CN115666549A - 用于治疗与镰状细胞病相关的血管闭塞危象的方法 - Google Patents
用于治疗与镰状细胞病相关的血管闭塞危象的方法 Download PDFInfo
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- CN115666549A CN115666549A CN202180013171.6A CN202180013171A CN115666549A CN 115666549 A CN115666549 A CN 115666549A CN 202180013171 A CN202180013171 A CN 202180013171A CN 115666549 A CN115666549 A CN 115666549A
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- naphthyl
- methoxy
- nitrooxy
- butyl
- propionate
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Abstract
本发明涉及通过施用治疗有效量的丙酸4‑(硝基氧基)丁基‑(2S)‑2‑(6‑甲氧基‑2‑萘基)酯治疗与镰状细胞病相关的血管闭塞危象(VOC)的方法。
Description
发明领域
本发明涉及用于治疗镰状细胞病血管闭塞危象(VOC)的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯。
发明背景
丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯是萘普生的一氧化氮(NO)释放衍生物并且也称作萘普西诺。
丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯
WO 98/09831和US 6,700,011公开了丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯的合成。
Schnitzer T.J.等人，Osteoarthritis and Cartilage 18(2010)629-639公开了萘普西诺是萘普生的NO释放衍生物，其合并了镇痛和抗炎作用以及与安慰剂相似但不同于萘普生的血压作用。在人患者膝盖的骨关节炎(OA)研究中，萘普西诺在控制OA的体征和症状中显示出临床功效和安全性。
White W.B.等人(Am J Cardiol 2011；107:1338-1345)公开了涉及萘普西诺在3个关键试验中对2,734名患有髋或膝骨关节炎患者的血压作用的大规模分析。分析结果表明，萘普西诺可以减轻大多数NSAID引起的一些高血压负担。
镰状细胞病(SCD)是由血红蛋白的β-球蛋白亚单位的第六个氨基酸上的突变引起的一组血红蛋白病。最常见的突变βS-球蛋白导致亲水性谷氨酸残基被疏水性缬氨酸替代，导致在脱氧时产生具有发生聚合倾向的血红蛋白S(Belanger AM,Keggi C,Kanias T等人，Effects of nitric oxide and its congeners on sickle red blood celldeformability.Transfusion,2015(55)2464-2472)。
缺氧条件下HbS的聚合使红血细胞扭曲成特有的镰刀形状，并且增加硬度和脆性，导致溶血。溶血反过来又有助于氧化性应激和血小板活化(Helms CC,Marvel M,Zhao W,Stahle M,Vest R,Kato GJ等人Mechanisms of hemolysis-associated plateletactivation.Journal of Thrombosis and Haemostasis.2013；11(12):2148-2154；Villagra J,Shiva S,Hunter LA,Machado RF,Gladwin MI,Kato GJ.Plateletactivation in patients with sickle disease,hemolysis-associated pulmonaryhypertension,and nitric oxide scavenging by cell-free hemoglobin.Blood 2007；110(6):2166-2172)。氧化性应激、镰状细胞与内皮的物理相互作用和其它因素导致炎性状态，其中内皮细胞和白细胞被激活，导致白细胞和多细胞粘附到内皮，从而产生VOC。