CN1929845B - Pdeⅲ抑制剂在制备用于降低患有心力衰竭的哺乳动物的心脏大小的药物中的用途 - Google Patents

Pdeⅲ抑制剂在制备用于降低患有心力衰竭的哺乳动物的心脏大小的药物中的用途 Download PDF

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CN1929845B
CN1929845B CN200580007590XA CN200580007590A CN1929845B CN 1929845 B CN1929845 B CN 1929845B CN 200580007590X A CN200580007590X A CN 200580007590XA CN 200580007590 A CN200580007590 A CN 200580007590A CN 1929845 B CN1929845 B CN 1929845B
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pimobendan
heart
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heart failure
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于尔根·戴姆根
奥拉夫·琼斯
雷纳·克利曼
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Abstract

本发明是关于III型磷酸二酯酶抑制剂或Ca2+敏化剂或其药学上可接受的衍生物用于制备降低患有心力衰竭的患者的心脏大小的药物的用途。

Description

PDEⅢ抑制剂在制备用于降低患有心力衰竭的哺乳动物的心脏大小的药物中的用途
发明背景
技术领域
本发明是关于III型磷酸二酯酶(phosphodiesterase type III)(PDE III)抑制剂或“Ca2+敏化剂(sensitizing agent)”或其药学上可接受的衍生物用于制备降低患有心力衰竭的患者的心脏大小的药物的用途。
现有技术
静脉内正性心肌收缩剂在急性心力衰竭的处理中起重要作用，并常可导致患有扩张型心肌症(DCM)的犬得到短期改善。许多患DCM的犬具有令人非常警惕的预后情况(Monnet等人，1995)，尤其是通常经历很短存活时间的德伯曼犬(Dobermanns)(Calvert等人，1982；Calvert等人，1997)。虽然患DCM的犬的生命研究的次分析(subanalysis)表明那些接受依那普利(enalapril)治疗失败的犬与安慰剂组相比时间上有了改善(存活时间分别为142.8天对56.5天)(Ettinger等人，1998)，但观察治疗作用对患DCM犬的生存时间的影响的研究仍很少。总的看来，在许多试验揭示尽管口服正性心肌收缩剂对短期血液动力学有益处但是对生存时间具有副作用之后(Packer等人，1991；Cowley及Skene，1994)，近年来其在治疗慢性心力衰竭人类患者方面已失去有利地位。近来已经提出钙敏化剂可导致正性心肌收缩作用而不会产生一些与诸如多巴酚丁胺(dobutamine)、氨力农(amrinone)及米力农(milrinone)的更传统正性心肌收缩剂相关的副作用(包括钙超载)。
匹莫苯(Pimobendan)是具有钙敏化作用及一定III型磷酸二酯酶抑制作用的强心扩张剂(inodilator)化合物。钙敏化剂是通过改变钙与肌钙蛋白-C(troponin-C)的结合使得收缩性蛋白对现存胞内钙敏感达成其正性心肌收缩作用，而非通过增加进入心肌细胞内的钙达成该作用。因此通过钙敏化作用所产生的正性心肌收缩作用可以避免一些胞内钙超载所产生的副作用。胞内钙含量增加与心律不齐及猝死趋势的增加有关。临床试验表明，患心力衰竭的人类患者长期以口服方式服用匹莫苯可改善运动耐受性及生活品质，而对存活时间无明显副作用(Kubo等人，1992；Katz等人，1992)。
