CN110225749A - Senicapoc用于治疗中风 - Google Patents
Senicapoc用于治疗中风 Download PDFInfo
- Publication number
- CN110225749A CN110225749A CN201880008645.6A CN201880008645A CN110225749A CN 110225749 A CN110225749 A CN 110225749A CN 201880008645 A CN201880008645 A CN 201880008645A CN 110225749 A CN110225749 A CN 110225749A
- Authority
- CN
- China
- Prior art keywords
- senicapoc
- apoplexy
- microglia
- ischemia
- injury
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
由小胶质细胞和浸润性外周免疫细胞介导的神经炎症是中风病理生理学的主要组成部分。钙激活的钾通道KCa3.1在小胶质细胞中在受损的CNS中选择性表达,并且KCa3.1功能与小胶质细胞的促炎活化相关。KCa3.1更涉及与脑损伤相关的局部缺血/再灌注(中风)的病理生理学。Senicapoc作为一种具有已证实的安全性并且显示可穿过血脑屏障的研究药物,是一种有效的选择性KCa3.1抑制剂,可干预缺血/再灌注后的炎症级联反应,是一种潜在的中风治疗药物。
Description
技术领域
本发明涉及使用Senicapoc治疗中风。
背景技术
中风是严重长期残疾的主要原因,也是美国的第五大死亡原因(Mozaffarian etal.,2015)。中风的治疗方法选择很少,且疗效有限(Prabhakaran et al.,2015)。针对急性缺血性中风的细胞反应,特别是免疫细胞的反应已有广泛研究,并于最近进行了详细的综论(Iadecola and Anrather,2011;Macrez et al.,2011)。中风后免疫反应的动力学在缺血后生理学中至关重要,脑缺血的双相或多相反应的概念现已得到认同(Hayakawa etal.,2010;Lo,2008;Maki et al.,2013)。缺血后炎症的特征在于涉及脑、其血管、循环血液和淋巴器官的一系列反应。许多这些过程在预处理介导的神经保护中起着重要作用(McDonough and Weinstein,2016)。
小胶质细胞是中枢神经系统(CNS)常驻免疫细胞(Benarroch,2013;Michell-Robinson et al.,2015),其衍生自卵黄囊巨噬细胞,在早期发育期间进入CNS并且保持自身作为不同于循环单核细胞的群体(Ginhoux et al.,2010)。小胶质细胞通过修剪突触,清除死亡或垂死的细胞以及为其他细胞提供营养支持来维持脑内稳态(Zuchero andBarres,2015)。这些功能表明小胶质细胞在CNS的正常生理和发育中起关键作用(Jha etal.,2015)。小胶质细胞在缺血的神经炎症反应中起重要作用(Weinstein et al.,2010)。小胶质细胞表达Toll样受体(TLRs)和其他模式识别受体使它们能够识别病原体并上调效应免疫细胞因子和趋化因子特有的来响应各种刺激(van Rossum and Hanisch,2004)。小胶质细胞表达最多的是TLR4,内源性和外源性TLR4激动剂均有效激活小胶质细胞中的典型促炎反应(Dave et al.,2006;van Rossum and Hanisch,2004)。
尽管小胶质细胞激活通常被认为是促炎过程,但是最近的出版物表明小胶质细胞可以通过诸如神经元的代谢和生理支持(van Rossum and Hanisch,2004),营养因子的产生(Nedergaard and Dirnagl,2005),损伤的自噬和损伤组织的修复(Cunningham et al.,2005)的多种机制在中风中发挥保护作用(Lalancette-Hebert et al.,2007;Nedergaardand Dirnagl,2005)。小胶质细胞是缺血性损伤的第一响应者,在外周单核细胞/巨噬细胞浸润CNS之前激活(Umekawa et al.,2015)。缺血诱导小胶质细胞数量激增(Denes et al.,2007;McDonough and Weinstein,2016)和增殖(Denes et al.,2007)。小胶质细胞的药理学或遗传性消融影响多种啮齿动物中风模型的结果(Lalancette-Hebert et al.,2007;Szalay et al.,2016)。这些发现提供了强有力的证据支持先天免疫信号和小胶质细胞在缺血诱导的损伤和神经保护中的关键作用。
小胶质细胞激活的影响及其在缺血后炎症中的作用如图1中示意(Staal et al.,Neurochem Res.2017)。如图1所示,星形胶质细胞(AS)通过多种机制为神经元(N)提供营养支持,并分泌转化生长因子β(TGFβ),其对内皮细胞(EC)具有修复作用。小胶质细胞(MG)和星形胶质细胞均响应缺血而分泌促炎细胞因子(肿瘤坏死因子α(TNFα)、IL-1β、IL-6、IL-17)。神经元还通过趋化因子(CX3CL1)向表达同源受体CX3CR1的小胶质细胞发出信号。星形胶质细胞和外周免疫细胞(PIC)都是1型干扰素(IFNα,β)的潜在来源,通过IFNAR向小胶质细胞发出信号,触发干扰素刺激基因(ISG)的转录。产生的ISG蛋白质可以在长时间缺血的情况下增强少突胶质细胞(OL)的活力,反过来增加白质中的轴突完整性。后者可能限制长期缺血诱导的神经网络损伤并保护白质基的连接。EC和其他细胞释放损伤相关分子模式(DAMP),例如纤连蛋白、高迁移率族蛋白1(HMGB1)、过氧化物氧还原蛋白(PRX)和热休克蛋白(HSP),它们是许多TLR的内源配体。PIC能够分泌许多不同的细胞因子,其对多种细胞类型有影响。