缺血、器官损伤、疼痛和潜在的死亡都是VOC继发的(Parise LV,Telen MJ.Erythrocyteadhesion in sickle cell disease.Current Hematology Reports.2003；2(2):102-108.,2003；Hoppe CC.Inflammatory mediators of endothelial injury in sicklecell disease.Hematol Oncol Clin.North Am.2014；28(2):265-86；Kutlar A,EmburySH.Cellular adhesion and the endothelium:P-Selectin.Hematol Oncol Clin.NorthAm.2014；28(2):323-339；Zhang DC,Xu CL,Manwani D,Frenette PS.Neutrophils,platelets,and inflammatory pathways at the nexus of sickle cell diseasepathophysiology.Blood.2016；127(7):801-839；Kim-Shapiro DB,Gladwin MT.Nitricoxide pathology and therapeutics in sickle cell disease.Clinical Hemorheologyand Microcirculation,2018；68:223-237)。
血管闭塞危象及其伴随的疼痛是镰状细胞病患者急诊科就诊和住院的常见原因。血管闭塞危象及其伴随的疼痛最常发生在四肢、胸部和背部，并且被认为是伤害性的，继发于组织损伤。典型的疼痛危象的临床特征被描述为腰背部或一个或多个关节或四肢之一突然疼痛发作。疼痛可能是局部的或迁移性的，并且是持续的和跳动的。严重的疼痛导致患者发出哼声、呻吟、哭泣、扭动和转身，并且在不成功的尝试中采取不正常的姿势来获得缓解。在尝试使用口服麻醉剂和/或药品核准标示外使用非处方NSAID药物控制疼痛失败后，严重的发作需要在医疗中心使用非肠道阿片类药物进行治疗。(Ballas SK,Gupta K,Adams-Graves P.Sickle cell pain:a critical reappraisal Blood,2012；120(18):3647-3656)。
血管闭塞疼痛危象通过四个阶段演变：前驱期、初始期、确立期和消退期。每次急性疼痛发作都与炎症相关，炎症会随着反复发作而恶化，通常最终导致严重的并发症和器官损伤，例如急性胸部综合征、多器官衰竭。前驱期是严重疼痛发作前的时期，并且持续1-2天，随后疼痛逐渐或突然增加(初始期)，3天后疼痛达到峰值，这导致进入确立期，持续到第6天或第7天，之后疼痛开始减轻(消退期)。危象的前驱期以三个主要的病理生理事件为特征：血管闭塞、炎症和伤害感受。因此，在组织缺血和炎症处于早期阶段的前驱期控制血管闭塞危象可以潜在地预防疼痛和组织损伤或将其减少至最低限度。(Ballas SK,Gupta K,Adams-Graves P.Sickle cell pain:a critical reappraisal Blood,2012；120(18):3647-3656)。
目前，控制血管闭塞危象的主要疗法包括治疗急性疼痛发作和减少血管闭塞危象的发生。
三种药物已被FDA批准用于治疗镰状细胞病中的血管闭塞危象并发症，
(羟基脲)、
(L-谷氨酰胺)和
(立赞利珠单抗-tmca)。所有产品均已显示降低血管闭塞危象的频率，但是这些药物并未显示减轻与VOC相关的疼痛。
近期批准的Adakveo在其批准的包装说明书中列出了18％的关节痛发生率和15％的与其产品相关的背痛，表明持续需要缓解疼痛。(Novartis,2019)
不幸地，虽然羟基脲(Droxia)降低了VOC的发生，但是它并不能消除VOC，当疼痛的血管闭塞危象发生时，患者需要保持减轻疼痛。此外，Droxia包装说明书包含针对骨髓抑制和恶性肿瘤的黑框警告。
目前FDA没有批准任何产品用于治疗患有镰状细胞病的患者的继发于血管闭塞危象的疼痛，但是多种镇痛剂通常在药品的标示外使用。指导原则建议使用NSAID用于轻度至中度疼痛，但是在良好控制的临床试验中没有显示NSAID对继发于VOC的疼痛具有作用。
随着VOC的进展，超过90％的成年患者需要住院治疗并且需要治疗疼痛，包括由哌替啶、吗啡或氢吗啡酮组成的非肠道阿片类药物治疗。(Ballas SK.Pain management ofsickle cell disease.Hematol Oncol Clin North Am.2005；19(5):785-802)。
尽管阿片类药物治疗是疼痛疗法的支柱，但由于副作用，阿片类药物疗法仍然是欠佳的方法，所述副作用例如镇静、头晕、恶心、呕吐、便秘、身体依赖、耐受性和呼吸抑制，而且在高剂量或长期使用后发生严重不良反应，包括阿片类药物耐受性(导致阿片类药物剂量增加)、免疫抑制、激素改变、痛觉过敏以及急性胸部综合征风险增加和镰状细胞患者中阿片类药物清除率的改变。(Ballas SK.Current issues in sickle cell pain andits management.Hematology Am SocHematolEduc Program.2007；97-105)。
