CN113905740A - 用于治疗微血管功能障碍的5,6-dihete内酯 - Google Patents
用于治疗微血管功能障碍的5,6-dihete内酯 Download PDFInfo
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- CN113905740A CN113905740A CN202080040992.4A CN202080040992A CN113905740A CN 113905740 A CN113905740 A CN 113905740A CN 202080040992 A CN202080040992 A CN 202080040992A CN 113905740 A CN113905740 A CN 113905740A
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Abstract
本发明提供5,6二羟基二十碳四烯酸(5,6‑diHETE)内酯或包含5,6‑diHETE内酯和药学上可接受的载体的药物组合物,及其用于诱导血管舒张、用于治疗与微血管功能障碍相关的疾病、病症或病况、或者用于预防发展与微血管功能障碍相关的心脏病况、或降低发展所述心脏病况的风险的用途。
Description
技术领域
本发明涉及5,6二羟基二十碳四烯酸(5,6-diHETE)内酯在微血管功能障碍和相关病况的治疗中的用途。
背景技术
高血压(Hypertension)或高血压(high blood pressure)是冠心病和中风的主要危险因素,并且它仍是世界范围内最常见的慢性疾病,在美国影响约76.4百万成人并在全球范围内影响超过10亿人(Heart disease and stroke statistics-2017update:Areport from the American heart association.Circulation.2017:135:e146)。尽管这种疾病普遍存在并且有许多有效的治疗方法,但在美国每两名高血压患者中几乎有一名仍是不受控制的。有五类用于抗高血压治疗的药理学药物,作为单一疗法或联合疗法:1)利尿剂,2)β-阻断剂,3)钙通道拮抗剂,4)血管紧张素转化酶(ACE)抑制剂和5)血管紧张素受体阻断剂。这些抗高血压治疗降低了与高血压(BP)相关的心血管(CV)病和致死事件的升高的发生率。然而,在患有高血压的美国成人中,11.8%符合难治性高血压的标准(收缩期BP/舒张期BP≥140/90mmHg,并且报道了使用来自3种不同药物种类的抗高血压药物或来自不考虑BP的≥4种抗高血压药物种类的药物)。这些数据强调需要通过新的作用机制来对抗高血压的新药。
血压(BP)由影响小动脉血管紧张度的各种因素调节。正常血压的维持依赖于有助于外周血管阻力的小直径动脉收缩和舒张的平衡。在生理情况下,大动脉仅对总冠状动脉阻力贡献约7%,而冠状小动脉(直径为50-150μm)被认为是流向心脏的主要调节部位。这些小血管响应于特定组织的变化的代谢需求而收缩或舒张的能力对于心血管(CV)内稳态是极其重要的,并且它依赖于内皮细胞(EC)和平滑肌细胞(SMC)中发生的受体介导的信号传导。阻力动脉中这些信号传导过程中的任何扰动可以使血压偏离内稳态。微血管功能障碍是指从减少的器官最大灌注至离体小动脉的内皮依赖性舒张受损的范围的多组病况。内皮依赖性松弛的丧失是高血压患者中CV事件的显著独立风险因素。它存在于所有已知的CV疾病的早期进程中,包括高胆固醇血症、动脉粥样硬化、心绞痛和糖尿病。
血管紧张度的局部调节和血管病理生理学之间的平衡可取决于从内皮释放的因子而变化。物理和化学刺激通过刺激包括前列腺素I2(前列环素;PGI2)、一氧化氮(NO)、以及内皮源性超极化因子(EDHF)的介质的产生来导致内皮介导的舒张。术语EDHF是指一组化学上不同的化合物,其特征在于它们严格依赖于内皮细胞的Ca2+-敏感性钾(K+)通道的活性。EDHF因子中突出的是花生四烯酸代谢物。
花生四烯酸是ω-6长链多不饱和脂肪酸(LC-PUFA)。花生四烯酸的细胞色素P450(CYP)依赖性代谢通常被称为是除了COX和LOX途径以外的花生四烯酸代谢的第三途径。CYP产生的产物、花生四烯酸衍生的环氧化物和二醇在它们对生理学和病理生理学的影响方面,与其它途径的代谢物相比占有优势。环氧二十碳三烯酸(EET)由近端小管、集合管和肾血管内皮中的CYP2C和CYP2J家族的酶形成。它们通过激活血管平滑肌细胞(VSMC)中的大钾(BK)通道而在肾微循环中起到EDHF的作用,并有助于入球小动脉对乙酰胆碱(ACh)、缓激肽、和腺苷的血管舒张响应的一氧化氮和COX非依赖性组分。
ω-3LC-PUFA构成在鱼中发现的另一类膳食脂质,并且具有与花生四烯酸相似的代谢。对该类的潜在代谢物5,6-diHETE内酯诱导内皮超极化和引发血管舒张的能力进行检测。
发明内容
在第一方面,本发明提供包含5,6二羟基二十碳四烯酸(5,6-diHETE)内酯和药学上可接受的载体的药物组合物。
在第二方面,本发明提供5,6二羟基二十碳四烯酸(5,6-diHETE)内酯或包含它的药物组合物,其用于在有需要的受试者中诱导血管舒张。
在第三方面,本发明提供5,6二羟基二十碳四烯酸(5,6-diHETE)内酯或包含它的药物组合物,其用于在有需要的受试者中治疗与微血管功能障碍相关的疾病、病症或病况。
在第四方面,本发明提供5,6二羟基二十碳四烯酸(5,6-diHETE)内酯或包含它的药物组合物,其用于在处于发展与微血管功能障碍相关的心脏疾病或病症的风险的患者中,预防发展所述心脏疾病或病症、或降低发展所述心脏疾病或病症的风险。
在第五方面,本发明提供在有需要的受试者中诱导血管舒张的方法,所述方法包括向受试者施用包含5,6二羟基二十碳四烯酸(5,6-diHETE)内酯和药学上可接受的载体的药物组合物。
在第六方面,本发明提供治疗与微血管功能障碍相关的疾病、病症或病况的方法,所述方法包括向有需要的受试者施用包含5,6二羟基二十碳四烯酸(5,6-diHETE)内酯和药学上可接受的载体的药物组合物。
在第七方面,本发明提供预防发展与微血管功能障碍相关的心脏病况、或降低发展所述心脏病况的风险的方法,所述方法包括向有需要的受试者施用包含5,6二羟基二十碳四烯酸(5,6-diHETE)内酯和药学上可接受的载体的药物组合物。