因此,可以在局部缺血的情况下特异性调节小胶质细胞基因表达和表型的药物治疗剂能够在更有利于神经元存活和轴突/白质完整性的方面有效地扭转神经免疫应答。
钙活化的钾通道KCa3.1通过脑血管细胞在CNS中组成型表达。它也在CNS损伤后由小胶质细胞表达(Chen et al.,2015)。KCa3.1导致钾外流,从而增加Ca2+进入的驱动力,并随后影响Ca2+依赖性免疫机制。已经表明小胶质细胞在体外表达KCa3.1并且其抑制作用减少了从适当刺激的小胶质细胞产生和释放一氧化氮(NO)和白细胞介素1β(IL-1β)(Dale etal.,2016)(图1)。其他研究表明,抑制KCa3.1可减少参与类二十烷酸(COX-2)和一氧化氮(iNOS)生成的酶的小胶质细胞合成(Nguyen et al.,2016)。因此,抑制了KCa3.1预期会有广泛的抗炎作用。
已经报道了几种KCa3.1抑制剂(Wulff and Castle,2010;Wulff et al.,2007)。然而,早期的抑制剂缺乏活性和选择性,并受到安全问题的阻碍(Suzuki et al.,2000;Wulffand Castle,2010;Zhang et al.,2002)。
TRAM-34被认为是KCa3.1的选择性抑制剂,具有良好的活性和CNS渗透性。TRAM-34在重组细胞系中有效抑制KCa3.1通道,IC50为20nM,并对细胞色素P450依赖性酶没有影响(Wulff et al.,2000)。它已被用于研究免疫细胞中KCa3.1通道的生理学和KCa3.1通道在几种中枢神经系统疾病中的作用,包括多发性硬化症(Reich et al.,2005)、视神经横断(Kaushal et al.,2007)、脊髓损伤(Bouhy et al.,2011)、缺血性中风(Chen et al.,2011;Chen et al.,2015),和胶质母细胞瘤(D'Alessandro et al.,2013)。Wulff及其同事在缺血性中风的大鼠模型中评估了TRAM-34(Chen et al.,2011)。在腹膜内(i.p.)给药TRAM-34 40mg/kg后,血浆和脑浓度在8小时达到~1μmol/L,12小时降至0.4μmol/L。测定游离血浆浓度约为2%。根据这些数据,估计在12小时(第二次剂量前)时,血浆和脑浓度分别为20nM和8nM。因此,当腹膜给药时,TRAM-34浓度等于或接近KCa3.1抑制的IC50值。然而,达到高于IC50值的浓度所需的高剂量表明TRAM-34的生物利用度是一个重大问题。
TRAM-34的游离CNS水平不远高于体外小胶质细胞中KCa3.1抑制的IC50,并且t1/2表明CNS KCa3.1抑制在给药后仅几小时就达到。虽然开发能够提供24小时覆盖甚至多剂量模式的CNS渗透性药物总是具有挑战性,但是实现药物水平以及t1/2还有很大的改进空间。调节神经免疫反应,特别是小胶质细胞/巨噬细胞表型,是急性缺血性中风治疗的一个有吸引力的目标,部分原因是这种反应在数天到数周内逐渐形成,而许多先前针对中风的生理现象,如谷氨酸依赖性兴奋性中毒,倾向于快速发生(中风发作后数分钟至数小时)(Dirnagl,2012)。因此,在中风中靶向神经免疫反应提供了更广泛的时间治疗窗口,并且可以转化为超过当前时间窗口三到六小时的治疗。腹膜给药TRAM-34 10和40mg/kg明显减轻了脑中风后梗死体积和神经元丢失。TRAM-34还改善了神经功能缺损评分并显著降低了小胶质细胞的ED1染色的程度。特别有前景的是,即使在缺血性损伤12小时后给药TRAM-34也改善了这种中风模型的结果。目前急性缺血性中风的药物治疗需要在3-4.5小时内进行(Prabhakaran et al.,2015),这种时间上的挑战严重限制目前可用的疗法。
尽管TRAM-34显示出针对KCa3.1高于其他钙激活的钾通道的选择性(Wulff etal.,2000),但它可能已经抑制了其他的靶标,从而混淆对任何结果的解释(Schilling andEder,2007)。Schilling和Eder已证明TRAM-34可阻断用溶血磷脂酰胆碱(LPC)刺激的原代小胶质细胞中的非选择性阳离子电流,其IC50与抑制KCa3.1通道的IC50相近(Schilling andEder,2007)。此外,另一种推测的KCa3.1阻断剂charybdotoxin对LPC信号没有影响(Schilling and Eder,2007)。因此,TRAM-34可通过与KCa3.1抑制无关的机制调节免疫细胞功能。此外,最近已经证明TRAM-34也抑制一些细胞色素P450同种型,即人CYP2B6、CYP2C19和CYP3A4,其IC50值在低微摩尔范围内(Agarwal et al.,2013)。
此外,TRAM-34显示代谢不稳定以及半衰期短(在大鼠和灵长类中约2小时),可能使慢性给药变得复杂(Maezawa et al.,2012)。因此,尽管TRAM-34是有价值的实验性和潜在有效的治疗剂,但它存在可能混淆临床前模型中机制的解释并且可能限制其临床效用的问题。
另一种报道的KCa3.1抑制剂是NS6180,(4-[[3-(三氟甲基)苯基]甲基]-2H-1,4-苯并噻嗪-3(4H)-酮)(et al.,2013)。据报道,NS6180具有与TRAM-34相似的活性和选择性。
另一种KCa3.1抑制剂是senicapoc(ICA-17043),一种有效的CNS渗透抑制剂,与TRAM-34相比具有改良的稳定性和选择性(Dale et al.,2016;et al.,2013;Schilling and Eder,2007)。Senicapoc是美国专利6,288,122中描述的实验药物。Senicapoc先前已被用于治疗镰状细胞性贫血(Ataga et al.2008)和疟疾(Tubman etal.2016)。然而,在镰状细胞病的III期临床试验中发现,尽管血液学参数有所改善,但观察到镰状细胞疼痛危象并没有改善,因此中止了开发(Ataga et al.,2011)。值得注意的是,镰状细胞临床试验未因安全性或毒性原因而终止。
