CN1444476A - 降低copd加重的方法 - Google Patents
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Abstract
本发明涉及通过给药磷酸二酯酶4(PDE4)抑制剂来降低COPD加重的发病率和/或严重性的方法。
Description
技术领域
本发明涉及通过给药磷酸二酯酶4(PDE4)抑制剂来降低COPD加重的发病率和/或严重性的方法。
发明背景
慢性阻塞性肺病(COPD)的特征在于呼气气流减少和肺用力排空缓慢，这些现象历经数月也没有明显的改变(1)。该疾病主要由吸烟所致，具有很高的死亡率和发病率，已有疗法很难见效。在英国，COPD约占男性死亡的6％和占女性死亡的约4％，并且在最常见致死病症中排名第三(2)。世界卫生组织的全球疾病负荷(The World Health Organization Global Burden)试验显示，COPD在1990年是世界性第六位的致死疾病，并且预计到2020年将上升为第三位。COPD往往与大量卫生健康费用有关，这主要是由于昂贵的治疗例如长期的氧疗法和住院费，以及间接的费用包括丧失劳动能力。最新的流行病学数据表明该疾病的流行被低估了。基于针对美国受治疗者的NHANES III(1988-1994)数据，估计4.6％的男性和3.7％的女性经诊断患有COPD，另有24.2％的男性和16.7％的女性患有未确诊的气流阻塞(4)。COPD患者经常会发展成疾病急性加重，这是发病率和死亡率的重要诱因，并会产生明显的经济影响。通常，患者每年加重1或2次，这种频率随着疾病的进展而增加(Anthonisen NR，Manfreda J，Warran CPW等，慢性阻塞性肺病加重的抗生素疗法.Ann Intezn.Med 1987，106：196-204；Fletcher C，PetoR.慢性气流阻塞的自然病史，BMJ，1977；1：1645-1648)。
环核苷酸磷酸二酯酶(PDEs)代表一族酶，它们能将普遍存在的胞内第二信使腺苷3′，5′-一磷酸(cAMP)和鸟苷3′，5′-一磷酸(cGMP)水解成其相应失活的5′-一磷酸代谢物。确信存在至少七种不同种类的PDE同功酶，每种均具有独特的生理学和动力学特性，并且每种酶都代表不同基因家族的产物。采用阿拉伯数字1-7以区别它们。
本发明制剂所用的靶酶是所有不同形式的PDE4同工酶，以及分布于所有细胞中的完整功能域(full domain)中的PDE4同工酶。它是较低Km(cAMPKm＝1-5μM)的cAMP-选择性酶，其对cGMP几乎没有活性(Km＞100μM)。该类酶的成员具有以两个或更多不可相互转化或缓慢互相转化的形式存在的有趣特性，所述形式以不同等级次序的效力与环戊苯吡酮和其他PDE IV抑制剂结合。因此，相同基因产物以一种以上的催化活性构象状态存在。重要的是，不同结合型的相对比例可随着组织细胞类型而改变。例如，炎症细胞可包含相对较高比例的低亲和力结合环戊苯吡酮形式，而脑和壁细胞可含有相对高比例的高亲和力结合环戊苯吡酮的形式。目前用于治疗炎症和支气管扩张剂的PDE抑制剂，例如茶碱和已酮可可碱药物，普遍抑制所有组织中的PDE同工酶。这些化合物具有副作用，这显然是因为其非选择性地抑制了所有组织中的所有PDE种类同工酶。采用这类化合物可有效治疗目标的疾病状态，但是可能表现出不需要的继发效应，如果它们能避免或最小化这些继发效应，则可增加该方法对某些疾病的整体治疗效果。尽管在理论上选择性同工酶PDE抑制剂优于非选择性抑制剂，但是迄今为止所试验的选择性抑制剂不能消除由于对不适当或非目标组织中同工酶的抑制作用的延伸而产生的副作用。例如，用选择性PDE4抑制剂环戊苯吡酮(在被开发为抗抑郁剂)的临床试验显示，它具有治疗精神病的活性并产生胃肠效应，例如胃灼热、恶心和呕吐。适应证是那些登布茶碱和其他靶向治疗多发性脑梗塞性痴呆的PDE4抑制剂的副作用，也包括胃灼热、恶心和呕吐。据信这些副作用是因为抑制了CNS和胃肠系统的特定区域中PDE4的结果。
业已发现，和那些更有力地与LPDE4(低亲和力环戊苯吡酮结合型)竞争的化合物相比，对环戊苯吡酮高亲和力结合型(HPDE4)有力竞争的某些化合物具有更多副作用或更强的副作用。目前得到的数据表明，化合物能靶向作用于低亲和力结合型的PDE4，并且该类型不同于以环戊苯吡酮为高亲和力结合物的结合型。现已发现，作用于高亲和力环戊苯吡酮结合型的抑制剂与低亲和力环戊苯吡酮结合型的抑制剂之间存在着不同的SARs。另外，这两种类型具有不同的功能作用。因此，作用于低亲和力环戊苯吡酮结合型的化合物表现出抗炎药活性，而那些作用于高亲和力环戊苯吡酮结合型的化合物产生副作用或表现出更强的副作用。
