CN109069507B - 匹莫苯减小心脏尺寸和/或延迟临床症状的发作的用途 - Google Patents
匹莫苯减小心脏尺寸和/或延迟临床症状的发作的用途 Download PDFInfo
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- CN109069507B CN109069507B CN201780021970.1A CN201780021970A CN109069507B CN 109069507 B CN109069507 B CN 109069507B CN 201780021970 A CN201780021970 A CN 201780021970A CN 109069507 B CN109069507 B CN 109069507B
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- heart failure
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Abstract
本发明涉及匹莫苯(pimobendan)，其用于在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭，优选充血性心力衰竭的患者中减小心脏尺寸和/或延迟临床症状的发作，和/或在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭，优选充血性心力衰竭的患者中延迟心力衰竭，优选充血性心力衰竭的发作的方法中，其中该患者优选是哺乳动物，更优选人类、狗、猫或马，且最优选狗。
Description
技术领域
本发明涉及医学，尤其是兽医学领域。特别地，本发明涉及匹莫苯的用途，其用于患有由(粘液瘤性)二尖瓣疾病[(M)MVD]和/或慢性心脏瓣膜病(CVHD；也称为慢性瓣膜病，CVD)和/或心房心室瓣膜功能不全(AVVI)所致的无症状(隐发性，临床前)心力衰竭(HF)的患者中减小心脏尺寸，和/或用于患有由(M)MVD和/或CVHD/CVD和/或AVVI所致的无症状(隐发性，临床前)HF的患者中延迟临床症状的发作，和/或延迟由(粘液瘤性)二尖瓣疾病[(M)MVD]和/或慢性心脏瓣膜病(CVHD；也称为慢性瓣膜病，CVD)和/或心房心室瓣膜功能不全(AVVI)所致的心力衰竭的发作。
发明背景
心力衰竭划分为不同阶段，其由不同分级体系定义，例如国际小动物心脏健康委员会(ISACHC)、纽约心脏协会(NYHA)功能性分级体系和目前使用的根据2009年美国兽医内科医学院(ACVIM)的共识声明的分级。
根据国际小动物心脏健康委员会(ISACHC)体系的分级：
I级：无症状(也称为隐发性或临床前)
IA级：无针对潜在心脏病的代偿的迹象(放射照相或超声心动图未检测到容量过度负荷或压力过度负荷)
IB级：针对潜在心脏病的代偿的临床征兆(放射照相或超声心动图检测到容量过度负荷或压力过度负荷)
II级：休息或轻度运动时具有临床征兆的轻度至中度心力衰竭(需要治疗)
III级：晚期心力衰竭；严重充血性心力衰竭的临床征兆
IIIA级：可家庭治疗
IIIB级：需要住院
纽约心脏协会(NYHA)功能性分级体系：
I级：描述患有无症状心脏病(例如，存在慢性心脏瓣膜病(CVHD)但即使在运动时无明显的临床征兆)的患者。
II级：描述患有仅在剧烈运动期间产生临床征兆的心脏病的患者。
III级：描述患有在常规日常活动或轻度运动时产生临床征兆的心脏病的患者。
IV级：描述患有即使在休息时产生严重临床征兆的心脏病的患者。
ACVIM体系描述心脏病和心力衰竭的四个基本阶段：
A阶段：患者具有患心脏病的高风险但目前无可识别的结构性心脏病症(例如，每只无心脏杂音的查尔斯国王骑士猎犬(Cavalier King Charles Spaniel))。
B阶段：患者患有结构性心脏病(例如，存在二尖瓣反流的典型杂音)，但从未发展为由心力衰竭(由于预后及治疗的重要临床含义，所以委员会进一步将B阶段细分为B1和B2阶段)引起的临床征兆。
B1阶段：无回应于CVHD的心脏重塑作用的放射照相或超声心动图迹象的无症状患者。
B2阶段：患有如由左侧心脏扩大的放射照相或超声心动图结果证明的血液动力学上显著的瓣膜反流的无症状患者。
C阶段：过去或现在具有与结构性心脏病相关的心力衰竭的临床征兆的患者。
D阶段：患有具有由“标准疗法”难以治疗的CVHD引起的心力衰竭的临床征兆的末期疾病的患者。
心脏病变开始于ISACHC I级、NYHA I级和ACVIM B2阶段，其中存在心杂音或心室扩大，但无临床症状(ISACHC I级或无症状/隐发性/临床前阶段)。在疾病的进展过程中，临床症状变得明显(ISACHC II级或III级，NYHA II级、III级或IV级，ACVIM C阶段和D阶段)。
(M)MVD或CVHD/CVD或AVVI心力衰竭的已知进展与心脏尺寸的增大相关。由心脏内形态变化所致的心脏重塑作用通常视为风险因素且与导致心力衰竭的病理生理变化的恶化有关。心力衰竭疗法的一个目标是减小心脏尺寸和延迟心脏的形态变化。