附图说明
图1A-1C显示由5,6-diHETE内酯诱导的剂量依赖性细胞内钙([Ca2+]i)增加。A.使用共焦显微镜、借助于Fluo4的荧光强度来测定的,由5,6-diHETE内酯以剂量依赖性方式(0.01-5μmol/L)诱导的HUVEC细胞中的[Ca2+]i的变化。F1表示各时间点处的强度,F0表示基础强度。溶剂(1.6%EtOH)用作阴性对照(N.C)。4α-佛波醇-12,13-二癸酸酯(4α-PDD;特定TRPV4(瞬时受体电位阳离子通道)激动剂;10μmol/L)用作阳性对照。B.最大强度(F1max)和基础强度(F0)之间的计算的比。C.用于EC50计算(EC50=0.009943μM)的浓度-响应曲线。RLU–相对单位。所有数据表示1-6个独立实验中每孔20个细胞的平均值±SD。柱表示F1max/F0。使用单向ANOVA和图基事后检验(Tukey’s post hoc test)进行统计学分析,星号表示与阴性对照的显著差异,**p<0.01。
图2显示由5,6-diHETE内酯与5,6-diHETE(水解异构体)引起的[Ca2+]i增加的比较。2μmol/L的5,6-diHETE内酯,而不是2μmol/L的水解异构体,在HUVEC中诱导[Ca2+]i的变化。溶剂(1.6%EtOH)用作阴性对照(N.C)。4α-佛波醇-12,13-二癸酸酯(4α-PDD;特定TRPV4激动剂;10μmol/L)用作阳性对照。所有数据表示1-2个独立实验中、各实验中3-5个孔、每孔20个细胞的平均值±SD。使用单向ANOVA和图基事后检验进行统计学分析。不同字母表示不同浓度之间的显著差异,并且星号表示内酯异构体与水解异构体之间的显著差异,**p<0.05。柱表示F1max/F0。
图3显示5,6-diHETE内酯介导小鼠肠系膜阻力动脉中的舒张。显示在用0.1μMU46619(PGH2的稳定合成类似物,起到血栓素A2(TP)受体激动剂的作用)收缩后,对增加的5,6-diHETE内酯浓度的累积舒张响应曲线。数据显示为来自4个独立实验中11条动脉的血管张力的平均%松弛(mN±SEM)(相对于对100μM罂粟碱的松弛响应来确定)。
图4显示由5,6diHETE内酯介导的健康脂肪小动脉的松弛(舒张)。显示在用内皮素-1(10-50nmol/L)收缩后,对5,6-diHETE内酯(10-4-10-1μmol/L)的累积舒张响应曲线(“对照”,圆圈)。施用L-NAME(一氧化氮合酶的抑制剂,100μmol/L)使该效果降低50%(正方形)。内皮细胞层的机械剥脱(mechanical denudation)显著降低5,6diHETE内酯诱导的舒张(三角形)。数据显示为来自7条动脉的血管张力的平均%松弛(mN±SEM)(相对于对100μM罂粟碱的松弛响应来确定)。
图5显示由5,6diHETE内酯介导的高血压受试者(HTN)的脂肪小动脉的松弛(舒张)。显示在用内皮素-1(10-50nmol/L)收缩后,5,6-diHETE内酯(10-10-10-7mol/L)的累积舒张响应曲线(圆圈)。施用L-NAME无效果(正方形)。数据显示为来自7条动脉的血管张力的平均%松弛(mN±SEM)(相对于对100μM罂粟碱的松弛响应来确定)。
图6A-6B显示5,6-diHETE内酯对钙激活的钾通道的激动剂效果。KCa3.1(IK,A)在CHO细胞中表达的钙激活的钾通道(由人KCNN4基因编码);和KCa2.3(SK3,B)在HEK293细胞中表达的钙激活的钾通道(由人KCNN3基因编码)。根据制造商的说明书,用铊通量测定(thallium flux assay)(Molecular Devices)进行测定。在8个测试浓度(0.05、0.15、0.3、0.65、1.25、2.5、5、和10μM,n=4)下,评价5,6-diHETE内酯的激动剂效果。为了计算效果,将在存在已知激动剂(1μM A-23187用于SK3,和10μM NS309用于IK)的情况下,由5mM铊激发的信号设定为100%激活,并将存在溶媒对照(vehicle control)(试验缓冲液+0.3%DMSO)的情况下的信号设定为0%激活。使用假设简单结合模型的非线性回归拟合公式、使用GraphPad prism 5软件计算EC50,对于IK通道为2.654并且对于SK3通道为9.991。如果平均值超过溶媒对照平均值三个或更多个标准偏差,则认为效果是显著的。RLU–相对单位。
图7A-7D显示5,6-diHETE内酯通过内皮KCa通道在HTN 5/6Nx大鼠模型中诱导血管舒张。在提取自5/6Nx大鼠的肠系膜动脉中评价5,6-diHETE内酯松弛效果。A.5/6Nx过程后2周(黑色箭头),收缩压(P sys)突然增加并从第4周至第12周进一步逐步增加,在第4周达到统计学显著(*p<0.05)。对照(空心圆),5/6Nx(实心圆)。分离来自NT(正常血压,野生型)大鼠与5/6Nx大鼠的肠系膜动脉,在不存在(-抑制剂)或存在TRAM-34(1μmol/L)和蜂毒明肽(apamin)(1μmol/L)(+抑制剂)(D)的情况下,测定它们对乙酰胆碱-ACh(B)或5,6-diHETE内酯(C)或5,6-diHETE内酯(1μmol/L)的松弛响应。数据显示为来自具有7条(NT)、和13条(5/6Nx)动脉的3-4个独立实验的血管张力的变化(mN±SD)。**表示p<0.01,通过Wilcoxon T检验来评估显著性。
图8A-8B显示单次(急性)施用5,6-diHETE内酯对收缩压(SBP)的效果。A.将注射0.3mg/kg 5,6-diHETE内酯后的收缩压(SBP)的变化与基线、拉贝洛尔、和氨氯地平相比较。B.注射5,6-diHETE内酯注射剂后,相对于基线的SBP的降低百分比。结果表示为基于3只大鼠的平均值和标准误差。
具体实施方式
ω-3长链多不饱和脂肪酸(LC-PUFA)衍生的δ–内酯5,6二羟基二十碳四烯酸(5,6-diHETE)内酯可以想到地由5,6-环氧二十碳四烯酸(二十碳五烯酸的C5上的环氧化物异构体,一种ω-3LC-PUFA代谢物)在人体中代谢。然而,据发明人所知,该内酯从未显示存在于动物组织中,并且从未对其生理作用做出过任何努力或建议。