发明内容
鉴于senicapoc对KCa3.1的选择性抑制,同时降低一氧化氮和对Ca++信号传导的调节,以及senicapoc穿过血脑屏障的能力,senicapoc发挥神经保护作用并且可以预防或降低在有中风或缺血性损伤风险的患者或急性缺血性中风患者中的中风或缺血性损伤。此外,由于抑制KCa3.1而带来的抗炎作用,senicapoc可用于治疗患有中风或缺血性损伤的患者并减轻与这些病症相关的神经炎症。
因此,在一个实施方案中,提供了一种通过向具有中风或缺血性损伤直接风险的患者或正患有急性中风或缺血性损伤的患者施用senicapoc来预防或治疗中风的方法。在一个实施方案中,senicapoc用于制备一种药物,所述药物通过向有中风或缺血性损伤或者具有中风或缺血性损伤风险的患者施用senicapoc来预防或治疗中风。在一个实施方案中,提供了senicapoc的一种口服剂型,用于通过向有中风或缺血性损伤或者具有中风或缺血性损伤的风险的患者施用senicapoc来预防或治疗中风。
附图说明
图1为缺血性炎症中CNS细胞与senicapoc活性位点之间的关键神经免疫途径和相互作用的示意图。
图2为KCa3.1的抑制对NO和Ca++信号调节的影响。小胶质细胞(以绿色显示)和脑血管内皮细胞(以红色显示)的所有下游效应被senicapoc电生理学减弱。
图3为暴露于对照或senicapoc的大鼠小胶质细胞中的KCa3.1电生理学。通过使用(A)去极化步骤或(B)电压斜坡方法从原代小胶质细胞中记录K+电流。在两种范例中,电流在0mV时反转,这是K+的平衡电位。Senicapoc剂量依赖性地抑制了K+电流的重要部分。
图4为KCa3.1的抑制对原代小胶质细胞NO和IL-1β释放的影响。(A)用溶剂或senicapoc预处理原代大鼠皮质小胶质细胞,浓度指示30分钟,然后加入脂多糖(LPS)(3EU/mL)并孵育共24小时。如代表性实验(n=3)所示,Senicapoc抑制NO的产生(通过其代谢物亚硝酸盐测量),EC50为0.9nM。(B)将原代大鼠皮质小胶质细胞与LPS(3EU/mL)一起孵育24小时以诱导IL-1β的表达。Senicapoc剂量依赖性地抑制原代小胶质细胞释放IL-1β,IC50为1.3nM(n=3)。
具体实施方式
中风是严重长期残疾的主要原因,并且是美国的第五大死亡原因。中风的治疗方法选择很少,且疗效有限。由小胶质细胞和浸润性外周免疫细胞介导的神经炎症是中风病理生理学的主要组成部分。中风后干扰炎症级联有望调节中风的结果。钙激活的钾通道KCa3.1通过小胶质细胞在受损的CNS中选择性表达。KCa3.1功能与小胶质细胞的促炎活化有关,并且最近有文献表明该通道在缺血/再灌注(中风)相关脑损伤的病理生理学中是重要的。因此,作为KCa3.1抑制剂的senicapoc可干预缺血/再灌注后的炎症级联,并限制由中风或其他缺血性损伤引起的损伤。
Senicapoc减弱小胶质细胞和上皮细胞中的促炎反应(减少细胞因子和一氧化氮的释放)并减轻缺血诱导的血脑屏障破坏(BBB)(图1)(Staal et al.,NeurochemRes.2017)。通过调节小胶质细胞和上皮细胞对局部缺血反应的因素,senicapoc可以通过多种方式间接地影响神经环境,例如通过增强白质完整性,如图1所示。
在与本申请于2017年10月23日共同提交的专利申请PCT/US17/57930中详细讨论了senicapoc抑制钾通道KCa3.1的能力。
KCa3.1在体外小胶质细胞上高度表达(Kaushal et al.,2007)。运用自动膜片钳分析,通过去极化步骤(图3A)或电压斜坡方法(图3B)引发的小胶质细胞K+电流来评估senicapoc的作用。Senicapoc剂量依赖性地(10、100、300和1000nM)抑制小胶质细胞K+电流,尽管不完全(图3A),IC50为10nM。该值与CHO-KCa3.1细胞的膜片钳研究中得出的IC50值(10nM)非常一致。一些可能不对KCa3.1敏感的残留的K+电流仍然存在(Kettenmann et al.,2011)。
为了显示一氧化氮和IL-1β的抑制,将原代大鼠皮质小胶质细胞与溶剂或senicapoc一起孵育30分钟,然后加入溶剂或超纯LPS(3EU/mL)以刺激iNOS表达和NO的释放。24小时后,测定培养基中的亚硝酸盐(NO的稳定代谢物)。Senicapoc剂量依赖性地抑制LPS处理过的小胶质细胞中NO的释放,平均IC50为39nM(图4A),与先前的研究一致(Kaushalet al.,2007;Khanna et al.,2001)。原代大鼠皮质小胶质细胞也用LPS(3EU/mL,3小时)处理以刺激pro-IL-1β的产生。随后,加入溶剂或senicapoc再孵育30分钟,然后加入BzATP(1mM)以激活P2X7受体并触发胱天蛋白酶1的激活,其裂解pro-IL-1β和释放解离的IL-1β(另外30分钟)。Senicapoc剂量依赖性地抑制原代小胶质细胞的IL-1β释放,IC50为15nM(图4B)。
与TRAM-34不同,senicapoc在阻断KCa3.1的浓度下没有已知的脱靶效应(Staal etal.,2017)。它也不受代谢不稳定的影响或对细胞色素P450产生影响。最重要的是,senicapoc已经在人体临床试验中进行了测试,没有任何明显的副作用。senicapoc也是CNS渗透剂的发现开辟了其用于CNS适应症的用途。
虽然许多恶劣性的神经疾病和精神疾病可能通过senicapoc进行有效治疗,但是具有高活性和良好CNS渗透的KCa3.1选择性抑制剂作为中风治疗的研究为使用senicapoc治疗中风患者奠定了基础。