这些发现的有用结果在于，目前有可能鉴定出优先抑制cAMP催化活性的化合物，其中所述酶是低亲和力结合环戊苯吡酮型从而降低了副作用，这些副作用显然与抑制高亲和力结合环戊苯吡酮型相关。本发明提供良好的治疗指数(即消炎剂和/或支气管扩张剂活性相对于副作用)。现已发现，其中以治疗COPD本身的剂量水平给药或以相同或较低的剂量给药时未产生不可接受的不需要不利反应的某些抑制剂，降低时常侵袭COPD患者的疾病加重的发病率和/或严重性。
发明概要
本发明一方面涉及用于降低患有COPD的哺乳动物的COPD加重的发病率和/或严重性的方法，该方法包括将有效量的PDE4抑制剂给药于患有COPD的患者。
本发明另一方面涉及PDE4抑制剂在制造用于降低COPD加重发病率和/或严重性的药物中的用途。
附图说明
图1：临床试验A中未加重-ITT患者百分比的Kaplan-Meier评估。
图2：临床试验B中未加重-ITT患者百分比的Kaplan-Meier评估。
图3：临床试验C中未加重-ITT患者百分比的Kaplan-Meier评估。
图4：主要试验中COPD加重的相对风险(95％CI)。
发明详述
COPD急性加重可定义为治疗中需要变化的COPD症状出现恶化，所述治疗包括抗微生物治疗、短疗程口服皮质类固醇或其他支气管扩张剂治疗。所述加重分为三个级别：
1级：患者可在家中使用治疗COPD的常用药物治疗而自我管理。
2级：需要家庭或初级治疗医师的处方的附加治疗或门诊患者就诊(包括到急诊室)治疗。
3级：患者需入院治疗。
在某些临床试验A和B中，与接受安慰剂的患者相比，接受Ariflo(顺-4-氰基-4-[3-(环戊烷氧基)-4-甲氧苯基]环己烷-1-羧酸)(15mg速释片，BID)的患者，其所有类型加重和需要医师或入院治疗治疗的更严重加重(2和3级)的发病率相对较低。
COPD患者中进行临床试验，以试验15mg速释片Ariflo的BID的效力。该试验是设计的为期6个月的安慰剂对照的、平行组、双盲试验，以证实Ariflo 15mg BID在治疗COPD方面的效力和安全性。
在临床试验A中，以Kaplan-Meier评估为基础，用Ariflo(15mg速释片，BID)治疗使加重的风险相对于安慰剂降低了39％(P＝0.002)，并且使需要医师或住院治疗的加重风险降低了45％(P＝0.001)(附图1)。同样地，在第二试验B中，用Ariflo治疗26周，使加重的风险相对于安慰剂降低了30％(P＝0.005)，并使需要医师或住院治疗(2和3级)的加重风险降低了32％(P＝0.004)(附图2)。在临床试验C中，用Ariflo(15mg BID)治疗6个月的结果(治疗COPD的效力)不明确。在该项试验中，Ariflo对加重的作用在边缘上(marginal)(附图3)。
以Kaplan-Meier评估(以时间对最初加重)为基础测定的未加重率(Exacerbation-free survival rate)，见表1。
表1：试验24周的未加重率概况
未加重率*治疗组 患者总数 未加重的 测定的未加重 下95％CI 上95％CI P值
患者数 的百分比 (％) (％)试验A所有加重安慰剂 216 141 62.4 55.5 69.3SB207499 431 336 74.0 69.3 78.6 0.0082和3级加重安慰剂 157 69.7 63.1 76.3SB207499 364 81.7 77.5 85.8 0.003试验C所有加重安慰剂 226 143 56.0 47.8 64.2SB207499 474 299 58.3 53.5 63.1 0.6622和3级加重安慰剂 164 71.0 64.7 77.3SB207499 354 70.9 66.5 75.3 0.793试验B所有加重安慰剂 242 135 51.1 44.4 57.8SB207499 469 318 63.9 59.1 58.6 0.0042和3级加重安慰剂 165 64.3 57.9 70.8SB207499 367 75.5 71.2 79.7 0.009
为意向治疗人群的结果
*采用Kaplan-Meier评估(时间对初次加重)测定未加重率。基于log-rank试验得到P值。
在两个临床试验A和B中，Ariflo(15mg IR，BID)在治疗COPD中显示出了效力，与接受安慰剂的患者相比，接受Ariflo(15mg IR片，BID)的患者测定的其未加重百分率明显提高(分别为P＝0.008和P＝0.004)(附图4)。