本发明是基于5,6-diHETE内酯能够导致血管的松弛的令人惊讶的发现。该效果看起来是由于其增加细胞内[Ca2+]水平的能力而导致的。实例显示,5,6-diHETE内酯以比对于水解异构体5,6-diHETE所发现的更高的功效在内皮细胞中介导细胞内[Ca2+]增加。在HUVEC细胞中进行的实验中,5,6-diHETE内酯已经以0.01μmol/L的低浓度导致显著的[Ca2+]增加(图1),而水解异构体5,6-diHETE仅从5μmol/L的浓度开始导致显著的[Ca2+]增加(图2)。
其它实例显示,5,6-diHETE内酯在小鼠的肠系膜动脉中介导血管舒张(实施例2)并在来自正常血压以及来自高血压人受试者的人脂肪小动脉(HAA)中介导血管舒张(实施例3)。
因此,在第一方面,本发明提供包含5,6二羟基二十碳四烯酸(5,6-diHETE)内酯和药学上可接受的载体的药物组合物。
在一些实施方案中,本发明的药物组合物实质上由5,6-diHETE内酯和药学上可接受的载体组成。
本文所用的短语“实质上由…组成”是指5,6-diHETE内酯是药物组合物中唯一的活性剂。然而,例如用于组合物、特别地用于药物组合物的那些非活性剂,包括载体、溶剂、分散介质、防腐剂、抗氧化剂、包衣、以及等渗剂和吸收延迟剂等,可包含在本发明的组合物中。
可使用一种或多种生理学上可接受的载体或赋形剂、以常规方法配制本发明的药物组合物。一种或多种载体在与组合物的其它成分相容和对其接受者无害的意义上必须是“可接受的”。
术语“载体”是指与活性剂一起施用的稀释剂、助剂、赋形剂或溶媒。药物组合物中的载体可包括粘结剂,例如微晶纤维素、聚乙烯吡咯烷酮(聚维酮(polyvidone或povidone))、黄蓍胶、明胶、淀粉、乳糖或乳糖一水合物;崩解剂,例如海藻酸、和玉米淀粉等;润滑剂或表面活性剂,例如硬脂酸镁、或十二烷硫酸钠;和助流剂,例如胶体二氧化硅。
可通过任何合适的途径施用药物组合物。在一些实施方案中,将药物组合物配制成用于全身施用。在一些实施方案中,将药物组合物配制成用于局部施用。
在一些实施方案中,将药物组合物配制成用于通过注射施用。在一些实施方案中,将药物组合物配制成用于通过肌内注射施用。
在一些实施方案中,将组合物配制成脂质体组合物,所述脂质体组合物进一步包含包封5,6-diHETE内酯的脂质体。
在一些实施方案中,将药物组合物配制成用于本发明的内酯的暂缓释放或受控释放。
本文可交换使用的术语“暂缓释放(suspended release)”、“延长释放(extendedrelease)”、“受控释放(controlled release)”或“持续释放(sustained release)”是指活性剂、在本情况中为本发明的内酯,在一段时间内从包含其的组合物逐步释放的模式。可通过以下来完成活性剂的延长释放制剂,例如,将活性剂包埋于在特定条件下缓慢溶解的物质的网中,使得活性剂从包衣缓慢且有规律地渗出,或者通过使活性剂溶胀以形成具有几乎不可渗透的表面的凝胶,其中药物缓慢离开该表面。
在一些实施方案中,5,6-diHETE内酯在药物组合物中的浓度为10-9M和10-6M之间。在一些实施方案中,5,6-diHETE内酯在药物组合物中的浓度为10-9M和10-7M之间。
在第二方面,本发明提供5,6二羟基二十碳四烯酸(5,6-diHETE)内酯或包含它的药物组合物,其用于在有需要的受试者中诱导血管舒张。
如本文所用,术语“有需要的受试者”是指需要治疗或血管舒张的任何受试者,特别地哺乳动物受试者,例如患有如高血压等需要通过血管舒张的治疗的病况的人类个体。
各种情况中可需要诱导血管舒张,包括治疗某些疾病或病症,例如如下所述的涉及微血管功能障碍的疾病或病症。其它情况可以是预防发展某些疾病(例如,心脏疾病)、或降低发展某些疾病(例如,心脏疾病)的风险,或减轻某些病况。对于此类用途的实例为需要维持低血压以降低发展心脏问题的风险。
因此,在第三方面,本发明提供5,6二羟基二十碳四烯酸(5,6-diHETE)内酯或包含它的药物组合物,其用于在有需要的受试者中治疗与微血管功能障碍相关的疾病、病症或病况。
本文所用的术语“微血管功能障碍”是指影响血管的功能或由血管的功能障碍导致的多组病况,范围为从降低的器官最大灌注、至离体小动脉的受损的内皮细胞依赖性舒张(Gutterman等,2016)。微血管功能障碍还意味着包括血管的不期望的血管收缩。
因此,在一些实施方案中,本发明的组合物用于治疗与血管收缩相关的疾病、病症或病况。换言之,微血管功能障碍涉及血管收缩。这些治疗受到由本发明的组合物诱导的血管舒张的影响。
本文所用的术语“血管收缩”涉及由血管的肌肉壁、特别是大动脉和小动脉的收缩导致的血管的变窄,这会增加血压。
本文所用的术语“血管舒张”是指血管的变宽,与作为血管的变窄的血管收缩相对。血管舒张由血管壁、特别是大静脉、大动脉和小动脉中平滑肌细胞的松弛引起。小动脉贡献了器官和组织中的大部分血管阻力。
在一些实施方案中,受微血管功能障碍影响的血管,或其中诱导血管舒张的血管为小动脉、动脉、或静脉。在一些实施方案中,血管为小动脉或动脉。在一些实施方案中,血管为小动脉。在一些实施方案中,血管为冠状小动脉。在一些实施方案中,动脉或小动脉直径小于约200μm。在一些实施方案中,血管为具有小于约200μm的直径的小动脉。由本发明的内酯舒张的血管可以已预先收缩,或已处于其正常未收缩状态。
由5,6diHETE内酯引起的血管舒张可能是由本发明的内酯所介导的内皮细胞中细胞内钙水平的增加而导致的。因此,在一些实施方案中,组合物导致内皮细胞中细胞内钙水平的增加。
许多病况与微血管功能障碍密切相关,包括衰老、淀粉样变性病、查加斯病(Chagas disease)、慢性血栓栓塞性肺动脉高压、痴呆、糖尿病、药物滥用(例如烟草滥用)、射血分数保留型心力衰竭(HFpEF)、射血分数降低型心力衰竭(HFrEF)、高血压、肥厚型梗阻性心肌病、特发性心肌病、炎性疾病(例如炎性肠病)、缺血性心肌病、无复流现象、肥胖、阻塞性睡眠呼吸暂停、周围神经病、精神分裂症、应激相关性心肌病、系统性红斑狼疮、系统性硬化症、肿瘤血管生成、和血管痉挛。
与血管收缩相关的其它病况包括心绞痛、充血性心力衰竭、勃起功能障碍、先兆子痫、偏头痛、中风、和雷诺现象(Raynaud phenomenon)。
因此,本发明的组合物可用于治疗任何上述列出的病况中的微血管功能障碍或血管收缩。
在一些实施方案中,可由本发明的组合物治疗的与微血管功能障碍相关的病况是高血压。