已知心力衰竭的进程与心脏大小的增加有关。在扩张型心肌症(DCM)中，左心室壁厚度与心房(chamber)直径的比例是减少的，而二尖瓣(mitral)及三尖瓣(tricuspid)环带圆周按照心房扩张程度的比例增加。DCM可能主要由诸如基因异常或其次由诸如瓣膜功能不足产生，此二者均导致心容积超载。然而，DCM通常包含心脏重塑作用，该作用可定义为基因表达、分子、细胞及间质的变化，这些变化在临床上表现为心脏大小、形状及功能变化。心脏重塑作用通常是不良征召，且与心力衰竭的进程相联系。逆转心脏重塑作用是心力衰竭治疗的目的。
心力衰竭治疗传统上主要集中于症状缓解而非集中于处理根本的疾病问题。
本发明的根本问题在于提供一种药物，该药物可重塑心脏的大小以降低患有冠心病的患者死亡的危险。详言之，本发明的根本问题在于提供一种药物，该药物可减小心脏的大小以降低患有心力衰竭的患者死亡的危险。
发明简述
已惊人地发现，III型磷酸二酯酶(PDE III)抑制剂及/或Ca2+敏化剂或其药学上可接受的衍生物可用于制备降低患有心力衰竭的患者的心脏大小的药物。
而且，本发明是关于一种降低患有心力衰竭的患者的心脏大小的方法，该方法包括给药于该患者有效量的PDE III抑制剂或其药学上可接受的衍生物。
此外，本发明是关于一种包含包装材料的制品，其中含有有效减小患有心力衰竭的患者的心脏大小的组合物，且该包装材料包含标签，其指示该组合物可用于降低患有心力衰竭的患者的心脏大小，其中该组合物包含至少一种PDE III抑制剂或Ca2+敏化剂或其药学上可接受的衍生物。
附图的简单说明
图1显示患有扩张型心肌症的英国可卡犬(English cocker)的侧面胸部射线照片，显示肺泡水肿及心脏增大。
图2a及2b显示图1中的同一犬在用呋塞米、依那普利、地高辛及匹莫苯治疗四个月后的胸部射线照片。
图3显示用匹莫苯(每一左侧黑色柱)或贝那普利(每一右侧灰色柱)治疗的犬在第0、7及56天的心功能不足评分(ISACHC)。
图4显示用匹莫苯(左侧黑色柱)或贝那普利(右侧灰色柱)治疗的犬在第56天时的整体临床效果。
图5显示用匹莫苯(上部-○-曲线)或贝那普利(下部-□-曲线)治疗的犬的存活函数(56天治疗期间)。
图6显示用匹莫苯(430天期间/上部-○-曲线)或贝那普利(228天期间/下部-□-曲线)治疗的犬的存活函数。
图7显示的为经匹莫苯治疗的犬(-0.15v)与经贝那普利治疗的犬(+0.22v)相比较平均心脏大小的减少。
发明详述
本发明是关于III型磷酸二酯酶(PDE III)抑制剂，优选是PDE III抑制剂、Ca2+敏化剂，或还表现出钙敏化作用(Ca2+敏化剂)的PDE III抑制剂，或其药学上可接受的衍生物用于制备降低患有心力衰竭的患者的心脏大小的药物上的用途。
用于上文及下文中的术语“PDE III抑制剂”是指III型磷酸二酯酶(PDE)抑制剂，其可防止cAMP分解为5′AMP并因此维持cAMP对蛋白激酶及其他第二信使活化的作用。
PDE III抑制剂的作用是作为常规正性心肌收缩剂及血管舒张剂，其可减轻心力衰竭患者的后负荷，使其感觉较好。
术语Ca2+敏化剂是指能增加心脏收缩性蛋白的Ca2+敏感性的化合物，意即在给定Ca2+浓度下增加所发展的收缩力。
优选的PDE III抑制剂或Ca2+敏化剂是西洛他唑(cilostazol)、匹莫苯(pimobendan)、米力农(milrinone)、左西孟旦(levosimendan)、氨力农(amrinone)、依诺昔酮(enoximone)及匹罗昔酮(piroximone)TZC-5665或其药学上可接受的盐类、衍生物类、代谢物类或前药类。最优选为匹莫苯及左西孟旦，或其药学上可接受的盐类、衍生物类、代谢物类或前药类。更优选为匹莫苯及左西孟旦。更优选为匹莫苯，其药学上可接受的盐类、衍生物类、代谢物类或前药类。
匹莫苯即众所周知的4，5-二氢-6-[2-(4-甲氧苯基)-1H-苯并咪唑-5-基]-5-甲基-3(2H)-哒酮，例如揭示于EP 008 391 B1中。左西孟旦为哒酮-二腈衍生物。详言之，左西孟旦为众所周知的(R)-[[4-(1，4，5，6-四氢-4-甲基-6-氧代-3-哒嗪基)苯基]腙]丙二腈，并早在例如GB 2228004、US 5,151,420及US5,569,657中已有所表述。
用于上文及下文中的术语“患者”是指患有心力衰竭的动物或人。术语“患者”包括诸如灵长类的哺乳动物，包括人类。