一种用于治疗心力衰竭的已知药物活性化合物为匹莫苯(4,5-二氢6-[2-(4-甲氧基苯基)-1H-苯并咪唑-5-基]-5-甲基-3(2H)-哒嗪酮)公开于EP 0 008 391且具有下式：
匹莫苯是用于治疗动物(尤其是狗)中起源于例如扩张型心肌症(DCM)或二尖瓣疾病(MVD)的充血性心力衰竭(CHF)的熟知化合物。在日本，还批准匹莫苯作为用于人类心血管治疗的药品。
若干出版物揭示了匹莫苯在治疗动物心力衰竭中的用途，例如以下出版物。
WO 2005/092343描述例如匹莫苯的PDE-III抑制剂对于减小患有心力衰竭患者的心脏尺寸的用途，然而未提及患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者。
Lombard和同事(Lombard CW et al.,J Am Anim Hosp Assoc 2006,42:249-261)揭示在治疗狗的临床获得性心房心室瓣膜病时匹莫苯对比贝那普利(benazepril)的临床效果。
WO 2007/054514针对诸如匹莫苯的PDE-III抑制剂于治疗无症状(也称为隐发性或临床前)心力衰竭的用途，然而未提及患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者。
Summerfield NJ及同事(Summerfield NJ et al.,J Vet Intern Med 2012,26:1337-1349)涉及关于匹莫苯在患有临床前扩张型心肌症(DCM)的杜宾犬中(DobermanPinscher)预防充血性心力衰竭或猝死的效果的临床研究。然而，他们未提及患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者。
互联网网站www.epictrial.com涉及EPIC试验，一个探究匹莫苯在延迟由二尖瓣疾病(MVD)所致的充血性心力衰竭的临床症状的发作的效果的研究。然而，在本专利申请的优先权日时，此试验仍在进行中且未公开研究结果。
然而，几个其他出版物涉及匹莫苯治疗的不利心脏效果，例如以下出版物。
Schneider P等人(ExpToxicPathol 1997,49:217-224)描述在雌性米格鲁犬(Beagle dog)中IV施用的匹莫苯的比较性心脏毒性。
Tissier R及同事(Tissier R et al.,CardiovascularToxicology 2005,5(1):43-51)揭示了在接受长期(慢性)临床匹莫苯疗法的两只狗中，不良反应加剧了二尖瓣反流和心肌肥大。
Amsallem E等人(Cochrane Database SystRev 2005,25:1)发现，磷酸二酯酶抑制剂、尤其诸如匹莫苯，与人类患者中显著升高17％的死亡率相关且此外显著加剧心脏死亡、猝死、心律不整和眩晕。作者得出结论，应避免心力衰竭患者长期使用磷酸二酯酶抑制剂。
Chetboul V和同事(Chetboul V et al.,J Vet Intern Med 2007,21:742-753)显示一项关于在患有轻度退行性无症状二尖瓣疾病的狗中匹莫苯和贝那普利单一疗法的比较性不良心脏作用的前瞻性、对照、盲法且随机研究的结果。
Ouellet M等人(J Vet Intern Med 2009,23:258-263)描述匹莫苯对患有无症状二尖瓣疾病的狗的超声心动图值的影响。然而，此研究未能确定在将匹莫苯加入ACE抑制剂治疗之后在二尖瓣反流的严重程度中的有益长期变化。
因此，本发明背后的目标是提供一种克服如上文所述的先前技术的问题的药物治疗。
发明内容
本发明涉及用于患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭，优选的由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)充血性心力衰竭，更优选的由粘液瘤性二尖瓣疾病(MMVD)所致的无症状(隐发性，临床前)充血性心力衰竭的患者中减小心脏尺寸和/或延迟临床症状的发作，和/或在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者中延迟心力衰竭的发作，优选的在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者中延迟充血性心力衰竭的发作，更优选的患有由粘液瘤性二尖瓣疾病(MMVD)所致的无症状(隐发性，临床前)心力衰竭的患者中延迟充血性心力衰竭的发作的方法中的匹莫苯。在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者中减小心脏尺寸和/或延迟临床症状的发作和/或在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者中延迟(充血性)心力衰竭的发作的相应方法，和用于制备在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者中减小心脏尺寸和/或延迟临床症状的发作和/或在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者中延迟心力衰竭、优选充血性心力衰竭的发作的药物组合物/药剂的用途也意指在本发明的范畴内。
