CN115605194A - 过度炎症综合征的治疗 - Google Patents
过度炎症综合征的治疗 Download PDFInfo
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- CN115605194A CN115605194A CN202180025176.0A CN202180025176A CN115605194A CN 115605194 A CN115605194 A CN 115605194A CN 202180025176 A CN202180025176 A CN 202180025176A CN 115605194 A CN115605194 A CN 115605194A
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Abstract
本发明描述了哺乳动物P2X7R的拮抗剂用于治疗哺乳动物患者的过度炎症综合征的用途,通过靶向初级淋巴结向所述患者施用所述P2X7R拮抗剂直至所述拮抗剂在所述靶向淋巴结中的浓度高于所述拮抗剂在所述哺乳动物中的最大可耐受血浆水平。
Description
本发明涉及哺乳动物P2X7受体(P2X7R)拮抗剂用于治疗哺乳动物患者的过度炎症综合征的用途,通过向所述患者的初级淋巴结靶向施用所述P2X7R拮抗剂直至所述拮抗剂在所述靶向淋巴结中的浓度高于所述拮抗剂在所述哺乳动物中的最大可耐受血浆水平。
背景技术
过度炎症综合征(或过度炎症)是医学领域中已知的一种现象,并且是多种疾病的症状,其导致患者的显著(如果并非致死)效应。本文所用的术语“过度炎症”由以下6个标准所定义(Webb等人,Lancet RheumatoL2020,2,(12)754-763):
(1)发热,定义为温度高于38.0℃;
(2)巨噬细胞活化,定义为铁蛋白浓度为700μg/L或更高;
(3)血液学功能障碍,定义为中性粒细胞与淋巴细胞比率为10或更高,或血红蛋白浓度为9.2g/dL或更低以及血小板计数为110×109个细胞/L或更低;
(4)凝血病,定义为D-二聚体浓度为1.5μg/mL或更高;
(5)肝损伤,定义为乳酸脱氢酶浓度为400U/L或更高,或天冬氨酸转氨酶浓度为100U/L或更高;
(6)细胞因子血症,定义为白介素-6浓度为15pg/mL或更高,或甘油三酯浓度为150mg/dL或更高,或CRP浓度为15mg/dL或更高。
呼吸困难和肺炎是常见且丰富的症状,与特别由于气道感染的过度炎症一致。发生过度炎症的主要事件是细胞内ATP的释放。在本领域中,将核苷酸(ATP、ADP、UTP和UDP)和核苷(腺苷)的细胞间信号传导称为嘌呤能信号传导。
在正常静息条件下,ATP的细胞外水平在纳摩尔浓度(2-3nM)下相当低,而在特定条件下ATP释放可升高超过1000倍;此类病症可发生于下文相应部分“涉及过度炎症的疾病”中提及的疾病,并且包括例如炎症反应、机械应力、表面活性物质释放、膜去极化、缺氧。
在嘌呤能信号传导中,已知多种受体,腺苷配体也称为P1受体,核苷酸配体称为P2受体。对于腺苷,达到基线和最大效应之间一半的效应所需的配体胞外浓度(半数最大有效剂量——EC50)处于纳摩尔范围内,而对于ATP、UTP或ADP,这些浓度在0.01至10μM的范围内。已知所有这些受体都经历脱敏作用。受体的脱敏被定义为对配体的活化无反应,导致零跨膜阴离子电流。然而,P2受体之一P2X7R不易于脱敏,并且ATP激活该受体的EC50高得多,即>1mM。在此类ATP水平下,所有其它P1和P2嘌呤能受体完全脱敏。
通过上述疾病,诸如严重感染,感染细胞释放大量细胞外ATP。这可能局限于气道粘膜和肺,或者可能广泛存在于多个器官中。已经观察到细胞外ATP累积至1.4mM(Zhao等人,Front ImmunoL2019,10,2524),导致P2X7R的剧烈活化,引起伴随大量促炎免疫应答的过度炎症、大量促炎和抗炎细胞因子释放以及伴随组织细胞破坏的大孔形成(Savio等人,Front Pharmacol 2018,9,52)。
作为P1和P2受体脱敏的结果,生理炎症反应失活(称为免疫麻痹),使患者对继发性感染敏感。
调节性T细胞(Treg)是控制过度炎症的关键要素,加速来自细胞外ATP的腺苷产生。P2X7R的活化抑制Treg的抑制潜力和稳定性。
P2X7R在多种慢性和急性疾病中发挥重要作用。这些疾病可局限于1个器官(阿尔茨海默氏病、多发性硬化症、结肠炎)或可如在细菌性败血症或严重微生物感染(诸如COVID-19)中扩散地散布,也参见下文部分“涉及过度炎症的疾病”。
目前对过度炎症的治疗实际上是抗炎治疗。药物确实通过抑制一种或多种促炎途径来阻断免疫应答的激活。这些治疗破坏了促炎免疫应答的生理功能,即识别入侵微生物的“攻击”(“警报阶段”),随后激活第一道防线(先天免疫系统),并且当需要时激活适应性免疫系统以特异性解除入侵者的武装。阻碍患者炎症反应的此类药物的实例是地塞米松、巴瑞替尼(baricitinib)和阿那白滞素(anakinra)。
因此,迄今为止对过度炎症的治疗颇为麻烦。本发明现在提供了一种方法,该方法用于治疗患有过度炎症的患者而不妨碍患者的炎症反应或至少在较小程度上妨碍患者的炎症反应。
本领域已经提出,当治疗过度炎症以及伴随的呼吸困难和肺炎时,P2X7R可以是靶向的良好候选物。P2X7R拮抗剂将阻断P2X7R的剧烈活化。因为P2X7R介导大部分ATP释放到细胞外空间,其拮抗作用将导致细胞外ATP浓度降低。这可能消除炎症过度和伴随的免疫麻痹。此外,已经描述了P2X7R的抑制在刺激CD4+T细胞的T细胞受体后促进CD4+T细胞向Treg的细胞自主转化(Schenk等人,Sci Signal 2011,4(162)ra12)。通过P2X7R抑制改善过度炎症似乎基于抗炎Treg群的活化和克隆扩增增加。
迄今已经鉴定了多种P2X7R拮抗剂(North和Jarvis,Mol Phar,2013(83)759-769;Sluyter,Adv Exp Med Biol Prot Rev 2017(19)17-53)。为了达到效果,已全身施用这些拮抗剂,以便通过血液输送到设想的作用部位。
例如,已经口服施用CE-224,535 500(Pfizer)、AZD9056(Astra-Zeneca)和JNJ54175446(Johnson&Johnson),但仍未取得很大成功。据报道,麻醉剂利多卡因是一种P2X7R拮抗剂(Okura等人,Anesth Analg 2015,120(3),597-605)。另外的P2X7R拮抗剂列于下文部分“P2X7R拮抗剂”中。
尽管P2X7R拮抗剂可消除过度炎症并恢复免疫系统对抗继发性共感染的能力,并改善患有严重气道感染的危重患者的临床状况,但这些化合物的问题在于以下事实:为了发挥效果,拮抗剂应结合P2X7R至有效抵消过度炎症和优选例如呼吸困难的伴随作用的程度。在抑制受体10%的受体拮抗剂浓度(所谓的IC10值)下,已经观察到此类效果。优选的抑制是50%受体抑制,即IC50值。然而,对于P2X7R拮抗剂,此类浓度高于所述拮抗剂的最大可耐受血浆水平,即导致不期望的副作用,诸如焦虑、头晕或甚至脊柱反射减少或更糟糕。例如,人对利多卡因的最大可耐受血浆水平为约4.7μg/ml,参见表1:
表1:人体中利多卡因的最大耐受血浆水平
对于每种P2X7R拮抗剂,技术人员将知道如何确定最大可耐受血浆水平。
然而,P2X7R拮抗剂尚未有效地用于治疗过度炎症,这是由于为了有效,全身剂量将远远超过最大可耐受血浆水平。
本发明现在提供了P2X7R拮抗剂,其用于治疗哺乳动物患者的过度炎症综合征,通过靶向初级淋巴结向所述患者施用所述P2X7R拮抗剂直至所述P2X7R拮抗剂在所述靶向淋巴结中的浓度高于所述拮抗剂在所述哺乳动物中的最大可耐受血浆水平。通过初级淋巴结靶向,可以在淋巴结中获得预期的ICx值,同时避免超过最大可耐受血浆水平。本发明人已经发现,在淋巴结中构建设想的ICx值导致对过度炎症的有效治疗,并显著减轻患有严重气道感染的患者的呼吸困难和过度炎症的其它症状。由于预期淋巴系统仅通过运输免疫细胞(即,幼稚()T细胞、活化T-细胞、B细胞、树突细胞、单核细胞、巨噬细胞、嗜中性粒细胞、肥大细胞、嗜酸性粒细胞、嗜碱性粒细胞和其它免疫学相关的细胞)聚集,从而预期靶向淋巴结。发现通过P2X7R拮抗剂选择性抑制淋巴系统免疫细胞的P2X7R,诱导Treg的克隆扩增。随后,这些Treg在全身迁移,发挥抗炎活性,减少全身和(远端)局部过度炎症。
术语“靶向初级淋巴结”是指施用或递送途径,其中大部分受体拮抗剂从施用部位直接递送至淋巴结,而所述受体拮抗剂在淋巴结中的有效量比在血浆中的有效量多至少5倍,优选至少10倍或至少15倍。特别地,施用优先于淋巴结。
施用的拮抗剂在靶向淋巴结中的浓度对应于所述受体的ICx,所述ICx高于所述拮抗剂在所述哺乳动物中的最大可耐受血浆水平,其中x≥10,优选≥20,更优选≥30,甚至更优选≥40,最优选约50。在IC10,观察到10%受体抑制,在IC20,观察到20%受体抑制,依此类推。x越高,受体抑制越多,治疗炎症越有效。本领域技术人员清楚,对于与受体结合较强的受体拮抗剂,IC值将低于与受体结合较弱的受体拮抗剂。拮抗剂结合越强,与结合较弱的拮抗剂相比,具有相同作用所需的所述拮抗剂的量越少。优选如上述Okura中所述测定IC值。
本领域技术人员知道用于靶向淋巴结施用的合适递送和施用途径。优选局部和侵入性施用。侵入性施用可能不适用于医院以外的环境。因此,局部施用受体拮抗剂非常有吸引力。作为局部途径,优选经粘膜和经皮施用。在此类情况下,拮抗剂优选以亲脂性形式施用,因为亲水性形式倾向于在血液中被优先吸收,导致血液中受体拮抗剂的血浆水平不期望地升高,并且倾向于在淋巴结中递送较少。为此,受体拮抗剂优选为其游离碱的形式。