除了灵长类外，多种其他哺乳动物亦可通过本发明方法进行治疗。例如，可治疗下列哺乳动物，包含(但不限于)牛、绵羊、山羊、马、犬、猫、豚鼠、大鼠或其他牛科、绵羊科、马科、犬科、猫科，啮齿科或鼠科动物。然而，该方法亦可用于诸如鸟类的其他动物身上。
优选是人类患者、犬、猫及马。人类患者为患有心力衰竭的女性或男性。通常这些人是年龄在6至80岁之间，优选是30至65岁之间的儿童、青年人、成年人或老年人。
用于上文及下文中的术语“心力衰竭(heart failure)”是指任何心脏收缩病症或心脏病。临床表现通常是心脏的细胞及分子成分变化及行使稳态控制的介质(mediator)变化的结果。心力衰竭通常伴有心脏大小的增加及心脏功能的退化。
患者所患有的心力衰竭主要是慢性充血性心力衰竭、由于因心肌梗塞(myocardial infarction)或心肌缺血(myocardial ischemia)而产生的心力衰竭，该心肌缺血是由心脏停搏(cardiac arrest)引起的。
用于上文及下文中的术语“降低心脏大小”是指降低患者的心脏大小，其可通过James W.Buchanan等人(Buchanan 1995)所建议的射线照片方法判定，并表示为椎体心脏大小(vertebral heart size)的相对变化。优选地，在用PDE III抑制剂及/或Ca2+敏化剂治疗时，该患者的相对平均椎体心脏总数(vertebral heart sum(VHS))在10至100天内减少了0.05至0.25，尤其是，在约60天内减少了约0.15。
本文所用的术语“有效量”意谓当该PDE III抑制剂或Ca2+敏化剂以单剂型给药时足以降低心脏大小的量。
该PDE III抑制剂及/或Ca2+敏化剂优选与第二活性治疗剂组合给药。该第二活性治疗剂优选选自：钙离子通道阻断剂、ACE抑制剂、利尿剂、血小板抑制剂、β阻断剂及血管紧张素II拮抗剂、醛固酮(aldosterone)拮抗剂、洋地黄苷(digitalis glycosides)、抗心律不齐剂或利尿剂。尤其是：
·其中钙离子通道阻断剂选自：地尔硫卓(diltiazem)、维拉帕米(verapamil)及非洛地平(felodipine)或其药学上可接受的衍生物；及/或
·其中ACE抑制剂选自：奥马曲拉(omapatrilat)、MDL100240、阿拉普利(alacepril)、贝那普利(benazepril)、卡托普利(captopril)、西拉普利(cilazapril)、地拉普利(delapril)、依那普利(enalapril)、依那普利拉(enalaprilat)、福辛普利(fosinopril)、福辛普利拉(fosinoprilat)、咪达普利(imidapril)、赖诺普利(lisinopril)、培哚普利(perindopril)、喹那普利(quinapril)、雷米普利(ramipril)、雷米普利拉(ramiprilat)、醋酸沙拉新(saralasin acetate)、替莫普利(temocapril)、群多普利(trandolapril)、群多普利拉(trandolaprilat)、西那普利(ceranapril)、莫西普利(moexipril)、喹普利拉(quinaprilat)及螺普利(spirapril)或其药学上可接受的衍生物；及/或
·其中β阻断剂选自：比索洛尔(bisoprolol)、卡维地洛(carvediol)、美托洛尔(metoprolol)、普萘洛尔(propranolol)及噻吗洛尔(timolol)或其药学上可接受的衍生物，及/或
·其中血管紧张素II拮抗剂选自：醋酸沙拉新、坎地沙坦西酯(candesartan cilexetil)、缬沙坦(valsartan)、坎地沙坦(candesartan)、氯沙坦钾(losartan potassium)、依普罗沙坦(eprosartan)、厄贝沙坦(irbesartan)、他索沙坦(tasosartan)、泊米沙坦(pomisartan)及替米沙坦(telmisartan)或其药学上可接受的衍生物，及/或
·其中醛固酮拮抗剂选自：螺内酯(spironolactone)、依普利酮(eplerenone)、坎利酮(canrenone)、坎利酮钾或其药学上可接受的衍生物，及/或
