Mod ProblOphthalmol.18:210-23(1977)。
本发明可用于治疗脉络膜新生血管化和黄斑裂孔外科手术治疗之后的其它并发症。在所报道的全层黄斑裂孔玻璃体切除外科手术并发症的研究中,注意到39只眼睛(41%)中的后段并发症。视网膜色素上皮细胞改变和视网膜脱落的发病率分别为33%和11%。一个由巨大视网膜裂孔引起的视网膜脱落的病例导致光感视敏度。其他并发症包括两只眼睛复通黄斑裂孔(2%)、一只眼睛黄斑囊样水肿(1%)、一只眼睛脉络膜新生血管膜(1%)和一只眼睛眼内炎(1%)。Banker,A.S.,“Vision-Threatening Complications ofSurgery for Full-Thickness Macular Holes.Vitrectomy for Macular Hole StudyGroup(全层黄斑裂孔外科手术中威胁视力的并发症。黄斑裂孔玻璃体切除术研究组)”,Ophthalmology.104(9):1442-52(1997)。初步研究已报道提示局部酮咯酸可补充玻璃体内雷珠单抗减少脉络膜新生血管化中中心黄斑厚度的平均6-月变化的活性。Russo,A.等,“ARandomised Controlled Trial ofRanibizumab With and Without KetorolacEyedrops for Exudative Age-Related Macular Degeneration(含有和不含酮咯酸滴眼剂的雷珠单抗用于渗出性的年龄相关性黄斑退化的随机对照试验)”,Br J Ophthalmol.97(10):1273-6(2013)。
脉络膜渗漏为脉络膜上腔空间中异常液体的积聚,是一种常见青光眼外科手术并发症,并且可通过实践本发明合适地抑制。脉络膜渗漏也可由其他眼内外科手术程序和许多病况,包括炎性和传染性疾病、创伤、肿瘤、药物反应和静脉充血引起。先天性原因落入葡萄膜渗漏综合征之下,该综合征为通常考虑排除性诊断的罕见病况。Reddy,A.C.,M.D,“Diagnosis and Management of Choroidal Effusions(脉络膜渗漏的诊断和处理)”,2014年11月23日可访问http://www.aao.org/publications/eyenet/201211/pearls.cfm?RenderForPrint=1&。
眼前房积脓被视为眼前房下面部分的淡黄色分泌液,由炎性细胞形成。其为白细胞渗出物,并且为前葡萄膜和虹膜炎症,即虹膜炎的标志,虹膜炎为前葡萄膜炎的一种形式。眼前房积脓已在处于晶状体乳化治疗中的患类风湿性关节炎的患者中报道。这名70岁的女性在左眼进行安全无事的晶状体乳化时维持系统性甲基氢化泼尼松剂量。术后第一天,她发展了无菌眼前房积脓,这使用局部和全身性疗法强有力地治疗,导致炎性反应的逐渐消退。患者随后在右眼进行晶状体乳化。此次术前处理中唯一的显著不同在于患者外科手术前四天接受局部氧氟沙星和酮咯酸。术后炎性反应得到更多控制。患者继续给予酮咯酸和醋酸泼尼松龙,导致常见的术后炎性反应。Caronia,R.M.,“Antiinflammatory Effectof Preoperative Ketorolac in Phacoemulsification(术前酮咯酸在晶状体乳化中的抗炎效应)”,J Cataract Refract Surg.28(10):1880-1(2002)。该报告提示本发明可具有抑制眼外科手术之后的眼前房积脓的功用。
素因性病况
本发明还提供用于通过鉴定具有患术后炎性病况的生理学风险的受试者和在眼外科手术程序期间眼内给予受试者在眼内冲洗载体中包含非甾类抗炎药物(NSAID)和α-1-肾上腺素能受体激动剂散瞳剂的溶液抑制眼外科手术程序之后的术后炎性病况的方法,其中NSAID和散瞳剂以足以抑制术后炎性病况的量包含在溶液中。
外科手术期间小瞳孔尺寸也与增加的术后并发症风险有关。(Artzen 2009);(Zare2009)。研究已经鉴定了帮助外科医生预测哪些患者可能在外科手术期间有并发症风险的风险因素。高龄、先前的眼外科手术和具有眼部表现的糖尿病在已与提高的术中并发症风险相关联的患者相关性因素之中。(Greenberg 2011)。糖尿病(DM)个体常常倾向于发展白内障;据估计超过25%的白内障患者也患有伴随性DM。2012年9月30日可访问NationalDiabetes Clearing House,diabetes.niddk.nih.gov;Ostri C.