高血压(Hypertension),也称为高血压(high blood pressure),是动脉中的血压持续升高的长期(慢性)医学病况。高血压通常不引起症状,但长期高血压是冠状动脉疾病、中风、心力衰竭、心房颤动、外周血管疾病、视力丧失、慢性肾疾病、和痴呆的主要风险因素。
在第四方面,本发明提供5,6二羟基二十碳四烯酸(5,6-diHETE)内酯或包含它的药物组合物,其用于在处于发展与微血管功能障碍相关的心脏病况的风险的受试者中预防发展所述心脏病况、或降低发展所述心脏病况的风险。
与微血管功能障碍相关的心脏病况的实例为心绞痛、和充血性心力衰竭。
本文所用的术语“处于…的风险的受试者”是指与普通人群相比,处于更高的发展与微血管功能障碍相关的心脏病况的风险的受试者。此类更高的风险可能是由于受试者所患有的另一病况、或者是由于受试者的家族史而引起。
在一些实施方案中,处于风险中的受试者患有与微血管功能障碍相关的疾病、病症、或病况。在一些实施方案中,处于风险中的受试者具有与微血管功能障碍相关的疾病、病症、或病况的家族史。在一些实施方案中,微血管功能障碍体现为家族成员的受试者中的高血压。
用于治疗微血管功能障碍、特别是高血压的现有药物属于若干组,包括利尿剂(例如噻嗪类(thiazides))、β-阻断剂(例如阿替洛尔)、钙通道拮抗剂(例如二氢吡啶类、苯烷基胺类、和苯并硫氮杂卓类)、血管紧张素转化酶(ACE)抑制剂(例如贝那普利、佐芬普利、培哚普利、群多普利、卡托普利、依那普利、赖诺普利、和雷米普利)、以及血管紧张素II受体阻断剂(例如缬沙坦、替米沙坦、洛沙坦、厄贝沙坦、阿齐沙坦、和奥美沙坦)。
在上述第二、第三和第四方面、以及下述方面的一些实施方案中,受试者对用于治疗疾病、病症或病况的至少一种药物无响应或部分地响应。
在一些实施方案中,受试者对用于治疗高血压的至少一种现有药物无响应或部分地响应。在一些实施方案中,受试者对用于治疗高血压的多于一种的现有药物,例如对两种、三种或更多种现有药物无响应或部分地响应。在一些实施方案中,受试者对用于治疗高血压的一组现有药物无响应或部分地响应。在一些实施方案中,受试者对用于治疗高血压的多于一组的现有药物,例如对两组、三组、或更多组的现有药物无响应或部分地响应。
本文中可交换使用的术语对治疗“无响应”、“难治性”、或“抗性”是指现有药物没有效果或具有低的效果,使得它们无法实现关于微血管功能障碍或高血压的治疗的令人满意的结果。术语“部分地响应”、“不充分地响应”是指现有药物具有一些效果,但该效果仅为部分的并且仍需要更有效的治疗。
在一些实施方案中,本发明的组合物与用于治疗与微血管功能障碍相关的疾病、病症、或病况的其它试剂联合施用,例如用于治疗微血管功能障碍或更具体地治疗高血压的试剂、或用于控制血压的试剂。此类其它试剂可选自,例如利尿剂(例如噻嗪类)、β-阻断剂(例如阿替洛尔)、钙通道拮抗剂(例如二氢吡啶类、苯烷基胺类、和苯并硫氮杂卓类)、血管紧张素转化酶(ACE)抑制剂(例如贝那普利、佐芬普利、培哚普利、群多普利、卡托普利、依那普利、赖诺普利、和雷米普利)、以及血管紧张素II受体阻断剂(例如缬沙坦、替米沙坦、洛沙坦、厄贝沙坦、阿齐沙坦、和奥美沙坦)。
在一些实施方案中,与如上所详述的其它试剂联合使用的本发明的组合物允许以较低剂量、甚至以亚治疗剂量(sub-therapeutic dose)使用其它试剂,从而预防或减轻副作用。
本文所用术语“亚治疗剂量”是指低于在试剂用于治疗高血压时产生治疗效果所需的试剂的治疗剂量。
在第五方面,本发明进一步提供在有需要的受试者中诱导血管舒张的方法,所述方法包括向受试者施用含有治疗有效量的5,6二羟基二十碳四烯酸(5,6-diHETE)内酯的药物组合物。
在第六方面,本发明进一步提供治疗与微血管功能障碍相关的疾病、病症或病况的方法,所述方法包括向有需要的受试者施用含有治疗有效量的5,6二羟基二十碳四烯酸(5,6-diHETE)内酯的药物组合物。
在第七方面,本发明提供预防发展与微血管功能障碍相关的心脏病况、或降低发展所述心脏病况的风险的方法,所述方法包括向有需要的受试者施用含有5,6二羟基二十碳四烯酸(5,6-diHETE)内酯和药学上可接受的载体的药物组合物。
本文所用术语“治疗有效量”是指将引发所寻求的组织、系统、动物或人的生物学或医学响应、即血管舒张的5,6-diHETE内酯的量。该量必须有效以实现上述期望的治疗效果,这尤其取决于待治疗的病况的类型和严重程度以及治疗方案。治疗有效量通常在适当设计的临床试验(剂量范围研究)中确定,并且本领域技术人员将悉知如何适当地进行此类试验以确定有效量。如通常已知的,有效量取决于各种因素,包括配体与受体的亲合性、其在体内的分布特征、例如体内半衰期等各种药理学参数,取决于如果存在的不期望的副作用,并且取决于例如年龄和性别等因素。
本文所用的术语“治疗”是指获得期望的生理效果的含义。该效果在部分地或完全地治愈疾病、和/或归因于疾病的症状方面可为治疗性的。该术语是指抑制疾病,即阻止其发展;或减轻疾病或其症状,即导致疾病的消退。
施用方法包括但不限于,口服、肠胃外,例如静脉内、腹膜内、肌内、皮下、粘膜(例如鼻内、经颊、阴道、直肠、眼内)、鞘内、局部或皮内途径。
施用方式可为全身的或局部的。在一些实施方案中,将组合物配制成用于通过注射施用。在一些实施方案中,将组合物配制成用于通过静脉内注射施用。在一些实施方案中,组合物通过肌内注射施用。
载体、施用方式、剂型等以下实例作为已知的可能性列出,可从其选择载体、施用方式、剂型等用于与本发明一起使用。然而,本领域普通技术人员将理解,应首先对选择的任何给定制剂和施用方式进行试验以确定其实现期望的效果。
组合物可配制成用于通过注射、例如通过弹丸式注射或连续输注来肠胃外施用。注射用制剂可以与添加的防腐剂存在于单位剂型中,例如,存在于安瓿或多剂量容器中。组合物可采用如油性或水性溶媒中的悬浮液、溶液或乳液等形式,并且可包含例如助悬剂、稳定剂和/或分散剂等配制剂。可选地,活性成分可为粉末形式,用于在使用前用例如无菌无热原水等合适的溶媒配制。
组合物还可配制成直肠组合物,例如栓剂或保留灌肠剂,例如包含常规栓剂基质如可可油或其它甘油酯类。
用于人类使用的活性成分的剂量的确定基于本领域中常规的实践,并且将在临床试验中由医师最终确定。用于施用至人的预期近似当量剂量可使用已知公式(例如Reagan-Show等(2007),Dose translation from animal to human studies revisited.TheFASEB Journal 22:659-661)、基于下文中公开的体内实验证据来计算。根据该范例,成人当量剂量(mg/kg体重)等于给予小鼠的剂量(mg/kg体重)乘以0.081。