Ariflo在两项试验中所表现出的降低COPD加重风险方面的益处是一个重要的临床发现，因为加重总是与较差的长期不良临床结果有关，这一发现对健康护理费用具有重要意义。
优选抑制剂的IC50比(高/低结合)约为0.1或更大(例如按US5,998,428中描述的IC50比测定法，其全部公开内容在此引入作为参考)。本发明所用PDE4-具体抑制剂的优选标准是该化合物的IC50比约为0.1或更大；所述比是：与1nM的[3H]R-环戊苯吡酮和PDE4(高亲合力结合环戊苯比酮形式)结合竞争的IC50值与抑制用1μM[3H]-cAMP作为反应物的PDE4(低亲和力结合环戊苯吡酮形式)的催化活性的IC50值之比。
可包含在这些制剂中的特定PDE4抑制剂包括US5,552,438(1996年9月3日公布)披露的那些，该专利及其公开的化合物全部在此引入作为参考。US5,552,438中披露的特别有有益的化合物是：顺式-4-氰基-4-[3-(环戊烷氧基)4-甲氧苯基]环己烷-1-羧酸及其盐、酯、前药或物理(physical)形式。这里通过其IUPAC名称，其注册商标Ariflo、其通用名cilomilast和字母数字编号SB207499来定义该化合物。其他有关的PDE4抑制剂包括：Astra公司的AWD-12-281(Hofgen，N.等。15th EFMC Int Symp Med Chem(9月6-10，爱丁堡)1998，摘要98页)；名为NCS-613的9-苄腺嘌呤衍生物(INSERM)；来自Chiroscience and Schering-Plough的D-4418；定义为CI-1018的苯并二吖庚因PDE4抑制剂(PD-168787；Parke-Davis/Warner-Lambert)；Kyowa Hakko在WO 9916766披露的苯并间二氧杂环戊烯衍生物；来自Napp的V-11294A(Landells，L.J.等.Eur Resp J[Annu Cong Eur Resp Soc(9月19-23，日内瓦)1998]1998，12(增刊28)：摘要2393页)；来自Byk-Gulden的roflumilast(CAS索引号162401-32-3)和pthalazinone(WO 9947505)；以及定义为T-440的化合物(Tanabe Seiyaku；Fujii，K.等.J Pharmacol Exp Ther，1998，284(1)：162)。本发明优选化合物是那些IC50比大于0.5的化合物，和尤其是那些IC50比大于1.0的化合物。最优选的化合物是roflumilast和顺式-4-氰基-4-[3-(环戊烷氧基)-4-甲氧苯基]环己烷-1-羧酸。
其他可用于治疗PDE4相关疾病方面的药物在此也引入该治疗中。按药物所治疗的疾病分类，其他示例药物包括：治疗炎性呼吸疾病的药物，例如支气管扩张剂、白三烯受体拮抗药和白三烯生物合成抑制剂；治疗非呼吸性炎症疾病，例如过敏性肠疾(IBD)的药物；免疫调节药物，认知增强剂；治疗风湿病性关节炎、风湿病性脊椎炎、骨关节炎、痛风性关节炎和其他关节炎疾病的药物；治疗败血症；脓毒性休克；内毒素性休克；革兰氏阴性脓毒症；中毒性休克综合征；成人呼吸窘迫综合征；脑型疟；矽肺；肺结节病的药物；治疗骨吸收疾病的药物；治疗再灌注损伤；移植物抗宿主反应；同种移植物排斥；感染所致发热和肌痛，所述感染例如流感、感染或肿瘤继发恶病质、人获得性免疫缺陷综合征(AIDS)、AIDS、ARC(AIDS有关复征)继发恶病质；瘢痕瘤形成、瘢痕组织形成、Crohn病；溃疡性结肠炎；pyresis；自身免疫疾病，例如多发性硬化症、自身免疫糖尿病和系统红斑狼疮的药物；治疗病毒性感染，例如巨细胞病毒(CMV)、流感病毒、腺病毒和疱疹病毒的药物，和治疗酵母菌和真菌感染的药物。
用于治疗呼吸疾病的示例性化合物是：白三烯拮抗剂；粘液溶解剂；镇咳剂和祛痰剂；抗生素；口服或吸入性β激动剂；磷酸二酯酶抑制剂(非PDE4-特异性抑制剂)；鼻减充血剂；弹性酶抑制剂；蛋白治疗剂例如IL4、IL5、IL8和IL13单克隆抗体，抗IgE；或口服或吸入性皮质类固醇。尤其优选的组合疗法是使用治疗量的皮质类固醇、β激动剂、抗胆碱能药、吸入性cromone、白三烯拮抗剂或抗生素，用于治疗继发性感染。
在治疗方法中，抑制剂的有效量为100μg-100mg/剂量，视需要每日给药1-4次。优选的范围为1-60mg/剂量，每日给药1或2次。更优选为5-30mg剂量，每日给药1或2次。最优选为10-20或10-15mg剂量，每日给药1或2次，例如，每日2次，15mg剂量，或每日1次30或60mg剂量。用于降低加重和/或严重性的剂量要低于治疗COPD本身的用量。