等,“Phacoemulsification cataract surgery in a large cohort ofdiabetes patients:visual acuity outcomes andprognostic factors(一大群糖尿病患者中的晶状体乳化白内障外科手术:视敏度结果和预后因素)”,J Cataract Refract Surg37(11):2006-2012(2011)。经受白内障外科手术的DM个体具有比无DM个体大的术中缩瞳的倾向。这可能导致更多的术后并发症,例如术后黄斑囊样水肿的发展、日益恶化的糖尿病性黄斑水肿、增殖性糖尿病性视网膜病变的进展和虹膜发红的发展。Oetting,T.,“Complicated cataractcases.Cataract surgery and diabetes(并发性白内障病例。白内障外科手术和糖尿病)”ASCRS EyeWorld,2014年11月25日可访问http://www.eyeworld.org/article-cataract-surgery-and-diabetes。
全身性疾病、术中并发症和预先存在的眼睛病况为影响CME发展的风险因素(Loewenstein 2010)。术后CME的全身性风险因素包括糖尿病,其甚至在不存在糖尿病性视网膜病变的情况下促进CME的发展。Schmier J.等,“Evaluation of costs for cystoidmacular edema refractory to topical medications(耐受局部用药的黄斑囊样水肿费用的评估)”,Ophthalmology 104:2003-2008(1997)。全身性高血压明显增加术后CME的发病率。Flach,A.,“The incidence,pathogenesis and treatment of cystoid macularedema following cataract surgery(白内障外科手术之后黄斑囊样水肿的发病率、发病机制和治疗)”,Trans Am Ophthalmol Soc96:557-634(1998)。全身性高血压也是视网膜静脉阻塞的风险因素,其本身增加CME。(Loewenstein 2010)。
某些外科手术并发症也提高CME的风险。后囊膜破裂,以及二次晶状体囊切开术,包括YAG晶状体囊切开术,与较高的CME发病率相关。玻璃体脱出使CME流行增加10-20%。虹膜嵌顿为CME的额外风险因素,与某些类型的人工晶状体,特别是虹膜固定型IOL和前房型IOL同样。(Loewenstein 2010)。关于平坦部玻璃体切除术之后CME患者的残存晶状体碎片的综述证实8%具有白内障摘除中植入的沟-固定(sulcus-fixated)后房型IOL的眼睛,以及46%无晶状体或具有前房型IOL的眼睛发展为CME。Cohen,S.等,“用于残存的晶状体碎片的平坦部玻璃体切除术后黄斑囊样水肿(Cystoid macular edema after pars planavitrectomy for retained lens fragments)”,J Cataract Surg32:1521-1526(2006)。
某些预先存在的病况也增加术后CME风险。这些病况可危害血-视网膜屏障的完整性,并且增强炎性活动。这些包括葡萄膜炎,其中CME为白内障外科手术之后不良视觉结果的最重要的原因。(Loewenstein 2010)。如上文所指出的,术前糖尿病性视网膜病变显著增加CME起始和持续的风险(Iliff,W.,“Aphakic cystoid macular edema and theoperating microscope:is there a connection?(无晶状体黄斑囊样水肿和手术显微镜:两者之间有关系吗?)”,Trans Am Ophthalmol Soc83:476-500(1985)),而视网膜静脉阻塞和视网膜前膜(ERM)的历史也预测CME的发展。Henderson,B.等,“Clinical pseudophakiccystoid macular edema.Risk factors for development and duration of treatment(临床人工晶状体眼黄斑囊样水肿。发展的风险因素与治疗时间)”,J Cataract RefractSurg33:1550-1558(2007)。拉坦前列素在青光眼患者中关于人工晶状体眼CME局部使用已有报道。Warwar,R.等,“Cystoid macular edema and anterior uveitis associatedwith latanoprost use.Experience and incidence in a retrospective review of 94patients(与拉坦前列素使用相关的黄斑囊样水肿和前葡萄膜炎。94名患者的回顾性调查中的经历和发病率)”,Ophthalmology105:263-268(1998)。