在一个非常有吸引力的实施方案中,靶向淋巴结施用包含在被粘膜覆盖的体腔内经粘膜施用,优选所述粘膜接近一个或多个淋巴结,以便能够快速和直接递送。特别地,口腔适于此类施用。然而,经鼻和口腔二者施用也是可能的。关于经鼻递送,必须小心以优选不吸入受体拮抗剂或达到最小程度,因为此类吸入可能引起受体拮抗剂血浆水平的不期望的升高。当施用于口腔时,施用优选为颊部、舌下、咽或其组合。粘膜优选具有低的全身渗透性,并且紧邻淋巴结。不同粘膜组织的渗透性例如描述于:Goyal等人,Nanomed Biotechnol2018,46(sup2),539-551;以及Lesch等人,J Dent Res 1989,68(9),1345-1349。
本领域已经考虑口服施用是药物递送的低效途径(Di Vergilio等人,Br JPharmacol 2020)。然而,舌下和颊部施用受体拮抗剂,特别是利多卡因,现在已经显示出非常有效,而不会显著提高血浆中的拮抗剂水平。据报道,皮肤和粘膜对水、药物等的渗透性取决于施用部位。例如,对于氚标记的水,口底(舌下粘膜)、舌侧缘和颊粘膜的渗透常数分别是人皮肤的22、17和13倍。此外,粘膜下毛细血管吸收分子的能力比皮下毛细血管高得多。盐酸利多卡因高度溶于水(在水中的溶解度为680mg/ml),因此将主要被粘膜下毛细血管吸收。相反,高亲脂性利多卡因碱(在水中的溶解度为4mg/ml,在95%乙醇中的溶解度为760mg/ml,在氯仿中的溶解度为790mg/ml)优选被粘膜下组织中的局部初始淋巴管吸收(等人,《原料药的分析概况(In Analytical Profiles of DrugSubstances)》,Florey,K.编著,学术出版社:1985;第14卷,第207-243页)。此外,口底淋巴引流范围广,涉及大量淋巴结。
优选舌下和口腔施用亲脂性利多卡因碱或任何其它P2X7R拮抗剂。在相对低的总剂量中的高浓度下,可以实现P2X7R在引流淋巴结中的IC50以控制全身性过度炎症并避免利多卡因或任何其它P2X7R拮抗剂的毒性血浆水平。应当注意,亲脂性利多卡因的舌下和颊部施用不同于利多卡因的口服施用。利多卡因的口服施用旨在药物在胃肠道中的再吸收,即全身性施用。
在另一个实施方案中,所述施用是经皮施用并且为乳膏剂、软膏剂或洗剂、贴剂或硬膏剂和/或涉及微针或其组合的形式。对于这种类型的施用,由于与上述相同的原因,受体拮抗剂优选是亲脂性的。经皮施用P2X7R拮抗剂,特别是亲脂性的,任选与皮肤渗透增强剂(诸如α-萜品醇、乙醇、基于脂质的纳米制剂)组合,可提供方便的应用。
在另一个实施方案中,施用是侵入性的,特别是选自皮内、皮下或皮下组织施用。真皮毛细血管可以将物质从血液输送到组织,但是如果有的话,物质从组织到血液的再吸收极低。显然,具有能够从间质吸收液体和分子的单向瓣膜小叶的特化初始淋巴管位于真皮中。然后通过收集带有节律性收缩肌肉层的淋巴管,将吸收的淋巴液在淋巴管网中向前推进。该系统将液体和颗粒带入淋巴结,在淋巴结中发生多种免疫过程。与深层皮下组织施用后相比,皮内施用到淋巴结中的吸收似乎慢10倍,并且在与这些淋巴管相关的淋巴结中导致更高的浓度。较小的颗粒比较大的颗粒更迅速地向淋巴管和淋巴节迁移。在人的手背皮内和皮下施用后的清除途径和速率导致在皮下注射后施用的化合物的清除1%/min,皮内注射为8-10%/min。
附加的优点是皮下组织施用的利多卡因的血浆浓度比静脉内施用的利多卡因的血浆浓度低得多。在猫中静脉内施用2mg/kg利多卡因后几乎立即出现3.6μg/mL的峰值血浆浓度(Thomasy等人,Am JVet Res 2005,66(7),1162-1166)。相比之下,皮下组织施用30mg/kg、20mg/kg和10mg/kg利多卡因后获得的平均峰值血浆浓度低得多:分别为1.69μg/mL、1.07μg/mL和0.77μg/mL(Hatef等人,Aesthet Surg J 209(2),122-128)。皮下组织施用的剂量分别比静脉内剂量高15、10和5倍。静脉内和皮下组织施用利多卡因后血浆浓度的差异由以下事实所引起:与静脉内施用相反,大部分皮下组织施用的利多卡因被引流到淋巴系统中。这减慢了利多卡因向静脉血的释放。
皮内施用后的淋巴吸收远高于深层皮下组织施用后的淋巴吸收。由于皮内输注利多卡因不是可接受的利多卡因施用途径,建议使用导管插入真皮正下方进行利多卡因的皮下施用,这将导致引流局部淋巴结中的利多卡因浓度高于深层皮下组织或静脉内输注。
对于本发明的侵入性施用,受体拮抗剂优选是亲水性的,特别是其水溶性药学上可接受的盐的形式,诸如氯化物盐。
在另一个实施方案中,施用是静脉内的,拮抗剂是亲脂性的并且被限制在药物递送系统中,避免在血液中直接释放,例如通过使用纳米尺寸的药物递送系统、脂质体或聚合物胶束。P2X7R拮抗剂的口服施用也可以使用用于肠淋巴药物转运的递送系统,诸如乳糜微粒等,其中避免递送至血浆。以不超过最大可耐受血浆水平的低剂量进行静脉内施用导致(如果有的话)不太显著的效果。对于利多卡因,可以采用0.6mg/kg/hr的静脉内施用。
特别地,P2X7R活化由细胞外ATP激活。然而,P2X7R也可以通过膜拉伸、来自凋亡细胞的蛋白质、LL-37、cathelicidin和抗微生物肽活化。应当注意,所有形式的此类受体活化都被P2X7R拮抗剂所拮抗。
在一个有吸引力的实施方案中,施用是速释剂型或缓释剂型。
施用优选包括一次或多次团注(bolus)施用,或包括连续施用,或其组合。团注应理解为单一片剂、小袋、注射剂、气雾剂等的施用,或当随后施用时以任何组合的多个团注施用,其间没有显著的时间间隔。以连续方式施用也是有吸引力的,例如作为输注,或者作为一次或多次团注施用和连续施用之间的组合。
在一个具体的实施方案中,团注剂量对应于在所述拮抗剂的最大可耐受血浆水平下1ml血浆中所含受体拮抗剂的量的至少1000倍,优选至少5000倍,更优选至少10000倍。这意味着,根据该实施方案,由在最大可耐受血浆水平下存在于1ml血浆中的受体拮抗剂的量来定义团注。例如,人体内利多卡因的最大可耐受血浆水平为4.7μg/mL。这意味着团注将是4.7μg的至少1000倍,即4.7mg。
团注优选每天施用2-10次。
优选在包含至少1w/v%、优选至少5w/v%、最优选至少10w/v%受体拮抗剂的液体介质中施用拮抗剂。此类高浓度的受体拮抗剂,特别是利多卡因,迄今未用于本领域。当根据本领域使用时,即涉及通过血液全身递送时,此类浓度将导致超出所述拮抗剂的最大可耐受血浆水平的不可接受的高血浆水平。例如,为了治疗患有严重呼吸道感染(例如SARS-CoV-2感染)的患者的过度炎症和伴随的呼吸困难。
当涉及侵入性施用时,靶向淋巴结施用优选通过连续皮内、皮下或皮下组织输注。特别地,被插管用于通气和/或保持昏迷的患者可能需要此类施用途径。
对于通过连续输注施用,剂量优选对应于每千克体重每小时的IC10值的至少10倍,更优选每千克体重每小时的IC20值的至少10倍,甚至更优选每千克体重每小时的IC30值的至少10倍,还甚至更优选每千克体重每小时的IC40值的至少10倍,最优选每千克体重每小时的IC50值的至少10倍、每千克体重每小时的IC10值的至少10倍、每千克体重每小时的IC10值的至少10倍。更优选地,剂量为每千克体重每小时的IC50值的至少15倍。对于利多卡因,后一值对应于约1mg/kg/hr。利多卡因的IC50值为66μg/mL(0.066×15=0.99)。
根据一个非常有吸引力的实施方案,所述治疗涉及选自以下的疾病的过度炎症综合征:自身免疫疾病和免疫相关疾病、诸如哮喘、变态反应和慢性肺病;治疗引起的免疫相关疾病,诸如化疗;感染性疾病,诸如病毒和细菌感染;心血管疾病和神经血管疾病;神经炎症和神经退行性疾病;癫痫疾病;情感障碍和精神病综合征;纤维化;癌症相关病症;肿瘤假性进展;癌症和赘生物;创伤和创伤后综合征;器官移植后综合征,包括移植器官排斥。然而,所述治疗可涉及其中P2X7R活化发挥作用且其中所述疾病可通过P2X7R拮抗剂治疗的任何疾病。下文部分“涉及过度炎症的疾病”中列出这些疾病。
所述过度炎症综合征优选包括呼吸困难,特别地,所述呼吸困难与病毒感染、细菌感染、癌症、慢性阻塞性肺病(COPD)、哮喘、变态反应、化疗相关。所述病毒感染特别是由病毒引起,所述病毒选自:冠状病毒,特别是SARS-CoV-2;流感病毒;埃博拉病毒;呼吸道合胞病毒;人类免疫缺陷病毒。
所述P2X7R拮抗剂优选选自:氨基酰胺衍生物,特别是利多卡因、布比卡因、罗哌卡因和甲哌卡因;抗P2X7R抗体,特别是单克隆抗体;氨基酯衍生物,特别是苯佐卡因和普鲁卡因;金刚烷酰胺衍生物;三唑衍生物;二芳基咪唑烷衍生物;焦谷氨酸酰胺衍生物;吡唑乙酰胺衍生物;二氢二苯并[a,g]喹嗪鎓衍生物;四唑衍生物;酪氨酸基衍生物;吡唑并二氮杂卓衍生物;咪唑衍生物;苯甲酰胺衍生物、KN62类似物和衍生物;金刚烷甲酰胺;芳基碳酰肼;氰基胍;芳基四唑和芳基三唑;PPADS四钠盐;亮蓝G(BBG);氧化ATP(o-ATP);massadine;stylissadine A和B;P2X7R抑制剂C23、C40和C60;[3H]A-804598([3H]2-氰基-1-[(1S)-1-苯基乙基]-3-喹啉-5-基胍);双环杂芳基化合物。然而,下文部分“P2X7R拮抗剂”给出了其它合适的P2X7R拮抗剂。
在一个非常有吸引力的实施方案中,P2X7R拮抗剂包含利多卡因。已显示利多卡因在治疗过度炎症中非常有效。利多卡因优选局部施用,优选以游离碱形式。优选在口腔中施用。优选在包含至少2.5w/v%、优选至少5w/v%、更优选至少10w/v%的受体拮抗剂的液体介质中施用利多卡因碱。此类液体介质可以是例如基于乙醇的。
在另一个有吸引力的实施方案中,所述治疗包含侵入性施用水溶性盐形式的利多卡因,特别是盐酸利多卡因。优选皮内、皮下或皮下组织施用利多卡因盐。优选通过连续皮内、皮下或皮下组织输注施用利多卡因盐。
哺乳动物患者优选人患者,但可以是患有由P2X7R活化介导的疾病的任何哺乳动物。
现在将通过以下附图和实施例进一步说明本发明。
图1a至图1f显示了用皮下利多卡因治疗的6例重症COVID-19。所有患者均为COVID-19病例、COVID-19检测阳性。2名患者接受了机械通气和体外膜氧合(ECMO)治疗,4名患者仅接受了机械通气治疗。最大静脉内利多卡因剂量为0.6mg/kg/小时,最大皮下利多卡因剂量为1mg/kg/小时。所有患者完全恢复健康。