众所周知，一氧化氮(NO)是自由基信号传导分子，其在广泛的生物功能中发挥作用，包括松弛血管、增加血流、减少血小板活化、减少循环血细胞与内皮的粘附和减少血栓形成。响应许多不同的刺激，血管内皮细胞产生一氧化氮，其激活鸟苷酸环化酶，导致胞内环状GMP(cGMP)水平升高。广泛的研究表明，一氧化氮水平在镰状细胞病中消耗，并且在VOC过程中进一步消耗(Goncalves R.P.,Rev Bras Hematol Hemoter 2012；34(4):254-64)。
补充或调节一氧化氮(NO)的治疗策略被公开为镰状细胞病和/或症状的潜在治疗方法。
例如，初步试验显示吸入NO对急性VOC有一些积极作用。然而，目前可获得的结果没有提供足够的证据来确定使用吸入一氧化氮治疗患有镰状细胞病患者的疼痛(血管闭塞)危象的作用。此外，吸入的NO需要专门的处理和施用。
另一个在镰状细胞患者中增加NO产生的公开策略是补充一氧化氮前体。SummarM.L.等人(US 2018/0289647)公开了治疗镰状细胞病及其并发症包括血管闭塞危象的方法，该方法包括施用瓜氨酸，其为精氨酸和一氧化氮(NO)内源性产生的前体。US 2018/0289647报告了一项研究，该研究证明了在患有镰状细胞病患者中静脉内施用瓜氨酸的安全性和药代动力学特性。然而，瓜氨酸的临床功效需要在临床研究中进一步评估。
因此，用于治疗患有镰状细胞病的患者的血管闭塞危象的有效且安全的疗法是一个严重未满足的需求。
申请人近期进行了临床前研究，并且发现，4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)能够提高镰状细胞动物模型中的环鸟苷一磷酸水平(cGMP水平)，因此，4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)可以在减轻镰状细胞患者的一氧化氮消耗方面发挥作用，进而改善血管稳态。此外，4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)的抗炎和镇痛活性可以减少炎性级联反应和与血管闭塞危象相关的疼痛。
发明概述
已经发现，丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯可以有益地干扰与镰状细胞贫血血管闭塞危象(VOC)相关的疼痛症状和并发症的发病机制和缓解与镰状细胞贫血血管闭塞危象(VOC)相关的疼痛症状和并发症。
本发明的一个实施方案涉及治疗镰状细胞病患者的血管闭塞危象的方法，该方法包括给需要的患者施用治疗有效量的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯。
本发明的另一个实施方案涉及治疗镰状细胞病患者的血管闭塞危象的方法，该方法包括给需要的患者施用治疗有效量的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯，其中一旦患者感觉到即将发生的危象，优选在血管闭塞危象的早期前驱体征和症状发作时，则施用丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯；施用丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯在血管闭塞危象的早期前驱体征和症状发作时开始并且至少持续至危象得到处置为止。
本发明的方法具有一些优势：一旦患者感觉到即将发生的危象(前驱期)，则丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯可以在家中施用于患者(自我施用)；在血管闭塞危象的早期阶段施用丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯可以有助于促进和加速危象的解决，因为减少了事件的级联，例如血管闭塞、炎症和疼痛(与血管闭塞危象相关)。
最大限度地减少血管闭塞和炎症可以减少镰状细胞患者的器官和组织损伤，通过减少(1)器官和组织通过毛细血管的血流阻塞引起的缺血而遭受的损伤量，(2)在缺血一段时间期限后血流已恢复的器官和组织中氧化自由基引起的损伤量，(3)从受损细胞中释放的炎性介质。
与血管闭塞危象相关的疼痛强度的降低可以减轻或避免使用阿片类药物来应对与镰状细胞患者的缺血危象相关的急性疼痛危象的需求，并且因此可以减少患者的住院治疗。
由于丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯是良好耐受的，所以可以将该化合物与通常用于治疗SCD的其它医学治疗联合施用，以不干扰此类其它治疗的方式施用。
本发明的另一个实施方案涉及用于减少患有镰状细胞病的个体中的血管闭塞事件的严重性或持续时间的方法，该方法包括施用治疗有效量的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯。
本发明的另一个实施方案是减轻由血管闭塞事件导致的器官和组织损伤的方法，该方法包括给患有镰状细胞病的个体施用有效量的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯。
本发明的一个实施方案提供了治疗患有镰状细胞贫血的患者在复发性缺血危象期间的疼痛的方法，通过施用治疗有效量的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯来进行。