根据本发明的一个方面,由于包括小的瞳孔直径(例如,小于6mm的术前扩大的瞳孔直径)、虹膜松弛综合征、葡萄膜炎、视网膜静脉阻塞、视网膜前膜、高龄(例如,超过65岁、高龄或老年人)、糖尿病、糖尿病黄斑水肿、糖尿病视网膜病变、黄斑变性或全身性高血压在内的术前生理学病况或特征,包括先前眼外科手术或使用α-1-肾上腺素能受体拮抗剂或拉坦前列素的药物治疗在内的术前治疗史,包括后囊膜破裂、二次晶状体囊切开术、虹膜嵌顿、残留的晶状体材料或玻璃体脱出在内的外科创伤,和尼龙缝线、虹膜固定型人工晶状体或前房型人工晶状体的外科手术安置,用本发明NSAID和α-1-肾上腺素能受体激动剂的溶液治疗的受试者被鉴定为具有提高的术后炎性病况风险。正如本文所使用的,术后炎性病况“提高的风险”指眼科程序之后经历术后炎性病况的风险比经受相同程序的不具有任何素因性风险特征的健康受试者中同种术后炎性病况的平均发病率高的受试者。
处于提高的术后炎症风险中的受试者可由外科医生在外科手术前基于患者的术前生理学病况或特征或术前治疗史或与增加的术后炎症发病率相关的缝线或眼内装置的有计划安置鉴定为具有提高的术后炎症风险。一经鉴定,外科医生可在手术程序期间给予本发明的溶液以预先降低或减少术后炎症的发病率或严重性。或者外科医生可在手术程序期间预防性地给予本发明的溶液以处理由于外科创伤的特性例如,后囊膜破裂、二次晶状体囊切开术、虹膜嵌顿、残留的晶状体材料或玻璃体脱出,或计划外使用与增加的术后炎症发病率相关的缝线或装置可在程序期间被鉴定的提高的术后炎症风险。
药剂
很大范围的眼外科手术程序诱导眼内炎症。如上述穿刺术研究所证明的,一旦炎性级联起始,前列腺素水平保持提高达七小时。本发明的方法提供NSAID和α-1-肾上腺素能受体激动剂散瞳剂的组合的术中递送。在本发明的优选实施方案中,NSAID为酮咯酸且α-1-肾上腺素能受体激动剂散瞳剂为苯肾上腺素。
NSAID通过环氧合酶(COX)酶类抑制前列腺素形成的影响已在一些研究中显示具对预防CME具有重要影响。Wolf,E.J.等,“Incidence of visually significantpseudophakic macular edema after uneventful phacoemulsification in patientstreated with nepafenac(用奈帕芬胺治疗的患者中安全无事的晶状体乳化后视觉上显著的人工晶状体眼黄斑水肿的发病率)”,J Cataract Refract Surg 33:1546-1549(2007);Cervantes-Coste,G.等,“Inhibition of surgically induced miosis and preventionof postoperative macular edema with nepafenac(用奈帕芬胺抑制外科手术诱导的缩瞳和预防术后黄斑水肿)”,Clin Ophthalmol3:219-226(2009);Donnenfeld,E.D.等,“Preoperative ketorolac tromethamine 0.4%in phacoemulsification outcomes:pharmacokinetic-response curve(晶状体乳化的结果中术前0.4%酮咯酸氨丁三醇:药物代谢动力学响应曲线)”,J Cataract Refract Surg.32:1474-1482(2006)。
用于本发明的合适的非甾类抗炎性药物(NSAID)包括氟比洛芬、舒洛芬、双氯酚酸、酮洛芬、酮咯酸、吲哚美辛、奈帕芬胺和溴芬酸。优选的NSAID为酮咯酸。如本文所使用的,“酮咯酸”意指盐形式的酮咯酸,例如酮咯酸氨丁三醇[(+/-)-5-苯甲酰基-2,3-二氢-1H-吡咯嗪(pyrrolizine)-1-甲酸:2-氨基-2(羟甲基)-1,3-丙二醇(1:1)]。在本发明的一个配方中酮咯酸作为酮咯酸氨丁三醇盐[(+/-)-5-苯甲酰基-2,3-二氢-1H-吡咯嗪-1-甲酸:2-氨基-2(羟甲基)-1,3-丙二醇(1:1)]包含在内。酮咯酸为非甾类抗炎药物吡咯并吡咯族中的成员。酮咯酸HCl为R-(+)和S-(-)对映体的外消旋混合物,其可以三种晶体形式存在,所有晶体形式在水中同等可溶。酮咯酸为抑制两种环氧合酶酶类(COX-1和COX-2)的非甾类抗炎药物,当根据本发明使用时导致前列腺素的组织浓度降低以减少外科创伤引起的疼痛。酮咯酸,通过抑制眼睛外科手术损伤或虹膜的直接机械刺激继发的前列腺素合成,当根据本发明使用时还预防外科手术诱导的缩瞳。