找到超过目前狭窄治疗窗口的治疗方法将是重大进步。KCa3.1抑制剂TRAM-34在这个狭窄的治疗窗外的疗效数据表明,抑制KCa3.1可能成为急性中风的一种有前景的治疗策略。有效及选择性的KCa3.1抑制剂senicapoc(IC50为11nM)最初用于治疗镰状细胞性贫血(Ataga et al.,2006;Ataga et al.,2011;Ataga et al.,2008;Ataga and Stocker,2009)。在1期临床试验中,该药物在健康志愿者和患有镰状细胞病的患者中耐受良好(Ataga et al.,2006;Ataga et al.,2011)。在一项双盲安慰剂对照的2期研究中,senicapoc(10mg/天)可减少溶血,并显著增加镰状细胞病患者的血细胞比容和血红蛋白水平(Ataga et al.,2008)。在随后的3期试验中,测试了senicapoc对血管闭塞性疼痛危象的影响(Ataga et al.,2011)。然而,尽管适当地参与红细胞KCa3.1,减少溶血和增加血红蛋白和血细胞比容水平,但是senicapoc对疼痛结果测量没有影响,并且试验终止(Ataga etal.,2011)。虽然结果是令人失望的,但重要的是要指出该药物在分子和细胞水平上已显示了其作用。临床试验的失败是因为所选择的结果测量远远超出了所提出的作用模式,并且可能并不完全依赖于这种机制。
重要的是,已经证明senicapoc可穿过血脑屏障。虽然已经详细描述了senicapoc的外周药代动力学(McNaughton-Smith et al.,2008),但最近才报道了senicapoc穿过血脑屏障的能力(Staal et al.,2017)。在大鼠中口服给药10mg/kg后,在给药1小时和4小时后,senicapoc在血浆中达到17和65nM的游离浓度以及在脑中达到37和136nM的游离浓度。在给药1小时和4小时后测定脑脊液(CSF)中的浓度为25和121nM,这与脑中的游离浓度一致。这些数据表明,senicapoc的CNS浓度大于其对KCa3.1通道的IC50值(11nM),因此应足以抑制它(McNaughton-Smith et al.,2008)。此外,senicapoc在大脑中的游离浓度比TRAM-34高好几倍。
在同一研究中,在约70个其他的神经药物靶标(50个神经元受体,8个酶,5个转运蛋白和7个离子通道)的筛选中评估了senicapoc的选择性(Staal et al.,2017)。所测试的靶标均未被1μM的senicapoc抑制,这提供了额外的证据,即senicapoc对KCa3.1通道具有选择性。在体内,在神经性疼痛的慢性收缩损伤模型中测试了senicapoc(Bennett and Xie,1988)。Senicapoc剂量依赖性地(10、30和100mg/kg口服剂量)减弱了由外周神经损伤诱导的机械超敏反应,尽管只有最高剂量是效果显著的(Staal et al.,2017)。此外,与报道的没有功能性KCa3.1的kcnn4-/-小鼠(Lambertsen et al.,2012)的运动效应相反,作者没有观察到senicapoc对运动活动的任何显著影响(Staal et al.,2017)。虽然该研究没有阐明CNS中表达KCa3.1的细胞类型,但它清楚地证明了senicapoc在改善周围神经损伤大鼠的疼痛行为方面是有效的,并且这些结论得到了血浆、大脑和脑脊液中游离药物浓度的支持。
许多活性细胞过程和复杂的细胞相互作用有助于解决缺血后炎症。senicapoc改善了神经性疼痛模型中的疼痛行为(Staal et al.,2017)。由于实验性手术相关的炎症在动物测试后7天得到解决,因此它支持功效通过抑制脊髓或脑中小胶质细胞的KCa3.1而不是外周免疫细胞来介导的假设。除了在大鼠中的先前研究之外,我们在此报道了senicapoc在小鼠中穿透CNS的能力(参见表1)。这些数据类似于在大鼠中senicapoc在大脑中达到比血浆更高的水平,并显示出类似的t1/2,这表明了senicapoc很容易穿过血脑屏障并达到远高于IC50的浓度。基于大鼠和小鼠的药代动力学数据,CNS在人体中的外显率似乎很有前景。
为了解决senicapoc的体内副作用,在疼痛模型中最相关的是镇静,因而测试了药物对大鼠运动活性的影响(Staal et al.,2017)。结果显示,在神经性疼痛的慢性收缩损伤模型中显效所需剂量下,senicapoc没有改变运动活性。数据表明KCa3.1的抑制几乎没有副作用。这些临床前发现的重要性通过人体临床试验得到了增强,这些试验表明,senicapoc是安全的并且副作用发生率低。
基于动物研究,TRAM-34和senicapoc的主要缺点是半衰期短(参见表1)。与啮齿动物的临床前研究相反,临床试验表明人体中t1/2出乎意料地为23天。这就产生了一个问题:senicapoc是否共价结合血浆蛋白,其t1/2约为21天,明显长于未结合药物的血浆蛋白。值得注意的是,潜在的共价蛋白结合不会影响senicapoc穿透CNS的能力,虽然它会使剂量调整变得更加复杂。
迄今为止,唯一评估了senicapoc的CNS疾病模型是神经性疼痛的慢性收缩损伤模型(Staal et al.,2017)。
表1 TRAM-34、NS6180和senicapoc的药代动力学报道的IC50是指在重组细胞中表达的人KCa3.1。所有数据均为化合物的口服给药。
hu:在人体受体体外测试。
化合物和制剂
在一个实施方案中,可以将senicapoc配制为口服药物制剂产品,用于预防或治疗如本文提供的中风或缺血性损伤。
口服剂型包括片剂、胶囊和用于在饮品中溶解或悬浮的粉末。此类片剂和胶囊可以通过本领域已知的各种方法配制,并且可以包括至少一种赋形剂。
Senicapoc此前仅作为口服制剂开发,但对于中风患者,可能静脉注射制剂更为合适。
参考文献
Agarwal,J.J.,Zhu,Y.,Zhang,Q.Y.,Mongin,A.A.,Hough,L.B.,2013.TRAM-34,aputatively selective blocker of intermediate-conductance,calcium-activatedpotassium channels,inhibits cytochrome P450 activity.PLoS One 8,e63028.