图1a:一名患有COVID-19引起的ARDS的63岁男性(实施例1)入院。CT扫描显示双侧磨玻璃影。共发病:COPD,每天吸烟60支香烟超过40年。入院前约40年,患者出现气胸。入院后,临床状况恶化,第4天需要转入ICU和机械通气。第11天,开始0.6mg/kg/hr的连续静脉内利多卡因,但患者状况保持恶化,肺动脉压力高,肺通气减少。第19天,0.6mg/kg/hr的连续静脉内利多卡因改为1mg/kg/hr的连续皮下利多卡因。之后,临床状况改善,第20天,肺的通气得到改善,但肺动脉压力保持较高。尽管如此,P/F比逐渐提高,第50天,ECMO撤机。在利多卡因治疗期间没有观察到新的ECG变化。血液MetHb在正常范围内(0.3-0.8%)。
图1b:一名患有COVID-19引起的ARDS(实施例2)的68岁男性入住ICU并需要机械通气。CT扫描显示双侧磨玻璃影。共发病:哮喘。入院后,患者病情恶化。第5天,开始0.6mg/kg/hr的连续静脉内利多卡因,但临床状况和P/F比保持恶化。第11天,0.6mg/kg/hr的静脉内利多卡因改为1mg/kg/hr的连续皮下利多卡因。几天后,临床状况和P/F比改善。在利多卡因治疗期间没有观察到新的ECG变化。血液MetHb在正常范围内(0.1-0.6%)。
图1c:一名59岁男性(实施例3),CT扫描显示呼吸窘迫和双侧磨玻璃影。共发病:糖尿病和痛风。在利多卡因治疗期间没有观察到新的ECG变化。血液MetHb在正常范围内(0.1-0.4%)。
图1d:一名51岁男性,因COVID-19发热、呼吸困难和咳嗽(实施例4)。CT扫描显示双侧磨玻璃影。共发病:无。在利多卡因治疗期间没有观察到新的ECG变化。血液MetHb在正常范围内(0.1-0.3%)。
图1e:一名58岁男性,因COVID-19(实施例5)出现发热、呼吸困难和咳嗽。CT扫描显示双侧磨玻璃影。共发病:脂肪肝。在利多卡因治疗期间没有观察到新的ECG变化。血液MetHb在正常范围内(0.1-0.3%)。
图1f:一名59岁男性,因COVID-19(实施例6)出现发热、呼吸困难和咳嗽。CT扫描显示双侧磨玻璃影。共发病:高血压用药。在利多卡因治疗期间没有观察到新的ECG变化。MetHb在正常范围内(0.1-0.3%)。
实施例1至6
从2020年4月至2020年7月底,6名COVID-19危重患者入院,并接受静脉和皮下连续输注利多卡因。基于同情用药开始该治疗。利多卡因输注溶液的浓度为20mg/ml(2%)。前2名患者开始静脉注射利多卡因治疗,这是每日实践中常用的连续施用利多卡因的施用途径。静脉内施用的剂量为0.6mg/kg/hr。由于静脉内利多卡因的有限功效和基于选择性靶向抑制免疫细胞的P2X7R的假说,在7天和6天后,分别将两个患者的输注转为1.0mg/kg/hr的皮下输注。其他4例患者仅接受皮下输注治疗。这6名患者的临床参数的时间进程如图1a至图1f所示。
患者1-实施例1
第一名患者,63岁男性(75kg,168cm),于2020年3月27日出现发热和恶心,三天后开始咳嗽,并出现呼吸困难。5天后,PCR COVID-19检测呈阳性,他因COVID-19引起的ARDS入院。共发病:COPD,每天吸烟60支香烟超过40年。约40年前,患者出现气胸。第3天,由于血液气体不良,患者恶化,接受插管和机械通气。未观察到血液动力学不稳定。CT扫描显示双侧磨玻璃影,与ARDS相符。第5天,由于呼吸进一步恶化,患者被转移到大学医院的ICU。因呼吸系统疾病进展而启动俯卧位机械通气,PaO2/FiO2比极低,为63.3mm Hg(根据柏林定义,为严重ARDS,ARDS的柏林定义包括重度PaO2/FiO2比≤100mm Hg、中度PaO2/FiO2 100至≤200mmHg、轻度PaO2/FiO2 200至≤300mm Hg、无ARDS PaO2/FiO2>300mm Hg[361])。初始呼吸机设置:APRV,P高27cm H2O,T高7.0s,P低0cm H2O,T低0.32s。PaCO2正常。超声心动图估计肺动脉收缩压(PASP)为80mm Hg。Krebs von Lungen 6(KL-6,肺纤维化的标记[362])血浆水平大幅度升高(1299U/mL;正常值<425U/mL),CRP也高(40.4mg/L;正常值<10mg/L),白蛋白为2.2g/dl。白细胞计数、血小板计数、尿量正常。第4天,胸部X线片未改善。第6天,PaO2/FiO2比略微增加,但保持较低,为103mm Hg,并且胸部X射线显示ARDS进展。由于通气策略耗尽,开始ECMO。第9天,PaO2/FiO2比提高,但保持较低,约153mm Hg,但CRP下降至约21.8mg/L。给予患者肌肉松弛剂。患者的ARDS状态从重度改善为中度ARDS。从第10天至第30天,铁蛋白水平良好>1000ng/ml(>100g/dl)。从第11天直到第62天,D-二聚体非常高,在第14天达到121.9nM/L。第11天,没有观察到血液气体的改善,决定用0.6mg/kg/hr的连续静脉内利多卡因治疗患者。第16天,CRP显示出从19(第12天)到12.8(第16天)和7.4(第19天)的渐进性下降,但是PaO2/FiO2比仍然较差(重度ARDS,根据柏林标准),为约90mm Hg,第15天,在静脉内利多卡因输注开始后3天的胸部X射线图像急剧恶化。第13天利多卡因血浆浓度为3.4μg/ml,第14天为5.4μg/ml。第19天,用1mg/kg/hr的连续皮下利多卡因输注代替连续静脉内利多卡因输注。虽然PaO2/FiO2比在第20天(转为连续皮下利多卡因后1天)保持不变,但胸部X射线明显改善。第21天,利多卡因血浆浓度为2.6g/ml,白蛋白为2.5g/dl。从第22天开始,PaO2/FiO2比逐渐提高,第34天达到151mm Hg(中度ARDS)。第22天,KL-6降至458U/L(这仅略高于<450U/l的正常值)。第31天,CRP低至1mg/L,利多卡因血浆浓度为1.2g/ml。停用肌肉松弛剂。白蛋白为2.3g/dl。第33天,胸部X线进一步改善,CRP保持在5.5mg/L。患者清醒,可与护士沟通。第38天,利多卡因血浆水平为2.3。第43天,PaO2/FiO2比增加至214mm Hg。根据ARDS的柏林定义[361],患者的ARDS状态从中度变为轻度。白蛋白为2.8g/dl。第50天,患者撤离ECMO。第51天,患者接受气管切开术。因为第55天用6.3mg/L的低CRP稳定患者的临床状况,所以第57天停止连续皮下利多卡因。第69天,他出现气胸,需要胸腔引流。第99天,他撤离机械呼吸机,并于第121天转出ICU。患者接受法匹拉韦14天。在利多卡因治疗期间没有观察到新的ECG变化。血液MetHb在正常范围内(0.3-0.8%)。患者于第187天出院,回家,可行走,但需要2L/min的额外供氧。入院后9个月,患者情况良好,已恢复工作。
患者2-实施例2
第二名患者,68岁男性,因COVID-19引起的ARDS和阳性PCR检测入院。共发病:哮喘。CT扫描显示双侧磨玻璃影。患者血液动力学稳定。第2天,呼吸病症恶化,PaO2/FiO2比为118mm Hg(根据柏林ARDS定义[361],为中度ARDS)。患者接受插管术,需要机械通气。初始呼吸机设置:压力控制,峰值吸气压力28cm H2O,PEEP13cm H2O,呼吸速率30/min。CRP为10.6mg/L,KL-6为486U/ml。白细胞计数、血小板计数、尿量正常。在整个ICU停留期间,铁蛋白水平保持>1000ng/ml(100μg/dl)。白蛋白为2.9g/dl。随后3天,PaO2/FiO2比提高到约150mm Hg。PaO2/FiO2比从第5天的152mm Hg降至第6天的84mm Hg。CRP增加到22.9,KL-6增加到762U/ml。患者俯卧位,给予肌肉松弛剂。开始0.6ml/kg/hr的连续静脉内利多卡因。白蛋白为1.8g/dl。第7天,PaO2/FiO2比增加至128mm Hg,CRP降至10.3mg/mL,利多卡因血浆浓度为2.2μg/ml。从第3天直到转出ICU的D-二聚体值在第14天升高达到75nM/L。第8天,尽管PaO2/FiO2比从84mm Hg改善至125mm Hg,但机械通气策略耗尽,患者接受ECMO。KL-6增加至845U/L,利多卡因血浆水平为2.9μg/ml。第9天,PaO2/FiO2比改善至238mm Hg,但在第10天,观察到PaO2/FiO2比急剧下降至60mm Hg,CRP为2.0mg/ml。根据柏林ARDS标准(Ranieri等人,Jama 2020,307(23),252–2533),患者的ARDS状态从中度变为重度。利多卡因治疗从连续静脉内换为连续皮下(剂量:1mg/kg/hr)。第14天,利多卡因血浆水平为2.7μg/ml。KL-6降至549U/l。第17天,患者临床状况改善,PaO2/FiO2比达到158mm Hg。患者撤离ECMO。PaO2/FiO2比进一步改善,第21天达到291mm Hg,患者的ARDS状态从中度变为轻度ARDS(Ranieri,同上)。第22天,停止机械通气,拔管。定向患者,未检测到混淆迹象。连续利多卡因治疗直至第30天转出ICU。患者在第8天接受托珠单抗,在第14天接受法匹拉韦。在利多卡因治疗期间没有观察到新的ECG变化。血液MetHb在正常范围内(0.1-0.6%)。入院后3个月,患者情况良好。
患者3-实施例3
第三名患者,59岁男性,因呼吸窘迫和CT扫描显示双侧磨玻璃样入院。共发病:糖尿病和痛风。患者需要立即插管和机械通气。初始呼吸机设置:压力控制,峰值吸气压力30cm H2O,PEEP 15cm H2O,呼吸速率25/min。入院时PaO2/FiO2比为160mm Hg(中度ARDS,根据柏林定义[361]),CRP为39.3mg/L,KL-6为294U/ml。白细胞计数升高13.10-9/L,血小板计数和尿量正常。白蛋白为2.1g/dl。血液动力学参数稳定。入院当天,以1mg/kg/hr开始连续皮下给予利多卡因。第2天,PaO2/FiO2比改善至283mm Hg,并且患者的ARDS状态从中度ARDS变为轻度ARDS。CRP为41mg/L,KL-6为268U/l,利多卡因血浆水平为3.7μg/mL。白蛋白为1.7g/dL。第4天,PaO2/FiO2比为302mm Hg,根据柏林ARDS标准,患者的ARDS状态从轻度ARDS变为无ARDS。第5天,PaO2/FiO2比进一步改善至328mm Hg,CRP降至16.4,患者拔管。定向患者,未检测到混淆迹象。第8天,患者转出ICU,CRP为2.3mg/mL。白蛋白为2.5g/dL。患者在第3天接受托珠单抗治疗,在第15天接受法匹拉韦治疗。在利多卡因治疗期间没有观察到新的ECG变化。血液MetHb在正常范围内(0.1-0.4%)。患者于第20天出院回家。3个月后,他表现良好。
