CN1440287A - 治疗外周血管疾病、外周神经病和自主神经病的方法 - Google Patents
治疗外周血管疾病、外周神经病和自主神经病的方法 Download PDFInfo
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- CN1440287A CN1440287A CN01812103A CN01812103A CN1440287A CN 1440287 A CN1440287 A CN 1440287A CN 01812103 A CN01812103 A CN 01812103A CN 01812103 A CN01812103 A CN 01812103A CN 1440287 A CN1440287 A CN 1440287A
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及一种通过给予cGMP PDE5抑制剂例如西地那非治疗外周血管疾病、外周神经病或自主神经病的方法。该方法特别适合于患有糖尿病性足部溃疡、Raynaud现象、肢端硬皮综合征、红细胞增多症、类风湿病、糖尿病性视网膜病和甲癣的患者。根据本发明，cGMP PDE5抑制剂可以作为预防剂施用于易形成外周血管疾病、外周神经病或自主神经病的患者。
Description
交叉参考的相关申请
本申请请求U.S.临时申请号60/215,065(2000年6月30日提交)和U.S.临时申请号60/219,029(2000年7月18日提交)的优先权，两者题目均为″治疗糖尿病性溃疡的方法″，两者的内容在此全文引入作为参考。
发明领域
本发明涉及3’，5’-环鸟苷酸V型(cGMP PDE5)抑制剂(包括化合物西地那非)在与外周血管疾病、外周神经病、自主神经病有关的疾病，特别是与糖尿病有关的疾病的治疗中的用途。
发明背景
与外周血管疾病和自主神经病有关的疾病多种多样但其慢性病理症状是一致的，而且难以治愈。许多此类疾病与糖尿病有关联。虽然不十分了解其它的此类疾病是否与糖尿病有关，但它们在对外周血管系统的生理学作用上是相似的。此类疾病包括：包括肢端硬皮综合征(CREST综合征)在内的Raynaud现象，自身免疫疾病，例如红细胞增多症、类风湿病，和糖尿病性视网膜病。
糖尿病是一种严重且普遍的慢性疾病。研究预测1996年全球糖尿病流行的一亿两千万人将在2025年倍增至两亿五千万，这主要归因于老龄化、肥胖、久坐的生活方式和饮食结构的变化。许多严重和昂贵的并发症影响着患有糖尿病的个体，包括心脏病、肾衰和失明。然而，足并发症付出的代价最高。可以肯定所有下肢截肢的40-70％与糖尿病有关。此外，与糖尿病有关的下肢截肢总数的约85％是先发生足部溃疡。
糖尿病患者处于恶化出现一种或多种足部溃疡的高危状态下，这是由该疾病形成的长期并发症导致的，其包括受损的神经官能(神经病)和/或局部缺血。
局部组织缺血是导致糖尿病性足部溃疡的关键因素。除了大血管疾病以外，糖尿病患者在其皮肤灌注上受到至少两种其它途径产生的威胁。首先，涉及非管状动脉的途径，其通过动脉粥样硬化进程产生有害影响。其次，并且也许是更重要的，通过损害微循环控制机制(小血管疾病)的途径。通常，当机体部分遭受某些形式的创伤时，作为机体愈合机制，机体部分将经历增加血流量。当出现小血管疾病和局部缺血时，在许多糖尿病情况中，这种自然增加的血流明显减少。该事实，连同糖尿病患者在微循环系统中低水平的血流期间形成血栓(血栓形成)的趋势一起，被认为是溃疡发病机理的重要因素。
神经病是糖尿病的另一种主要并发症。目前还没有成熟的治疗用于其症状性治疗或用于预防神经机能的进行性衰退。据估计在糖尿病中神经病的流行率变化多样，从低的5％到高的80％，主要归因于对神经病的多种定义和临床描述。然而，糖尿病患者中神经病的加合效应是公知的并且已见报导。
神经病的作用很复杂。足部源感觉信息的丧失与足部区域上异常且持续的压力有关(感觉神经病)。运动神经病导致畸形，进一步增高足部承受的压力。在自主神经病中，汗腺神经支配的丧失导致皮肤干燥，其裂缝为感染侵入提供了环境条件。微循环血流的分布改变进一步导致自主机能障碍，使血流定向经过分路并离开营养型皮肤毛细管。就整体而言，这些因素，结合足部创伤，导致皮肤破裂和溃疡。