本发明进一步涉及用于患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭，优选的由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)充血性心力衰竭，更优选的由粘液瘤性二尖瓣疾病(MMVD)所致的无症状(隐发性，临床前)充血性心力衰竭的患者中减小心脏尺寸和延迟临床症状的发作，和在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者中延迟心力衰竭的发作，优选的在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者中延迟充血性心力衰竭的发作，更优选的患有由粘液瘤性二尖瓣疾病(MMVD)所致的无症状(隐发性，临床前)心力衰竭的患者中延迟充血性心力衰竭的发作的方法中的匹莫苯。在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者中减小心脏尺寸和延迟临床症状的发作和/或在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者中延迟(充血性)心力衰竭的发作的相应方法，和用于制备在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者中减小心脏尺寸且延迟临床症状的发作和在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的患者中延迟心力衰竭、优选充血性心力衰竭的发作的药物组合物/药剂的用途也意指在本发明的范畴内。
根据本发明的匹莫苯的医学用途的优点如下：
-延长未表现出充血性心力衰竭的临床症状的临床前阶段(也称为无症状或隐发性)
-延迟充血性心力衰竭(的临床症状)的发作
-与安慰剂治疗相比提高经治疗患者的存活时间
-改善经治疗患者的生活质量
-与基线(即治疗开始之前)相比减小经治疗患者的心脏尺寸
-改善经治疗患者的心脏功能/输出
-降低患者由心脏原因所致的心源性猝死/安乐死
-降低患充血性心力衰竭的风险
通过全因死亡率分析中在匹莫苯组中观察到的较长存活期，任何先前产生的关于药物的安全性的担忧应得以减轻。在所观察到的可能不良事件的等级或类型中，各组之间不存在差异。尽管事实是匹莫苯组中的狗在研究中花费了较长时间，且因此在较长时间段处于经历不良事件的风险中。
发明详述
在进一步详细描述本发明的实施例之前，应注意的是如本文和附加的权利要求中所使用，除非上下文清楚地另有规定，否则单数形式“一(a)”、“一(an)”和“该(the)”包括复数指代。
除非另有定义，否则本文中所用的所有技术及科学术语具有与本发明所属领域的一般技术人员通常所理解的相同的含义。除非另外规定或本领域技术人员另外已知的，否则所有给出的范围和值可以1至5％的变化，因此，在说明书和权利要求中通常省略术语“约(about)”。尽管可使用与本文所述类似或等同的任何方法和材料来实践或测试本发明，但现描述了优选的方法、设备和材料。出于描述和公开如在可结合本发明使用的出版物中所报道的物质、赋形剂、载剂和方法的目的，本文提及的所有出版物通过引用并入本文中。不应将本文中的任何内容解释为承认本发明无权凭借先前发明而先于此公开内容。
如上文和下文所用术语“患者”是指患有(充血性)心力衰竭的动物或人。术语“患者”涵盖哺乳动物，诸如灵长类，包括人类。除灵长类之外，各种其他哺乳动物可根据本发明的方法治疗。例如，可治疗哺乳动物，包含但不限于：马、狗、猫、或马科(equine)、犬类、猫类(feline)物种。优选的是人类患者、狗、猫和马。人类患者是患有心力衰竭的女性或男性人员。通常，此类人员是儿童、青壮年、成人或老年人，其年龄在6岁与80岁之间，优选地在30岁与65岁之间。最优选的是狗。
如上文和下文所用术语“心力衰竭”，优选“充血性心力衰竭”，是指任何心脏收缩病症或疾病。临床表现通常为心脏细胞和分子组分的变化和驱动体内自稳调节的介质的变化的结果。心力衰竭，优选充血性心力衰竭，通常伴随着心脏尺寸的增大和心脏功能的退化。
如上文和下文所用的术语“心脏尺寸减小”是指患者的心脏尺寸减小，其是使用超声波心动描记述诊断且可根据由James W.Buchanan等人(Buchanan JW et al.,J Am VetMed Assoc 1995,206(2),194-199)提出的放射照相方法来测定且以椎体心脏尺寸的相对变化表示。优选地，相比于基线，即在匹莫苯治疗开始之前，优选地用匹莫苯治疗10至100天内，甚至更优选30至40天内，最优选35天内，该患者的相对心脏尺寸减小至少5％，优选至少10％、15％、20％、25％或至少30％。