·其中抗心律不齐剂选自：胺碘酮(amiodarone)、betrylium、丙吡胺(disopyramide)、多非利特(dofetilide)、氟尼卡(flecainide)、伊布利特(ibutilide)、美西律(mexiletine)、妥卡尼(tocainide)、普鲁卡因胺(procainamide)、普罗帕酮(propafenone)、奎尼丁(quinidine)、索他洛尔(sotalol)或其药学上可接受的衍生物；及/或
·其中利尿剂选自：呋塞米(furosemide)、托拉塞米(torasemide)、布美他尼(bumetanide)、依他尼酸(etacrynic acid)、阿佐塞米(azosemide)、莫唑胺(muzolimine)、吡咯他尼(piretanide)、曲帕胺(tripamide)、苄氟噻嗪(bendroflumethazide)、氯噻嗪(chlorothiazide)、氢氯噻嗪(hydrochlorothiazide)、氢氟噻嗪(hydroflumethiazide)、甲氯噻嗪(methychlothiazide)、泊利噻嗪(polythiazide)、三氯噻嗪(trichlormethiazide)、氯噻酮(chlorthialidone)、吲哒帕胺(indapamide)、美托拉宗(metolazone)、喹乙宗(quinethazone)、依托唑啉(etozolin)、氨苯蝶啶(triamteren)、阿米洛利(amiloride)或其药学上可接受的衍生物；及/或
·其中洋地黄苷选自：地高辛(digoxin)、洋地黄毒苷(digitoxin)、毒毛花苷G(g-strophantin)、β-甲基地高辛(β-methyldigoxin)、β-乙酰基地高辛(β-acetyldigoxin)或其药学上可接受的衍生物。
最优选将PDE III抑制剂或Ca2+敏化剂，尤其为匹莫苯或左西孟旦，更佳是匹莫苯，与一种或多种选自以下的药物一起给药：一种或多种ACE抑制剂、一种或多种利尿剂及一种或多种洋地黄苷。
本发明的化合物可以诸如下列形式的口服剂型给药：片剂、胶囊剂(各胶囊包含缓慢释放或延时释放的制剂(formulation))、丸剂、散剂、颗粒、酏剂、酊剂、悬浮剂、糖浆及乳剂。这些化合物亦可以静脉内(推注或输液)、腹膜内、皮下或肌肉内方式给药，所有方式都使用为一般药学技术者所熟知的剂型。这些化合物可单独给药，但通常根据给药路径及标准药学实践的选择而与药学载体一起给药。
本发明中化合物的给药方案当然视已知因素而变化，诸如具体药物的药效特征及其给药模式及途径；接受者的物种、年龄、性别、健康状况、医疗状况及体重；症状的性质及程度；当前治疗的种类；治疗频率；给药途径、患者的肝肾功能状态、欲达到的效果。医师或兽医可决定及规定欲预防、逆转或停止病症进程的所需药物的有效量。
就大体用药指导而言，当各有效成分(优选是匹莫苯或左西孟旦)用于达到指示的效果时，其日口服剂量范围为约10μg/kg至10mg/kg，优选为0.05mg/kg至5mg/kg，尤其为0.1mg/kg至2mg/kg。
匹莫苯最优选是每天给药约0.1mg/kg至1.5mg/kg。
PDE III抑制剂及/或Ca2+敏化剂可以单一日剂量给药，或总日剂量每天可以两次、三次或四次分剂量给药。
PDE III抑制剂及/或Ca2+敏化剂可经由局部使用适当鼻腔内媒剂(vehicle)以鼻腔内形式给药，或以经皮路径使用经皮贴剂给药。当以经皮传递系统形式给药时，整个剂量方案的剂量给药当然是持续给药而非间歇给药。
PDE III抑制剂及/或Ca2+敏化剂通常与适当的药学稀释剂、赋型剂或载体(本文共同称作药学载体)混合给药，这些物质是相对于所要给药形式即口服片剂、胶囊、酏剂、糖浆等而适当选择，且PDE III抑制剂及/或Ca2+敏化剂与常规药学实践相一致。