患者4-实施例4
第四名患者,51岁男性。入院前10天出现发热,入院前2天出现呼吸困难和咳嗽。入院当天,PCR COVID-19检测为阳性。CT扫描显示双侧磨玻璃影。共发病:无。患者在入院时接受插管和机械通气。第3天,由于肺状况恶化,他被转移到大学医院。初始呼吸机设置:压力控制,峰值吸气压力24cm H2O,PEEP 12cm H2O,呼吸速率15/min。血液动力学条件稳定。白细胞计数和血小板计数正常。白蛋白为2.6g/dl。立即开始连续皮下利多卡因。第3天,PaO2/FiO2比为214(中度ARDS,根据柏林定义[361])。KL-6为177U/L,CRP为17.4mg/L。第5天,PaO2/FiO2比增加至382(患者的ARDS状态从轻度ARDS变为无ARDS),并且利多卡因血浆浓度为5.2μg/ml。CRP为27.3mg/L。第3天和第4天的利多卡因血浆水平分别为3.4μg/ml和4.2μg/ml。KL-6为163U/L。患者拔管。定向患者,未检测到混淆迹象。第8天,患者转出ICU,CRP为9.3mg/L。患者接受法匹拉韦14天。在利多卡因治疗期间没有观察到新的ECG变化。血液MetHb在正常范围内(0.1-0.3%)。他于第28天出院回家。在3个月时,他表现良好并返回工作。
患者5-实施例5
第五名患者,58岁男性。入院前9天,他出现咽喉痛。一天后他出现发热。入院前2天,患者开始咳嗽,呼吸困难。入院当天,PCR COVID-19检测为阳性。CT扫描显示双侧磨玻璃影。共发病:脂肪肝。患者最初送入医院病房。第3天,患者恶化,必须插管并进行机械通气。第4天,患者因肺部疾病恶化转院。初始呼吸机设置:压力控制,峰值吸气压力27cm H2O,PEEP 12cm H2O,呼吸速率25/min。PaO2/FiO2比为188(中度ARDS,根据柏林定义)。血液动力学参数稳定,CRP为12.9mg/ml。白细胞计数增加(14.4.109/L),但血小板计数正常。KL-6为330U/L。以1mg/kg/hr开始连续皮下利多卡因。白蛋白为2.8g/dl。第5天,PaO2/FiO2比不变,CRP为10.4mg/L,利多卡因血浆水平为4μg/ml。第6天,利多卡因血浆水平为3.2μg/ml。KL-6保持稳定在400U/L。白蛋白为2.3g/dl。第10天,呼吸功能不全已清除,尽管PaO2/FiO2比保持184,但CRP降至2.4mg/L,KL-6为322U/L。患者拔管并定向患者,未检测到混淆迹象。第14天,患者转出ICU。患者在第7天接受托珠单抗治疗,在第10天接受法匹拉韦治疗。在利多卡因治疗期间没有观察到新的ECG变化。血液MetHb在正常范围内(0.1-0.3%)。第20天,患者出院回家,入院后3个月表现良好。
患者6-实施例16
第六名患者,59岁男性,因COVID-19导致发热、呼吸困难和咳嗽。CT扫描显示双侧磨玻璃影。共发病:高血压用药。患者入住普通病房。KL-6为233U/L,白细胞计数和血小板计数正常。白蛋白为3.6g/dl。第3天,呼吸功能恶化,需要转入ICU和机械通气。初始呼吸机设置:压力控制,峰值吸气压力22cm H2O,PEEP 10cm H2O,呼吸速率20/min。在进入ICU后开始1mg/kg/hr的连续皮下利多卡因。血液动力学参数稳定。CRP为6.3mg/L,KL-6为263U/L。第4天,发生进行性呼吸衰竭,需要插管和机械通气。PaO2/FiO2比为218mm Hg,血液动力学参数保持稳定。CRP为6.3mg/L,白细胞计数和血小板计数正常。利多卡因血浆水平为4.6μg/ml。第5天,PaO2/FiO2比进一步降至164mm Hg。利多卡因血浆水平为3.4μg/ml。白蛋白为3.2g/dl。第9天,患者的临床状况改善。呼吸机设置可降低,撤离期间PaO2/FiO2比仍为207mm Hg,CRP为0.7mg/L。第10天,患者拔管,定向患者,未检测到混淆迹象。第13天,患者转出ICU。第4天,给予托珠单抗。患者接受法匹拉韦11天。在利多卡因治疗期间没有观察到新的ECG变化。血液MetHb在正常范围内(0.1-0.3%)。他于第20天出院,入院后3个月,他表现很好,打了高尔夫球并返回工作。
实施例7-COVID-19
2020年3月24日,49岁女性,出现咳嗽、呼吸困难、肌痛、髋关节和腹股沟疼痛、颤抖但无发热。未进行COVID-19检测。这发生在与一名同事密接工作一周后,该同事罹患确诊重症COVID-19,需要住院。症状出现后4小时开始用利多卡因治疗。开始0.5mg/kg/hr的连续皮下(浅表皮下组织)输注利多卡因后,症状逐渐消退,几小时后她几乎没有症状。12小时后停用利多卡因。几小时后,症状复发并在重新开始连续皮下输注利多卡因后再次消退。利多卡因治疗连续3天。
2020年4月1日,患者症状恢复,重新开始利多卡因皮下输注。几天后,临床状况改善,停止利多卡因治疗。患者可在家工作,但出现疲劳。4周后,患者的所有症状消失,完全恢复健康。
2020年7月12日(第1天),患者出现新的症状,包括颤抖、关节痛(膝、髋、肩)和左眼结膜炎。她报告工作时生病。感染可能发生于2020年7月1日。那天,她在办公室工作期间会见了许多人,晚上她与一些同事一起喝酒。尽管保持社交距离和手部清洁,但仍发生感染。那时没人佩戴口罩。患者接受皮下输注利多卡因(0.63mg/kg/hr)治疗。她的症状在几小时内得以改善。7月15日(第4天),停止利多卡因输注数小时,她前往GP进行COVID-19检测。2020年7月21日(第10天),COVID-19的IgA抗体检测结果为阳性。一周后,由于输注系统和注射泵严重妨碍日常活动,日间停止利多卡因输注。
第11天,症状加重:肺部刺痛感、胸痛、颤抖、呼吸困难、频繁打哈欠和头晕。每天给予利多卡因输注24小时。症状逐渐好转。
第12天,她出现胸痛、颤抖和近端肌肉和关节疼痛。温度35.9摄氏度,SpO2(氧饱和度)86%,HR(心率)70/min,BP(血压)110/70mm Hg。在肺的左下叶听到支气管呼吸音,而在右下叶听到支气管呼吸音的程度小得多。仍进行皮下利多卡因输注(0.63mg/kg/hr),此外,她在怀疑继发性细菌性肺炎的情况下用阿莫西林3×500mg/天治疗。她睡着了,第二天所有症状都得到了明显改善,连续不断地继续输注。
第18天,因为输注系统和注射泵严重妨碍了患者的日常活动,停止皮下利多卡因输注。几小时后,出现严重疲劳、胸痛和右上臂疼痛的临床恶化。将该治疗转化为经皮利多卡因乳膏。制剂:2.5%α-松油醇、20%利多卡因、10%蓖麻油、1%聚山梨酯20、0.5%卡伯波(Carbopol)和56%水(利多卡因乳膏200mg/ml)。在皮肤上施用多达400mg的乳膏,并用Tegaderm透明伤口敷料覆盖。但1小时后症状未改善,开始皮下利多卡因输注40mg/小时。1小时后,临床改善明显。但6小时后,由于持续症状,输注速率增加至63mg/小时(1mg/kg/hr)。此后症状消失,上臂疼痛除外。
第19天,右臂疼痛持续数周。疼痛主要在上臂肌肉中感觉到,有时在肩、肘和下臂中感觉到。这导致严重的冻结肩综合征。
第22天,哈欠过多和体温(口腔测量)34℃的时间段。
第23天,患者出现波动性颤抖,伴有咳嗽、呼吸困难、肺部刺痛感、胸痛、咽喉痛、头痛、打哈欠、左眼结膜炎和关节痛。利多卡因输注将症状降低至可耐受水平。
第24天,患者已经具有足够的输注,并且将利多卡因输注转化成经皮利多卡因乳膏,将400mg的20%施用在2×50cm2的表面上并用Tegaderm覆盖。6小时后乳膏几乎完全被吸收,每次用新的剂量替换。
第25天,Tegaderm伤口敷料在夜间受损,部分剂量的乳膏丢失。她醒来时出现胸骨疼痛,右侧背阔肌区疼痛,感觉不适。SpO2 98%,HR 74/min,BP 114/71,温度35.3摄氏度。施用新的乳膏剂量并将额外的100mg乳膏以团注剂量擦入皮肤。1小时后,临床状况改善。将利多卡因400mg乳膏设定为每6小时施用一次。
第26天,看起来施用在腹壁上的乳膏在夜间并未被皮肤良好吸收。她的症状恢复,在大腿上使用新剂量的利多卡因乳膏,在1小时内减轻了症状。在16:00,乳膏被完全吸收,症状再次恢复。新的利多卡因乳膏剂量再次有效。
第27天,施用在手臂和腹壁上的利多卡因乳膏的再吸收远小于内上腿上的再吸收。
第32天,07:30,利多卡因乳膏的吸收小于80%。她的临床状况较差,SpO2定期下降至90%。给予倍氯米松鼻喷雾2×200μg。她需要定期叹息和咳嗽以保持SpO2高于92%。将额外的100mg乳膏以团注剂量擦入皮肤,使得症状在30分钟内改善。在12:00,左膝变得极度疼痛,再次用新的乳膏剂量治疗,将额外的100mg乳膏再次以团注剂量擦入皮肤,使得症状改善。利多卡因乳膏的总日剂量为2000mg。
第32至33天夜晚,除了右上臂疼痛之外没有任何症状。从第1天(2020年7月12日)起第一个晚上没有症状。
第33天11:10,患者肩胛骨间出现突然和极度疼痛。她呼吸困难,呼吸过度,面部苍白。SpO2 97%,HR 66/min,BP 112/60mm Hg,温度35.3摄氏度。医院分析显示肺X线正常,MetHb正常和d-二聚体正常。进一步的常规实验室结果也正常。
第35天,除右上臂疲劳和疼痛外,患者无其他症状。利多卡因乳膏逐渐减少至4×100mg/d,没有Tegaderm覆盖。
第46天,03:30,报告SpO2为86%,HR为55/min,BP为115/70mm Hg,肺部刺痛感,左结膜炎。取出利多卡因乳膏,开始连续皮下输注0.63mg/kg/hr利多卡因。30分钟内症状好转。疼痛的右上臂保持不变。