本发明的另一个实施方案是用于治疗镰状细胞贫血患者的继发于镰状细胞病血管闭塞危象(VOC)的疼痛的方法，通过联合施用治疗有效量的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯与在此类疼痛危象期间所用的阿片类药物疗法来进行。
在一个实施方案中，本发明包括本发明的方法，其中药物组合物中存在治疗有效量的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯，该药物组合物还包括一种或多种药学上可接受的载体。在一个实施方案中，药物组合物适合于口服、鼻、局部、口腔、舌下、直肠、阴道或非肠道施用。
本发明还涉及丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯或包含丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯和一种或多种药学上可接受的载体的药物组合物，其用于上述报道的治疗方法的任一种。
本发明还涉及丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯在制备用于上述报道的治疗方法的任一种的药物中的用途。
附图简述
图1：是显示在纯合型镰状细胞转基因小鼠中静脉内施用丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯(萘普西诺)或萘普生后亚硝酸盐血液浓度(浓度-时间)的示意图。萘普西诺增加血浆中亚硝酸盐浓度。N＝4-7；*p<0.01
图2：是显示在纯合型镰状细胞转基因小鼠中静脉内施用丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯(萘普西诺)或萘普生后cGMP浓度(浓度-时间)的示意图。萘普西诺增加血小板cGMP产生。N＝4-7；*p<0.01
发明详述
提供了用于治疗镰状细胞贫血患者的急性疼痛危象的方法。该方法包括施用治疗有效量的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯(萘普西诺)。
下文的描述提供了具体细节以提供对本发明的透彻理解。然而，本领域技术人员会理解，可以在不采用这些具体细节的情况下实施本发明。为了解释本说明书的目的，将应用以下定义，并且在适当时，以单数形式使用的术语也将包括复数，反之亦然。
如本文所定义的“治疗”是指血管闭塞事件的严重性或持续时间的任何降低，至终止危象，或与镰状细胞贫血相关的疼痛的任何减轻。疼痛的减轻可以包括频率、持续时间或疼痛的强度的减少。疼痛的强度可以通过标准方法来测量，例如测痛计、触压计、10点疼痛量表等。
如本文所定义的“血管闭塞危象前驱体征和症状”包括：疲倦、头晕、虚弱、眼睛发黄、苍白、胃肠道症状例如恶心、呕吐和食欲改变、肌肉骨骼症状例如手/足肿胀、压痛或关节僵硬以及呼吸例如流鼻涕、咳嗽和呼吸改变。
如本文所用，术语化合物的“治疗有效量”是治疗或预防如本文所述的疾病、障碍和/或病症所必需或足够的量。有效量可以取决于个体的大小和体重、疾病的类型或本发明的具体化合物等因素而不同。本领域普通技术人员之一将能够研究本文中包含的因素并且无需过度试验确定本发明化合物的有效量。
本发明药物组合物中活性成分的实际剂量水平可以不同，以获得有效实现特定患者、组合物和施用方式的期望的治疗响应、而对患者无毒性的活性成分的量。
选择的剂量水平将取决于多种因素，包括所采用的本发明特定化合物的活性、施用途径、施用时间、所采用的特定化合物的排泄速率、治疗的持续时间、与所使用的特定化合物组合使用的其它药物、化合物和/或材料、待治疗患者的年龄、性别、体重、状况、一般健康状况和既往病史，以及医学领域中众所周知的类似因素。
具有本领域普通技术的临床医师可以容易地确定和开出所需药物组合物的有效量。例如，临床医师可以在低于达到期望的治疗作用所需的水平开始药物组合物中使用的本发明化合物的剂量，并且逐渐增加剂量直至达到期望的作用。
通常，本发明化合物的适合日剂量将是有效产生治疗作用的最低剂量的化合物的量。此类有效剂量通常取决于上述因素。
如果期望，活性化合物的有效日剂量可以作为两个、三个、四个、五个、六个或更多个亚剂量在全天以适当的间隔分开施用，任选以单位剂型施用。
尽管本发明的化合物能够单独施用，但优选将化合物作为药物组合物施用。
对于本治疗中的用途，口服施用丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯；成人剂量范围为100mg/天-3000mg/天或100mg/天-2000mg/天，优选375mg/天-1500mg/天，最优选750mg/天-1500mg/天；儿童剂量(超过2岁且低于16岁)范围为15-22.5mg/Kg/天。
施用的确切剂量和时间表将取决于在每个特定情况下提供缓解所需的量而不同。