例如，对以片剂或胶囊形式口服给药而言，活性药物成分可与口服的、无毒性的、药学上可接受的惰性载体组合，该载体诸如乳糖、淀粉、蔗糖、葡萄糖、甲基纤维素、硬脂酸镁、磷酸氢钙、硫酸钙、甘露糖醇、山梨糖醇等；对以液体形式口服给药而言，口服药物成分可与任何口服的、无毒性的，药学上可接受的惰性载体组合，该载体诸如乙醇、甘油、水等。而且，必要时或必需时，亦可将适当的粘合剂、润滑剂、崩解剂及着色剂加入该混合物中。适当的粘合剂包括淀粉、明胶、诸如葡萄糖或β-乳糖的天然糖类、玉米甜味剂、诸如阿拉伯树胶、黄蓍胶的天然及合成胶，或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。这些剂型中所用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、醋酸钠、氯化钠等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
PDE III抑制剂及/或Ca2+敏化剂亦可以脂质体传递系统形式给药，诸如小单层微脂粒(vesicle)、大单层微脂粒、多层微脂粒。也可由诸如胆固醇、硬脂胺(stearylamine)或磷脂酰胆碱的多种磷脂形成脂质体。
PDE III抑制剂及/或Ca2+敏化剂亦可与作为靶向药物载体的可溶性聚合物混合。这些聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺-苯酚、聚羟乙基天冬酰胺苯酚(polyhydroxyethylaspart-amidephenol)或经棕榈酰残基取代的聚氧化乙烯聚赖氨酸(polyethyleneoxidepolylysine)。
此外，PDE III抑制剂及/或Ca2+敏化剂可与一类用于达成药物的控制释放作用的可生物降解聚合物混合，例如，聚乳酸、聚乙醇酸、聚乳酸与聚乙醇酸的共聚物、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯(polycyanoacylates)及水凝胶的交联或两亲嵌段共聚物。
适于给药的剂型(药物组合物)每剂量单位可含有约1mg至约100mg的活性成分。
在这些药物组合物中，活性成分通常占以组合物的总重量计约0.5-95％重量比的量存在。
明胶胶囊可含有活性成分及粉状载体，诸如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸及等。可使用类似稀释剂以用于制备压缩片剂。片剂与胶囊二者均可制成缓慢释放产品以在数个小时期间内提供药物的持续释放。压缩片剂可涂覆糖衣或膜衣以掩盖任何不愉快的气味且保护片剂不与大气接触，或涂覆肠衣以选择性地在胃肠道中崩解。
口服给药的液体剂型可含有着色剂及调味剂以增加患者的接受性。
一般来说，水、适当的油、盐水、水性右旋糖(葡萄糖)及相关糖溶液及乙二醇(诸如丙二醇或聚乙二醇)是用于非经肠溶液的适当载体。非经肠给药的溶液优选含有活性成分的水溶性盐、适当稳定剂，及必要时的缓冲物质。抗氧化剂是适当的稳定剂，诸如亚硫酸氢钠、亚硫酸钠或抗坏血酸，其可单独使用或组合使用。亦可用柠檬酸及其盐及EDTA钠。此外，非经肠溶液可含有防腐剂，诸如苯扎氯铵、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯及氯丁醇。
适当的药学载体是如Reminqton′s Pharmaceutical Sciences，MackPublishing Company(此领域中的标准参考文章)中所述。
当两种或两种以上前述第二治疗剂与PDE III抑制剂及/或Ca2+敏化剂一起给药时，鉴于治疗剂组合给药时的累加效应或协同效应，典型日剂量及典型剂型中的各成分量通常相对于药物单独给药时的常用剂量减少。
尤其是当作为单一剂量单位给药时，在组合的活性成分之间存在潜在的化学相互作用。因此，当式1的组合物与第二治疗剂以单一剂量单位组合时，是如此配制，使得虽然活性成分以单一剂量单位组合，但这些活性成分之间的物理接触减至最小(即减少)。例如，可将一种活性成分涂覆肠衣。通过肠衣涂覆活性成分中的一种，不仅可使得组合的活性成分之间的接触减至最小，亦可在胃肠道中控制这些成分中的一种的释放，以使这些成分中的一种不在胃中释放而是在肠中释放。活性成分中的一种亦可涂覆有使之在这个胃肠道内缓慢释放并且亦可使组合的活性成分之间的物理接触减至最小。