在一些实施方案中,组合物以一次剂量施用,下文中称为“急性施用”。
在一些实施方案中,组合物以多于一次的剂量施用,例如以多个剂量施用,例如一天一次、一天多于一次如一天两次或三次,或一天少于一次如每两天、三天、或一周一次。这些施用方式在下文中称为“长期施用”。
为了清晰的目的并且绝不限制教导的范围,除非另外指出说明,否则本文列举的表示量、百分比或比例的所有数、和其它数值在所有情况中应解释为以术语“约”开头。因此,除非有相反的说明,否则本说明书中记载的数值参数为近似的,取决于本发明所要获得的期望的性质,可以变化至多加或减10%。
下文中将通过以下非限定性实施例说明本发明。
实施例
材料和方法
材料
5,6二羟基二十碳四烯酸(5,6-diHETE)内酯购自Cayman Chemical of AnnArbor,Michigan,USA(作为外消旋混合物,目录号18343)。5,6-diHETE(水解异构体)购自Cayman Chemical of Ann Arbor,Michigan,USA(目录号10467)。4α-佛波醇-12,13-二癸酸酯(4α-PDD)购自mercury(目录号MBS524394)。L-NAME(盐酸盐)购自Cayman Chemical ofAnn Arbor,Michigan,USA(目录号80210)。U-46619购自Cayman Chemical of Ann Arbor,Michigan,USA(目录号16450)。A23187(激活SK3通道的钙离子载体(calcium ionophore))、和NS309(激活IK通道)购自Sigma-Aldrich。
5,6-diHETE内酯的制备
由制造商在乙醇中提供内酯。蒸发乙醇,然后添加乙醇至预定体积。然后,添加HEPES缓冲液以获得内酯的最终期望浓度。最终溶液中乙醇浓度为≤1.6%。
细胞培养
自Padeh-Medical Center in Poriah(Helsinki approval#0100/14)提供的脐带提取人脐静脉内皮细胞(HUVEC)。如先前所述(Levi-Rosenzvig等,2017),用PBS清洗脐带,并且通过胶原酶分离细胞并将其维持在完全生长培养基(EGM-2,Lonza)中。从不同批次的提取物获得HUVEC并培养在湿润的37℃、5%CO2培养箱中,在90-95%汇合时分开,并在第5-8代之间使用。
将HEK293细胞(ATCC,Manassas,VA)培养在补充有10%胎牛血清、100U/mL的青霉素G钠、100μg/mL的硫酸链霉素和选择抗生素的杜尔贝科氏改良伊格尔培养基/营养混合物F-12(Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12,D-MEM/F-12)中。
将CHO细胞(ATCC,Manassas,VA)培养在补充有10%胎牛血清、100U/mL的青霉素G钠、100μg/mL的硫酸链霉素和合适的选择抗生素的Ham’s F-12中。
转染
钾通道基因在HEK293或CHO细胞中表达(参见表1)。SspI和PvuI酶用于线性化pcDNA3.1质粒(Thermo Fisher)。用Lonza Nucleofector稳定地转染质粒。如通过通道的表达(免疫印迹法)和激活(膜片钳和膜电位检测)所验证的,转染效率>80%。
表1:钙和钾通道表达系统
钾通道活性
根据制造商的说明,使用荧光成像读板机(Fluorescence Imaging PlateReader)(FLIPRTETRATM)仪器、使用钾染料(铊通量测定,Molecular Devices)进行电压门控钾通道的功能活性。将细胞以每孔15,000至30,000个细胞接种在384孔黑壁、平透明底微量滴定板(BD Biocoat Poly-D Lysine Multiwell Cell Culture Plate)中。将细胞在37℃下培养过夜或直至细胞在孔中达到足够的密度(几乎汇合单层)以用于荧光测定。典型顺序是记录预培养期间(刺激前第一次添加试验品)的基线,接着在刺激物缓冲液中激活。对于每次添加,以最大速率(1个样品/秒)获取前60秒的数据,并且对于剩余的9-19分钟(取决于每次添加的记录时间);每5秒取样数据。
钙成像
将HUVEC接种至24孔板并生长至70%汇合。为了监测细胞溶质Ca2+信号,将细胞装载有fluo-3AM(4μmol/L;Molecular Probes)并在含有20%普流尼克酸(pluronic acid)的完全培养基中在37℃下培养40分钟。在用含有(以mmol/L计)1.25CaCl2、5.5D-葡萄糖、10HEPES、5KCl、0.5MgCl2、和140NaCl的HEPES缓冲液(用NaOH使其pH为7.4)洗涤两次后;在荧光成像前,将板在37℃下培养另外的15分钟。在用4α-佛波醇-12,13-二癸酸酯(4α-PDD;特定TRPV4激动剂;10μmol/L)、5,6-diHETE((±)5,6-二羟基-8Z,11Z,14Z,17Z-二十碳四烯酸)1,5内酯(0.01-5μmol/L)和5,6-diHETE(5,6-EEQ的水解异构体;2和5μmol/L)处理的细胞中,在5分钟期间每1秒获取荧光图像。对于各个试验确定最大强度(F1)和基础强度(F0)之间的计算的比并表示为平均值±SD。
实验动物
C57BL/6J雄性小鼠(3-6月龄,获自Harlan实验室(目前为Envigo))可自由获取水和食物,并根据国家动物实验委员会(National Council for Animal Experimentation)(#IL-17-14-138)进行处理。
小鼠血管中的血管反应性
