CN1178661C - 布林佐拉米预防视野缺损的用途 - Google Patents

布林佐拉米预防视野缺损的用途 Download PDF

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CN1178661C
CN1178661C CNB988117452A CN98811745A CN1178661C CN 1178661 C CN1178661 C CN 1178661C CN B988117452 A CNB988117452 A CN B988117452A CN 98811745 A CN98811745 A CN 98811745A CN 1178661 C CN1178661 C CN 1178661C
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brinzolamide
tim
cpsd
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安杰拉·C·科特
H
刘易斯·H·西尔弗
��R���ϰ�
托马斯·R·迪安
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

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Abstract

本发明公开了布林佐拉米在制备用于预防或减缓与青光眼或高眼压症有关的视野缺损的局部施用的药物中的应用。

Description

布林佐拉米预防视野缺损的用途
本发明涉及布林佐拉米(brinzolamide)的局部应用以预防视野缺损。
发明背景
尽管不是唯一的危险因素，但是眼内压升高是发展成青光眼性视神经病变的主要危险因素。眼内压(IOP)和青光眼之间的关系是：在接受治疗或进行手术治疗中，具有或发展成青光眼性视神经病变或者患进行性损害的风险直接与眼内压的水平相关。参见，Crick等，青光眼(Glaucoma)，7：208-219(1995)；Sommer，美国眼科学杂志(American Journal of Ophthalmology)，第7卷第2期(1989年2月)；和Mao等，美国眼科学杂志(American Journal of Ophthalmology)，第111卷第1期(1991年1月)。此外，不对称性损害与不对称性IOP之间存在相关性，眼内压越高，对眼睛所观察到的损害程度越严重，Crichton等，眼科学(Ophthalmology)，第96卷第9期(1989年9月)。流行病学调查(如巴尔的摩眼调查、鹿特丹研究和巴巴多斯(Barbados)眼研究)也证实，原发性开角型青光眼的高发病率与IOP的升高有关。
Wegner等(欧洲眼科协会，1997)评价了用多佐拉米(dorzolamide)治疗1年(2％局部用碳酸酐酶抑制剂)对患原发性开角型青光眼(POAG)患者视野的作用。使用Octopus视野检查法评价视野。49名患者中，39名需要辅助降IOP治疗，只有10名患者单独使用多佐拉米治疗。
单独使用多佐拉米治疗的患者，其视野有了改善，测得的Octopus平均缺损由9.36dB降至8.26dB，而平均视觉敏感度由17.72dB增至18.77dB。39名同时接受多佐拉米加上辅助治疗的患者，也显示出视野的改善，平均缺损由8.07dB降至7.52dB，而平均敏感度则由18.51dB增至18.96dB。所报导的变化具有显著性(p＜0.01)。
在共同转让的美国专利5240923和5378703中，公开了布林佐拉米在控制眼内压，特别是治疗青光眼方面的用途。这些专利在此引入作为参考。
发明概述
本发明涉及布林佐拉米(brinzolamide)制剂的局部应用以预防或减缓患眼压增高或青光眼患者的视野缺损。
优选实施方案描述
MD(平均偏差)和CPSD(校正图像的标准偏差)是由Humphrey视野分析仪统计包提供的通用的指标(global indices)。CPSD是测量患者视野的总形状偏离正常的年龄-校正的参考视野的程度。如果敏感度梯度是非规律性的(如，由于青光眼而出现的盲点)，则记录下高的CPSD。CPSD值为正值，而在正常视野时接近零。MD是测量患者的整个视野与正常参考视野相比的平均升高或降低。MD值在正常视野时接近零，既可呈正值也可呈负值。MD正值表明患者的总视野较正常的年龄-校正的参考视野好，而MD负值表示患者的总视野较正常的年龄-校正的参考视野差。
据信青光眼导致视野敏感度的局部缺损而不是弥散性缺损。既然MD不能将深度局部缺损(青光眼引起的盲点)和弥散性缺损(由小瞳孔、未校正的屈光不正、白内障的发展等导致)区分开来，那么，CPSD在检测和跟踪早期到中期青光眼性视野缺损中是更为相关和有用的。一旦视野缺损达到相当严重的程度(CPSD＞10dB和MD＜-25dB)，分析CPSD便不再有任何意义，因为缺损的严重性增加，缺损的定位性质消失。
眼护理技术论坛(Eye Care Technology Forum)特别推荐，为研究青光眼和高眼压症(OHT)，分析过程要基于定位变化，如由CPSD指出的那些变化。参见Johnson，眼科学(Ophthalmology)第103卷，第1期(1996年1月)。
现已惊奇地发现，布林佐拉米(brinzolamide)，(R-(+)-乙氨基-3，4-二氢-2-(3-甲氧基)丙基-2H-噻吩并[3，2，e]1，2-噻嗪-6-氨磺酰-1，1-二氧化物)，在维持患原发性开角型青光眼或高眼压症患者的视野上具有与噻吗洛尔相等的效力。考虑到β-受体阻断剂噻吗洛尔(timolol)和布林佐拉米的卓越的降低IOP效力，以及前面讨论的IOP升高与青光眼的关系，这一结果是令人吃惊的。(布林佐拉米使升高的IOP降低15-19％，而噻吗洛尔使升高的IOP降低22-26％)。
下面的表总结了在长期研究中观察到的视野数据，所述研究对使用BID-和TID-剂量的布林佐拉米和使用BID-剂量的噻吗洛尔进行了比较。