此外，缓慢释放的组合物可还经肠衣涂覆，以使该成分的释放仅发生在肠。还有另一个方法涉及配制组合产物，其中一种成分涂覆有缓慢释放及/或肠衣释放的聚合物，而另一种成分亦涂覆有诸如低粘度等级的羟丙基甲基纤维素(HPMC)的聚合物或本领域中已知的其他适当材料，以更进一步分离开这些活性成分。聚合物涂层可形成额外屏障以阻止与其他成分相互作用。
以实施例说明的制备根据本发明的组合物的方法在下文中将会更详细表述。以下实施例仅作为详细说明，并非限制本发明的主题。
实施例1
为评估长期功效及对匹莫苯的耐受性及其对患DCM的可卡犬(cockerspaniels)及德伯曼犬长期生存时间的影响，进行双盲试验。
材料及方法：经主人同意，招募因患DCM出现在R(D)SVS心肺科的可卡犬(n＝10)及德伯曼犬(n＝10)用于研究。在用地高辛、依那普利及呋塞米常规治疗稳定后，使用双盲研究设计，这些犬另外接受匹莫苯或安慰剂。
结果：相对于安慰剂组可卡犬平均存活时间为589天(自51天至1127天范围)，匹莫苯组可卡犬平均存活时间为612天(自61天至1428天范围)。差异无统计学上显著性(Wilcoxon-Mann-Whitney-U检验，p＞0.05)。
相对于安慰剂组德伯曼犬平均存活时间为72天(自13天至196天范围)，匹莫苯组德伯曼犬平均存活时间为280天(自42天至369天范围)。差异具有统计学上显著性不同(Student’s t-检验，p＜0.05)。该药具有良好耐受性且在任一品种犬上未见与治疗相关的副作用。
结论：与安慰剂组相比，匹莫苯能显著改善患有DCM的德伯曼犬的生存时间，但对可卡犬生存时间无统计学上显著影响。德伯曼犬的改善存活时间在疾病处理上是重大进展，因为该疾病在诊断后通常导致急速死亡。
在两个品种犬中，在标准治疗方式中加入匹莫苯可显著改善病人的NYHA级状况(NYHA-class status)。因此匹莫苯疗法的益处与呋塞米、依那普利及地高辛的有益作用是累加的，且可在可卡犬上观察到，与许多患DCM的犬相比，曾认为用常规疗法可使这些可卡犬具有有益的临床过程(Monnet等人，1995)。
在用匹莫苯治疗的德伯曼犬(Doberman pinscher)上可发现存活时间具有显著差异。虽然已知该品种犬在充血症状发展后有不良预后情况，但用匹莫苯治疗的动物可见存活时间显著延长。
实施例2
为评价匹莫苯治疗(日剂量为0.4-0.6mg/kg)与血管紧张素转换酶(ACE)抑制剂治疗(盐酸贝那普利日剂量为约0.25-0.5mg/kg身体重量)相比的临床功效，进行双盲随机、阳性对照多中心域试验(positive controlled multi-centrefield trial)。两种治疗均可适当组合呋塞米(多达每天8mg/kg)或抗心律不齐药物。该研究在药品优良临床试验规范(Good Clinical Practice(GCP))的准则下，由经验丰富的兽医心脏病专家在欧洲十一个研究中心进行。对每一个患者治疗的强制最短期限为56天。这些犬在首次治疗前第0天及开始治疗后第7天及第56天进行检查。为获取长期存活时间资料，研究者可选择在56天后继续进行治疗。在可选研究期间，由于不允许在贝那普利组中加入匹莫苯，为了维持适当匹莫苯对照组，可放开动物治疗规则(treatment code)。可允许进行所有其他得到许可的伴随疗法。就存活时间分析而言，剔除的动物或因治疗失败而改变疗法的动物亦列入死亡。然而，这些状况在统计学上作为经过检查的数据来评价。
功效结论的主要参数为心力衰竭症状的临床严重程度，根据国际小动物心脏健康协会(ISACHC)的规则进行分类。次要参数为运动耐受性、行为、呼吸及循环系统的研究结果、整体功效等级及心脏超声描记术资料。
总共包括76只犬，匹莫苯组中41只及贝那普利组35只。所有犬临床上表现出因瓣膜关闭不全而导致心力衰竭的明显症状。在进行之前，匹莫苯组中症状的平均持续时间为4.05个月，贝那普利组中则为2.77个月。在开始治疗前，两组之间无任何所研究的参数的临床相关性差异。
依据ISACHC心力衰竭分类标准，在56天治疗周期后，84％的匹莫苯治疗组主要参数改善，仅56％的贝那普利治疗组改善。在此时间点，ISACHC分类的Ib(评分为2)，即无临床症状者，在匹莫苯组中报导76％，而在贝那普利组仅报导48％。两组关于主要参数的差异在统计学上显著有利于匹莫苯组，表现在第7天(p＝0.0280)及第56天(p＝0.0201)。结果，在匹莫苯组中有85％整体功效评价列入“非常好”或“好”，但在贝那普利组中仅41％(p＜0.0001)。其他次要参数结果与心力衰竭分类标准的临床结果一致。