在实验前一天,将成年雄性小鼠(年龄3-6个月)断头,并且分离肠系膜组织并置于具有包含以下的冰冷的HEPES-生理盐水溶液(PSS)的琼脂板上:123mM NaCl、4.7mM KCl、2.5mM CaCl2*2H2O、1.2mM MgSO4*7H2O、20mM NaHCO3、1.2mM KH2PO4、26μM EDTA、11mM葡萄糖和2.38mg/ml HEPES。小心地去除脂肪和结缔组织,将小动脉(150-200μm直径)切割为3mm片段并在4℃下保存过夜。然后,将血管小心地安装在两根钨丝(0.025mm直径)上并小心不损伤内皮,并安装在四腔线性肌动描记器(four-chamber wire myograph)(DMT,Denmark,型号620M)上。然后,将动脉在填充有PSS的肌动描记器腔中在37℃下平衡30分钟,用含有21%O2、74%N2、和5%CO2的气体持续鼓泡,并设定为在LabChart Pro软件(AD instruments,Oxfordshire,UK)中获得的1mN静息张力。实验方案开始前,刺激动脉两次;第一次用KCl(127mM),第二次用血栓素模拟物U-46619(100nM),分别刺激5分钟和10分钟。丢弃在收缩中不显示至少2mN的值的动脉。在收缩达到稳定状态后,添加DMSO(至多0.16%)中的累积浓度的5,6-diHETE内酯(1μM至10μM),并且相对于对100μM罂粟碱的松弛响应来确定%松弛响应。
人受试者(自其提取血管)
表2:受试者的特性
性别(M/F) | 6/11 |
年龄,年(平均值±SEM) | 54.3±3.62 |
BMI(平均值±SEM) | 28.01±0.84 |
BMI≥30 | 3/18 |
潜在疾病/风险因素:
冠状动脉疾病(CAD) | 0 |
高血压(HTN) | 9 |
高胆固醇血症(HL) | 2 |
糖尿病(DM) | 4 |
充血性心力衰竭(CHF) | 0 |
以上皆无 | 6 |
统计学分析
结果报告为平均值±标准误差。统计学分析使用单向ANOVA和图基事后检验进行,字母表示不同浓度之间的显著差异,并且星号表示与阴性对照的显著差异。5%以下的P值被认为是统计学显著的。使用GraphPad Prism 5软件分析数据。
实施例1:5,6-diHETE内酯介导细胞内[Ca2+]增加
为了研究5,6-diHETE((±)5,6-二羟基-8Z,11Z,14Z,17Z-二十碳四烯酸)内酯对细胞溶质[Ca2+]i的效果(图1),将HUVEC暴露于乙醇/HEPES缓冲液中的梯度剂量的5,6-diHETE内酯(0.01–5μmol/L),并借助荧光强度来确定细胞内[Ca2+]的变化。结果显示,细胞溶质[Ca2+]i响应于5,6-diHETE内酯以剂量依赖性方式增加至高达0.1μM。在超过0.5μM内酯时,未检测到细胞溶质[Ca2+]i水平的显著差异。超过此浓度,细胞溶质[Ca2+]i水平达到饱和。
将CYP代谢物酯化为磷脂或由可溶性环氧化物水解酶(sEH)水解为活性较低的形式二羟基二十碳三烯酸[DHET])。这些快速途径导致环氧化物浓度的降低,由此导致它们的活性的减低。因此,我们测试了水解形式与未水解形式相比增加细胞内钙的能力(图2)。结果显示2μmol/L的5,6-diHETE内酯,而不是2μmol/L的水解异构体5,6-diHETE,诱导HUVEC中细胞[Ca2+]i的变化。
实施例2:5,6-diHETE内酯在阻力动脉中介导舒张
为了评价由5,6-diHETE内酯介导的血管舒张,提取来自C57BL的肠系膜动脉并在生理条件下在线性肌动描记器中监测它们的舒张。用血栓素模拟物U-46619(0.1μmol/L)预收缩动脉,接着暴露于5,6-diHETE内酯(1-10μmol/L)。结果(图3)显示5,6-diHETE内酯在小鼠肠系膜动脉中介导浓度依赖性舒张(在10-5mol/L下高达29.4±3.1%收缩;n=11)。
实施例3:5,6-diHETE内酯在人小动脉中诱导舒张
从由不患有冠状动脉疾病的受试者(7名正常血压和7名高血压)获得的脂肪组织提取人脂肪小动脉(HAA)。将HAA(100-200μm直径)在器官腔(organ chamber)中用2个玻璃微量移液管插管,并用影像系统测定小动脉的内径。用内皮素-1(10-50nmol/L)预收缩小动脉以使被动直径(passive diameter)降低30-50%。响应于增加浓度的5,6-diHETE内酯(10-4-10-1μmol/L)测量松弛。为了检验NO参与5,6-diHETE内酯诱导的舒张,在存在或不存在一氧化氮合酶(NOS)拮抗剂(100μmol/L N[ω]-硝基-L精氨酸甲酯[L-NAME])的情况下测量松弛响应。
图4显示5,6-diHETE内酯在正常血压受试者中产生浓度依赖性血管舒张(10-7mol/L下的最大舒张=58.6%,n=5),并且施用L-NAME)使该效果降低50%,意味着5,6-diHETE内酯在正常血压受试者中的活性不完全依赖于NO。然而,内皮细胞层的机械剥脱显著降低5,6DiHETE内酯诱导的舒张,表明5,6DiHETE内酯诱导的舒张的内皮细胞依赖性机制。
如先前所述(H.Miura,Circ.Res.92(2003)),通过用预热的空气灌注血管来实现内皮细胞剥脱。在各个实验结束时,添加罂粟碱(100μmol/L)(内皮细胞非依赖性血管舒张剂)以确定相对于舒张剂响应的归一化的最大舒张。血管舒张剂响应表示为最大舒张的百分比,其中100%表示完全松弛(最大直径)。
图5显示5,6-diHETE内酯在高血压受试者中产生浓度依赖性血管舒张(10-7mol/L下的最大舒张=40.9%,n=5),并且施用100μmol/L L-NAME无效果,意味着5,6-diHETE内酯在高血压动脉中的活性完全不依赖于NO。该最终结果可能与以下相关:高血压受试者中的NO信号途径可能受损并且其生物利用度降低,内皮细胞依赖性舒张通常由EET或H2O2的补偿性产生来维持(Freed和Gutterman,2017)。
实施例4:5,6-diHETE内酯对钾通道的激动剂效果
刺激钙激活的钾(KCa)通道以超极化内皮细胞是获得下层血管平滑肌的内皮细胞依赖性超极化的前提。内皮SK(KCa2.3)和IK(KCa3.1)激活的展现被认为对于内皮源性超极化因子(EDHF)的可接受的定义是关键的,其起到在高血压中保持动脉松弛的作用。