数据作为诊断为POAG或OHT以及只患有POAG(因为，在研究的一开始就将那些诊断限定为OHT，未显示青光眼性视野缺损)的患者的功能进行分析。另外，患者再分为两组：一组12月内只接受研究药物，一组需要用另一种降眼压剂(缩瞳剂、α-受体激动剂、拟交感神经药、前列腺素，等)辅助治疗。在数据描述中使用下列缩写：布林佐拉米(BZ)；噻吗洛尔(TM)；ΔMD＝第12个月MD-第0个月MD；ΔCPSD＝第12个月CPSD-第0个月CPSD。
参数                    诊断为POAG(n＝144)或OHT(n＝81)的患者
            仅用研究药物       研究药物联合或不联合辅助治疗
BZ BID BZ TID TIM BID BZ BID BZ TID TIM BID
ΔMD -0.38dB -0.78dB -0.30dB -0.28dB -0.85dB -0.30dB
p值  0.0745  0.0003  0.3033  0.2006  0.0002  0.3195
                  BZ BID＝BID TIMp＝0.8299BZ TID＝BID TIMp＝0.1892                    BZ BID＝BID TIMp＝0.9513BZ TID＝BID TIMp＝0.1466
ΔCPSD -0.03dB +0.21dB -0.16dB +0.09dB +0.27dB -0.07dB
p值  0.8795  0.2607  0.5300  0.6262  0.1639  0.7819
                  BZ BID＝BID TIMp＝0.6745BZ TID＝BID TIMp＝0.2418                     BZ BID＝BID TIMp＝0.6108BZ TID＝BID TIMp＝0.2946
N 84 83 44 91 87 47
注意：对于Humphrey视野计而言，ΔMD负值表明恶化，而ΔMD正值表明改善；ΔCPSD负值表明改善，而ΔCPSD正值表明恶化。
结果表明：BID-或TID-剂量的布林佐拉米对于视野的影响(用MD或CPSD评价)在统计学和临床学上均与BID-剂量的噻吗洛尔相似。
参数                              仅诊断为POAG(n＝144)的患者
             仅用研究药物        研究药物联合或不联合辅助治疗
  BZ BID   BZ BIT   TIM BID   BZ BID   BZ TID   TIM BID
ΔMD   +0.02dB   -0.82dB   -0.39dB   +0.13dB   -0.92dB   -0.38dB
p值    0.9420    0.0051    0.3384    0.6601    0.0023    0.3627
                  BZ BID＝BID TIMp＝0.4099BZ TID＝BID TIMp＝0.3844                    BZ BID＝BID TIMp＝0.3187BZ TID＝BID TIMp＝0.2869
ΔCPSD   -0.02dB   +0.30dB   -0.18dB   +0.17dB   +0.38dB   -0.03dB
p值    0.9428    0.2338    0.6096    0.5082    0.1398    0.9232
                  BZ BID＝BID TIMp＝0.7072BZ TID＝BID TIMp＝0.2683                   BZ BID＝BID TIMp＝0.6463BZ TID＝BID TIMp＝0.3460
N   52   51   26   59   56   29
注意：对于Humphrey视野计而言，ΔMD负值表明恶化，而ΔMD正值表明改善；ΔCPSD负值表明改善，而ΔCPSD正值表明恶化。
结果表明：BID-或TID-剂量的布林佐拉米对于视野的影响(用MD或CPSD评价)在统计学和临床学上均与BID-剂量的噻吗洛尔相似。
布林佐拉米优选制成pH值为4.5-7.8的局部眼用悬浮液。通常，制剂的浓度为0.1-10重量％，优选0.25-5.0重量％。因此，对于局部应用，根据有经验的临床医师的例行处理，可以将这些制剂的1～3滴滴入患者眼球表面，每日1～4次。
下列制剂对于预防与青光眼或高眼压症有关的视野缺损非常有用。
           实施例
组分                         百分比w/v
布林佐拉米                     1.0
甘露醇                         3.3
聚羧乙烯974P                   0.4
泰洛沙泊                       0.025
EDTA二钠                       0.01
氯化苯甲烃铵                   0.01+5％过量
氯化钠                         0.25
氢氧化钠/盐酸                  pH7.5
纯净水                         加至100

Claims (4)

1.布林佐拉米在制备用于预防或减缓与原发性开角型青光眼或高眼压症有关的视野缺损的局部施用的药物中的应用。
2.权利要求1所述应用，其中在所述的局部施用的药物中的布林佐拉米为悬浮液形式。
3.权利要求1或2所述应用，其中在所述药物中布林佐拉米的浓度为0.1-10.0重量％。
4.权利要求3所述应用，其中在所述药物中布林佐拉米的浓度为0.25-5.0重量％。
CNB988117452A 1997-12-23 1998-11-05 布林佐拉米预防视野缺损的用途 Expired - Fee Related CN1178661C (zh)

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