CN1774258A - 肺病治疗 - Google Patents
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Abstract
本发明特征在于通过吸入给予抗凝血酶III来治疗肺病例如肺炎症和损伤受试者的方法。
Description
发明概述
本发明部分基于雾化抗凝血酶III(ATIII)可有效治疗肺病例如肺炎症和损伤的发现。发现较低剂量的雾化ATIII比高剂量静脉内给予的ATIII更有效治疗急性脓毒性肺损伤。因此，吸入给予ATIII比静脉内给药提供了更有效的肺病例如肺炎症和损伤的治疗。
因此，本发明一方面特征在于治疗肺病例如肺炎症和/或损伤受试者的方法，包括通过吸入给予治疗有效量的ATIII。该肺病可以是急性或慢性肺病。在一个实施方案中，该肺病是急性肺损伤，例如脓毒性急性肺损伤或急性呼吸窘迫综合征(ARDS)。肺损伤和/或炎症可以是诸如接触外部作用物，如病毒剂(例如肺炎假单孢菌(Pseudomonaspneumonia))、烟雾或石棉引起的。在其它实施方案中，该肺病可以是肺或胸膜肿瘤、间质性肺病和/或机化性胸膜炎(organizingpleuitis)。
在一个实施方案中，使用喷射气溶胶或超声雾化器***、或利用干粉吸入***给予ATIII。这类气溶胶给药***为人所知。
在一个实施方案中，该ATIII是人ATIII。该ATIII可以是天然来源，例如来自血浆，或重组制备。血浆来源ATIII可商品化获得。在一个优选实施方案中，抗凝血酶III由转基因制备，例如ATIII得自转基因diary动物诸如奶牛、山羊、兔子或小鼠的乳汁。在转基因动物乳汁中制备ATIII的方法如美国专利5,843,705所述，其内容在此引入以供参考。
在一个优选实施方案中，给予受试者包括ATIII和药物可接受载体的气溶胶组合物。药物可接受载体的例子包括水和盐溶液。
在一个实施方案中，定期通过吸入给予受试者ATIII，例如每隔一定时间给予受试者ATIII。例如，在肺炎症和/或损伤发作时以及初次给药后按设定时间给予受试者气溶胶ATIII，例如每小时、2小时、3小时、4小时、6小时、每日2次或每日3、4、5、6次通过吸入给予ATIII。给药周期可以是约24、48、72、96、120、144或168小时的一段时间。在另一实施方案中，按需要通过吸入给予受试者ATIII，例如在肺炎症或损伤的一个或多个持续或复发症状指征时给予ATIII。
ATIII例如转基因制备的ATIII的有效剂量可以介于约10-300U/kg、25-125U/kg、50-100U/kg或60-75U/kg体重。另一方面，有效剂量可以大于约1mg/kg、5mg/kg、10mg/kg，但小于约150mg/kg、100mg/kg、70mg/kg。
在一个优选实施方案中，所用气溶胶ATIII的剂量小于经静脉内给药治疗相同疾病(例如，对肺炎症或损伤的一个或多个症状具有相同效果)的ATIII剂量的10％、20％、30％、40％、50％、60％。
在另一实施方案中，本发明特征在于治疗肺病的试剂盒。优选地，该试剂盒包括治疗有效量的气溶胶形式ATIII和使用说明。优选地，该气溶胶另外包括药物可接受的载体。药物可接受载体的例子包括水和盐溶液。
在一个实施方案中，ATIII例如转基因制备的ATIII的有效剂量可以介于约10-300U/kg、25-125U/kg、50-100U/kg或60-75U/kg体重。另一方面，有效剂量可以大于约1mg/kg、5mg/kg、10mg/kg，但小于约150mg/kg、100mg/kg、70mg/kg。
在一个优选实施方案中，该试剂盒是用于治疗急性或慢性肺病的试剂盒。优选地，该肺病是急性肺损伤，例如脓毒性急性肺损伤或急性呼吸窘迫综合征(ARDS)。肺损伤和/或炎症可以是诸如接触外部作用物，如病毒剂(例如肺炎假单孢菌)、烟雾或石棉引起的。在其它实施方案中，该肺病可以是肺或胸膜肿瘤、间质性肺病和/或机化性胸膜炎。
在一个实施方案中，该试剂盒包括处于喷射气溶胶或超声雾化器***、或干粉吸入***中的ATIII。