因此,该研究的目的在于评价5,6-diHETE内酯对在HEK-293或CHO细胞中稳定表达的两种克隆的人通道的体外激动剂效果。根据制造商的说明,用铊通量测定(Potassium Assay,Molecular Devices)进行试验。简言之,将细胞以每孔15,000至30,000个细胞接种在384孔黑壁、平透明底微量滴定板(BD Biocoat Poly-D-Lysine MultiwellCell Culture Plate)中。将细胞在37℃下培养过夜或直至细胞在孔中达到充分的密度(几乎汇合单层)以用于荧光试验。染料负载:去除生长培养基并在室温下用染料负载缓冲液替换60分钟(避光)。激动剂效果:将5次重复的在具有5mM Tl+的无K+缓冲液中的(5μL)试验品和溶媒或对照溶液(试验缓冲液=0.3%DMSO)添加至各孔约5五分钟。试验品为5,6-diHETE内酯(8个浓度:0.05、0.15、0.3、0.65、1.25、2.5、5、和10μM,n=4)。在此期间通过使用荧光成像读板机(FLIPRTETRATM)仪器来评价试验品对钾通道的激动剂效果。
为了计算效果,将在存在已知激动剂(1μM A-23187用于SK3和10μM NS309用于IK)的情况下、由5mM铊激发的信号设定为100%激活,并将在存在溶媒对照(试验缓冲液+0.3%DMSO)的情况下的信号设定为0%激活。使用GraphPad prism 5软件、使用假设简单结合模型的非线性回归拟合公式来计算EC50。
表3-5,6-diHETE内酯对IK通道的激动剂效果(图6A)
如果平均值高于溶媒对照平均值三个或更多个标准偏差,则认为效果是显著的。溶媒(试验缓冲液中0.3%DMSO)平均值的3x SD=7.73;值>7.73被认为是显著的(加粗强调)。
表4-5,6-diHETE内酯对SK3通道的激动剂效果(图6B)
如果平均值高于溶媒对照平均值三个或更多个标准偏差,则认为效果是显著的。溶媒(试验缓冲液中0.3%DMSO)平均值的3x SD=0.41;值>0.41被认为是显著的(加粗强调)。
实施例5:5,6-diHETE内酯通过内皮钙激活的钾(KCa)通道诱导血管舒张
5/6大鼠肾切除术模型(5/6Nx)–所有动物实验根据机构动物伦理委员会指南来进行,其符合美国国立卫生研究院(US National Institutes of Health)所出版的实验动物的护理和使用指南(第八版2011)(Ethics#:26-04-2016)。在该研究中,我们使用250-300克Sprague-Dawley雄性大鼠。将动物维持在机构实验手术单元(Experimental SurgicalUnit)并且用正常啮齿动物饲料喂养,并随意饮用自来水。将大鼠在正常光/暗时间表(12:12)下、在恒定温度和相对湿度下饲养。
如先前所述(M.Verkaik,等,Physiol.Rep.6(2018)1–13),使用5/6Nx模型诱导高血压。简言之,在87mg/kg氯胺酮和13mg/kg赛拉嗪麻醉(肌内)下,通过右肾动脉和静脉的完全闭塞来进行肾次全消融(subtotal renal ablation)。其后,通过将左肾动脉的两个分支结扎以使2/3的左肾梗塞,导致5/6的大鼠肾单位的局部缺血,即5/6Nx。在手术结束时,缝合腹部肌肉和皮肤,并将动物放回其笼中进行恢复。
使用CODA非侵入性血压NIBP系统(Kent Scientific Corporation,TorringtonCT,USA),通过经验证的尾套体积描记法(tail-cuff plethysmography method)在清醒大鼠中监测血压。
用氯胺酮(87mg/kg)、赛拉嗪(13mg/kg)深度麻醉雄性Sprague-Dawley大鼠(300-350克)。获得肠系膜动脉(250-300μm)的完整的2级或3级分支,并且小心去除脂肪和结缔组织。然后,将动脉在含有以下(以mmol/L计)的冷(4℃)生理盐水溶液(PSS-HEPES)中保存过夜:123mM NaCl、4.7mM KCl、2.5mM CaCl2*2H2O、1.2MgSO4*7H2O、20mM NaHCO3、1.2mMKH2PO4、0.026mM EDTA、11mM葡萄糖、和2.38mg/ml HEPES,pH 7.4。将血管切割为片段(2mm长),小心不损伤内皮细胞,置于2根钨丝(25μm直径)上,并安装在4腔线性肌动描记器(型号620M;Danish Myo Technology)上。然后,将动脉在填充有PSS的肌动描记器腔中在37℃下平衡30分钟,用含有21%O2、74%N2、和5%CO2的气体持续鼓泡,并设定为2mN静息张力。在实验方案开始前,刺激动脉两次:第一次用KCl(60mmol/L),第二次用血栓素模拟物U-46619(100nmol/L),每次5分钟。为了检验内皮功能,第二次收缩后接着用乙酰胆碱(100nmol/L)舒张,然后用罂粟碱(100μmol/L)达到最大舒张。在放置30分钟后,由U-46619(100nmol/L)再收缩动脉,接着添加5,6-diHETE内酯(以0.01-5μmol/L的累积剂量)。相对于对100μmol/L罂粟碱的松弛响应,确定松弛响应%。所有试验中对于动脉的选入标准包括响应于U-46619和KCl的收缩>3mN和由Ach的舒张>50%。KCa通道由蜂毒明肽(SKCa阻断剂,1μmol/L)和TRAM-34(IKCa阻断剂,1μmol/L)抑制,其在用U-46619收缩前20分钟添加至浴中。
在提取自5/6Nx大鼠的肠系膜动脉中评价5,6-diHETE内酯松弛效果。如从图7A-7D中可以看到的:图7A显示5/6Nx血压的增加,这表明肾功能障碍和HTN的发展。收缩压在手术后2周内增加30mmHg(达到165±5mmHg),并且在12周期间逐步增加至183±5mmHg。因此,对提取自大鼠模型(NT和5/6Nx)的肠系膜小动脉(2级,直径<200μm)测试它们响应于增加浓度的乙酰胆碱(图7B)或5,6-diHETE内酯(图7C)的舒张。乙酰胆碱诱导的NT血管的松弛显著(<0.05%)高于5/6Nx血管,分别达到94.8±5.5%和63.2±15.6%松弛(n=7-13),而5,6-diHETE内酯在10-6M下诱导的5/6Nx血管的松弛(达到73.3±20.2%松弛)高于NT血管松弛(58.6±25.0%)(n=11)。用TRAM-34和蜂毒明肽(分别为IKCa和SKCa阻断剂)的预处理显著减弱5,6-diHETE内酯诱导的松弛(p<0.01,图7D)。
实施例6:5,6-diHETE内酯的急性(一次)施用体内降低高血压