可采用常规方法给药所述抑制剂。例如，可经口服或者以吸入粉末或气雾剂形式给药。也可以将这些抑制剂配制成外用贴剂、缓释注射剂或栓剂形式，据信口服制剂或吸入给药的制剂是较好的给药剂型。
对于本发明的目的，制剂优选为速释或控释口服片剂，其中含有约1mg-200mg的Ariflo、更优选5-100mg和最优选5或10-60mg的活性组分。在这些范围中，优选剂量用量为10、15、20、30、40、50、60、70、80或90mg/制剂。
具体实施例
按以下描述实施临床试验方案：
符合条件的患者具有一定的临床诊断的COPD(按照国际治疗指导方针)，他们的％预计FEV1≥30％和支气管扩张剂后≤70％，FEV1/FVC≤0.7，固定的气道阻塞定义为给药β2-激动剂后≤15％可逆性。在每一试验中，对患有COPD的患者进行4周的安慰剂试验(run-in)期，然后以2∶1的比例随机地每日2次给药15mg Ariflo或安慰剂。治疗后的1、2和4周监控患者，然后以4周的间隔进行监控。在试验期间，可允许患者接受伴随的沙丁胺醇(prn)和/或稳定剂量的短效抗胆碱能药物疗法。
试验B包括2周的随机、双盲、耗尽(run-out)期，以检测治疗中止的影响。为了进行耗尽期的试验，将在最初24周中接受Ariflo的患者随机(1∶1比例)分成Ariflo(15mg BID)组或安慰剂组；在耗尽期间，已在最初24周中接受安慰剂的患者继续给药安慰剂。
测定每一受试者的肺功能(除第1周外)。在基线和12、24周(或在停药时)给予St.George氏呼吸调查表(SGRQ)。对每一受试者进行日常顺应性、生命体征和实验室评估。这些试验包括频繁的ECG评估以及对患者报告的与临床潜在相关的胃肠不利体验进行广泛性监控，以评价SB207499对心血管和胃肠身体系统的可能效应。在筛选期(基线期给药之前)和双盲治疗期对每一受试者给药之前，进行12-导联(lead)ECG评估。另外，在首日和最后日给药后，进行3小时的12-导联ECGs。在试验期和1、20周，对患者进行24小时的Holter ECG监控。测定所有患者的直立性生命体征和排泄物潜血，以获得该患者总体中异常评估的总发生率。在筛选、基线和双盲治疗结束时，测定直立性生命体征。在筛查和基线之间以及20周和双盲治疗结束(24周)之间，进行排泄物潜血试验。
对意向治疗总体(ITT)的所有效力测量数据进行分析，所述ITT定义为所有接受随机试验药物治疗的患者，对其进行了基线评价并在双盲期进行了至少一项治疗效力评价。对每一方案总体(PP)(定义为未明显违反方案的患者)的效力分析限于最低(trough)FEV1和SGRQ总评分(效力的综合(co-primary)测量)，和次级参数，运动耐量试验、运动后呼吸困难、综合性症状评分，和最低FVC。
Claims (2)
1.用于降低患有COPD哺乳动物的COPD加重的发病率和/或严重性的方法，该方法包括将有效量的PDE4抑制剂给药于患有COPD的患者。
2.PDE4抑制剂在制造用于降低COPD加重的发病率和/或严重性的药物中的用途。
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| CN01813330A Pending CN1444476A (zh) | 2000-07-27 | 2001-07-26 | 降低copd加重的方法 |
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| Country | Link |
|---|---|
| EP (1) | EP1320361A4 (zh) |
| JP (1) | JP2004505039A (zh) |
| KR (1) | KR20030019620A (zh) |
| CN (1) | CN1444476A (zh) |
| AR (1) | AR029984A1 (zh) |
| AU (2) | AU7902301A (zh) |
| BR (1) | BR0112682A (zh) |
| CA (1) | CA2417336A1 (zh) |
| CZ (1) | CZ2003141A3 (zh) |
| HU (1) | HUP0300685A3 (zh) |
| IL (1) | IL153919A0 (zh) |
| MX (1) | MXPA03000714A (zh) |
| NO (1) | NO20030332D0 (zh) |
| PL (1) | PL365612A1 (zh) |