1周后停止利多卡因输注。
第61天04:20,出现新发肺部刺痛感、左结膜炎和右上臂疼痛加重。开始连续皮下输注0.63mg/kg/hr利多卡因,症状消退。8小时后停止利多卡因输注。晚餐后19:40,患者出现颤抖,感觉不适,不得不上床睡觉。温度34.1,BP 96/60mm Hg,SpO2 100%,HR 86/min。重新开始连续皮下输注0.63mg/kg/hr利多卡因,伴随400μg倍氯米松鼻喷雾剂和口服氢化可的松。症状迅速消退。
第66天,除了右上臂疼痛外,她感觉良好。上臂的疼痛强度波动,有时会转移到肩或肘。全科医生不认为这与COVID-19有关。停止利多卡因输注。
第67天,她搭乘汽车旅行,在离家200公里的地方探访朋友。
第85天,在几乎3周后除了上臂的波动疼痛外没有症状,肺的刺痛感恢复。SpO296%,HR 90/min,BP 95/68mm Hg,温度33.5摄氏度。开始舌下利多卡因3×100mg/d。将利多卡因在口中保持15分钟,然后吞咽。避免吸入利多卡因溶液。利多卡因制剂:利多卡因5g/50ml(10%溶液,100mg/ml)、96%乙醇、聚乙二醇400、香蕉香精和纯净水。
从第85天开始,在开始舌下利多卡因治疗后,患者在服用药物前的早晨以及服用舌下利多卡因前一天结束时在其胸部经历刺痛感和压迫感。这些症状在施用舌下利多卡因20分钟后消失。这几乎每天重复发生。
实施例8-COVID-19
2020年12月20日,46岁男性,出现流鼻涕、轻度头痛、颈部和右肩僵硬和严重疼痛、嗅觉丧失和强烈味觉减退。他感到疲倦和昏睡。5天前,患者与COVID-19患者接触。症状开始后第2天,COVID-19的PCR拭子检测为阳性。随后几天症状进展。
第5天,患者使用计量剂量接受5×60mg利多卡因。将药物舌下施用并在口中保持15分钟。此后,吞咽利多卡因溶液。避免吸入利多卡因。利多卡因制剂:利多卡因5g/50ml(10%溶液,100mg/ml)、96%乙醇、聚乙二醇400、香蕉香精和纯净水。第6天(治疗开始后24小时),流鼻涕、头痛、颈部疼痛和颈部僵硬消失。第6天,患者接受利多卡因4×60mg/d,从第7天开始,患者接受利多卡因3×60mg/d治疗。第9天,患者昏睡要少得多,感觉有更多精力并开始彻底清洁他的房子。他首次报告口干感。第8天,除口干感和轻度疲劳外,所有症状完全消失。第11天,患者行走1小时,感觉良好。
实施例9-葡萄球菌败血症引起的ARDS
利多卡因作为治疗患有严重ARDS的患者的最终药物(终极药物)的标签外用途的实施例。43岁女性,于2019年底入住Hague区的ICU。她从葡萄球菌败血症发展为严重ARDS。这种败血症在静脉内给予MRI图像的造影剂后发展。患者接受机械通气。尽管有足够的抗生素治疗,ARDS和败血病进一步恶化,导致机械通气下的氧合不足,血液动力学不稳定,需要非常高剂量的去甲肾上腺素和加压素。她被连接到ECMO(体外膜氧合)并被转移到鹿特丹大学医院。计划将患者保持在ECMO上,可操作地移除肺并用抗生素治疗患者2个月以清除胸腔中的微生物。随后进行肺移植。即使使用ECMO疗法,血液动力学不稳定和氧合不良也促使负责治疗患者的专科医师使用旨在抑制P2X7R的连续低剂量利多卡因。在开始1mg/kg/小时的连续输注利多卡因后1.5小时内,患者的状况稳定。在随后的几天中,去甲肾上腺素和血管加压素药物可逐渐减少,几天后ECMO断开,因为恢复了常规通气的氧合作用。无需赘言,计划的肺移植被取消了。在1.5个月后,患者撤离呼吸机,并转移到病房。患者接受利多卡因2周。
实施例10-风湿性多肌痛
2012年1月,59岁男性,患有进行性肌肉疼痛,最初被称为他汀相关。在床上几乎不能翻身。患者出现不同程度的力量丧失,体重保持稳定54kg。无发热。此外,患者报告疲劳和全身不适。无家族性皮肤或肌肉疾病,但有哮喘和CVD。18个月前,患者出现蜱叮咬,出现红斑伴慢性迁移性红斑(ECM)。怀疑伯氏疏螺旋体感染,患者接受阿莫西林治疗4周。实验室结果显示红细胞沉降速率增加47mm/hr(2012年11月1日)和85mm/hr(2013年2月)。胸部X线以及胸腹部CT扫描无异常。诊断为风湿性多肌痛。患者开始接受高剂量皮质类固醇治疗。该药物逐渐减少,6个月后停止。
2019年9月,症状复发。患者最初接受夜间0.5mg/kg/hr连续皮下利多卡因输注治疗8小时,频率为2次/周。首次治疗后症状消失。数月后,每天两次用经皮5%利多卡因软膏300mg代替利多卡因皮下输注。该治疗无效。2020年9月10日,患者开始使用舌下利多卡因2×60mg/d。将利多卡因在口中保持15分钟,然后吞咽。避免吸入利多卡因溶液。利多卡因制剂:利多卡因5g/50ml(10%溶液,100mg/ml)、96%乙醇、聚乙二醇400、香蕉香精和纯净水。症状在1小时内消失,(治疗期间)直到2021年1月2日随访结束才恢复。
实施例11-银屑病关节炎
60岁女性,背部皮肤带状疱疹感染,延伸至腹壁。4年前她出现银屑病。在前一年,她发展为进行性类风湿性关节炎和扁平苔藓。症状是进行性的,从几周后她不能做饭。她几乎不能穿衣和脱衣。患者接受了皮质类固醇和甲氨蝶呤治疗。2020年7月初,躯干出现非常疼痛的带状疱疹感染,患者接受吗啡治疗。吗啡没有减轻疼痛,但她出现顽固性便秘。这就是她向我们陈述的情况。2020年8月8日,患者开始接受利多卡因乳膏10%的治疗。制剂:2.5%α-松油醇、10%利多卡因、10%蓖麻油、1%聚山梨酯20;0.5%卡伯波和66%水(利多卡因乳膏100mg/ml)。利多卡因乳膏的剂量为2×200mg/天,施用在她前臂的皮肤上,并用Tegaderm透明伤口敷料覆盖。每天,施用的乳膏的位置交替地在左和右前臂上。吗啡治疗逐渐减少。由于Tegaderm覆盖物损伤皮肤,她改为用弹性绷带包裹的粘贴膜覆盖物。
顽固性便秘在2天内消失,带状疱疹感染迅速下降,14天后她的良好感从3增加到7.5、10。她可以正常在家中进行日常活动。4周后,她很容易做一些园艺,她的日常活动能力恢复正常。
实施例12-脊椎关节病
来自意大利的62岁患者,患有顽固性进行性和衰弱性椎体退行性疾病(L2-L3、L3-L4和L4-L5)。他遭受严重疼痛,难以行走,不能再做起重机操作者的工作,并且不能再培养他的爱好(修理赛车)。症状进展了20年。止痛药无效。
2019年12月,患者接受2×1400mg/d利多卡因贴剂。为了防止皮肤刺激,在皮肤上的交替位置施用贴剂。根据患者情况,分别在4天和2周后70%和90%的症状消失。他几乎没有痛苦,回到工作中,能够再次培养他的爱好。
实施例13-慢性间质性膀胱炎(慢性炎性膀胱病症)
88岁女性,共发病高血压、青光眼、II型糖尿病伴肾功能不全、子宫和膀胱慢性炎症。在过去两年中,她抱怨膀胱的顽固性进行性极度疼痛,尤其是在排尿期间。羟考酮(吗啡类似物)、扑热息痛和抗生素治疗对她的症状没有影响。1mg/kg/hr的连续皮下组织利多卡因治疗逐渐减轻了她的症状,2天后她几乎没有症状。1周后,由于药物供应问题停止治疗,症状再次出现。重新开始注射利多卡因后,她的症状再次消失。
实施例14-膝关节病
43岁女性,右膝膝关节病(膝骨关节炎)。右膝有积液,极度疼痛。在疼痛迫使她停止行走和坐下之前,她的最大行走范围是100m。她几乎不能在家中爬楼梯,她不能骑自行车。MRI显示右膝关节积液。由于MRI显示股胫软骨组织腹侧部分存在缺损,她被拒绝接受膝关节拔除治疗。2020年1月25日,患者接受2×1400mg/d利多卡因贴剂治疗。6周内,右膝积液和疼痛改善,她的行走范围扩大到>500m,她可以爬楼梯,8周后她可以骑自行车。
实施例15-多发性硬化症
46岁患者,2005年被诊断为复发缓解型多发性硬化症(RRMS)。2005-2006年,患者接受Avonex治疗。2020年1月,患者出现疲劳。上午10点至14:00,因疲劳她不得不休息。她的神经症状包括右臂感觉异常。我们用1×700mg/48小时利多卡因贴剂治疗她。4周后,她的疲劳改善,她白天可以不休息,并且她感觉对她的日常活动有更多精力。
实施例16-晚期宫颈癌和肾功能障碍
65岁女性患者,2018年7月诊断为晚期宫颈癌。肿瘤块阻塞了两个输尿管并导致双侧肾积水。肾积水成功引流,患者接受紫杉醇和贝伐珠单抗治疗。2018年10月出现肾功能损害。2019年8月,胸腹部CT扫描显示骨盆腔中的大肿瘤块、多个髂旁淋巴结转移和胰腺周围的块。她出现了与癌症相关的腹水。结论是肿瘤生长是进行性的。但由于肾功能的进行性损害,使用卡铂和吉西他滨的预期治疗被推迟。
2019年9月15日,患者开始接受1mg/kg/hr的连续皮下利多卡因输注。肾功能改善。6周后,肾功能改善使得患者可以用卡铂和吉西他滨治疗。5个月后,在2020年2月,肿瘤生长稳定,可以停止化疗。当时她仍在输注利多卡因。
实施例17-各种癌症
10名患者:前列腺癌(2名患者)、胰腺外分泌癌(4名患者)、结肠癌(2名患者)、宫颈癌(1名患者)和乳腺癌(1名患者)。所有患者没有更多选择用于进一步癌症治疗,并且所有患者用姑息性阿片制剂治疗。我们给患者连续皮下给予利多卡因1mg/kg/hr代替吗啡。
7名患者在2小时内缓解疼痛、恶心和/或极度疲劳,其余患者在48小时内缓解。这在下周进一步改善并稳定数周。
例如,一名81岁的晚期转移性结肠癌患者,疼痛、不适和恶性腹水都有很大改善,3周后,他可以在轮椅中和他的摇滚乐队一起表演。
疾病对残疾的影响概况(SIP68)应用于库存数据。治疗前:SIP68:48(范围18-68)。3天后:SIP68:33(范围12-58),所有患者均得到改善。7天后:SIP68:28(范围12-56),所有患者均得到改善。
实施例18-肌萎缩性侧索硬化症(ALS)
63岁男性,被转诊到门诊就诊,分析双腓肠肌肌肉痉挛、左足下垂和双手、肩和腿无力。肌肉痉挛几乎仅在意向性运动后发生。未观察到记忆缺陷和家族病史。
体检发现双侧冈下肌、冈上肌、鱼际和小鱼际隆起和左小腿萎缩。下肢反射亢进和拇趾双侧伸肌反应(阳性Babinski征)。在小腿和肩部可见肌纤维化。根据MRC量表(医学研究委员会,英国,mrc.ukri.org)的肌肉力量身体检查得分:上臂外展左4,右4;上臂内收左5,右5;肘屈曲左4,右4;肘延伸件左5,右5;膝盖屈曲左4右4;膝盖伸展左5,右5;脚延伸件左1,右1;左脚屈曲2,右脚屈曲2;其余肌肉未受影响。