对于本治疗中的用途，优选从血管闭塞危象的早期前驱体征和症状的发作开始给患者施用丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯，直至危象得到控制为止。该治疗也可以用于血管闭塞危象控制后的维持疗法。
施用方案可以影响有效量的构成。可以每天或依次施用数个分开的剂量以及交错的剂量，或者可以连续输注剂量，或者可以是推注。此外，本发明化合物的剂量可以根据治疗或预防情况的紧急情况按比例增加或减少。
如本文所用，术语“药物组合物”包括适合施用于哺乳动物例如人的制剂。当本发明化合物作为药物施用于哺乳动物例如人时，它们可以本身给予或作为包含例如0.1-99.5％(更优选0.5-90％)活性成分与药学上可接受的载体组合的药物组合物给予。
如本文所用，术语“药学上可接受的载体”是本领域公认的并且包括药学上可接受的材料、组合物或媒介物，其适合于将本发明化合物施用于哺乳动物。载体包括液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料，其涉及将主题活性剂从一个器官或身体的一部分携带或运输到另一器官或身体的一部分。在与制剂的其它成分相容且对患者无害的意义上，每种载体必须是“可接受的”。可以用作药学上可接受的载体的材料的一些实例包括：糖，例如乳糖、葡萄糖和蔗糖；淀粉，例如玉米淀粉和马铃薯淀粉；纤维素及其衍生物，例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素；粉状黄蓍胶；麦芽；明胶；滑石粉；赋形剂，例如可可脂和栓剂蜡；油，例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；二醇，例如丙二醇；多元醇，例如甘油、山梨醇、甘露醇和聚乙二醇；酯，例如油酸乙酯和月桂酸乙酯；琼脂；缓冲剂，例如氢氧化镁和氢氧化铝；藻酸；无热原水；等渗盐水；林格液；乙醇；磷酸盐缓冲溶液；和其它用于药物制剂的无毒相容物质。
润湿剂、乳化剂和润滑剂，例如十二烷基硫酸钠和硬脂酸镁，以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂也可以存在于组合物中。
药学上可接受的抗氧化剂的实例包括：水溶性抗氧化剂，例如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等；油溶性抗氧化剂，例如抗坏血酸棕榈酸酯、丁羟茴醚(BHA)、丁羟甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等；和金属螯合剂，例如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
本发明的制剂包括适合于口服、鼻、局部、口腔、舌下、直肠、阴道和/或非肠道施用的那些。制剂可以便利地以单位剂型存在并且可以通过药学领域中众所周知的任何方法制备。可以与载体材料组合以制备单一剂型的活性成分的量通常是产生治疗作用的化合物的量。通常，在百分之一百中，该量范围为约1％至约99％的活性成分，优选约5％至约70％，最优选约10％至约30％。
制备这些制剂或组合物的方法包括使本发明化合物与载体和任选一种或多种辅助成分结合的步骤。通常，通过将本发明化合物与液体载体或细分的固体载体或两者均匀且紧密地结合，然后，如果需要，使产品成形来制备制剂。
适合于口服施用的本发明制剂可以是胶囊剂、扁囊剂、丸剂、片剂、锭剂(使用矫味的基料，通常是蔗糖和阿拉伯胶或黄蓍胶)、散剂、颗粒剂或者作为水性或非水性液体形式的溶液剂或混悬剂，或者作为水包油或油包水液体乳剂，或者作为酏剂或糖浆剂，或者作为软锭剂(使用惰性基质，例如明胶和甘油，或蔗糖和阿拉伯胶)和/或作为漱口剂等，每一种都包含预定量的本发明化合物作为活性成分。本发明化合物也可以作为大丸剂、药膏或糊剂施用。
无论选择何种施用途径，通过本领域技术人员已知的常规方法将本发明化合物和/或本发明药物组合物配制成药学上可接受的剂型。
实施例1
丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯(萘普西诺)对镰状细胞小鼠模型的一氧化氮血液和cGMP水平的作用
进行本试验以评估丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯(萘普西诺)在纯合型Townes镰状细胞转基因小鼠中增加亚硝酸盐(NO的前体)和cGMP的功效。
试验设计
通过静脉内注射用丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯(萘普西诺)(15mg/kg)或萘普生(15mg/kg-作为对照)或盐水(作为媒介物对照)治疗纯合型镰状细胞转基因小鼠。1小时后，给小鼠注射凝血酶(1u/20g)以诱导血小板活化。在凝血酶施用后15、30和1小时抽取血液。测量血浆亚硝酸盐水平作为一氧化氮生物利用度的标志物。在添加IBMX(3-异丁基-1-甲基黄嘌呤)(100uM)以防止cGMP降解后测量cGMP水平。分离血小板并且通过p-选择蛋白的表面表达测量活化。
结果