| WO (1) | WO2002009689A1 (zh) |
| ZA (1) | ZA200300476B (zh) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2165768B1 (es) | 1999-07-14 | 2003-04-01 | Almirall Prodesfarma Sa | Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen. |
| US7776315B2 (en) | 2000-10-31 | 2010-08-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and additional active ingredients |
| DE10110772A1 (de) * | 2001-03-07 | 2002-09-12 | Boehringer Ingelheim Pharma | Neue Arzneimittelkompositionen auf der Basis von Anticholinergika und PDE-IV-Inhibitoren |
| GB0118373D0 (en) * | 2001-07-27 | 2001-09-19 | Glaxo Group Ltd | Novel therapeutic method |
| MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| DE10230769A1 (de) * | 2002-07-09 | 2004-01-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Arzneimittelkompositionen auf der Basis neuer Anticholinergika und PDE-IV-Inhibitoren |
| ME00524B (me) | 2003-03-10 | 2011-10-10 | Astrazeneca Ab | Novi postupak za dobijanje roflumilasta |
| EP2100599A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
| EP2100598A1 (en) | 2008-03-13 | 2009-09-16 | Laboratorios Almirall, S.A. | Inhalation composition containing aclidinium for treatment of asthma and chronic obstructive pulmonary disease |
| EP2510928A1 (en) | 2011-04-15 | 2012-10-17 | Almirall, S.A. | Aclidinium for use in improving the quality of sleep in respiratory patients |
| KR102087661B1 (ko) * | 2018-07-27 | 2020-03-11 | 강원대학교산학협력단 | Ｇｅｂｒ―７ｂ 화합물을 유효성분으로 포함하는 만성폐쇄성 폐질환의 예방 또는 치료용 조성물 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DZ3019A1 (fr) * | 1999-03-01 | 2005-05-20 | Smithkline Beecham Corp | Utilisation d'un inhibiteur de pde4 dans la préparation d'un médicament contre la copd. |
| SE9902937D0 (sv) * | 1999-08-18 | 1999-08-18 | Astra Pharma Prod | Pharmaceutical compositions |
| DZ3249A1 (fr) * | 1999-10-29 | 2001-05-10 | Smithkline Beecham Corp | Procédé d'administration d'un inhibiteur phosphodiesterase 4 |
-
2001