Ataga,K.I.,Orringer,E.P.,Styles,L.,Vichinsky,E.P.,Swerdlow,P.,Davis,G.A.,Desimone,P.A.,Stocker,J.W.,2006.Dose-escalation study of ICA-17043inpatients with sickle cell disease.Pharmacotherapy 26,1557-1564.
Ataga,K.I.,Reid,M.,Ballas,S.K.,Yasin,Z.,Bigelow,C.,James,L.S.,Smith,W.R.,Galacteros,F.,Kutlar,A.,Hull,J.H.,Stocker,J.W.,Investigators,I.C.A.S.,2011.Improvements in haemolysis and indicators of erythrocyte survival do notcorrelate with acute vaso-occlusive crises in patients with sickle celldisease:a phase III randomized,placebo-controlled,double-blind study of theGardos channel blocker Senicapoc(ICA-17043).Br J Haematol 153,92-104.DOI:10.1111/j.1365-2141.2010.08520.x
Ataga,K.I.,Smith,W.R.,De Castro,L.M.,Swerdlow,P.,Saunthararajah,Y.,Castro,O.,Vichinsky,E.,Kutlar,A.,Orringer,E.P.,Rigdon,G.C.,Stocker,J.W.,Investigators,I.C.A.,2008.Efficacy and safety of the Gardos channel blocker,Senicapoc(ICA-17043),in patients with sickle cell anemia.Blood 111,3991-3997.
Ataga,K.I.,Stocker,J.,2009.Senicapoc(ICA-17043):a potential therapyfor the prevention and treatment of hemolysis-associated complications insickle cell anemia.Expert Opin Investig Drugs 18,231-239.
Benarroch,E.E.,2013.Microglia:Multiple roles in surveillance,circuitshaping,and response to injury.Neurology 81,1079-1088.
Bennett,G.J.,Xie,Y.K.,1988.Aperipheral mononeuropathy in rat thatproduces disorders of pain sensation like those seen in man.Pain 33,87-107.
Bouhy,D.,Ghasemlou,N.,Lively,S.,Redensek,A.,Rathore,K.I.,Schlichter,L.C.,David,S.,2011.Inhibition of the Ca(2)(+)-dependent K(+)channel,KCNN4/KCa3.1,improves tissue protection and locomotor recovery after spinal cordinjury.J Neurosci 31,16298-16308.
Chen,Y.J.,Raman,G.,Bodendiek,S.,O'Donnell,M.E.,Wulff,H.,2011.TheKCa3.1 blocker TRAM-34 reduces infarction and neurological deficit in a ratmodel of ischemia/reperfusion stroke.J Cereb Blood Flow Metab 31,2363-2374.
Chen,Y.J.,Wallace,B.K.,Yuen,N.,Jenkins,D.P.,Wulff,H.,O'Donnell,M.E.,2015.Blood-brain barrier KCa3.1 channels:evidence for a role in brain Nauptake and edema in ischemic stroke.Stroke 46,237-244.DOI:10.1161/STROKEAHA.114.007445
Cunningham,L.A.,Wetzel,M.,Rosenberg,G.A.,2005.Multiple roles for MMPsand TIMPs in cerebral ischemia.Glia 50,329-339.
D'Alessandro,G.,Catalano,M.,Sciaccaluga,M.,Chece,G.,Cipriani,R.,Rosito,M.,Grimaldi,A.,Lauro,C.,Cantore,G.,Santoro,A.,Fioretti,B.,Franciolini,F.,Wulff,H.,Limatola,C.,2013.KCa3.1 channels are involved in the infiltrativebehavior of glioblastoma in vivo.Cell Death Dis 4,e773.
Dale,E.,Staal,R.G.,Eder,C.,Moller,T.,2016.KCa 3.1-a microglial targetready for drug repurposing?Glia 64,1733-1741.
Dave,K.R.,Saul,I.,Prado,R.,Busto,R.,Perez-Pinzon,M.A.,2006.Remoteorgan ischemic preconditioning protect brain from ischemic damage followingasphyxial cardiac arrest.Neurosci Lett 404,170-175.
Denes,A.,Vidyasagar,R.,Feng,J.,Narvainen,J.,McColl,B.W.,Kauppinen,R.A.,Allan,S.M.,2007.Proliferating resident microglia after focal cerebralischaemia in mice.J Cereb Blood Flow Metab 27,1941-1953.
Dirnagl,U.,2012.Pathobiology of injury after stroke:the neurovascularunit and beyond.Ann N Y Acad Sci 1268,21-25.
Ginhoux,F.,Greter,M.,Leboeuf,M.,Nandi,S.,See,P.,Gokhan,S.,Mehler,M.F.,Conway,S.J.,Ng,L.G.,Stanley,E.R.,Samokhvalov,I.M.,Merad,M.,2010.Fatemapping analysis reveals that adult microglia derive from primitivemacrophages.Science 330,841-845.
Hayakawa,K.,Nakano,T.,Irie,K.,Higuchi,S.,Fujioka,M.,Orito,K.,Iwasaki,K.,Jin,G.,Lo,E.H.,Mishima,K.,Fujiwara,M.,2010.Inhibition of reactiveastrocytes with fluorocitrate retards neurovascular remodeling and recoveryafter focal cerebral ischemia in mice.J Cereb Blood Flow Metab 30,871-882.