在1小时时，与单独的凝血酶或萘普生施用相比，使用萘普西诺的亚硝酸盐浓度在统计学上更高(图1)。在30分钟和60分钟时，与单独的凝血酶或萘普生施用相比，使用萘普西诺的cGMP水平显著增加(p<0.01)(图2)。
数据支持如下断言：丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯(萘普西诺)对治疗患有镰状细胞贫血的患者的复发性缺血危象有用和有帮助，实际上，4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)能够增加cGMP水平，从而减轻镰状细胞病中一氧化氮的消耗以及随后的血管病变，其是导致血管闭塞的因素，此外，该化合物的抗炎组分减轻炎症和疼痛。
因此，尽管已经描述了目前认为是本发明的优选实施方案，但本领域技术人员将认识到可以对其进行改变和修饰而不背离本发明的精神，并且旨在要求所有此类改变和修饰落入本发明的真实范围内。
Claims (14)
1.丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯，其用于治疗镰状细胞贫血患者的血管闭塞危象。
2.用于权利要求1的用途的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯，其中施用丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯在血管闭塞危象的前驱体征和症状发作时开始。
3.用于权利要求1或权利要求2的用途的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯，其中所述治疗包括降低血管闭塞危象的严重性或持续时间。
4.用于权利要求1或权利要求2的用途的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯，其中治疗包括治疗与血管闭塞危象相关的疼痛。
5.用于权利要求1或权利要求2的用途的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯，其中治疗包括降低或防止由血管闭塞危象导致的器官和组织损伤。
6.用于权利要求1的用途的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯，其中将丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯作为药物组合物施用，所述药物组合物还包含一种或多种药学上可接受的载体。
7.用于权利要求6的用途的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯，其中所述药物组合物适合于口服、鼻、局部、口腔、舌下、直肠、阴道或非肠道施用。
8.丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯在制备用于治疗镰状细胞贫血患者的血管闭塞危象的药物中的用途。
9.权利要求8的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯的用途，其中施用丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯在血管闭塞危象的前驱体征和症状发作时开始。
10.权利要求8或权利要求9的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯的用途，其中所述治疗包括降低血管闭塞危象的严重性或持续时间。
11.权利要求8或权利要求9的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯的用途，其中治疗包括治疗与血管闭塞危象相关的疼痛。
12.权利要求8或权利要求9的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯的用途，其中治疗包括降低或防止由血管闭塞危象导致的器官和组织损伤。
13.权利要求8的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯的用途，其中将丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯作为药物组合物施用，所述药物组合物还包含一种或多种药学上可接受的载体。
14.权利要求13的丙酸4-(硝基氧基)丁基-(2S)-2-(6-甲氧基-2-萘基)酯的用途，其中所述药物组合物适合于口服、鼻、局部、口腔、舌下、直肠、阴道或非肠道施用。
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| US20110054020A1 (en) * | 2009-05-05 | 2011-03-03 | Auspex Pharmaceuticals, Inc. | Napthylene inhibitors of cyclooxygenase |
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