如上文和下文所用术语“由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)(充血性)心力衰竭”是指由于/继发于MVD，但尚无任何(充血性)心力衰竭的临床症状的任何心脏收缩病症或疾病。特别是，其是指ISACHC I级(IA级和/或IB级)、NYHA I级和ACVIM B2阶段的心力衰竭。
术语“延迟临床症状的发作”和“延长在临床症状发作前的时间”在上文和下文中可互换地使用，且是指自诊断出患者的心脏形态变化起至由二尖瓣疾病(MVD)所致的心力衰竭、优选充血性心力衰竭的临床症状开始之间的时间段。特别是，其是指延长自ISACHC I级(IA级和/或IB级)、NYHA I级和ACVIM B2阶段的仍无症状(隐发性，临床前)心力衰竭至ISACHC II级且进一步至III级(IIIA级和/或IIIB级)、NYHA II级、III级和IV级及ACVIM C阶段和D阶段的临床上明显心力衰竭，优选充血性心力衰竭的时间。
为了本发明过程中无歧义，医学适应症术语“二尖瓣疾病(MVD)”、“粘液瘤性二尖瓣疾病(MMVD)”、“慢性心脏瓣膜病(CVHD)”、“慢性瓣膜病(CVD)”和“心房心室瓣膜功能不全(AVVI)”全部可互换地使用。至于ISACHC I级(IA级和/或IB级)、NYHA I级和ACVIM B2阶段心力衰竭，其全部彼此同义且具有相同的医学含义。
如上文和下文所用术语“降低达到充血性心力衰竭的风险”是指经历临床上明显心力衰竭、优选充血性心力衰竭的相对风险。优选地，相对风险减小了至少5％，优选至少10％、15％、20％、25％或至少30％。
如本文所用术语“有效量”意指在以单一剂型施用匹莫苯时，足以实现在患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭(HF)的患者中减小心脏尺寸和/或实现在患有由MVD所致的无症状(隐发性，临床前)HF的患者中延迟临床症状的发作和/或达成在患有由MVD所致的无症状(隐发性，临床前)HF的患者中延迟心力衰竭、优选充血性心力衰竭的发作的量。
在一方面中，本发明涉及根据上文和下文所公开的方面和优选的实施方案使用的匹莫苯，其中由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭，优选由二尖瓣疾病MVD所致的无症状(隐发性，临床前)充血性心力衰竭，更优选由粘液瘤性二尖瓣疾病(MMVD)所致的无症状(隐发性，临床前)充血性心力衰竭是ISACHC I级、较佳ISACHC IA级或IB级的阶段，更更优选是ISACHC IB级、NYHA I级和ACVIM B2阶段的阶段。
在另一方面中，本发明涉及根据上文和下文所公开的方面和优选的实施方案使用的匹莫苯，其中匹莫苯治疗实现患者的已病理性增大的心脏的心脏尺寸减小。换言之，此类患者患有ISACHC I级(IA级和/或IB级)、NYHA I级和ACVIM B2阶段的由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭且已具有病理性增大的心脏(例如借助于超声波心动图可见)，但尚未显示心力衰竭，优选充血性心力衰竭的任何临床症状。
在另一方面中，本发明涉及根据上文和下文所公开的方面和优选的实施方案使用的匹莫苯，其中匹莫苯治疗与安慰剂治疗或非匹莫苯治疗相比，匹莫苯实现患者的生存时间延长。就此而言，非匹莫苯治疗是指一种比较治疗，其中对应的患者组接受除匹莫苯之外的代替匹莫苯或安慰剂的有效药物成分。优选地，与安慰剂治疗或非匹莫苯治疗相比，此匹莫苯治疗实现患者的生存时间延长至少30天，更优选至少2个月，甚至更优选至少3个月，甚至更优选至少4个月，甚至更优选至少5个月，甚至更优选至少6个月，甚至更优选至少7个月，甚至更优选至少8个月，甚至更优选至少9个月，甚至更优选至少10个月，甚至更优选至少11个月，甚至更优选至少12个月，甚至更优选至少13个月，甚至更优选至少14个月，甚至更优选至少15个月。
在另一方面中，本发明涉及根据上文和下文所公开的方面和优选的实施方案使用的匹莫苯，其中匹莫苯治疗实现未表现出充血性心力衰竭的临床症状的临床前阶段的延长，实现充血性心力衰竭的(临床症状的)发作的延迟，与安慰剂治疗相比增加经治疗患者的生存时间，改善经治疗患者的生活质量，与基线(即治疗开始之前)相比引起经治疗患者的心脏尺寸减小，改善经治疗患者的心脏功能/输出，减少患者的由心脏原因所致的心源性猝死/安乐死和/或降低患充血性心力衰竭的风险。
在另一方面中，本发明涉及根据上文和下文所公开的方面和优选的实施方案使用的匹莫苯，其中患者是哺乳动物，优选人类、狗、猫或马，最优选狗。
当然，匹莫苯的给药方案将取决于已知因素，诸如药效学特征和其模式和施用途径；接受者的物种、年龄、性别、健康、医学病况和体重；症状的性质和程度；并行治疗的种类；治疗的频率；施用途径、患者的肾和肝功能以及所期望的效果。医师或兽医可确定预防、对抗、延迟或遏止病症的进展所需的药物有效量且开具该有效量药物的处方。