在一个实施方案中，该试剂盒包括气溶胶形式的人ATIII。该ATIII可以是天然来源，例如来自血浆，或重组制备。在一个优选实施方案中，抗凝血酶III由转基因制备，例如ATIII得自转基因diary动物诸如奶牛、山羊、兔子或小鼠的乳汁。
本发明一个或多个实施方案的细节如下文附图和说明所述。本发明的其它特征、目的和优点从说明和附图以及权利要求书中所显见。
附图描述
图1是描述因烟雾吸入而致脓毒病的绵羊模型中，给予雾化ATIII对肺气体交换(PaO2/FiO2比值)的影响。
图2是描述因烟雾吸入而致脓毒病的绵羊模型中，给予雾化ATIII对肺分流系数(shunt fraction)的影响。
图3是描述因烟雾吸入而致脓毒病的绵羊模型中，给予雾化ATIII对平均动脉压的影响。
图4是描述因烟雾吸入而致脓毒病的绵羊模型中，给予雾化ATIII对左房压的影响。
图5是描述因烟雾吸入而致脓毒病的绵羊模型中，给予雾化ATIII对肺动脉压的影响。
图6是描述因烟雾吸入而致脓毒病的绵羊模型中，给予雾化ATIII对心脏指数的影响。
图7是描述因烟雾吸入而致脓毒病的绵羊模型中，给予雾化ATIII对左室搏功指数(left ventriculars troke work index，LVSWI)的影响。
图8是描述因烟雾吸入而致脓毒病的绵羊模型中，给予雾化ATIII对体温的影响。
图9是描述因烟雾吸入而致脓毒病的绵羊模型中，给予雾化ATIII对左血浆Nox水平的影响。
图10是描述因烟雾吸入而致脓毒病的绵羊模型中，ATIII活性的变化。
发明详述
发现相比静脉内给予ATIII，使用气溶胶形式ATIII可在较低剂量下减少急性脓毒性肺损伤。因此，本发明特征在于包括ATIII的气溶胶制剂以及使用该气溶胶形式ATIII治疗具有肺病例如肺损伤或炎症的的受试者的方法。
此处所用术语″治疗″是指减轻或减少肺病有关的一种或多种症状。例如，肺损伤和/或炎症的症状包括：1)降低的肺气体交换；2)降低的肺分流系数；3)细胞外纤维蛋白沉积；4)增加的血管通透性；5)降低的脂蛋白表面活化剂沉积；6)组织再造；7)凝血；和/或8)增加的肺泡张力。此处所用有效治疗肺病的气溶胶化形式ATIII的量、或″治疗有效量″是指单一或多个剂量给予受试者时，超出未经该治疗所预期之外，有效治愈、减轻、舒解或改善此处所述肺病受试者的ATIII气溶胶的量。
ATIII可以单独给药，例如以干粉制剂，或连同药物可接受载体给药。药物可接受载体包括例如无菌的水、盐溶液和乙醇。药用ATIII气溶胶组合物可另外包括其它治疗剂(例如减轻或降低肺炎症或损伤的其它药物)或其它药用佐剂、稀释剂等。可以按脂质体复合物或在脂质体中胶囊化给予ATIII。
对于吸入给药，可以从包含合适喷射剂(例如二氧化碳等气体)或雾化器的压力容器或分配器中喷射气溶胶的形式输送化合物。此处所用术语″气溶胶″是指在固体或液体颗粒气中的分散物，其颗粒大小足够细微，因而沉降速度低，具有相对的空气传播稳定性(参见Knight，V.，Viral and Mycoplasmal Infections of the Respiratory Tract.1973，Lea and Febiger，Phila.Pa.，第2页)。
可利用气体压力或超声实现ATIII的雾化。一般而言，雾化器是一种允许气溶胶给药的装置。可能是任何类型雾化器，其结构为本领域技术人员已知，这些装置可商品化获得。可以利用各种已知的雾化技术，使包含ATIII的溶液雾化，来制备本发明的气溶胶。一种雾化***是″二相(wo-phase)″***，由处于液体喷射剂中的活性成分的溶液或悬浮液组成。在加压容器中存在液气两相，开启容器阀门时，释放出包含溶液或悬浮液的液体喷射剂。产生细小的气溶胶烟雾或气溶胶湿气喷雾。
可获得多种制备气溶胶的雾化器，包括小体积雾化器。压缩机驱动的雾化器结合了喷射技术，并使用压缩空气或医用氧气产生气溶胶。
可商品化获得的装置可得自Healthdyne Technologies Inc.；InvacareInc.；Mountain Medical Equipment Inc.；Pari RespiratoryInc.；Mada Mediacal Inc.；Puritan-Bennet；Schuco Inc.；OmronHealthcare Inc.；DeVilbiss Health Care Inc.和Hospitak Inc.。也可以使用超声雾化器输送ATIII，例如具备高频石英水晶振荡的超声类型雾化器。