在本发明中用作散瞳剂的合适的α-1-肾上腺素能受体激动剂包括,例如,苯肾上腺素、肾上腺素、羟甲唑啉和萘甲唑啉。优选的α-1-肾上腺素能受体激动剂为苯肾上腺素。如本文所使用的,“苯肾上腺素”意指盐形式的苯肾上腺素,例如苯肾上腺素HCl[(-)-m-羟基-a-[(甲基氨基)甲基]苄基乙醇盐酸盐]。苯肾上腺素为α-1-肾上腺素能受体激动剂,并且,在眼睛中通过收缩虹膜的放射肌充当散瞳剂。
根据本发明,NSAID和α-1-肾上腺素能受体激动剂溶液在程序期间通过冲洗和/或注射眼内给予,以通过促进散瞳和抑制缩瞳维持瞳孔直径,从而减少对虹膜和通过虹膜操作的眼内结构的外科手术创伤。因此外科手术程序期间散瞳剂(例如,苯肾上腺素)和抗缩瞳剂(例如,酮咯酸)二者的局部眼内存在提供互补机制以预先限制程序期间创伤引起的炎症。上述(Graff 1998)在外科创伤兔子模型中使用穿刺术的体内研究证明,眼睛外科手术创伤之后,前列腺素水平在高达7小时的时期内保持提高。下面实施例2中所述的在狗中测定前房内给予苯肾上腺素和酮咯酸溶液之后视网膜和其它眼组织中的酮咯酸浓度的体内研究证明术中视网膜和其它眼睛组织中对酮咯酸的吸收出人意料地处于足以在药物给予之后至少8小时抑制眼组织中至少90%的COX-1和COX-2水平,和在药物给予之后至少10小时在眼组织中抑制了至少85%的水平。因此,本发明通过凭借互补的散瞳和抗缩瞳作用减轻创伤和通过预先抑制前列腺素释放抑制外科手术程序期间的炎症,并且在术后环氧合酶水平提高最多的时期内继续抑制炎症。
制剂
NSAID和α-1-肾上腺素能受体激动剂包含在作为载体的水性溶剂中以提供药物组合物或溶液。水性载体合适地是注射用水(WFI),其为无菌、无溶质的蒸馏水制备物。或者,可使用对眼内组织无害并且不将不利影响制剂的稳定性的其它水性载体,例如去离子水或首次评估对稳定性的潜在影响后,盐水或平衡盐溶液,例如下文所述的。
合适地将本发明NSAID和α-1-肾上腺素能受体激动剂的溶液调节至pH 5.8-6.8,优选地至约6.3。可根据需要加入氢氧化钠和盐酸以将制剂调节至该pH。通过使用缓冲系统合适地维持期需的pH。一个这样的合适系统为包含一水柠檬酸和脱水柠檬酸钠的柠檬酸盐缓冲液,另一个合适的系统为包括二碱式磷酸钠和一碱式磷酸钠的磷酸钠缓冲液。任一缓冲体系中均可在10mM-100mM范围内的合适浓度下使用,并且合适地可为20mM。如下述实施例1中所述,柠檬酸钠为优选的用于无防腐剂和抗氧化剂的制剂中的缓冲液。柠檬酸盐缓冲液中的柠檬酸,具有螯合二价阳离子的能力并且因此也可预防氧化,提供抗氧化作用和缓冲作用。如本文所使用的,术语“无抗氧化剂”排除了其他抗氧化剂的使用,但是不排除缓冲剂的使用,例如作为缓冲系统的部分包含在内的柠檬酸。
本发明NSAID和α-1-肾上腺素能受体激动剂的溶液,例如,苯肾上腺素和酮咯酸组合药物溶液,在通过眼内冲洗或注射给予前通过注射到袋、瓶子或其他眼内冲洗液容器中合适地稀释成眼内冲洗液。合适的眼内冲洗液包括盐水、乳酸林格氏液、平衡盐溶液或与水性制剂相容并且对眼组织无害的任何其它冲洗液。一种合适的眼内冲洗载体包括一种或多种,优选所有,下列佐剂:充足的电解质以提供生理学平衡的盐溶液、细胞能量来源、缓冲剂和自由基清除剂。一种合适的溶液(在下文的实施例中称为“平衡盐溶液”或“BSS”)包括:50-500毫摩钠离子、0.1-50毫摩钾离子、0.1-5毫摩钙离子、0.1-5毫摩镁离子、50-500毫摩氯离子和0.1-10毫摩磷酸根的电解质、浓度为10-50毫摩的作为缓冲液的碳酸氢盐、选自右旋糖和葡萄糖的浓度为1-25毫摩的细胞能量来源和浓度为0.05-5毫摩的作为自由基清除剂(即抗氧化剂)的谷胱甘肽。
稀释和给予本发明优选的苯肾上腺素和酮咯酸组合物的合适方法的一个实例使用下述表1中所描述的本发明制剂。该溶液的4.5mL等分试样,包括作为单次使用的预期量的4.0mL和溢装量0.5mL,包含在无菌密闭的单次使用小瓶内,且意在用于与眼外科手术期间给予的冲洗液混合。通过注射器从该小瓶中取出4mL并通过注射到500mL BBS袋或瓶中与500mL BBS混合以提供用于局部递送至眼的在冲洗液中483μM苯肾上腺素和89μM酮咯酸的终浓度。