经由一般指导，当用于指示效果时，匹莫苯的每日口服剂量将在约0.2mg/kg至0.6mg/kg体重SID之间的范围，特别是每天施用匹莫苯范围自0.2mg/kg至0.6mg/kg(EU)和每天施用匹莫苯0.5mg/kg(US)。优选地，每日匹莫苯剂量是以两个0.1mg/kg至0.3mg/kg体重的剂量每12小时施用，优选地两个0.1mg/kg至0.3mg/kg体重的剂量每12小时(EU)，更优选两个0.25mg/kg体重的剂量每12小时(USA)施用。
在另一方面中，本发明涉及根据上文和下文所公开的方面和优选的实施方案使用的匹莫苯，其中匹莫苯以0.2mg/kg至0.6mg/kg体重SID的每日剂量施用，特别是以每日0.2mg/kg至0.6mg/kg体重施用匹莫苯(EU)和以每日0.5mg/kg体重施用匹莫苯(US)。优选地，匹莫苯每日剂量是以两个0.1mg/kg至0.3mg/kg体重的剂量每12小时施用，优选地两个0.1mg/kg至0.3mg/kg体重的剂量每12小时(EU)，更优选两个0.25mg/kg体重的剂量每12小时(USA)施用。
根据本发明的另一方面，匹莫苯与至少一种第二活性药物成分(API)组合施用。此至少一种第二API优选地选自由以下组成的组：后负荷减缓剂(动脉扩张剂)例如ACE抑制剂、前负荷减缓剂(静脉扩张剂)例如利尿剂、血小板抑制剂、β阻断剂和血管紧张素II拮抗剂、醛固酮拮抗剂、抗心律不齐试剂(若出现心律不齐)和/或利尿剂，特别是，
-其中ACE抑制剂选自由以下组成的组：奥马曲拉(omapatrilat)、MDL100240、阿拉普利(alacepril)、贝那普利、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)、醋酸肌丙抗增压素(saralasinacetate)、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)和/或螺普利(spirapri)；和/或
-其中后负荷减缓剂(动脉扩张剂)选自由以下组成的组：联胺肼、钙离子通道阻断剂地尔硫卓(diltiazem)、维拉帕米(verapamil)和氨氯地平(amlodipine)、硝普盐(nitroprusside)和磷酸二酯酶抑制剂，例如昔多芬(sildenafil)；和/或
-其中β阻断剂选自由以下组成的组：比索洛尔(bisoprolol)、卡维洛尔(carvedilol)、美托洛尔(metoprolol)、普萘洛尔(propranolol)、阿替洛尔(atenolol)、艾司洛尔(esmolol)、和/或噻吗洛尔(timolol)；和/或
-其中血小板抑制剂选自由以下组成的组：阿司匹林(aspirin)、氯吡格雷(clopidogrel)、Xa因子抑制剂、肝素及低分子量肝素；和/或
-其中血管收缩素II拮抗剂选自由以下组成的组：乙酸色拉新、坎地沙坦(candesartan)、沙坦西(cilexetil)、缬沙坦(valsartan)、坎地沙坦、洛沙坦(losartanpotassium)、依普罗沙坦(eprosartan)、依贝沙坦(irbesartan)、他索沙坦(tasosartan)、泊米沙坦(pomisartan)和/或替米沙坦(telmisartan)；和/或
-其中醛固酮拮抗剂选自由以下组成的组：螺内酯、胺苯喋啶(triampterene)、依普利酮(eplerenone)、坎利酮(canrenone)、坎利酮钾(potassiumcanrenone)；和/或
-其中抗心律不整剂选自由以下组成的组：胺碘酮(amiodarone)、溴苄胺(bretylium)、丙吡胺(disopyramide)、多非利特(dofetilide)、氟卡尼(flecainide)、伊布利特(ibutilide)、美西律(mexiletine)、妥卡尼(tocainide)、普鲁卡因胺(procainamide)、利多卡因(lidocaine)、普罗帕酮(propafenone)、地尔硫卓、维拉帕米(verapamil)、地高辛(digoxin)、洋地黄(digitalis)、奎尼丁(quinidine)和/或索他洛尔(sotalol)；和/或
-其中利尿剂选自由以下组成的组：呋喃苯胺酸(furosemide)、螺内酯、托拉塞米(torasemide)、布美他尼(bumetanide)、依他尼酸(etacrynicacid)、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、氢氯噻嗪、氢氟噻嗪、甲基氯噻嗪、多噻嗪、三氯甲噻嗪、氯噻酮(chlorthialidone)、吲达帕胺(indapamide)、美托拉宗(metolazone)、喹乙唑酮(quinethazone)、乙氧唑啉(etozolin)、胺苯喋啶(triamterene)、和/或阿米洛利(amiloride)；和/或
-其中前负荷减缓剂(静脉扩张剂)选自由硝化甘油、硝普盐及异山梨酯(isorbide)组成的组；和/或