科学家迄今没有确定糖尿病中导致神经损伤的机理，但可以肯定是由多因素造成的。这些因素包括遗传素质，代谢和血管异常，以及缺乏生长因子的微扰。外周神经系统对糖尿病的代谢作用的应答在I型和II型糖尿病之间似乎没有差异，它暗示这两种主要形式的糖尿病对治疗具有相似临床应答的可能性。对于神经病的恶化，似乎存在许多敏感性因子，但人们仍然不了解，这些因子在血糖过多(高血糖)存在下运转。
科学家已经发现神经局部缺血涉及神经传导的发病机理。在试验糖尿病性神经病中，该领域的医师已经得出理论，降低一氧化氮(NO)水平可以导致神经血流减少。NO是一种具有宽谱代谢功能的短寿命原子团，包括血管紧张度的介导。NO的作用是由环鸟苷酸(cGMP)介导的。许多治疗性干预，全部都是提高NO的水平，已经显示出可以在导致NO水平降低的试验糖尿病神经病中增加神经血流和神经传导。
cGMP PDE5抑制剂是已知的，例如柠檬酸西地那非，它是竞争性、有效和选择性的cGMP特异性磷酸二酯酶(PDE5)的抑制剂，一种导致cGMP降解的化合物。所以，此类抑制剂化合物提高细胞内一氧化氮衍生cGMP的浓度，由此增强NO的作用，西地那非在雄性勃起机能障碍的治疗中的功效归因于此。
虽然近年来西地那非在勃起机能障碍治疗中的有益效果业已充分报导并公开，但这种化合物在糖尿病足部溃疡中的有效性完全是意外的。洛山矶加州大学的Stanley Korenman博士在男性糖尿病患者中进行的市售(西地那非)产品VIAGRATM(Pfizer)的控制研究的ReutersTM(路透社健康信息(Reuters Health Information)，2000年6月18日)的最新报告表示出用于勃起机能障碍治疗中的西地那非在糖尿病患者中应用的兴趣。然而，不曾报告过关于cGMP PDE5抑制剂在糖尿病足部溃疡治疗中的兴趣或关注。
发明概述
令人惊奇地，本发明人发现在治疗男性糖尿病患者的勃起机能障碍中，那些还患有慢性、不愈合足部溃疡的患者其足部溃疡获得意外、快速和完全的愈合。反复将该抑制化合物施用于其它糖尿病患者，他们中的一些患有长达一年的不愈合足部溃疡，同样获得令人惊奇的结果。在治疗其它与外周血管疾病有关的病症中也发现相似的惊奇结果。
显然，此类抑制剂化合物的使用对患有糖尿病性足部溃疡的患者是一种非常有效的治疗。已知血管内皮释放NO并通过松弛血管平滑肌来调节局部血流。这种体系在糖尿病中被破坏，因此升高一氧化氮衍生cGMP的细胞内浓度(参见例如西地那非)被认为可以逆转患有糖尿病性足部溃疡患者的微血管病变，从而提高愈合速率。而本发明不受本发明的生理机制的这种理论局限，本发明人相信这样的机理，就是本发明人的西地那非给药可以增加溃疡四肢的供血并由此提高糖尿病性足部溃疡的愈合速率。
因此，本发明的一个目的是提供一种治疗患有糖尿病性溃疡的患者的方法，其包括用有效量的cGMP PDE5抑制剂或其药物组合物治疗该患者。
本发明的另一目的是为那些易感染糖尿病性溃疡的患者提供一种预防方法，并由此挽救许多糖尿病患者免遭有害作用和通常由糖尿病性足部溃疡导致的截肢的可能。
此外，cGMP PDE5抑制剂或其药物组合物还可以与其它现在或者可能在将来用于上述病症治疗的治疗剂或疗法组合。
本发明还提供cGMP PDE5抑制剂在制备用于糖尿病性溃疡治疗的组合物中的用途。
本发明的概念内还包括治疗外周血管疾病，例如Raynaud现象，包括肢端硬皮综合征；自身免疫疾病，例如全身性红斑狼疮、类风湿病和糖尿病性视网膜病。
本发明还将有益于外周和自主神经病或者任何由微血管疾病和直接大血管疾病导致的其它疾病实体。
本发明的另一目的是指甲的甲癣(onychiomycosis)(真菌)感染的治疗。
许多有效和选择性cGMP PDE5抑制剂是已知的且其活性很容易按照公开方法通过对多种来源的cGMP PDE酶的体外筛选来鉴定。因此，例如，在EPO 0463756，EPO 0526004，WO93/12095，WO94/05661，WO94/00453，WO95/19978和WO98/49166中描述了多种吡唑并嘧啶酮类化合物是cGMP PDE5抑制剂，这些文献的全部内容在此引入作为参考。