在本发明的另一个方面,可提供用于冲洗的无菌液体药物制剂,其中苯肾上腺素和酮咯酸已在眼内冲洗载体中混合,使其已经稀释至外科手术期间局部递送至眼内组织所需的每种活性药物成分的浓度,并且包含在无菌袋、瓶或其它冲洗载体中。例如,这样的用于冲洗的制剂可包含浓度为30-720μM的苯肾上腺素和浓度为10-270μM的酮咯酸,或优选地可包含浓度为90-720μM的苯肾上腺素和浓度为44-134μM酮咯酸。
如上所述,示例性的稳定的本发明液体药物制剂包含在缓冲水性载体中的苯肾上腺素和酮咯酸。本发明组合药物组合物中苯肾上腺素的合适浓度的范围为10mM-500mM,优选地45mM-112mM。本发明组合药物组合物中酮咯酸的合适浓度的范围为2mM-75mM,优选地8.5mM-24mM。缓冲系统,例如柠檬酸钠缓冲系统,以10-100mM,优选约20mM的浓度合适地包含在内。用于根据本发明使用的示例性制剂在下表1中阐述。如果需要,当制备制剂时可加入氢氧化钠和/或盐酸调节pH至约6.3。
表1
制剂实例
*相当于20mM柠檬酸盐缓冲剂
**相当于10mM-100mM柠檬酸盐缓冲剂
制剂中所包含的药物活性成分的量可表述为摩尔比率。苯肾上腺素与酮咯酸的摩尔比率范围可为1:1-13:1,更合适地范围从3:1到10:1。如上表1中所表现的,一个示例性的苯肾上腺素与酮咯酸的摩尔比率为5.4:1的苯肾上腺素:酮咯酸。
将本发明的这种示例性制剂稀释至用于局部递送的眼内冲洗载体中之后,苯肾上腺素的给药浓度可为3-7,200μM,更合适地30-720μM,更优选地90-720μM,甚至更优选地240-720μM,最优选地约483μM。将本发明的制剂稀释至用于局部递送的眼内冲洗载体中之后,酮咯酸的给药浓度可为3-900μM,更合适地10-270μM,更优选地44-134μM,甚至更优选地30-90μM,且最优选地约90μM。
必须注意的是如本文和所附的权利要求中所使用的,单数形式“a”、“an”和“the”包括多个所指物,除非上下文另外清楚地指示。因此,例如,提及“一种赋形剂”包括多个这种赋形剂和本领域技术人员所知的其等价物等。如本文所使用的术语“约”理解为意指所述条件或数量可存在变更,所述变更可为所给值的5%、10%、15%或最高且包括20%。
本文所论述的出版物为其在本申请提交日之前的公开内容单独提供。本文中无内容解释为承认本发明无权凭借在先发明先于这些出版物。此外,所提供的出版物的日期可能与实际出版日期不同,这需要独立确认。所有引文通过引用结合到本文中。
实施例
实施例1
评估白内障外科手术和人工晶状体置换中1%苯肾上腺素/0.3%酮咯酸的散瞳维持和术后疼痛预防的临床研究本实施例描述为评估当用于在白内障外科手术和人工晶状体(IOL)置换期间维持散瞳和之后预防术后疼痛时如表1中所述配制的1%苯肾上腺素和0.3%酮咯酸注射剂的有效性和安全性而实施的两个三期临床研究。
方法
进行两个关键的、多中心、随机的、平行组、双盲的、安慰剂对照的三期研究(研究1和研究2)以支持1%苯肾上腺素和0.3%酮咯酸注射剂(OMS302)用于维持术中散瞳、防止术中缩瞳和减少与白内障手术和IOL置换相关的早期术后眼睛疼痛的用途。这些研究中在美国和荷兰总共有20个点登记受试者。
受试者随机接受OMS302或安慰剂。将单次给予的研究药物OMS302(配制在20mM柠檬酸钠缓冲液中的483μM苯肾上腺素和89μM酮咯酸)或安慰剂(20mM柠檬酸钠缓冲液)加至平衡盐溶液(BSS,500mL)中,并在程序期间作为标准冲洗液的部分前房给予。进行长达14天(研究1)或90天(研究2)的术后评估;综合安全分析限于直至术后14天收集的数据。研究中的所有受试者(OMS302处理的和安慰剂处理的)接受标准护理术前局部散瞳剂和麻醉剂。
对于综合分析预先指定了两个联合的主要终点:1)外科手术期间的术中瞳孔直径和2)外科手术之后术后早期的眼睛疼痛。将每个受试者的外科手术程序用视频记录,并通过单个隐蔽的中央阅读器以一分钟的间隔测量从切开伤口的时间(外科手术基线)直至伤口缝合(外科手术终点)的瞳孔直径变化。术后眼睛疼痛在外科手术后2、4、6、8和10-12小时以及第2、7和14天使用受试者-评估视觉模拟量表(VAS)测量。
次要关键终点包括在皮层清理结束后瞳孔直径<6mm、外科手术期间任何时候瞳孔直径<6mm、术中瞳孔收缩≥2.5mm、术后第一个12小时内评估的任何时间点的中度至重度眼睛疼痛(VAS≥40)和术后第一个12小时内评估的所有时间点的无眼睛疼痛(VAS=0)。事后二级分析包括受试者术中瞳孔收缩和外科手术当天止痛剂使用的分类。
统计分析