Iadecola,C.,Anrather,J.,2011.The immunology of stroke:from mechanismsto translation.Nat Med 17,796-808.
Jha,M.K.,Lee,W.H.,Suk,K.,2015.Functional polarization of neuroglia:Implications in neuroinflammation and neurological disorders.BiochemPharmacol.
Kaushal,V.,Koeberle,P.D.,Wang,Y.,Schlichter,L.C.,2007.The Ca2+-activated K+channel KCNN4/KCa3.1 contributes to microglia activation andnitric oxide-dependent neurodegeneration.J Neurosci 27,234-244.
Lalancette-Hebert,M.,Gowing,G.,Simard,A.,Weng,Y.C.,Kriz,J.,2007.Selective ablation of proliferating microglial cells exacerbatesischemic injury in the brain.J Neurosci 27,2596-2605.
Lambertsen,K.L.,Gramsbergen,J.B.,Sivasaravanaparan,M.,Ditzel,N.,Sevelsted-Moller,L.M.,Olivan-Viguera,A.,Rabjerg,M.,Wulff,H.,Kohler,R.,2012.Genetic KCa3.1-deficiency produces locomotor hyperactivity andalterations in cerebral monoamine levels.PLoS One 7,e47744.
Lo,E.H.,2008.Anew penumbra:transitioning from injury into repairafter stroke.Nat Med 14,497-500.
Macrez,R.,Ali,C.,Toutirais,O.,Le Mauff,B.,Defer,G.,Dirnagl,U.,Vivien,D.,2011.Stroke and the immune system:from pathophysiology to new therapeuticstrategies.Lancet Neurol 10,471-480.
Maezawa,I.,Jenkins,D.P.,Jin,B.E.,Wulff,H.,2012.Microglial KCa3.1Channels as a Potential Therapeutic Target for Alzheimer's Disease.Int JAlzheimers Dis 2012,868972.
Maki,T.,Hayakawa,K.,Pham,L.D.,Xing,C.,Lo,E.H.,Arai,K.,2013.Biphasicmechanisms of neurovascular unit injury and protection in CNS diseases.CNSNeurol Disord Drug Targets 12,302-315.
McDonough,A.,Weinstein,J.R.,2016.Neuroimmune Response in Ischemic Preconditioning.Neurotherapeutics 13,748-761.
McNaughton-Smith,G.A.,Burns,J.F.,Stocker,J.W.,Rigdon,G.C.,Creech,C.,Arrington,S.,Shelton,T.,de Franceschi,L.,2008.Novel inhibitors of the Gardoschannel for the treatment of sickle cell disease.J Med Chem 51,976-982.
Michell-Robinson,M.A.,Touil,H.,Healy,L.M.,Owen,D.R.,Durafourt,B.A.,Bar-Or,A.,Antel,J.P.,Moore,C.S.,2015.Roles of microglia in brain development,tissue maintenance and repair.Brain 138,1138-1159.
Mozaffarian,D.,Benjamin,E.J.,Go,A.S.,Arnett,D.K.,Blaha,M.J.,Cushman,M.,de Ferranti,S.,Despres,J.P.,Fullerton,H.J.,Howard,V.J.,Huffman,M.D.,Judd,S.E.,Kissela,B.M.,Lackland,D.T.,Lichtman,J.H.,Lisabeth,L.D.,Liu,S.,Mackey,R.H.,Matchar,D.B.,McGuire,D.K.,Mohler,E.R.,3rd,Moy,C.S.,Muntner,P.,Mussolino,M.E.,Nasir,K.,Neumar,R.W.,Nichol,G.,Palaniappan,L.,Pandey,D.K.,Reeves,M.J.,Rodriguez,C.J.,Sorlie,P.D.,Stein,J.,Towfighi,A.,Turan,T.N.,Virani,S.S.,Willey,J.Z.,Woo,D.,Yeh,R.W.,Turner,M.B.,American Heart AssociationStatistics,C.,Stroke Statistics,S.,2015.Heart disease and stroke statistics--2015 update:a report from the American Heart Association.Circulation 131,e29-322.
Nedergaard,M.,Dirnagl,U.,2005.Role of glial cells in cerebralischemia.Glia 50,281-286.
Nguyen,H.M.,Grossinger,E.M.,Horiuchi,M.,Davis,K.W.,Jin,L.W.,Maezawa,I.,Wulff,H.,2016.Differential Kv1.3,KCa3.1,and Kir2.1 expression in"classically"and"alternatively"activated microglia.Glia.
Prabhakaran,S.,Ruff,I.,Bernstein,R.A.,2015.Acute stroke intervention:a systematic review.JAMA313,1451-1462.
Reich,E.P.,Cui,L.,Yang,L.,Pugliese-Sivo,C.,Golovko,A.,Petro,M.,Vassileva,G.,Chu,I.,Nomeir,A.A.,Zhang,L.K.,Liang,X.,Kozlowski,J.A.,Narula,S.K.,Zavodny,P.J.,Chou,C.C.,2005.Blocking ion channel KCNN4 alleviates thesymptoms of experimental autoimmune encephalomyelitis in mice.Eur J Immunol35,1027-1036.
Schilling,T.,Eder,C.,2007.TRAM-34 inhibits nonselective cationchannels.Pflugers Arch 454,559-563.
Staal,R.G.,Khayrullina,T.,Zhang,H.,Davis,S.,Fallon,S.M.,Cajina,M.,Nattini,M.E.,Hu,A.,Zhou,H.,Poda,S.B.,Zorn,S.,Chandrasena,G.,Dale,E.,Cambpell,B.,Biilmann Ronn,L.C.,Munro,G.,Mller,T.,2017.Inhibition of the potassiumchannel KCa3.1 by senicapoc reverses tactile allodynia in rats withperipheral nerve injury.Eur J Pharmacol 795,1-7.