-其中正性肌力药选自由以下组成的组：多巴酚丁胺、地高辛、洋地黄、多巴胺、氨利酮(amrinone)及米利酮(milrinone)；和/或
-其中超极化活化的环核苷酸门控(HCN)通道阻断剂或负性变时试剂选自由西洛雷定(cilobradine)、伊伐布雷定(ivabradine)和腺苷组成的组。
优选地，匹莫苯与一种或多种选自由一或多种ACE抑制剂和一种或多种利尿剂组成的组的API一起施用。
在另一方面中，本发明涉及根据上文和下文所公开的方面和优选的实施方案使用的匹莫苯，其中匹莫苯在施用一种或多种额外的活性药物成分之前、期间或之后施用，该一种或多种额外的活性药物成分选自由ACE抑制剂，优选贝那普利；和利尿剂，优选呋喃苯胺酸组成的组。更优选地，匹莫苯与贝那普利和呋喃苯胺酸附随地施用。
匹莫苯可以如片剂、咀嚼片剂、咀嚼片、胶囊(其中每种包括持缓释或定时释放制剂)、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液、溶液、糖浆和乳剂的口服剂型施用。其还可以静脉内(快速注射或输注)、腹膜内、皮下或肌肉内形式施用，所有使用的剂型为本领域普通技术人员所熟知。其可以单独施用，但通常会与基于所选施用途径和标准药学实践选择的药物载剂施用。
在另一方面中，本发明涉及根据上文和下文所公开的方面和优选的实施方案使用的匹莫苯，其中匹莫苯经口服或非肠道施用，优选口服，更优选以片剂或胶囊形式口服，最优选以片剂形式。
匹莫苯可经由局部使用适合的鼻内媒剂以鼻内形式施用，或使用经皮皮肤贴剂经由经皮途径施用。当然，当以经皮递送系统形式施用时，剂量施用将在整个给药方案中是连续而非间断的。
匹莫苯通常以与根据预期施用形式(即口服片剂、胶囊、酏剂、糖浆等)适当选择的且与常规药学实践一致的适合的药物稀释剂、赋形剂和/或载剂(在本文中统称为药物载剂)的添加物形式施用。
例如，对于以片剂或胶囊形式口服施用，活性药物组分可与以下口服、无毒、药学可接受的惰性载剂组合，诸如乳糖、淀粉、蔗糖、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、硫酸钙、甘露醇、山梨醇等；对于以液体形式口服施用，口服药物组分可与以下任何口服、无毒的药学可接受的惰性载剂组合，诸如乙醇、甘油、水等。此外，当需要或必要时，还可将适合的粘合剂、润滑剂、崩解剂和着色剂并入混合物中。适合的粘合剂包括淀粉、明胶、天然糖(如葡萄糖或β-乳糖)、玉米甜味剂、天然及合成树胶(诸如阿拉伯树胶、黄蓍胶或海藻酸钠)、羧甲基纤维素、聚乙二醇、蜡等。用于这些剂型种的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、皂土、黄原胶等。
匹莫苯还可以脂质体递送系统的形式施用，诸如小单层囊泡、大单层囊泡和多层囊泡。脂质体可由多种磷脂如胆固醇、硬脂胺或磷脂酰胆碱形成。
匹莫苯还可以脂质包衣形式作为固体药物制剂的一部分施用(参见例如WO 2015/082389)。
匹莫苯还可结合可溶性聚合物作为靶向药物载剂。此聚合物可包括经棕榈酰残基取代的聚乙烯吡咯啶酮、哌喃共聚物、聚羟基丙基甲基丙烯酰胺苯酚、聚羟乙基天冬酰胺苯酚或聚氧化乙烯聚离胺酸。
此外，匹莫苯可结合以下适用于实现药物控制释放的一类可生物降解聚合物，例如，聚乳酸、聚乙醇酸、聚乳酸和聚乙醇酸的共聚物、聚ε己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢哌喃、聚氰基丙烯酸酯、和水凝胶的交联或两亲嵌段共聚物。
适合施用的剂型(药物组合物)每剂量单位可含有约1毫克至约100毫克的活性成分。
在这些药物组合物中，活性成分通常将以基于组合物的总重量的约0.5-95％的量存在。
明胶胶囊可包括活性成分和粉末状载剂，例如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸等。相似稀释剂可用于制造压缩片。片剂和胶囊二者都可制造为缓释产物以提供药物经数小时时间段内的连续释放。压缩片可以是糖包衣或薄膜包衣以掩盖任何令人不愉快的味道且保护片剂不受空气影响，或肠溶包衣以便在胃肠道中选择性崩解。
用于口服施用的液体剂型可包括着色剂和调味剂以提高患者接受度。一般而言，水、适合的油、生理盐水、水性右旋糖(葡萄糖)和相关糖溶液和二醇类(例如丙二醇或聚乙二醇)是用于非肠道溶液的合适载剂。用于非肠道施用的溶液优选地包括活性成分的水溶性盐、合适的稳定剂和(若需要)缓冲物质。单独或组合的抗氧化剂，例如亚硫酸氢钠、亚硫酸钠或抗坏血酸，是适合的稳定剂。还使用柠檬酸及其盐和EDTA钠。此外，非肠道溶液可包括防腐剂，例如氯化苯甲烃铵、对羟基苯甲酸甲酯或丙酯和氯丁醇。
适合的药物载剂描述于本领域的标准参考文献Remington's PharmaceuticalSciences,Mack Publishing Company中。
在上述第二API中的两种或以上与匹莫苯一起施用时，鉴于当组合施用时API的添加或协同效应，典型的每日剂量和典型剂型中的各组分的量通常相对于单独施用API的常规剂量时可减少。