各个研究独立进行。两项研究的样品大小计算相同:每个研究中总计400名受试者(每个治疗方案中200名受试者),提供99%的能力检测瞳孔直径从基线变化的平均曲线下面积(AUC)中0.6mm(标准偏差[SD]:0.7mm)的差异,并提供96%的能力使用双侧t-检验以α=0.05检测术后第一个12小时期间眼睛疼痛VAS的平均AUC中5.0mm(SD:13.3mm)的差异。
外科手术期间瞳孔直径从基线变化的平均AUC计算如下:1)使用梯形法则计算从外科手术基线到伤口缝合的瞳孔直径的AUC,2)将结果除以最终瞳孔直径值的时间以获得平均AUC,和3)从平均AUC减去基线瞳孔直径。术后第一个10-12小时期间眼睛疼痛VAS的AUC也使用梯形法则计算,平均AUC定义为AUC除以该时间范围内从第一个VAS得分到最后一个VAS得分的小时数。对于两个主要终点,使用通过随机化层分层的一般化Cochran-Mantel-Haenzel(CMH)检验比较组合的两个研究的两个治疗方案(LaVange等,2005)。
如果在分类中频率小于5,使用卡方检验或Fisher精确检验对所有呈现的二级功效分析进行治疗比较。所有统计分析均使用SAS软件(版本9.3,SAS Institute,Inc.,CaryNC)进行。
结果-功效白内障外科手术或IOL置换程序期间,OMS302在维持散瞳方面优于安慰剂。在具有用于测定瞳孔直径的可用视频图像的759名受试者中,对于OMS302组(n=379)瞳孔直径从基线变化的平均AUC为0.08mm,相比之下安慰剂组(n=380)为-0.50mm,CMH加权均数差(OMS302-安慰剂)(标准误差[SE])为0.58mm(0.04)(95%置信区间[CI]:0.51,0.65;p<0.0001)。外科手术开始之后,用OMS302处理维持基线瞳孔直径,而用安慰剂处理观察到瞳孔逐渐缩小(图1)。用皮层清洗完成时和外科手术期间任何时间瞳孔直径<6mm评估受试者发病率的二级功效分析的结果也对OMS302处理有利(表2)。皮层清洗完成时瞳孔直径<6mm、外科手术期间任何时间瞳孔直径<6mm和术中瞳孔收缩度≥2.5mm的受试者的比例在OMS302-处理的受试者中显著低于安慰剂处理的受试者(每个终点p<0.0001)。比安慰剂受试者少得多的OMS302-处理的受试者经历大于1mm的术中瞳孔收缩(图2)。
表2
支持性功效终点
a.卡方检验
b.外科手术期间瞳孔直径从基线的最大减小
c.认为术后12小时期间缺少VAS的受试者并非无疼痛
与安慰剂相比,用OMS302处理与早期术后眼睛疼痛显著减少相关。OMS302组术后第一个12小时期间的眼睛疼痛VAS得分(平均AUC=4.16mm,n=403)比安慰剂组(平均AUC=9.06mm,n=403)低超过50%。眼睛疼痛得分AUC中CMH加权均数差(OMS302–安慰剂)(SE)为-4.89mm(0.80)(95%CI:-6.46,-3.31;p<0.001)。用OMS302处理的受试者中在每个术后时间点的平均VAS得分更低(图3)。与安慰剂相比,OMS302在所有术后时间点均无眼睛疼痛(VAS=0)的受试者的比例显著较高(分别25.8%对17.1%,p=0.0027;表2),并且与安慰剂相比,OMS302在任何术后时间点中度到重度眼睛疼痛(VAS≥40)的受试者的比例显著较低(分别7.2%对14.1%,p=0.0014)。值得注意地,除了OMS302组中VAS疼痛得分较低外,与安慰剂相比用OMS302处理的受试者手术当天止痛剂的使用也显著较低(分别24.6%对35.1%,p=0.0010)。
结果-安全性
在汇集的安全性分析中所包含的808名受试者(403名OMS302,405名安慰剂)中,513名(63.5%)经历至少一次治疗-紧急不良事件(TEAE)。接受OMS302处理的受试者中报告TEAE的受试者的比例(242/403[60.0%])比接受安慰剂处理的受试者(271/405[66.9%])中略低。多数TEAE严重性为轻度或中度。在两个研究中仅报道了一例严重不良事件。该事件(由于认为与研究药物无关的触电死亡)也是导致研究过早停药的唯一事件。
最频繁报道的TEAE由眼睛疼痛(受试者总体35.1%报道)、眼睛炎症(15.5%)、前房炎症(8.7%)、头痛(7.9%)、眼内压升高(4.1%)、后囊膜浑浊(4.1%)、眼睛不适(4.1%)、畏光(4.0%)、角膜水肿(2.8%)、视觉模糊(2.7%)、结膜充血(2.6%)和眼睛异物感(2.2%)组成。这些事件在每个治疗组中以相似的受试者比例报告,除了眼睛疼痛、头痛、眼睛不适、畏光和视觉模糊,略多(治疗组之间>1%的差异)的安慰剂受试者(分别为40.0%、9.4%、5.2%、4.9%、4.2%)比OMS302受试者(分别为30.3%、6.5%、3.0%、3.0%、1.2%)经历这些事件。眼内压升高为唯一在略高(>1%的差异)比例的OMS302-处理的受试者中发生的常见TEAE(4.7%OMS302对3.5%安慰剂)。