直接血压测量-对于直接血压(BP)评价,通过注射87mg/kg氯胺酮和13mg/kg赛拉嗪(肌内)混合物来深度麻醉Sprague-Dawley 5/6Nx大鼠。然后,用静脉管和动脉管对大鼠进行处理。具体地,使用26G静脉内插管(BD Neoflon,Helsinborg,Sweden),我们刺破一条尾静脉并安装插管。然后,施用1ml的肝素盐水(500IU/ml)混合物以避免血液凝固。同时,我们安装了动脉管,在切开颈部后,我们直接暴露右侧颈动脉并将其远端结扎。然后,近端夹紧动脉并在结扎和夹具之间切开。使100PE管进入动脉并通过第二次结扎而紧固其以避免血液泄漏,然后我们移除动脉夹具。将外部管附接至Luer活塞阀,通过该活塞阀可注射盐水、抽血,或与压力传感器连接。
在连接和稳定后,通过MPVS-300系统以200个样品/秒的取样速率连续取样信号,并记录。通过PowerLab System和Chart5软件(AD Instruments,Colorado Springs,CO,USA)在个人电脑上显示并记录数据。
记录基础BP 10分钟,然后将溶解于盐水+DMSO(9:1)的0.5ml 5,6-diHETE内酯(0.3mg/kg和3mg/kg)通过静脉管注射,并且在注射后记录BP另外的10分钟。对于对照,连续使用两种不同的已知的BP降低剂,拉贝洛尔(10mg/kg)(已知的α和β肾上腺素抑制剂),和氨氯地平(1.5mg/kg)(钙通道阻断剂)(各自通过0.5ml静脉注射)。在每次注射后,记录BP另外的10分钟。具体地,在内酯效果记录后,施用拉贝洛尔,并且10分钟后,施用氨氯地平。我们通过静脉施用过量的1M KCl直至心脏停止来终止试验。
如从图8A和8B中可以看到的,与基线(188.0±5.5mmHg)相比,在注射0.3mg/kg 5,6-diHETE内酯后,表现出收缩压(SBP)的降低(162.5±12.3mmHg)。该效果与拉贝洛尔诱导的SBP降低类似,尽管拉贝洛尔以较高浓度(10mg/kg)施用。如从图8B中可以看到的,在注射5,6-diHETE内酯或注射拉贝洛尔后,相对于基线的SBP的降低百分比为约20%。
实施例7:长期施用5,6-diHETE内酯体内降低高血压
通过一天一次静脉内注射、持续5天来用5,6-diHETE内酯处理Sprague-Dawley 5/6Nx大鼠。然后对大鼠监测血压的变化并通过血液和尿化学来评价肾功能。在三个时间点获取数据:0(肾切除术前),用内酯处理后(第5天注射结束时),和另一周的洗出(wash out)后。
参考文献
Eryanni-Levin S,Khatib S,Levy-Rosenzvig R,Tamir S,Szuchman-Sapir A.5,6-delta-dhtl,a stable metabolite of arachidonic acid,is a potential substratefor paraoxonase 1.Biochim Biophys Acta.2015:1851:1118-1122.
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Levi-Rosenzvig R,Beyer AM,Hockenberry J,Ben-Shushan RS,Chuyun D,AtiyaS,Tamir S,Gutterman DD,Szuchman-Sapir A.5,6-delta-dhtl,a stable metabolite ofarachidonic acid,is a potential EDHF that mediates microvasculardilation.Free Radic Biol Med.2017:103:87-94.
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Claims (13)
1.一种药物组合物,其包含5,6二羟基二十碳四烯酸(5,6-diHETE)内酯和药学上可接受的载体。
2.根据权利要求1所述的药物组合物,其配制成通过注射施用。
3.根据权利要求1或2所述的药物组合物,其中,所述5,6-diHETE内酯在所述组合物中的浓度为10-9M和10-6M之间。
4.根据权利要求1-3中任一项所述的5,6二羟基二十碳四烯酸(5,6-diHETE)内酯或药物组合物,其用于在有需要的受试者中诱导血管舒张。
5.根据权利要求1-3中任一项所述的5,6二羟基二十碳四烯酸(5,6-diHETE)内酯或药物组合物,其用于在有需要的受试者中治疗与微血管功能障碍相关的疾病、病症或病况。
6.根据权利要求5使用的5,6-diHETE内酯或药物组合物,其中,所述与微血管功能障碍相关的疾病、病症或病况选自衰老、淀粉样变性病、查加斯病、慢性血栓栓塞性肺动脉高压、痴呆、糖尿病、药物滥用(例如烟草滥用)、射血分数保留型心力衰竭(HFpEF)、射血分数降低型心力衰竭(HFrEF)、高血压、肥厚型梗阻性心肌病、特发性心肌病、炎性疾病(例如炎性肠病)、缺血性心肌病、无复流现象、肥胖、阻塞性睡眠呼吸暂停、周围神经病、精神分裂症、应激相关性心肌病、系统性红斑狼疮、系统性硬化症、肿瘤血管生成、和血管痉挛。
7.根据权利要求6使用的5,6-diHETE内酯或药物组合物,其中,所述与微血管功能障碍相关的疾病、病症或病况是高血压。
8.根据权利要求5-7中任一项使用的5,6-diHETE内酯或药物组合物,其中,所述受试者对用于治疗所述与微血管功能障碍相关的疾病、病症或病况的至少一种药物无响应。
9.根据权利要求5-8中任一项使用的5,6-diHETE内酯或药物组合物,其适于与用于治疗与微血管功能障碍相关的疾病、病症或病况的其它药剂,例如用于治疗高血压的药剂联合施用。
10.根据权利要求1-3中任一项所述的5,6二羟基二十碳四烯酸(5,6-diHETE)内酯或药物组合物,其用于在处于发展与微血管功能障碍相关的心脏病况的风险的受试者中预防发展所述心脏病况、或降低发展所述心脏病况的风险。
11.一种在有需要的受试者中诱导血管舒张的方法,所述方法包括向所述受试者施用根据权利要求1-3中任一项所述的药物组合物。
12.一种治疗与微血管功能障碍相关的疾病、病症或病况的方法,所述方法包括向有需要的受试者施用如权利要求1-3中任一项所限定的药物组合物。
13.一种预防发展与微血管功能障碍相关的心脏病况、或降低发展所述心脏病况的风险的方法,所述方法包括向有需要的受试者施用根据权利要求1-3中任一项所述的药物组合物。
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