本发明可以使用的一些cGMP-PDE5抑制剂包括，例如，5-(2-乙氧基-5-吗啉乙酰基苯基)-1-甲基-3-正丙基-1-6-二氢-7H-20吡唑并[4，3-d]嘧啶-7-酮；5-(5-吗啉乙酰基-2-正丙氧基苯基)-1-甲基-3-正丙基-1-，6-二氢-7H吡唑并[4，3-d]嘧啶-7-酮；5-[2-乙氧基-5-(4-甲基-1-哌嗪-1-基-磺酰基)-苯基]-1，6-二氢-1-甲基-3丙基吡唑并[4，3-d]嘧啶-7-酮；5-[2-烯丙氧基-5-(4-甲基-1-哌嗪基磺酰基)-苯基]-1-甲基-3-正丙基-1，6-二氢7H-吡唑并[4，3-d]嘧啶-7-酮；5-(2-乙氧基-5-[4-(2-丙基)-1-哌嗪基-磺酰基]苯基}-1-甲基-3-正丙基-1，6-二氢-7H吡唑并[4，3-d]嘧啶-7-酮；5-(2-乙氧基-5[4-(2-羟乙基-1-哌嗪基-磺酰基]苯基)-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮；5-(5-[4-(2-羟乙基)-1-哌嗪基磺酰基]-2-n-丙氧基苯基)-1-甲基-3-正丙基-1-，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮；5-[2-乙氧基-5-(4-甲基-1-哌嗪基羰基)-苯基]-1-甲基-3-正丙基-1，6-二氢-7H-吡唑并[4，3-d]嘧啶-7-酮；5-[2-乙氧基-5-(1-甲基-2-咪唑基)苯基]-1-甲基-3-正丙基-1，6-二氢-7H吡唑并[4，3-d]嘧啶-7-酮，3-乙基-5-[5-[4-乙基哌嗪-1-基)磺酰基]-2-(2-甲氧基乙氧基)吡啶-3-基]-2-(2-吡啶基甲基)-6，7-二氢-2H-吡唑并[4，3-d]嘧啶-7-酮，和3-乙基-5-[5-(4-乙基哌嗪-1-基磺酰基)-2-正丙氧基苯基]-2-(吡啶-2-基)甲基-2，6-二氢-7H-嘧啶-7-酮。
本发明业已测定了下列优选化合物5-[2-乙氧基-S-(4-甲基哌嗪-1-基磺酰基)-苯基]-1，6-二氢-1-甲基-3-丙基吡唑并[4，3-d]嘧啶-7-酮(西地那非)，和其药学可接受盐；包括其柠檬酸盐，被发现在与糖尿病有关的足部溃疡治疗中非常有效。
对于已被证明在糖尿病性足部溃疡的治疗中有效的3’，5’-环鸟苷酸V型(cGMP PDE5)抑制剂，包括化合物西地那非在内，的其它用途也属于本发明的治疗其它外周血管疾病例如Raynaud现象(包括肢端硬皮综合征在内)，自身免疫疾病例如全身性红斑狼疮、类风湿病和糖尿病性视网膜病的概念内。本发明的治疗方法还有益于外周和自主神经病或任何其它由小血管疾病和直接大血管疾病导致的其它疾病实体。本发明人还发现当用西地那非治疗时而不使用抗真菌药可以完全治愈甲癣(指甲的真菌感染)，特别是下肢。这种情况的患者请求勃起机能障碍的治疗，并且本发明人发现了这种意外有益效果。本发明人已经在具有外周血管疾病或外周神经病的常规要素的不同疾病中观察到这种结果。该方法的有益效果被认为是归因于提高小血管的血流，这有助于机体本身愈合。
实施例：
1号患者是胰岛素依赖型糖尿病患者，其业已患有勃起机能障碍并且随后患有糖尿病性足部溃疡。在勃起机能障碍的治疗期间，注意到足部溃疡愈合。这种足部溃疡开始于约2年之前并且患者已经通过血管研究，看了血管医生、脚病医生，并且在创伤护理诊所中最好也只获得很低的效果。他还住院约1个月使用IV抗生素等，和非常现实的威胁是该患者需要膝以下截肢。溃疡有时似乎愈合，但只恢复到其预处理的大小和深度。一旦开始使用西地那非治疗其勃起机能障碍时，就注意到溃疡在尺寸上减小，并且指导患者开始每天摄取一次50mg的西地那非。由此在一个月内使糖尿病性足部溃疡完全消散，并且患者在以后2年内持续该治疗没有复发。