可以利用标准药学程序，例如测定LD50(50％群体的致死剂量)和ED50(50％群体的治疗有效剂量)，在细胞培养物或实验动物中测定这类ATIII气溶胶的毒性和疗效。毒性和疗效之间的剂量比值即为治疗指数，可以表示为LD50/ED50比值。优选显现高治疗指数的化合物。虽然可能使用显现毒副作用的化合物，但应小心设计靶向这类化合物到达患病组织的输送***，以使对未患病细胞的可能损伤减至最小，从而降低副作用。
从细胞培养分析和动物研究中获得的数据可用于配制多种剂量，供人使用。这类化合物的剂量优选位于包含ED50而没有或几乎没有毒性的循环浓度范围内。根据所用剂型和给药途径，剂量可能在此范围内变动。对于本发明方法所用的任何化合物，最初都可以从细胞培养分析中评价治疗有效剂量。与细胞培养中的测定一样，可能在动物模型中配制剂量，以达到包括IC50(即，达到症状一半最大抑制的待测化合物浓度)的循环血浆浓度范围。可以使用此类信息更准确地确定人用剂量。例如通过高效液相层析，可测定血浆中水平。
测定ATIII剂量的其它方法包括在ATIII治疗之前测量受试者的循环ATIII水平。根据循环ATIII水平，可以调整ATIII剂量高出初始循环水平的50％、100％、150％、250％、300％。
气溶胶制剂的给药量一般位于约10U/kg-250U/kg体重的范围内，优选约25U/kg-175U/kg体重。
熟练技术人员应当理解，某些因素可能影响有效治疗受试者所需的剂量和时间，包括但不限于疾病或紊乱的严重性、先前的治疗、受试者的一般健康状态和/或年龄以及其它疾病存在。此外，利用治疗有效量的蛋白质、多肽或抗体治疗受试者可以包括单次治疗，或优选包括系列治疗。
实施例
将重组制备的ATIII溶于盐溶液中(42mg/ml)。手术准备10只美丽诺羊(merino ewe)供研究。5-7天后，动物接受气管切开术并48次呼吸棉花烟雾(＜40℃)。将绿脓假单胞菌(Pseudomonas aeruginosa)悬浮于30mL盐溶液中，其中包含2-5×1011cfu，通过使用支气管镜注入气道。在细菌攻击之后，利用100％O2为动物机械换气。使用盐溶液作为对照。损伤后1小时、其后每隔4小时，直至24小时研究中，利用超声雾化器雾化盐溶液(n＝5)或ATIII(n＝5)(每次10ml)。
如下表I所示，ATIII雾化显著降低了肺气体交换(PaO2/FiO2比值)、分流系数和肺湿/干重比值。
表I
| 治疗 | 盐溶液 | 抗凝血酶III |
| PaO2/FiO2 | 94±22 | 206±41* |
| 分流系数(％) | 45±5 | 23±4* |
| MAP(mmHg) | 71.3±9.0 | 84.6±12.0 |
| 肺湿/干比 | 6.4±0. | 5.4±0.1* |
*相比盐溶液p＜0.05
即使ATIII的总剂量是先前静脉内研究所用的一半(参见Murakami(2001)Am.J.Resp.Crit.Care Med.163：A553)，但结果比静脉内给药更为有效。未观察到副作用。因此，气溶胶化的ATIII对绵羊继烟雾吸入后的脓毒性急性肺损伤和肺炎有利。
已经描述了本发明多个实施方案。尽管如此，应当理解，可能不背离本发明的实质和范围而进行很多改变。因此，其它实施方案位于以下权利要求书的范围之内。
Claims (13)
1.治疗受试者急性肺损伤的方法，包括：通过吸入给予治疗有效量的抗凝血酶III以治疗所述肺损伤。
2.权利要求1的方法，其中该肺损伤是脓毒性急性肺损伤。
3.权利要求1的方法，其中该肺损伤是急性呼吸窘迫综合征(ARDS)。
4.权利要求1的方法，其中该肺损伤是接触病毒剂引起的。
5.权利要求1的方法，其中该病毒剂是肺炎假单孢菌(Pseudomonas pneumonia)。
6.权利要求1的方法，其中该肺损伤是一种或多种烟雾和石棉引起的。
7.权利要求1的方法，其中使用超声雾化器给予该抗凝血酶III。