总计18名受试者(13名[3.2%]安慰剂受试者和5名[1.2%]OMS302受试者)经历了严重的TEAE。除了用OMS302处理的受试者经历意外触电事件外,所有严重的TEAE由眼睛病症,包括眼睛炎症(n=11)、前房炎症(n=2)和结膜水肿、角膜水肿、结膜充血、眼睛疼痛和畏光(每一种n=1)组成。需要注意的是,认为所有严重的TEAE均与发生在接受安慰剂的受试者中的研究处理有关。这些事件包括两例前房炎症以及角膜水肿、眼睛疼痛、畏光、眼睛炎症和结膜充血事件。
外科手术后两个治疗组中的一些受试者观察到眼内压力升高。到第2天,与基线相比的升高不太显著;然而,这种异常在一些受试者中持续出现直到研究结束。在这些受试者中未报道显著TEAE,并且在每个评估日两个处理组之间未观察到眼内压力升高受试者的比例差异。此外,对于任何其它系列安全性评估(即,生命体征或眼科检查)处理组之间未观察到差异。
结论
对于在IOL置换期间维持散瞳和之后减少眼睛疼痛OMS302优于安慰剂。OMS302的瞳孔直径从基线变化的平均曲线下面积(AUC)为0.08mm,相比之下安慰剂为-0.50mm(p<0.0001)。OMS302术后12小时内受试者眼睛疼痛视觉模拟量表(VAS)得分的平均AUC(平均AUC=4.16mm)相比安慰剂(平均AUC=9.06mm,p<0.001)下降了超过50%。所有二级功效分析的结果均证明了与OMS302相关的显著治疗功效。治疗-紧急不良事件如对于经受IOL置换的群体所预期的;治疗组之间未观察到临床上显著的安全措施差异。
此两个关键三期研究的综合结果证明了与安慰剂相比OMS302在伴随晶状体置换或屈光性晶状体交换程序的白内障摘除期间维持瞳孔直径和防止缩瞳,以及之后预防术后眼睛疼痛方面的优越性,尽管所有的受试者接受标准的术前局部散瞳剂和麻醉药。功效分析是强健的;综合分析的联合主要终点的AUC分析(为显示OMS302对外科手术期间瞳孔直径和早期术后疼痛的聚集效应而进行),和所有二级功效分析均为支持性的。此外,与安慰剂相比,OMS302不与任何新的或额外的毒性相关。目前所进行的OMS302临床研究中观察到的常见的不良事件和安全性发现(例如,眼内压升高)与经受这些程序的患者中所通常报道的事件一致,并且处理组之间未观察到临床上显著的差异。
实施例2
人工晶状体置换期间给予狗1%苯肾上腺素/0.3%酮咯酸之后眼睛组织的酮咯酸分布本实施例描述在狗中测定在狗的IOL置换期间前房给予如表1中所述配制的1%苯肾上腺素和0.3%酮咯酸注射剂(OMS302)之后视网膜和其他眼睛组织中的酮咯酸浓度的体内研究结果。
方法
通过晶状体乳化在20只雌性比格犬上进行IOL置换。程序期间,经由冲洗和前房注射在程序后立即给予在BSS溶液中的OMS302。酮咯酸的靶剂量水平为5.71mg/眼,稀释在BSS溶液中的OMS302靶剂量体积为250mL每眼。程序后0、2、6、8和10小时的每个时间点处死四只动物。收集血液和眼房水样品。将摘出的眼睛冷冻,并解剖以收集视网膜、视网膜色素上皮-脉络膜、角膜、虹膜-睫状体、玻璃体液、巩膜和晶状体囊膜。酮咯酸的组织浓度使用液相色谱/质谱(LCMS)法定量。使用已公布的酮咯酸抑制环氧合酶(COX)的IC50值(Waterbury等,Curr Med Res Opin22(6):1133-40(2006),得出每一时间点的抑制百分数的估算值。
结果
图4-6说明了前房给予OMS302之后特定时间点的平均酮咯酸浓度,图4显示角膜、晶状体囊膜、虹膜-睫状体(ICB)、眼房水和前部巩膜中的酮咯酸浓度;图5显示球结膜和眼睑结膜中的酮咯酸浓度;图6显示玻璃体液、视网膜、脉络膜-RPE(外周)、脉络膜-RPE(反光色素层)和后部巩膜中的酮咯酸浓度。图7显示视网膜组织中从t=0到t=10小时的COX-1和COX-2的平均百分比抑制,基于COX-120nM的IC50和10nM的Ki以及COX-2120nM的IC50和60nM的Ki。视网膜中的酮咯酸浓度在紧接着IOL置换结束后为1400±1004ng/g,程序后八小时时为164±39ng/g,与所评估的t=0时99.3%/96.0%和t=8小时时98.4%/91.1%的COX-1/COX-2抑制相对应。视网膜的半衰期为~3.8小时。令人惊讶地,眼房水、玻璃体液和RPE-脉络膜中组织浓度在t=8小时时与>90%的COX-1和COX-2抑制一致。同样令人惊讶地,t=10小时时,COX-1的视网膜组织浓度为97.74%(标准偏差为0.36%),COX-2为87.82%(标准偏差为1.75%)。t=0时酮咯酸的平均血浆水平为4.73±1.46ng/mL,t≥2小时时下降到无法检测的水平。