2号患者患有外周血管疾病和糖尿病的继发性两条下肢慢性病变。他患有糖尿病并且主诉有勃起机能障碍的麻烦，而一旦开始西地那非治疗，不但其勃起机能障碍明显改善，而且其外周血管疾病和糖尿病的继发性两条下肢的慢性病变也显著改善或者完全消散。
3号患者患有动脉硬化继发的严重外周血管疾病。常规治疗例如股骨膝后弯旁路手术、血栓预防支架(umbrella)的手术插入(格林费尔德氏滤器)、肝素的给药和苄丙酮香豆素钠的给药均无法减轻病症。使用西地那非治疗勃起机能障碍而患者在密切检测下发现动脉硬化病症有所改善。
4号患者患有勃起机能障碍。他还患有甲癣(指甲的真菌感染)。他被指导根据需要接受西地那非治疗摄取一丸50mg。通过该治疗方案其勃起机能障碍得到改善并且意外地治愈真菌感染。
cGMP PDE5抑制剂适宜作为药物组合物给药。因此，所述的化合物可以以任何常规口服、非肠道、直肠或透皮剂型给药，一般与药学可接受载体或稀释剂一起给药。这些给药方法是现有技术公知的并且公开在美国专利号5,520,534；5,346,901；5,719,283；5,272,147；5,426,107；5,482,941；5,591,742；5,734,053；6,025,494；5,859,006中，其全部内容在此引入作为参考。
药物组合物的口服给药可以是溶液、混悬剂、片剂、丸剂、散剂等形式。含有多种赋形剂，例如柠檬酸钠、碳酸钙和磷酸钙的片剂与多种崩解剂，例如土豆淀粉或木薯淀粉，和某些复合硅酸盐，以及粘合剂，例如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶合用。此外，润滑剂例如硬脂酸镁、十二烷基硫酸钠和滑石常常用于压片目的。相似类型的固体组合物也可以在软和硬填充明胶胶囊中用作填充剂；有关的优选材料还包括乳糖或奶糖，以及高分子聚乙二醇。当口服给药需要水混悬液和/或酏剂时，所述的化合物可以与多种甜味剂、矫味剂、着色剂、乳化剂和/或助悬剂，以及吸收剂如水、乙醇、丙二醇、甘油和其多种相似联合形式组合。本发明的概念还包括给予与食品或饮料混合在一起的所述有效化合物。
出于非肠道给药的目的，可以采用存在于油或水丙二醇中的溶液，以及相应水溶性盐的灭菌水溶液。如果必要所述水溶液可以进行适当缓冲，并且液体稀释剂首先用足够的盐水或葡萄糖调至等渗。这些水溶液尤其适合静脉内、肌肉内、皮下和腹膜内注射目的。因此，所用的灭菌含水介质均很容易得自标准技术，其对于所属领域技术人员来说是熟知的。
出于透皮(例如局部)给药的目的，制备稀释灭菌、含水或部分含水的溶液(浓度一般为约0.1％-5％)，或者类似于上述非肠道溶液。在烟碱贴剂和预防晕车的情况中，治疗目的的化合物的透皮给药日益增多，成为一种常规实践。最近，较大分子的透皮使用，例如含在抗原和佐剂的组合物中的那些较大分子，业已被证实有效，公开在美国专利5,910,306和美国专利5,980,898中，其全部内容在此引入作为参考。透皮给药可以通过直接在皮肤上使用来完成，与载体混合，例如油膏或霜剂，或者覆盖或使用贴剂，将其置于患者的皮肤上。
具有一定量活性成分的不同药物组合物的制备方法是所属领域技术人员熟知的，或者可以参考文献中的方法来确定，这是所属领域技术人员可以获得的。
cGMP PDE5抑制剂给药的精确剂量将根据医嘱的具体化合物、被治疗的对象、该病症的严重性、给药方式和主治医生的判断来变化。因此，由于患者与患者之间存在着差异，剂量只是指导性的并且医生可以调整化合物的剂量来获得医生认为适合该患者的有效治疗水平。鉴于预期治疗程度，医生必须平衡多种因素，例如患者的年龄和存在的其它疾病或症状(例如心血管疾病)。通常，cGMP PDE5抑制剂的给药范围是0.5-400mg/天，如美国专利号5,520,534；5,346,901；5,719,283；5,272,147；5,426,107；5,482,941；5,591,742；5,734,053；6,025,494；5,859,006所述，其全部内容均在此引入作为参考。更加具体地，优选的治疗剂量是25-100mg/天，如WO98/49166所述，其全部内容在此引入作为参考。基于上述专利的内容和医师对具体患者健康状况的个人认识，医生应该熟知适合个体的安全和有效的剂量。