在56天研究期间，匹莫苯组中2只犬及贝那普利组中7只犬死亡或因心脏原因处安乐死(euthanise)。根据Kaplan-Meier法对存活时间分析揭示显著差异有利于匹莫苯组(p＝0.0368)。长期存活资料的分析证实了56天研究期间的结果。经匹莫苯治疗的犬的中值存活时间为430天，而未接受匹莫苯治疗的犬为228天。此外，根据Kaplan-Meier法对存活时间分析揭示显著差异有利于匹莫苯组(p＝0.0020)。
拍摄从左至右侧视的射线照片。用椎体测量系统(vertebral scale system)测定心脏大小。
在侧面射线照片中，心脏的长轴(L)用两脚规测量，该两脚规自左主干支气管(气管分叉门，隆凸)的腹面延伸至左心室顶端的最远端周线。两脚规沿脊柱重新定位，开始于第四胸椎的脊(carinal)边缘处。将心脏长度记录为那点的尾端椎体(vertebral)数目，且估计到最接近椎体的0.1。最大垂直短轴(S)可用同样方式在第四胸椎处开始测量。
然后将长轴及短轴的椎体(v)长度相加以获得椎体心脏总数(VHS)，其可提供单独数目，其代表与犬大小成比例的心脏大小。对健康犬而言，VHS的正常范围是自8.5v至10.5v(平均为9.7v)。
在匹莫苯组犬中，第0天及第56天射线照片上所量测的平均椎体心脏总数显示出改善。关于自基线值的变化，平均值的差异指示经匹莫苯治疗的犬平均心脏大小的降低。两组犬之间关于整体临床功效的平均差异在统计学上显著有利于匹莫苯治疗组(p＜0.0001)。见表1。贝那普利对照组平均得分显示相对于自基线值的变化的恶化(图7)。此证明心脏大小的降低通常不能在因瓣膜功能不全(valve insufficiency)而致心力衰竭的犬身上用标准疗法达成。在标准疗法(ACE抑制剂+/-利尿剂)(平均心脏大小恶化0.22v)及匹莫苯治疗(平均大小改善-0.15v)之间的惊人差异是意想不到的，并因而具有创造性。
表1：椎体测量系统-心脏总数
Figure G200580007590X01D00111
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Claims (10)

1.匹莫苯或其药学上可接受的盐在制备用于降低患有心力衰竭的患者的心脏大小的药物中的用途。
2.根据权利要求1的用途，其中匹莫苯或其药学上可接受的盐是以口服方式或非经肠方式应用。
3.根据权利要求1的用途，其中匹莫苯或其药学上可接受的盐是以10μg/kg至10mg/kg的日剂量给药。
4.根据权利要求1的用途，其中匹莫苯或其药学上可接受的盐与选自以下的药物一起给药：钙通道阻断剂、ACE抑制剂、利尿剂、阿司匹林、β-阻断剂及血管紧张素II拮抗剂。
5.根据权利要求4的用途，其中该ACE抑制剂选自：奥马曲拉、阿拉普利、贝那普利、卡托普利、西拉普利、地拉普利、依那普利、依那普利拉、福辛普利、福辛普利拉、咪达普利、赖诺普利、培哚普利、喹那普利、雷米普利、雷米普利拉、醋酸沙拉新、替莫普利、群多普利、群多普利拉、西那普利、莫西普利、喹普利拉及螺普利。
6.根据权利要求4的用途，其中该血管紧张素II拮抗剂选自：醋酸沙拉新、坎地沙坦西酯、缬沙坦、坎地沙坦、氯沙坦钾、依普罗沙坦、厄贝沙坦、他索沙坦及替米沙坦。
7.根据权利要求4的用途，其中匹莫苯或其药学上可接受的盐与一种或多种选自以下的药物一起给药：一种或多种ACE抑制剂、一种或多种利尿剂及一种或多种洋地黄苷。
8.根据权利要求1-7中任一项的用途，其中该患者的相对平均椎体心脏总数经以匹莫苯或其药学上可接受的盐治疗10至100天内降低了0.05至0.25。
9.根据权利要求1-7中任一项的用途，其中该心力衰竭是慢性充血性心力衰竭、由心肌梗塞引起的心力衰竭，或由心肌缺血引起的心力衰竭，其中心肌缺血是由心绞痛恶化或心脏停搏引起的。
10.根据权利要求1-7中任一项的用途，其中该患者是选自以下哺乳动物：包括人类的灵长类、犬、猫及马。
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