Staal,R.G.W.,Weinstein,J.R.,Nattini,M.et al.Senicapoc:Repurposing aDrug to Target Microglia KCa3.1 in Stroke.Neurochem Res(2017)42:2639.DOI:10.1007/s11064-017-2223-y
D.,Brown,D.,Jenkins,D.,Chen,Y.-J.,Coleman,N.,Ando,Y.,Chiu,P.,S.,Demnitz,J.,Wulff,H.and Christophersen,P.(2013),NS6180,a newKCa3.1 channel inhibitor prevents T-cell activation and inflammation in a ratmodel of inflammatory bowel disease.Br J Pharmacol,168:432–444.doi:10.1111/j.1476-5381.2012.02143.x
Suzuki,S.,Kurata,N.,Nishimura,Y.,Yasuhara,H.,Satoh,T.,2000.Effects ofimidazole antimycotics on the liver microsomal cytochrome P450 isoforms inrats:comparison of in vitro and ex vivo studies.Eur J Drug MetabPharmacokinet 25,121-126.
Szalay,G.,Martinecz,B.,Lenart,N.,Kornyei,Z.,Orsolits,B.,Judak,L.,Csaszar,E.,Fekete,R.,West,B.L.,Katona,G.,Rozsa,B.,Denes,A.,2016.Microgliaprotect against brain injury and their selective elimination dysregulatesneuronal network activity after stroke.Nat Commun 7,11499.
Umekawa,T.,Osman,A.M.,Han,W.,Ikeda,T.,Blomgren,K.,2015.Residentmicroglia,rather than blood-derived macrophages,contribute to the earlier andmore pronounced inflammatory reaction in the immature compared with the adulthippocampus after hypoxia-ischemia.Glia 63,2220-2230.
van Rossum,D.,Hanisch,U.K.,2004.Microglia.Metab Brain Dis 19,393-411.
Weinstein,J.R.,Koerner,I.P.,Moller,T.,2010.Microglia in ischemicbrain injury.Future Neurol 5,227-246.DOI:10.2217/fnl.10.1
Wulff,H.,Castle,N.A.,2010.Therapeutic potential of KCa3.1 blockers:recent advances and promising trends.Expert Rev Clin Pharmacol 3,385-396.
Wulff,H.,Kolski-Andreaco,A.,Sankaranarayanan,A.,Sabatier,J.M.,Shakkottai,V.,2007.Modulators of small-and intermediate-conductance calcium-activated potassium channels and their therapeutic indications.Curr Med Chem14,1437-1457.
Wulff,H.,Miller,M.J.,Hansel,W.,Grissmer,S.,Cahalan,M.D.,Chandy,K.G.,2000.Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+channel,IKCa1:a potential immunosuppressant.ProcNatl Acad Sci U S A97,8151-8156.
Zhang,W.,Ramamoorthy,Y.,Kilicarslan,T.,Nolte,H.,Tyndale,R.F.,Sellers,E.M.,2002.Inhibition of cytochromes P450 by antifungal imidazolederivatives.Drug Metab Dispos 30,314-318.
Zuchero,J.B.,Barres,B.A.,2015.Glia in mammalian development anddisease.Development 142,3805-3809.
Claims (6)
1.一种通过向有中风或缺血性损伤风险或患有中风或缺血性损伤的患者施用senicapoc以预防或治疗中风的方法。
2.senicapoc在制备用于通过向有中风或缺血性损伤风险或患有中风或缺血性损伤的患者施用senicapoc以预防或治疗中风的药物中的应用。
3.senicapoc用于预防或治疗中风,所述预防或治疗中风通过向有中风或缺血性损伤风险或患有中风或缺血性损伤的患者施用senicapoc进行。
4.一种用于预防或治疗中风的senicapoc的口服剂型,所述预防或治疗中风通过向有中风或缺血性损伤风险或患有中风或缺血性损伤的患者施用senicapoc进行。
5.如权利要求4所述的剂型,其中所述口服剂型是片剂、胶囊、或溶解或悬浮于可饮用液体中的粉末。
6.如权利要求5所述的剂型,其还包含至少一种赋形剂。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762452319P | 2017-01-30 | 2017-01-30 | |
US62/452,319 | 2017-01-30 | ||
PCT/US2018/016014 WO2018140965A1 (en) | 2017-01-30 | 2018-01-30 | Use of senicapoc for treatment of stroke |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110225749A true CN110225749A (zh) | 2019-09-10 |
Family
ID=62978983
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201880008645.6A Pending CN110225749A (zh) | 2017-01-30 | 2018-01-30 | Senicapoc用于治疗中风 |
Country Status (6)
Country | Link |
---|---|
US (1) | US11395807B2 (zh) |
EP (1) | EP3573609A4 (zh) |
CN (1) | CN110225749A (zh) |
AU (1) | AU2018213412B2 (zh) |
IL (1) | IL268187A (zh) |
WO (1) | WO2018140965A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110177548A (zh) * | 2016-10-25 | 2019-08-27 | 罗兰·斯塔尔 | Senicapoc用于治疗神经性疼痛的用途 |
US20230045322A1 (en) * | 2019-07-29 | 2023-02-09 | Paracelsus Neuroscience II, LLC | Use of senicapoc for treatment of stroke |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101437403A (zh) * | 2005-12-20 | 2009-05-20 | Icagen公司 | 使用三芳基甲烷化合物的治疗方法 |
WO2011034860A1 (en) * | 2009-09-18 | 2011-03-24 | Icagen, Inc. | Treatment methods using triaryl methane compounds |
WO2012006117A2 (en) * | 2010-06-28 | 2012-01-12 | The Regents Of The University Of California | Reduction of microglia-mediated neurotoxicity by kca3.1 inhibition |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050009733A1 (en) | 2003-04-22 | 2005-01-13 | Pharmacia Corporation | Compositions of a cyclooxygenase-2 selective inhibitor and a potassium ion channel modulator for the treatment of central nervous system damage |
KR101345860B1 (ko) | 2011-10-25 | 2013-12-30 | 이화여자대학교 산학협력단 | 모다피닐 또는 이의 유도체를 포함하는 혈관질환 치료용 조성물 |
US10758569B2 (en) | 2014-01-13 | 2020-09-01 | The General Hospital Corporation | Heteroaryl disulfide compounds as allosteric effectors for increasing the oxygen-binding affinity of hemoglobin |
US10179115B2 (en) | 2015-02-20 | 2019-01-15 | The Children's Medical Center Corporation | Methods for treating malaria using potassium channel inhibitors |