对于优选化合物西地那非，有效剂量是5-125mg/天，更优选10-110mg/天并首选25-100mg/天，其可以作为片剂或胶囊每天最多给药3次。然而，精确剂量是由主治医生决定并且应根据患者的年龄和体重以及症状的严重程度来变化，如上所述。
本发明的化合物的有效剂量的给药还可以提供一种有助于预防糖尿病患者的足部溃疡的预防方法。有技能的医生可以利用上述剂量并根据被治疗患者的具体需要开出有效剂量的化合物。
Claims (7)
1.一种治疗选自外周血管疾病、外周神经病和自主神经病类型疾病的方法，该方法包括施用有效量的含有cGMP PDE5抑制剂或其衍生物或盐的药物组合物。
2.权利要求1所述的方法，其中所述疾病选自Raynaud现象、肢端硬皮综合征、红细胞增多症、类风湿病和糖尿病性视网膜病。
3.一种治疗甲癣的方法，该方法包括施用有效量的含有cGMP PDE5抑制剂或其衍生物或盐的药物组合物。
4.一种治疗患有糖尿病性足部溃疡的患者的方法，其包括采用有效量的含有cGMP PDE5抑制剂或其衍生物或盐的药物组合物对所述患者进行治疗。
5.一种预防糖尿病患者形成足部溃疡的方法，该方法包括对所述患者施用有效量的含有cGMP PDE5抑制剂或其衍生物或盐的药物组合物。
6.一种制备糖尿病性足部溃疡治疗剂的方法，该方法包括提供选自cGMP PDE5抑制剂、其衍生物和其盐的有效成分并且将该有效成分与一种适合对患者进行给药的载体混合。
7.权利要求4或5的方法，其中所述的cGMP PDE5抑制剂是西地那非。
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| US21506500P | 2000-06-30 | 2000-06-30 | |
| US60/215,065 | 2000-06-30 | ||
| US21902900P | 2000-07-18 | 2000-07-18 | |
| US60/219,029 | 2000-07-18 |
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| EP (1) | EP1303279A1 (zh) |
| JP (1) | JP2004511433A (zh) |
| KR (1) | KR20030047907A (zh) |
| CN (1) | CN1440287A (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101072870B (zh) * | 2004-10-27 | 2013-01-30 | 巴黎国立医院（Ah-Hp） | 对真性红细胞增多症中jak2突变的鉴定 |
| CN111491630A (zh) * | 2017-12-19 | 2020-08-04 | 马莱西尔研究与技术有限责任公司 | 糖尿病足溃疡的治疗方法 |
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| GB0020588D0 (en) * | 2000-08-21 | 2000-10-11 | Pfizer Ltd | Treatment of wounds |
| US8133903B2 (en) | 2003-10-21 | 2012-03-13 | Los Angeles Biomedical Research Institute at Harbor—UCLA Medical Center | Methods of use of inhibitors of phosphodiesterases and modulators of nitric oxide, reactive oxygen species, and metalloproteinases in the treatment of peyronie's disease, arteriosclerosis and other fibrotic diseases |