特别地，当以单一剂量单位形式提供时，组合的API之间可能存在化学相互作用。出于此原因，当匹莫苯与至少一种第二API以单一剂量单位形式组合时，配制它们，使得虽然各API组合在单一剂量单位中，但API之间的物理接触是最小化的(即减少的)。例如，一种API可以是肠溶包衣的。通过肠溶包衣的一种API，不仅可能使组合的各API之间的接触最小化，而且可能控制这些组分之一在胃肠道中的释放，使得这些组分之一不在胃中释放，而是在肠道中释放。一种API还可由实现在整个胃肠道中持续释放且还使组合的API之间的物理接触最小化的材料包衣。
此外，缓释组分可以额外地肠溶包衣，使得此组分的释放仅在肠道中发生。另一方法将涉及组合产品的制剂，其中一种组分由缓释和/或肠溶释放聚合物，且另一组分也由例如低粘度级别的羟丙基甲基纤维素(HPMC)的聚合物或本技术领域中已知的其他适合材料包衣，以便进一步隔开活性组分。聚合物包衣用以形成针对与另一组分相互作用的额外屏障。
实施例
以下实例用以进一步说明本发明；但不应将其视为对本文所公开的本发明的范围的限制。
实施例1-期间分析数据
先前研究已表明匹莫苯治疗显著降低患有CHF的狗中病死率和发病率。匹莫苯治疗在延迟狗的由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭进展的潜在益处尚未阐明。匹莫苯是具有强效正性心肌收缩和血管舒张作用的苯并咪唑哒嗪酮。此前负荷和后负荷减小的组合作用连同正性心肌收缩支持使得患有由二尖瓣疾病所致的隐发性心力衰竭的狗的心脏的心脏尺寸和充盈压力减小。
向患有由二尖瓣疾病(MVD)所致的无症状(隐发性，临床前)心力衰竭的狗施用匹莫苯，充血性心力衰竭的临床征兆的发作前的时间与安慰剂相比延长约359天(12.0个月)且生存时间(全因死亡率)与安慰剂相比延长约168天(5.6个月)。因此，用匹莫苯治疗处于心力衰竭的临床前期的狗产生改善性结果。
实施例2-最终研究结果的初步分析
360只狗的盲法、安慰剂对照研究的最终结果的初步分析显示，向患有MMVD且具有心脏增大的超声波心动图和放射照相证明的狗施用匹莫苯引起临床前时间段的延长且其是安全和良好耐受的。
在匹莫苯组中达到主要终点的中值时间是1228天(95％CI 856NA)且在安慰剂组中是766天(95％CI 667-875)(P＝0.0038)。临床前时间段延长约15个月代表实质性临床益处。
如由全因死亡率所确定，匹莫苯组的总存活期亦显着长于安慰剂组(P＝0.012)，且这也代表着临床益处。
在研究的最初35天内量测时，与安慰剂组相比，匹莫苯还引起心脏尺寸减小(P＜0.0001)。
同时，最终研究结果已经发表(Boswood A et.al.,J Vet Intern Med 2016,30(6):1765-1779)。
实施例3-心脏尺寸的减小
椎体心脏总和，另一种心脏尺寸的测量，是从研究中的那些动物每隔8个月定期获得的。各组间比较各种方法。在研究期间用于概括和比较各组中平均椎体心脏得分的最有用方法是产生“曲线下面积”值，其代表每只狗的单一概括统计数值，从中获得两次以上的测定值[Matthews JN et al.,BMJ 1990,300(6719):230-235]。此方法在先前用于兽医研究中。
当在研究期间计算两组中狗的平均椎体心脏得分且在组间比较时，获得下列结果。
因此，由此可见，研究中狗的椎体心脏得分中位数大约为0.35椎骨，低于接受匹莫苯的狗(表1)。因此，超声心动图结果显示心脏尺寸的严重减小，这在一个月后是明显的。射线照相的发现指示当心脏尺寸的测定在研究期间平均化时心脏尺寸的差别仍然存在。
表1
参考文献
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Claims (46)
1.匹莫苯在药物制备中的用途，所述药物用于在患有由粘液瘤性二尖瓣疾病(MMVD)所致的无症状(隐发性，临床前)心力衰竭的患者中减小心脏尺寸和延迟临床症状的发作，其中该匹莫苯治疗实现减小该患者的已病理性扩大的心脏的心脏尺寸与延迟该患者中的心力衰竭的临床症状的发作，以及与安慰剂治疗或非匹莫苯治疗相比，延长该患者的生存时间的组合。
2.根据权利要求1的用途，其中该由粘液瘤性二尖瓣疾病(MMVD)所致的无症状(隐发性，临床前)心力衰竭属于ISACHCI级阶段。
3.根据权利要求2的用途，其中该无症状(隐发性，临床前)心力衰竭属于ISACHCIA级或IB级阶段。
4.根据权利要求2的用途，其中该无症状(隐发性，临床前)心力衰竭属于ISACHC IB级、NYHA I级和ACVIM B2阶段的阶段。
5.根据权利要求1的用途，其中相比于基线，即在匹莫苯治疗开始之前，在用匹莫苯治疗10至100天内，该匹莫苯治疗实现减小该患者的已病理性扩大的心脏的心脏尺寸。
6.根据权利要求5的用途，其中在用匹莫苯治疗30至40天内，该匹莫苯治疗实现减小该患者的已病理性扩大的心脏的心脏尺寸。
7.根据权利要求5的用途，其中在用匹莫苯治疗约35天内，该匹莫苯治疗实现减小该患者的已病理性扩大的心脏的心脏尺寸。
8.根据权利要求5的用途，其中该心脏尺寸减小至少5％。