-
2018
- 2018-01-30 EP EP18744812.1A patent/EP3573609A4/en active Pending
- 2018-01-30 WO PCT/US2018/016014 patent/WO2018140965A1/en unknown
- 2018-01-30 CN CN201880008645.6A patent/CN110225749A/zh active Pending
- 2018-01-30 AU AU2018213412A patent/AU2018213412B2/en active Active
- 2018-01-30 US US16/481,779 patent/US11395807B2/en active Active
-
2019
- 2019-07-21 IL IL268187A patent/IL268187A/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101437403A (zh) * | 2005-12-20 | 2009-05-20 | Icagen公司 | 使用三芳基甲烷化合物的治疗方法 |
WO2011034860A1 (en) * | 2009-09-18 | 2011-03-24 | Icagen, Inc. | Treatment methods using triaryl methane compounds |
WO2012006117A2 (en) * | 2010-06-28 | 2012-01-12 | The Regents Of The University Of California | Reduction of microglia-mediated neurotoxicity by kca3.1 inhibition |
Also Published As
Publication number | Publication date |
---|---|
US11395807B2 (en) | 2022-07-26 |
IL268187A (en) | 2019-09-26 |
US20200000749A1 (en) | 2020-01-02 |
EP3573609A1 (en) | 2019-12-04 |
AU2018213412B2 (en) | 2024-03-28 |
WO2018140965A1 (en) | 2018-08-02 |
AU2018213412A1 (en) | 2019-08-29 |
EP3573609A4 (en) | 2020-07-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Qiu et al. | The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling | |
Kiaei et al. | Celastrol blocks neuronal cell death and extends life in transgenic mouse model of amyotrophic lateral sclerosis | |
Medrano-Jiménez et al. | Malva parviflora extract ameliorates the deleterious effects of a high fat diet on the cognitive deficit in a mouse model of Alzheimer’s disease by restoring microglial function via a PPAR-γ-dependent mechanism | |
Littlejohn et al. | Opposing tissue-specific roles of angiotensin in the pathogenesis of obesity, and implications for obesity-related hypertension | |
Wen et al. | Tetramethylpyrazine nitrone improves motor dysfunction and pathological manifestations by activating the PGC-1α/Nrf2/HO-1 pathway in ALS mice | |
Liu et al. | GJ-4 ameliorates memory impairment in focal cerebral ischemia/reperfusion of rats via inhibiting JAK2/STAT1-mediated neuroinflammation | |
Cvjetićanin et al. | Dried leaf extract of Olea europaea ameliorates islet-directed autoimmunity in mice | |
Watson et al. | SIGIRR modulates the inflammatory response in the brain | |
Du et al. | Menthol protects dopaminergic neurons against inflammation-mediated damage in lipopolysaccharide (LPS)-Evoked model of Parkinson’s disease | |
Timaru-Kast et al. | Angiotensin II receptor 1 blockage limits brain damage and improves functional outcome after brain injury in aged animals despite age-dependent reduction in AT1 expression | |
de Araújo et al. | Aminochrome decreases NGF, GDNF and induces neuroinflammation in organotypic midbrain slice cultures | |
Tian et al. | 2-(2-benzofuranyl)-2-imidazoline (2-BFI) improved the impairments in AD rat models by inhibiting oxidative stress, inflammation and apoptosis | |
CN110225749A (zh) | Senicapoc用于治疗中风 | |
Ye et al. | Protective effect of n-butyl alcohol extracts from Rhizoma Pinelliae Pedatisectae against cerebral ischemia-reperfusion injury in rats | |
US20200138890A1 (en) | Pharmaceutical composition for prevention and treatment of prostatic hyperplasia and erectile dysfunction caused by andropause comprising extract of lespedeza cuneata and trigonellae semen | |
Chen et al. | Prevention of postoperative fatigue syndrome in rat model by ginsenoside Rb1 via down-regulation of inflammation along the NMDA receptor pathway in the hippocampus | |
Nna et al. | Hepatotoxicity following separate administration of two phosphodiesterase-5 inhibitors (sildenafil & tadalafil) and opioid (tramadol); evaluation of possible reversal following their withdrawal | |
Lee et al. | Neuroprotective effects of bornyl acetate on experimental autoimmune encephalomyelitis via anti-inflammatory effects and maintaining blood-brain-barrier integrity | |
JP2005526768A (ja) | 炎症関連遺伝子を調節するデキサナビノール及びデキサナビノール類似体 | |
MX2015001888A (es) | Laquinimod para tratamiento de trastornos mediados por ácido gamma-aminobutírico. | |
WO2008047880A1 (fr) | Agent thérapeutique pour la polyarthrite rhumatoïde | |
Manera et al. | Synthetic cannabinoid receptor agonists and antagonists: implication in CNS disorders | |
KR101306599B1 (ko) | 코리난테 종의 수피로부터의 추출물 및 이의 용도, 및 상기추출물을 포함하는 약제, 식이요법 식품 및 약제학적 제제 | |
US20230045322A1 (en) | Use of senicapoc for treatment of stroke | |
CN114028376A (zh) | Mg在制备高尿酸血症肾病和/或痛风性关节炎的nlrp3通路抑制剂中的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190910 |
|
WD01 | Invention patent application deemed withdrawn after publication |