8.权利要求1的方法，其中该抗凝血酶III是血浆来源的抗凝血酶III。
9.权利要求1的方法，其中该抗凝血酶III是重组制备的抗凝血酶III。
10.权利要求9的方法，其中该重组制备的抗凝血酶III是转基因制备的抗凝血酶III。
11.权利要求1的方法，其中给予该受试者多于一剂量的抗凝血酶III。
12.权利要求1的方法，其中按约10-300U/kg体重的剂量给予该抗凝血酶III。
13.权利要求1的方法，其中按约25-125U/kg体重的剂量给予该抗凝血酶III。
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| US20050192226A1 (en) * | 2004-02-20 | 2005-09-01 | Perenlei Enkhbaatar | Method of preventing fibrin clots in pulmonary tissue through the use of aerosolized anticoagulants |
| US20050245444A1 (en) * | 2004-04-30 | 2005-11-03 | Yann Echelard | Method of using recombinant human antithrombin for neurocognitive disorders |
| US20060121004A1 (en) * | 2004-12-07 | 2006-06-08 | Yann Echelard | Methods of reducing the incidence of rejection in tissue transplantation through the use of recombinant human antithrombin |
| US8753882B2 (en) | 2010-10-12 | 2014-06-17 | Vetgel Technologies | Methods and compositions for treating respiratory conditions using platelet enriched plasma |
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| TW201446962A (zh) | 2013-02-13 | 2014-12-16 | Lab Francais Du Fractionnement | 具有修飾的糖化作用之蛋白質及其製造方法 |
| JP2016508515A (ja) | 2013-02-13 | 2016-03-22 | ラボラトワール フランセ デュ フラクショヌマン エ デ ビオテクノロジーＬａｂｏｒａｔｏｉｒｅ Ｆｒａｎｃａｉｓ ｄｕ Ｆｒａｃｔｉｏｎｎｅｍｅｎｔ ｅｔ ｄｅｓ Ｂｉｏｔｅｃｈｎｏｌｏｇｉｅｓ | 高ガラクトシル化抗ＴＮＦ−α抗体およびその使用 |
| KR20160029840A (ko) | 2013-07-05 | 2016-03-15 | 라보라토이레 프란카이즈 듀 프락티온네먼트 에트 데스 바이오테크놀로지스 | 친화성 크로마토그래피 매트릭스 |
| EP3154694A1 (en) | 2014-06-13 | 2017-04-19 | Children's Medical Center Corporation | Products and methods to isolate mitochondria |
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| US6355626B1 (en) * | 1994-05-13 | 2002-03-12 | The Trustees Of The University Of Pennsylvania | Antithrombin agents in treatment of asthma |
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