结论
在本研究中,IOL置换手术期间OMS302的使用导致在前房冲洗液中给予药物后视网膜和其它眼睛组织对酮咯酸的吸收处于足以抑制眼内组织中大于90%的COX-1和COX-2水平至少8小时和抑制眼内组织中大于85%的COX-1和COX-2水平至少10小时的水平,其作用持续时间是意想不到的。全身性暴露低且短暂。
实施例3
评估白内障外科手术前局部酮咯酸给予之后的前房酮咯酸浓度的临床研究本实施例描述测定在白内障外科手术前接受局部酮咯酸的受试者中的术后前房酮咯酸浓度的临床研究的结果。
方法
经受白内障摘除和晶状体置换(CELR)的患者为合格的。从14名受试者获得了知情同意书面证明,其每个根据外科医生的惯例从术前一天开始接受局部眼用酮咯酸。紧邻外科手术切开前,外科医生使用30号结核菌素注射器从手术眼睛抽取100-μL眼房水样品。在前房最后再膨胀和伤口缝合之前CELR结束时,外科医生从前房中抽取另一个100-μL样品。前房液体样品的酮咯酸浓度由分析实验室分析。
结果
14名受试者中的13名在外科手术前天使用四剂酮咯酸,一名受试者在外科手术前天使用三剂。所有14名受试者均在外科手术当天在外科手术中心接受局部酮咯酸。眼房水样品不经意间没有从两名受试者采集。从其收集样品的12名受试者中的术前酮咯酸浓度的范围为4.9-369ng/mL。程序结束的样品范围为<1.0(定量下限或LLOQ)-6.32ng/mL,12名受试者中的8名的酮咯酸水平在LLOQ之下。
结论
局部酮咯酸的家用顺应性普遍良好,92.9%的受试者按照指导使用局部酮咯酸。CELR之后,外科手术程序结束时眼房水中的酮咯酸水平低下,可能由于被冲洗洗去,因为66.7%的受试者具有不可检测的酮咯酸浓度。
实施例2和3的体内和临床研究分别证明白内障和IOL置换手术期间前房递送酮咯酸/苯肾上腺素溶液中的酮咯酸应导致大体上比术前局部给予酮咯酸所引起的更长的术后时间的眼中药理学活性酮咯酸水平,从而提供持久的术后炎症抑制。
虽然为了清楚理解的目的前述发明已经以例证和实施例的方式详细描述,但根据本发明的教导将对本领域普通技术人员显而易见的是,可对其进行某些改变和修饰而不脱离所附权利要求的精神或范围。
Claims (3)
1.在眼内冲洗载体中包含酮咯酸和苯肾上腺素的溶液在制备用于在经鉴定具有提高的患术后黄斑囊样水肿的风险的受试者中降低眼外科手术程序之后的术后黄斑囊样水肿的发生率或严重程度的药物中的用途,其中所述具有提高的患术后黄斑囊样水肿的风险的受试者年龄超过65岁或患有糖尿病,其中在眼外科手术程序期间眼内给予所述受试者在眼内冲洗载体中包含酮咯酸和苯肾上腺素的溶液,其中所述酮咯酸和苯肾上腺素以足以通过促进散瞳和抑制缩瞳维持术中瞳孔直径的量包含在溶液中,并且给予充足量的溶液以使在眼组织内摄入足以在术后至少六个小时的时期内抑制环氧合酶的量的酮咯酸,并且其中所述溶液包含浓度为240-720μM的苯肾上腺素并且酮咯酸以44-134μM的浓度存在。
2.权利要求1的用途,其中所述溶液导致在术后至少六个小时的时期内对眼组织中基线环氧合酶-1和环氧合酶-2活性水平至少90%的抑制。
3.权利要求1的用途,其中所述溶液导致在术后至少八个小时的时期内对眼组织中基线环氧合酶-1和环氧合酶-2活性水平至少90%的抑制。
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AU2013201465B2 (en) | 2012-10-24 | 2016-03-03 | Rayner Surgical (Ireland) Limited | Stable preservative-free mydriatic and anti-inflammatory solutions for injection |
TWI705812B (zh) | 2014-12-01 | 2020-10-01 | 奥默羅斯公司 | 用於抑制術後眼睛炎性病況的抗炎和散瞳前房溶液 |
US20190290614A1 (en) * | 2016-11-09 | 2019-09-26 | Beth Israel Deaconess Medical Center, Inc. | Methods for Reducing Recurrence of Tumors |
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