| EP1605925A1 (en) * | 2003-03-17 | 2005-12-21 | Pfizer Products Inc. | Treatment of type 1 diabetes with pde5 inhibitors |
| WO2006074443A2 (en) * | 2005-01-07 | 2006-07-13 | The Johns Hopkins University | Pde5 inhibitor compositions and methods for immunotherapy |
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| US6043252A (en) * | 1997-05-05 | 2000-03-28 | Icos Corporation | Carboline derivatives |
| US6075028A (en) * | 1999-09-23 | 2000-06-13 | Graham; Richard | Method of treating Tourette's syndrome and related CNS disorders |
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- 2001-06-29 AU AU2001279275A patent/AU2001279275A1/en not_active Abandoned
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- 2001-06-29 EP EP01957540A patent/EP1303279A1/en not_active Withdrawn
- 2001-06-29 JP JP2002506740A patent/JP2004511433A/ja active Pending
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101072870B (zh) * | 2004-10-27 | 2013-01-30 | 巴黎国立医院（Ah-Hp） | 对真性红细胞增多症中jak2突变的鉴定 |
| CN111491630A (zh) * | 2017-12-19 | 2020-08-04 | 马莱西尔研究与技术有限责任公司 | 糖尿病足溃疡的治疗方法 |
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| Publication number | Publication date |
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| WO2002002118A1 (en) | 2002-01-10 |
| BR0112100A (pt) | 2003-05-20 |
| JP2004511433A (ja) | 2004-04-15 |
| IL153426A0 (en) | 2003-07-06 |
| CA2414352A1 (en) | 2002-01-10 |
| MXPA03000033A (es) | 2003-09-25 |
| EP1303279A1 (en) | 2003-04-23 |
| HUP0301451A3 (en) | 2004-10-28 |
| HUP0301451A2 (hu) | 2003-09-29 |
| AU2001279275A1 (en) | 2002-01-14 |
| PL365565A1 (en) | 2005-01-10 |
| KR20030047907A (ko) | 2003-06-18 |
| NZ523108A (en) | 2005-04-29 |
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