脊柱成像(CT扫描和MRI扫描)排除了运动神经束的任何结构碰撞。EMG显示肢体肌肉去神经。诊断为ALS。
用4×100mg/d的舌下亲脂性利多卡因碱(在计量喷雾瓶中的利多卡因喷雾5g/50ml)治疗患者。患者在口中保持利多卡因溶液15分钟,然后患者按预期吞咽溶液。
一周后,患者注意到肌肉痉挛逐渐消失。3周后,他的肌肉力量开始逐渐改善。开始利多卡因治疗6个月后,重复肌肉力量检查(使用MRC量表)显示:上臂外展左5,右5(改进的);肘屈曲左4,右4(无变化);膝关节左侧屈曲5,右侧屈曲5(改善);左脚延伸部2,右脚延伸部2(改进的);左脚屈曲3,右脚屈曲3(改善);其余肌肉未受影响。治疗使得疾病症状在临床上显著改善。
实施例19-阿尔茨海默氏痴呆症
72岁男性,越来越频繁发生记忆丧失。症状在6年前开始,发作性记忆丧失,随后无法记住新信息。相反,旧的记忆似乎是完整的。这些症状发展到严重影响社会功能、日常活动如烹饪、园艺和购物的程度。没有心血管、精神病或神经病家族史。
体格检查未发现异常。小型精神状态检查(MMSE)检测总分为15(严重认知损害)。常规血液化学和血液学正常。甲状腺功能分析、血液风湿病学筛查维生素B12和同型半胱氨酸未见异常。尿液(24小时样品)分析显示没有重金属中毒的迹象。常规胸部X线片正常。脑部MRI无异常。诊断为阿尔茨海默氏病。
腰椎穿刺显示β-淀粉样蛋白(Aβ42)水平降低。
患者被转移到痴呆症护理院。患者接受舌下亲脂性利多卡因碱4×100mg/d(在计量喷雾瓶中的利多卡因喷雾5g/50ml)。患者将利多卡因溶液保持在口中最长15分钟,然后按预期吞咽溶液。由专业护士确保药物依从性。
记忆印记容量逐渐增加,3个月后MMSE检测总评分为23(轻度认知损害)。治疗使得疾病症状在临床上显著改善。
实施例20-特发性帕金森病
76岁男性,患有进行性跌倒倾向(体位不稳定)。症状在患者转诊到诊所前8年开始。此外,3年后他出现右臂的进行性震颤,尤其是当手臂不移动时(静止性震颤)。左臂静止性震颤在右臂震颤发作后2年发展。
患者接受左旋多巴治疗,最初症状明显改善。6年后症状恢复,增加左旋多巴剂量后,患者出现左旋多巴引起的舞蹈病。患者从未接受过精神抑制药治疗。
没有重复中风、重复头部损伤、脑炎、眼病危象、核上凝视麻痹、记忆丧失自主症状或MPTP((1-甲基-4-苯基-1,2,3,6-四氢吡啶)滥用史。脑MRI无异常。诊断为特发性帕金森病。
用4×100mg/d的舌下亲脂性利多卡因碱(在计量喷雾瓶中的利多卡因喷雾5g/50ml)治疗患者。患者将利多卡因溶液保持在口中最长15分钟,然后患者按预期吞咽溶液。
1个月后,患者报告称跌倒趋势逐渐改善。震颤几乎消失。治疗使得疾病症状在临床上显著改善。
实施例21-癫痫发作
30岁女性,在汽车碰撞后被转移到急诊室。她坐在驾驶员旁边。她主诉头痛。她的病史没有问题。
体格检查显示,入院时格拉斯哥昏迷评分(GCS)为15/15。在她的前额上观察到皮下血肿。未发现其他异常。
头部和颈椎CT扫描无异常。到达后1小时,她的意识水平开始下降,并且她发展为全身性癫痫发作。
用重复的10mg静脉内地西泮治疗没有效果,患者被插管并用连续咪达唑仑输注深度镇静。到达急诊室后4小时重复CT扫描显示左顶叶出血性挫伤病变。患者入住ICU,机械通气,并在EEG监测下进入戊巴比妥昏迷。5天后,患者撤离戊巴比妥,全身癫痫发作开始以增加的强度发展。诊断为创伤后癫痫发作。
开始用1mg/kg/小时的皮下(浅表皮下)盐酸利多卡因(20mg/ml溶液)治疗,30分钟内癫痫发作消失。EEG显示脑的癫痫活动已经消失。8小时后,患者恢复意识,4小时后,患者从机械呼吸机上脱离并拔管。
第二天,GCS为15/15,体格检查未发现神经功能缺损。患者连续皮下利多卡因治疗2周。治疗使得创伤后癫痫发作在临床上显著改善。
实施例22-多发性硬化症
56岁女性,在10年前被诊断为原发性进展型多发性硬化症(PPMS)。通过脑脊液MRI和CSF结果证实了诊断。
用ocrelizumab和地塞米松治疗不能改善症状。
在她被转诊给我们时,Kurtzke扩展残疾状态量表EDSS的评分为7.5(Kurtzke(1983)Neurology.33(11):1444-52)。患者被限制在轮椅上,不能行走超过几步。
我们用舌下亲脂性利多卡因碱4×100mg/d(在计量喷雾瓶中的利多卡因喷雾5g/50ml)治疗患者。患者将利多卡因溶液保持在口中最长15分钟,然后患者按预期吞咽溶液。
在接下来的几周,她的临床状况改善。3个月后,EDSS从7.5改善到5.5,她可以在没有帮助的情况下行走约120米,但是她仍然需要帮助来完成她的全天活动。治疗使得舌下利多卡因治疗后EDSS评分在临床上显著改善。
实施例23-糖尿病性多发性神经病
72岁女性,糖尿病患者,被诊断为糖尿病性多发性神经病。她的双手和双脚感觉对称,双手肌肉力量丧失。用药:中效胰岛素2×12U/d和3×500mg/d二甲双胍。
体格检查显示她的双手和双脚感觉异常和感觉丧失,以及手指屈肌和手伸肌肌肉力量丧失(MRC4/5)。用4×100mg/d的舌下亲脂性利多卡因碱(在计量喷雾瓶中的利多卡因喷雾5g/50ml)治疗患者。患者将利多卡因溶液保持在口中最长15分钟,然后患者按预期吞咽溶液。
几天后,她的手和脚的刺痛感完全消失,3个月后,她的双手肌肉力量显著提高。该治疗使得糖尿病性多发性神经病在临床上显著改善。
实施例24-重症肌无力
36岁男性,被诊断为重症肌无力。他在身体活动后出现手臂和手的肌肉无力。用EMG和针对乙酰胆碱受体(AChR)的抗体的阳性检测证实诊断。他用口服抗胆碱酯酶药(美斯地浓(mestinon))4×60mg/d治疗。在甲型流感病毒感染期间,患者手臂和手出现严重虚弱,抗胆碱酯酶治疗不再有效。用4×100mg/d的舌下亲脂性利多卡因碱(在计量喷雾瓶中的利多卡因喷雾5g/50ml)治疗患者。患者将利多卡因溶液保持在口中最长15分钟,然后患者按预期吞咽溶液。4小时内,手臂和手的肌肉无力显著改善。此外,甲型流感病毒感染症状几乎完全消失。治疗连续2周。该治疗使得重症肌无力症状恶化中肌无力在临床上显著改善。
实施例25-慢性阻塞性肺病(COPD)
67岁女性,被诊断为COPD。肺活量计检测期间发现FEV1为72%(中度COPD)证实了诊断。胸部X线和常规血液检查无异常。患者接受倍氯米松2×40微克/天治疗。在随后的6年中,她在体育锻炼(如在家中爬楼梯和骑自行车)期间遭受进行性呼吸短促。她的日常活动受到她的症状的严重影响。FEV1降至60%。用4×100mg/d的舌下亲脂性利多卡因碱(在计量喷雾瓶中的利多卡因喷雾5g/50ml)治疗患者。患者将利多卡因溶液保持在口中最长15分钟,然后患者按预期吞咽溶液。在一周内,她好转,可以爬楼梯、骑自行车,而不会出现呼吸急促。3个月后,重复肺活量计检测显示她的FEV1改善至84%(轻度COPD)。利多卡因治疗减轻了她的COPD症状。
实施例26-格雷夫斯病
50岁女性,被诊断患有格雷夫斯病几年。甲状腺功能亢进已经得到治疗并处于控制之下,但是眼睛症状仍然明显存在。直到一年前,她接受了5次类固醇输注,仅表现出眼短期改善。最后的治疗方案是对眼眶进行双侧手术减压。由于可能产生复视的副作用,患者尚未同意该手术。将利多卡因乳膏施用于眼睑之前的双眼状态如下:结膜发红;中度非液体性眶周肿胀;无眼睑红斑;没有视神经病变或角膜暴露的体征或症状。每日三次眼睑施用5%利多卡因软膏使得结膜发红和眶周肿胀显著改善。治疗使得疾病症状在临床上显著改善。
实施例27-溃疡性结肠炎
40岁女性,5年前被诊断为溃疡性结肠炎。其症状是腹痛、血性腹泻伴粘液、贫血和体重减轻。除贫血外,常规血液实验室检查无异常。CT扫描显示几段结肠壁增厚约8mm。结肠镜检查显示节段性结肠炎症伴红斑、正常血管模式损失、粒度、糜烂、出血和溃疡。在发炎肠粘膜和正常肠粘膜之间具有清楚的区别。未观察到异型增生或恶性转化的迹象。组织病理学显示隐窝密度降低、粘膜形态不规则和弥漫性炎症。未发现肉芽肿。在先前的结肠炎恶化发作中,患者对口服3×400mg/天的美沙拉嗪CR的治疗反应良好。但是在这种恶化发作中,症状对美沙拉嗪治疗没有反应。用4×100mg/d的舌下亲脂性利多卡因碱(在计量喷雾瓶中的利多卡因喷雾5g/50ml)治疗患者。患者将利多卡因溶液保持在口中最长15分钟,然后患者按预期吞咽溶液。48小时内症状逐渐减轻,3天后症状完全消失。舌下含服利多卡因连续2周,随后的几个月患者保持无症状。利多卡因根除了疾病的症状。
实施例28-炎性肠病
5岁犬在肛周区出现小孔,白色不透明液体从孔开口渗出。孔的尺寸逐渐变大,瘘管开始难闻,开始出现腹泻。狗尤其在排便期间疼痛。体格检查显示肛周瘘非常疼痛和发炎。犬被诊断为炎性肠病伴肛周瘘。诊断为炎性肠病伴肛周瘘。兽医决定操作和取出肛囊。术后疾病进展加速,痛苦显著增加。将狗用亲脂性利多卡因碱4×100mg/d(在计量喷雾瓶中的利多卡因喷雾5g/50ml)处理,施用到最大的瘘管中。1周后,渗出的不透明液体分泌物和不良气味消失。即使在排便期间,疼痛也显著减轻。瘘管内衬开始产生肉芽组织。利多卡因减轻了肛瘘的症状和感染。
实施例29-对列队毛虫(processionary caterpillar)毒素的过敏反应
33岁男性,意外压过橡树列队毛虫。他立即在手臂、胸部、面部和颈部出现瘙痒性皮疹。几分钟后他呼吸困难,难以呼吸。我们用舌下利多卡因碱100mg(在计量喷雾瓶中的利多卡因喷雾5g/50ml)治疗患者。患者将利多卡因溶液保持在口中最长15分钟,然后患者按预期吞咽溶液。10分钟内症状开始好转。15分钟后所有呼吸症状消失,1小时后瘙痒皮疹显著改善。48小时后停止治疗(4×100mg/d),症状未恢复。治疗使得对列队毛虫毒素的过敏反应在临床上显著改善。
实施例30-类风湿性关节炎