- 2001-07-25 AR ARP010103546A patent/AR029984A1/es not_active Application Discontinuation
- 2001-07-26 EP EP01957262A patent/EP1320361A4/en not_active Withdrawn
- 2001-07-26 CN CN01813330A patent/CN1444476A/zh active Pending
- 2001-07-26 AU AU7902301A patent/AU7902301A/xx active Pending
- 2001-07-26 BR BR0112682-2A patent/BR0112682A/pt not_active IP Right Cessation
- 2001-07-26 JP JP2002515242A patent/JP2004505039A/ja not_active Withdrawn
- 2001-07-26 KR KR10-2003-7001144A patent/KR20030019620A/ko not_active Application Discontinuation
- 2001-07-26 CA CA002417336A patent/CA2417336A1/en not_active Abandoned
- 2001-07-26 PL PL01365612A patent/PL365612A1/xx not_active Application Discontinuation
- 2001-07-26 WO PCT/US2001/023542 patent/WO2002009689A1/en not_active Application Discontinuation
- 2001-07-26 AU AU2001279023A patent/AU2001279023B2/en not_active Ceased
- 2001-07-26 CZ CZ2003141A patent/CZ2003141A3/cs unknown
- 2001-07-26 MX MXPA03000714A patent/MXPA03000714A/es unknown
- 2001-07-26 IL IL15391901A patent/IL153919A0/xx unknown
- 2001-07-26 HU HU0300685A patent/HUP0300685A3/hu unknown
-
2003
- 2003-01-17 ZA ZA200300476A patent/ZA200300476B/en unknown
- 2003-01-22 NO NO20030332A patent/NO20030332D0/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR20030019620A (ko) | 2003-03-06 |
| AR029984A1 (es) | 2003-07-23 |
| CZ2003141A3 (cs) | 2004-07-14 |
| IL153919A0 (en) | 2003-07-31 |
| EP1320361A1 (en) | 2003-06-25 |
| AU7902301A (en) | 2002-02-13 |
| HUP0300685A3 (en) | 2004-10-28 |
| NO20030332L (no) | 2003-01-22 |
| AU2001279023B2 (en) | 2005-11-10 |
| HUP0300685A2 (hu) | 2003-12-29 |
| BR0112682A (pt) | 2003-06-24 |
| CA2417336A1 (en) | 2002-02-07 |
| NO20030332D0 (no) | 2003-01-22 |
| JP2004505039A (ja) | 2004-02-19 |
| MXPA03000714A (es) | 2003-06-04 |
| ZA200300476B (en) | 2004-04-23 |
| WO2002009689A1 (en) | 2002-02-07 |
| EP1320361A4 (en) | 2006-04-05 |
| PL365612A1 (en) | 2005-01-10 |
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