9.根据权利要求5的用途，其中该心脏尺寸减小至少10％。
10.根据权利要求5的用途，其中该心脏尺寸减小至少15％。
11.根据权利要求5的用途，其中该心脏尺寸减小至少20％。
12.根据权利要求5的用途，其中该心脏尺寸减小至少25％。
13.根据权利要求5的用途，其中该心脏尺寸减小至少30％。
14.根据权利要求1的用途，其中该匹莫苯治疗与安慰剂治疗或非匹莫苯治疗相比，实现该患者的生存时间延长至少30天。
15.根据权利要求14的用途，其中该患者的生存时间延长至少2个月。
16.根据权利要求14的用途，其中该患者的生存时间延长至少3个月。
17.根据权利要求14的用途，其中该患者的生存时间延长至少4个月。
18.根据权利要求14的用途，其中该患者的生存时间延长至少5个月。
19.根据权利要求14的用途，其中该患者的生存时间延长至少6个月。
20.根据权利要求14的用途，其中该患者的生存时间延长至少7个月。
21.根据权利要求14的用途，其中该患者的生存时间延长至少8个月。
22.根据权利要求14的用途，其中该患者的生存时间延长至少9个月。
23.根据权利要求14的用途，其中该患者的生存时间延长至少10个月。
24.根据权利要求14的用途，其中该患者的生存时间延长至少11个月。
25.根据权利要求14的用途，其中该患者的生存时间延长至少12个月。
26.根据权利要求14的用途，其中该患者的生存时间延长至少13个月。
27.根据权利要求14的用途，其中该患者的生存时间延长至少14个月。
28.根据权利要求14的用途，其中该患者的生存时间延长至少15个月。
29.根据权利要求1的用途，其中该匹莫苯治疗实现未表现出充血性心力衰竭的临床症状的临床前阶段的延长，实现充血性心力衰竭的临床症状的发作延迟，与安慰剂治疗相比提高了经治疗患者的存活时间，改善经治疗患者的生活质量，引起经治疗患者的心脏尺寸与基线相比减小，改善经治疗患者的心脏功能/输出，减少患者的由心脏原因所致的心源性猝死/安乐死和/或降低达到充血性心力衰竭的风险。
30.根据权利要求1的用途，其中该患者是哺乳动物。
31.根据权利要求30的用途，其中该患者是人类、狗、猫或马。
32.根据权利要求30的用途，其中该患者是狗。
33.根据权利要求1的用途，其中匹莫苯以每日剂量0.2mg/kg至0.6mg/kg体重施用。
34.根据权利要求33的用途，其中匹莫苯以每日剂量0.5mg/kg体重施用。
35.根据权利要求33的用途，其中该匹莫苯每日剂量按两个0.1mg/kg至0.3mg/kg体重的剂量施用。
36.根据权利要求35的用途，其中该匹莫苯每日剂量按两个0.1mg/kg至0.3mg/kg体重的剂量每12小时施用。
37.根据权利要求35的用途，其中该匹莫苯每日剂量按两个0.25mg/kg体重的剂量每12小时施用。
38.根据权利要求1的用途，其中匹莫苯口服或非肠道施用。
39.根据权利要求38的用途，其中匹莫苯口服施用。
40.根据权利要求38的用途，其中匹莫苯以片剂或胶囊形式口服施用。
41.根据权利要求38的用途，其中匹莫苯以片剂形式口服施用。
42.根据权利要求1的用途，其中在施用选自ACE抑制剂和利尿剂中的一种或多种额外活性药物成分之前、期间或之后，施用匹莫苯。
43.根据权利要求42的用途，其中该ACE抑制剂为贝那普利(benazepril)。
44.根据权利要求42的用途，其中该利尿剂为呋喃苯胺酸。
45.根据权利要求42的用途，其中匹莫苯与贝那普利和/或呋喃苯胺酸附随地施用。
46.根据权利要求45的用途，其中匹莫苯与贝那普利和呋喃苯胺酸附随地施用。
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| Application Number | Priority Date | Filing Date | Title |
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| EP16164041 | 2016-04-06 | ||
| EP16164041.2 | 2016-04-06 | ||
| EP16172394.5 | 2016-06-01 | ||
| EP16172394 | 2016-06-01 | ||
| PCT/EP2017/057970 WO2017174571A1 (en) | 2016-04-06 | 2017-04-04 | Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
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| CN109069507A CN109069507A (zh) | 2018-12-21 |
| CN109069507B true CN109069507B (zh) | 2022-08-12 |
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