62岁女性,被诊断为手腕和手指双侧关节类风湿性关节炎。她患有严重疼痛、肿胀和温暖的关节。她完成日常活动的能力严重中断,她几乎完全依赖其他人。类风湿因子(RF)和抗瓜氨酸化蛋白抗体(ACPA)的血液检测明显呈阳性。类风湿性关节炎的临床疾病活动指数评分(Aletaha和Smolen,Clin.Exp.Rheumatol.2005年9月至10月;23(5增刊39):S100-8)为52分(总分76),表明高疾病活动性。诊断为类风湿性关节炎。
用改善疾病的抗风湿药物(DMARD)(诸如甲氨蝶呤和托珠单抗)治疗不能改善症状,并且患者患有副作用。用4×100mg/d的舌下亲脂性利多卡因碱(在计量喷雾瓶中的利多卡因喷雾5g/50ml)治疗患者。患者将利多卡因溶液保持在口中最长15分钟,然后患者按预期吞咽溶液。
4周后,她的腕和手的发炎关节几乎消失。她仍然抱怨这些关节僵硬。类风湿性关节炎的临床疾病活动性指数评分从52分改善为2分(总分76),表明缓解。在用舌下利多卡因治疗严重类风湿性关节炎后,治疗使得临床疾病活性在临床上显著改善。
实施例31-糖尿病患者的缺血性心肌病
61岁男性,有15年糖尿病史。8年前,由于三支血管病变,他接受了支架植入术,随后进行了冠状动脉旁路移植术(CABG)。最近5年,患者出现反复胸痛、夜间和运动期间呼吸困难逐渐增加以及极度疲劳。他的血压为140/90mm Hg。他被诊断为缺血性心肌病。估计经胸超声心动图心脏射血分数为31%。诊断为缺血性心肌病。患者不适合接受手术治疗,要求我们用利多卡因治疗。我们用舌下亲脂性利多卡因碱4×100mg/d(在计量喷雾瓶中的利多卡因喷雾5g/50ml)治疗患者。患者将利多卡因溶液保持在口中最长15分钟,然后患者按预期吞咽溶液。3周后,患者报告胸痛发作显著减少,呼吸困难明显改善,他感觉白天更有精力。3个月后,重复经胸超声心动图显示心脏射血分数从31%改善至42%。治疗使得严重缺血性心肌病患者症状和心脏功能在临床上显著改善。
实施例32-具有风湿性多肌痛病史的患者的急性腰痛
67岁男性,有风湿性多肌痛病史,患有严重背痛。前一天,他一直在45km的距离上骑自行车,该自行车配备有活动手把。由于大部分行程中强劲的逆风,骑行很是艰难。
第二天早晨,他醒来,伴有严重的下背痛。腰痛使他的背部伸直。他可以以极端弯曲的姿势谨慎地行走,并且难以爬楼梯。用4×100mg/d的舌下亲脂性利多卡因碱(在计量喷雾瓶中的利多卡因喷雾5g/50ml)治疗患者。患者在口中保持利多卡因溶液15分钟,然后患者按预期吞咽溶液。30分钟后95%的症状消失。患者可以恢复正常的直立姿势,行走和爬楼梯没有困难。
实施例33-系统性红斑狼疮(SLE)
79岁的SLE确诊患者被转诊到医院。患者42岁时被诊断为SLE。在此期间,由于复发性SLE引起的心包炎伴心包积液、腹膜炎和胸膜炎,他定期入院。他被转诊到我们前几天,开始出现新的腹膜炎事件。患者因腹水出现腹痛、恶心和明显腹胀。患者感觉缺乏精力。腹腔液的实验室检查:IL-6为11.000pg/ml(而血清IL-6为28pg/ml),LDH为102IU/L。用4×100mg/d的舌下亲脂性利多卡因碱(在计量喷雾瓶中的利多卡因喷雾5g/50ml)治疗患者。患者在口中保持利多卡因溶液15分钟,然后患者按预期吞咽溶液。临床症状在6天内消失,2周后腹胀完全消失。继续用舌下利多卡因治疗。
部分A:P2X7R拮抗剂
A.特异性针对P2X7R的单克隆抗体
B.化合物
a.酰胺衍生物
i.如KR101398264B1中所述的氧代-脯氨酸酰胺衍生物
ii.氨基酰胺基团:利多卡因、阿替卡因、布比卡因、辛可卡因(地布卡因)、依替卡因、左布比卡因、利多卡因(利多卡因(Lignocaine))、甲哌卡因、丙胺卡因、罗哌卡因、曲美卡因
b.氨基酯衍生物
i.普鲁卡因、苯佐卡因、氯普鲁卡因、可卡因、环美卡因、二甲卡因(拉罗卡因)、哌罗卡因、丙氧卡因、丙美卡因、丁卡因(阿美卡因)
c.苯基取代的5,6-二氢-[1,2,4]三唑并[4,3-a]吡嗪P2X7拮抗剂
d.作为P2X7调节剂的双环杂芳基化合物及其用途(WO2007/109192)
C.用于临床试验以及在人体中试验的P2X7R抑制剂
a.CE-224,535500(Pfizer),
b.AZD9040(Astra-Zeneca)
c.JNJ-54175446(Johnson and Johnson)。
a.Mehta N等人Bioorg Med Chem,201422(1)54-88公开的P2X7R抑制剂,仅对P2X7R没有选择性的现有P2XR抑制剂:PPADS四钠盐、亮蓝G(BBG)、氧化ATP(o-ATP)
b.现有的特定2X7R抑制剂:KN-62、AZ9040、A-740003、A-438079、GSK314181A、A-804598、A-839977和AZ-116453743。
c.基于母体支架的分类,181种化合物:金刚烷酰胺衍生物、三唑衍生物、二芳基咪唑烷衍生物、焦谷氨酸酰胺衍生物、吡唑乙酰胺衍生物、二氢二苯并[a,g]喹嗪鎓衍生物、四唑衍生物、酪氨酸基衍生物、吡唑并二氮杂卓衍生物、咪唑衍生物、苯甲酰胺衍生物、KN62类似物衍生物、P2X7R的天然拮抗剂。
d.来自天然产物提取物的三种P2X7R抑制剂:Massadine、Stylissadine A和Stylissadine B。
a.Caseley EA等人.Biochem PharmacoL2016(116)130-13973公开的P2X7R抑制剂,在针对hP2X7R中的ATP结合口袋虚拟筛选约100000个结构不同的化合物后,排名最高的化合物:C1直至C73。
b.由于P2X7R活化和大孔形成(YO-PRO-1摄取),这些化合物中的三种似乎有效抑制跨膜电流:C23、C40和C60。
Bin Dayel A等人Mol Pharmacol 2019,96(3)355-363公开的P2X7R抑制剂AZ11645373、亮蓝G、KN-62、西米达唑和ZINC58368839。
a.NorthRA等人Physiol Rev 2002,82,(4),1013-67公开的P2X7R抑制剂。现有P2XR抑制剂仅对P2X7R没有选择性:BBG、PPADS、苏拉明、o-ATP。
b.现有的特定2X7R抑制剂:A-438079、A-804598、A-740003.0、KN-62、AZ10606120、AZ11645373、GW791343和JNJ47965567
d.Sluyter Adv Exp Med Biol-Prot Rev 2017,(19)-17-53公开的P2X7R抑制剂。现有P2XR抑制剂仅对P2X7R没有选择性:BBG、o-ATP、PPNDS、PPADS、MRS2159、NF279、NF449。
e.现有的特定2X7R抑制剂:AACBA、AstraZeneca、A-438079、A-804598、A-740003.0和KN-62。
D.Carroll等人Purinergic signal 2009,5,(1)63-73公开的P2X7R抑制剂
57种化合物:金刚烷甲酰胺、芳基碳酰肼、氰基胍、芳基四唑/芳基三唑
E.Donnelly-Roberts DL等人,Neuropharmacology 2009,56,(1),223-9公开的P2X7R抑制剂。
[3H]A-804598([3H]2-氰基-1-[(1S)-1-苯基乙基]-3-喹啉-5-基胍)
F.Ruiz-Ruiz q等人,Front Mol Neurosci 2020,13,93公开的P2X7R抑制剂。
AZ11645373、AZD-9056、A-438079、A740003、CE-224,535、GSK-1482160、JNJ-47965567、A-804598,2、JNJ-54175446、JNJ-55308942
部分B:涉及过度炎症的疾病-涉及免疫系统的P2X7R活化
1.自身免疫疾病和免疫相关疾病
2.治疗引起的免疫相关疾病
3.感染性疾病
4.心血管疾病和神经血管疾病
5.神经炎性和神经退行性疾病
6.癫痫疾病
7.情感障碍和精神病综合征
8.纤维化
9.癌症相关病症
10.癌症和肿瘤
11.创伤和创伤后综合征
12.器官移植后综合征,包括移植器官排斥。
1.自身免疫疾病和免疫相关疾病
原发性免疫缺陷
全身性炎性疾病:
(1)进展性癌症中的全身性综合征(SIRS);(2)败血症:a.细菌性败血症:假单胞菌属、葡萄球菌属、链球菌属,b.病毒性败血症和ARDS:甲型流感病毒、SARS、MERS、COVID-19等,c.脾切除术后极重度败血症:肺炎链球菌、流感嗜血杆菌、脑膜炎奈瑟氏球菌,d.巴贝虫病:田鼠巴贝虫(美国)、分歧巴贝虫(欧洲),e.伴有败血症和脑膜炎的脑膜炎球菌血症,f.洛基山斑疹热(RMSF):立克次氏体,g.暴发性紫癜:美国肺炎链球菌、流感嗜血杆菌、脑膜炎球菌,h.红皮病、中毒性休克综合征:A组链球菌、金黄色葡萄球菌,i.坏死性筋膜炎:A组链球菌、混合好氧/厌氧菌群、社区相关耐甲氧西林金黄色葡萄球菌(CA-MRSA),j.梭菌性肌坏死:产气荚膜梭菌,k.气性坏疽;(3)过度炎症和细胞因子风暴;(4)包括休克的过敏性反应;(5)全身性过敏反应;(6)创伤后的全身性反应(SIRS);(7)急性术后(移植后)炎症和SIRS。
内分泌疾病:
(1)I型和II型糖尿病;(2)阿狄森氏病;(3)自身免疫性多内分泌综合征(APS)1、2和3型;(4)自身免疫性胰腺炎(AIP);(5)自身免疫性甲状腺炎;(6)Ord's甲状腺炎;(7)格雷夫斯病;(8)桥本氏病;(9)自身免疫性卵巢炎;(10)子宫内膜异位症;(11)自身免疫性睾丸炎;(12)干燥综合征;(13)骨质疏松症;(14)佩吉特氏病。
结缔组织疾病:
(1)混合性结缔组织病;(2)未分化结缔组织病;(3)痛性肥胖症;(4)系统性红斑狼疮(SLE);(5)药物引起的狼疮;(6)成年型斯蒂尔病;(7)CREST综合征;(8)肠炎相关关节炎;(9)嗜酸性筋膜炎;(10)费尔蒂综合征;(11)IgG4相关疾病;(12)Parry-Romberg综合征;(13)Parsonage-Turner综合征;(14)结节病(15)Schnitzler综合征;(16)未分化结缔组织病(UCTD)。
眼部疾病:
(1)糖尿病性视网膜病;(2)自身免疫性视网膜病;(3)自身免疫性葡萄膜炎;(4)中间葡萄膜炎;(5)干性和湿性年龄相关性黄斑变性(AMD);(6)色素性视网膜炎(RP);(7)木样结膜炎;(8)莫伦氏溃疡;(9)巩膜炎;(10)交感性眼炎。
耳部疾病
(1)自身免疫性内耳疾病(AIED)。
肺部疾病:
(1)哮喘;(2)过敏性鼻炎;(3)慢性阻塞性肺病(COPD);(4)自身免疫性内耳疾病(AIED)。
胃肠疾病:
(1)药物引起的肝脏疾病;(2)自身免疫性肝炎;(3)炎性肠综合征;(4)克罗恩病;(5)溃疡性结肠炎;(6)肠易激综合征;(7)显微镜结肠炎;(8)自身免疫性肠病;(9)乳糜泻;(10)谷蛋白不耐受;(11)乳糖不耐受;(12)Plummer-Vinson综合征;(13)失弛缓症;(14)特发性腹膜炎。
肌肉、骨骼和皮肤疾病:
(1)昆虫叮咬后的皮肤免疫反应;(2)接触性皮炎;(3)多肌炎;(4)肌炎;(5)皮肌炎;(6)不同起因的皮炎;(7)包涵体肌炎;(8)纤维肌痛;(9)系统性硬皮病;(10)牛皮癣;(11)斑秃;(12)自身免疫性血管性水肿;(13)自身免疫性孕酮皮炎;(14)自身免疫性荨麻疹;(15)大疱性类天疱疮;(16)瘢痕性类天疱疮;(17)妊娠性类天疱疮;(18)疱疹样皮炎;(19)盘状红斑狼疮;(20)后天性大疱性表皮松解;(21)结节性红斑,(22)化脓性汗腺炎;(23)扁平苔藓;(24)硬化性苔藓;(25)线性IgA疾病(LAD);(26)硬斑病;(27)寻常型天疱疮;(28)糠疹:a.白糠疹,b.慢性苔藓样糠疹,c.玫瑰糠疹,d.环状糠疹,e.毛发红糠疹,f.花斑糠疹,g.头皮屑,历史上称为头状糠疹,h.天牛糠疹,i.急性苔藓痘疮样糠疹(PLEVA),j.Mucha-Habermann病;(29)白癜风;(30)血管性水肿:a.获得性血管性水肿,b.遗传性血管性水肿,c.抗神经性水肿(Quincke's水肿);(31)湿疹;(32)类风湿性关节炎;(33)膝关节、髋关节、脊柱关节等的慢性炎症;(34)慢性脊椎关节病;(35)慢性骨软骨炎和骨关节炎;(36)幼年型关节炎;(37)强直性脊柱炎;(38)银屑病关节炎;(39)复发性多软骨炎;(40)复发性多软骨炎;(41)风湿性多肌痛;(42)抗合成酶综合征。
泌尿生殖道疾病
(1)慢性间质性膀胱炎;(2)复发性膀胱炎;(3)药物引起的肾病;(4)糖尿病肾病;(5)肾病综合征;(6)肾炎综合征;(7)快速进展性肾小球肾炎;(8)急性肾衰竭;(9)继发性肾功能障碍。
2.治疗引起的免疫相关疾病
(1)放射性脑病;(2)化疗相关性肾损伤:a.复杂肾囊肿,b.间质性肾炎,c.肾乳头坏死,d.肾梗塞,e.急性肾小管坏死;(3)化疗相关性膀胱损伤:a.化疗引起的膀胱炎,b.出血性膀胱炎;(4)化疗相关性胃肠损伤:a.口腔炎,b.咽炎,c.食道咽炎(Oesophagopharyngitis),d.粘膜炎,e.口腔和肛门炎症或溃疡,f.肠坏死,g.胃肠溃疡,h.肠炎,i.胰腺炎,j.急性肝炎。
3.感染性疾病
病毒性疾病:
甲型、乙型、丙型和丁型肝炎(HAV、HBV、HCV和HDV);人类逆转录病毒;人类免疫缺陷病毒(HIV);HTLV-1;爱柏森鼠类白血病病毒;劳斯肉瘤病毒;寨卡病毒(ZiKV);甲型和乙型流感病毒(IAV和IBV);冠状病毒:MERS、SARS、SARS-CoV-2;鼻病毒;人呼吸道合胞病毒;腺病毒;肠道病毒;人偏肺病毒;单纯疱疹或带状疱疹脑炎;单纯疱疹或带状疱疹性皮炎;疱疹病毒6、7和8型;登革病毒;西尼罗病毒;埃博拉病毒和马堡病毒感染;亨德拉病毒;尼帕病毒;人乳头瘤病毒(HPV);爱泼斯坦-巴尔病毒(EBV);传染性单核细胞增多症;乳晕:麻疹病毒;风疹;流行性腮腺炎;天花;水痘;黄热病;病毒性心肌炎;病毒性出血热;狂犬病;手足口病;Orf副痘病毒;传染性软疣恙虫病;诺如病毒;巨细胞病毒(CMV);尖锐湿疣;细小病毒;节肢动物传播的和啮齿动物传播的病毒感染。
细菌感染:
猫抓病;兔热病;多瘤病毒病;诺卡氏菌病;放线菌病和惠普尔病;伤寒;钩端螺旋体病;Q热病;布鲁氏菌病;类鼻疽;棘球蚴病;慢性骨髓炎;莱姆病(伯氏疏螺旋体);蜱传斑点热;结核病;布路里溃疡:溃疡分枝杆菌;皮肤结核:结核分枝杆菌;麻风:麻风分枝杆菌;幽门螺杆菌;血吸虫病;组织胞浆菌病;溶组织内阿米巴;贾第虫病;丝虫病;移居内脏幼虫;炭疽:炭疽芽孢杆菌;溃疡型土拉菌病;土拉热弗朗西斯菌;腺鼠疫:鼠疫耶尔森氏菌;软下疳:杜克雷嗜血杆菌;原发性梅毒:梅毒螺旋体;淋球菌感染;梅毒;密螺旋体病;肺炎支原体感染;衣原体感染;沙眼衣原体感染;脑膜炎,脑炎和脑脓肿;细菌性脑膜炎;脑脓肿,化脓性颅内感染;脑型疟疾:恶性疟原虫;脊髓硬膜外脓肿;日本脑炎;丹毒蜂窝织炎;毛囊炎;肌炎和肌坏死;破伤风;军团菌感染;感染性胃肠炎;肺炎;急性呼吸窘迫综合征(ARDS);肺脓肿;感染性心内膜炎。
真菌感染:真菌病
球孢子菌病;组织胞浆菌病;芽生菌病;真菌病;青霉病;孢子丝菌病;副球孢子菌病;念珠菌病;曲霉病;隐球菌病;毛霉菌病(接合菌病);赛多孢子菌病;毛孢子虫病;镰状细胞病;肺囊虫病。
原生动物感染:
溶组织内阿米巴;疟疾:恶性疟原虫;巴贝虫病;利什曼病;查加斯病和非洲锥虫病;弓形体病;滴虫病。
蠕虫感染。
4.心血管疾病和神经血管疾病
脑:(1)大脑常染色体显性动脉病伴皮质下梗死和白质脑病(CADASIL),(2)缺血性中风,(3)动脉瘤性蛛网膜下腔出血,(4)蛛网膜下腔出血后的脑缺血,(5)脑血管痉挛;动脉粥样硬化;全身性动脉高血压;肺动脉高压;深静脉血栓形成和肺栓塞;心脏:(1)心绞痛,(2)心肌局部缺血,(3)心肌梗塞,(4)心肌致昏,心肌冬眠,(5)缺血后心肌功能障碍,(6)缺血性心肌病,(7)心房和心室心律失常,包括心房纤颤,(8)心肌梗塞后综合征,(9)心包切开术后综合征,(10)心包炎,(11)心肌炎,(12)风湿热,(13)脑损伤后心脏并发症:a.应激性心肌病,b.心脏破裂综合征,c.蛛网膜下腔出血后的心功能不全和心律失常,d.创伤性脑损伤后的心功能不全和心律失常。
5.神经炎性和神经退行性疾病
阿尔茨海默氏病;帕金森病;亨廷顿氏病;锥体外系症状:(1)急性张力障碍反应,(2)动眼危象,(3)静坐不能,(4)假性帕金森症,(5)迟发性运动障碍,Sydenham氏舞蹈病;急性播散性脑脊髓炎(ADEM);桥本脑病;白塞氏脑炎;抗N-甲基-D-天冬氨酸(抗NMDA)受体脑炎;脊髓小脑共济失调;索萨克综合征;图洛萨-亨特综合征;梅尼埃病;多发性硬化症;特发性炎性脱髓鞘疾病;横贯性脊髓炎;视神经脊髓炎(Devic's病);视神经炎;巴洛同心硬化;获得性神经病:a.慢性继发性多神经病,b.慢性炎性脱髓鞘性多发性神经病(CIDP),c.进行性炎性神经病,d.格林-巴利综合征e.危重病多发性神经病,f.急性和慢性运动性轴突神经病;遗传性神经病:a.1、2和3型腓骨肌萎缩症,b.遗传神经痛的肌肉萎缩;强直性肌营养不良I型和II型;肌萎缩性侧索硬化症(ALS);神经痛性肌萎缩(Parsonage-Turner综合征);神经肌强直;重症肌无力;多动腿综合征;僵人综合征。
6.癫痫疾病
全身性癫痫发作(大发作),包括癫痫连续状态;局灶性癫痫发作:a.额叶癫痫,b.颞叶癫痫,c.良性运动性癫痫,d.儿童良性枕叶癫痫;常染色体显性夜间额叶癫痫;儿童期失神性癫痫;Dravet综合征;患有智力迟钝的女性中的癫痫;幼年型肌阵挛性癫痫;Lennox-Gastaut综合征;发热性感染相关性癫痫综合征;西方综合征;Ohtahara综合征;反射性癫痫;进行性肌阵挛性癫痫;拉斯穆森脑炎。
7.情感障碍和精神病综合征
精神分裂症;抑郁症;双相性精神障碍;职业性倦怠;与链球菌相关的儿科自身免疫性神经精神障碍(PANDAS);注意力缺陷多动障碍;创伤后应激障碍;纤维肌痛。
8.纤维化
原发性纤维化:
间质性肺纤维化(ILD);腹膜后纤维化;原发性胆汁性胆管炎(原发性胆汁性肝硬化或原发性肝硬化)。
疾病引起的纤维化:
继发性肺纤维化;由于囊性纤维化引起的继发性炎症;原发性硬化性胆管炎;间质性膀胱纤维化;继发性肝硬化:a.酒精性肝硬化丙型肝炎引起的肝硬化,c.人类免疫缺陷病毒引起的肝硬化,d.转移性癌病肝硬化。
癌症引起的纤维化:由癌症引起的纤维化形成。
肿瘤假性进展:治疗引起的纤维化模拟肿瘤进展,特别是在神经内分泌肿瘤中。
治疗引起的纤维化:
由内科、外科或放射性治疗引起的纤维化形成,即具有或不具有肠梗阻的腹部手术后腹膜纤维化;器官移植后的纤维化;化疗引起的慢性胃肠纤维化。
9.副肿瘤综合征:
小脑副肿瘤变性;朗伯-伊顿肌无力综合征;小脑副肿瘤变性;脑脊髓炎,边缘性脑炎;脑干脑炎;视肌阵挛性共济失调综合征;抗NMDA受体脑炎;多肌炎;黑棘皮病;皮肌炎;Leser-Trélat标志;坏死性游走性红斑;Sweet's综合征;多花皮肤乳头状瘤病;坏疽性脓皮病;获得性全身性多毛症。
10.癌症和肿瘤
免疫相关和肿瘤性血液病:
再生障碍性贫血;抗磷脂综合征(APS,APLS);血栓性血小板减少性紫癜(TTP);特发性血小板减少性紫癜(ITP);自身免疫性溶血性贫血;自身免疫性淋巴组织增生综合征;自身免疫性嗜中性白细胞减少症;冷凝集素病;原发性混合性冷球蛋白血症;伊文氏综合征;恶性贫血;纯红细胞发育不全;血小板减少症;淋巴管炎癌病;骨髓增生异常/骨髓增生性肿瘤(MPN/MPD):(1)真性红细胞增多症,(2)原发性血小板增多症,(3)原发性骨髓纤维化,(4)纤维化的骨髓纤维化,(5)淋巴瘤:a.非霍奇金淋巴瘤,b.儿童非霍奇金淋巴瘤(伯基特淋巴瘤),c.霍奇金病,d.皮肤淋巴瘤,e.巨球蛋白血症,f.多发性骨髓瘤(Kahler's病),g.原发性脑淋巴瘤,(6)白血病:a.急性髓性白血病,b.慢性髓性白血病,c.急性淋巴细胞白血病,d.慢性淋巴细胞白血病,(6)无法分类的MPN/MPD。
实体瘤:
A.神经内分泌肿瘤(NET)
(1)垂体:垂体前叶NET,(2)甲状腺:神经内分泌甲状腺肿瘤和髓样癌,(3)甲状旁腺NET,(4)胸腺和纵隔类癌肿瘤,(5)肺NET:a.支气管NET,b.肺类癌瘤:典型类癌和非典型类癌,c.小细胞肺癌(SCLC),d.肺大细胞神经内分泌癌(LCNEC),e.肺外小细胞癌(ESCC或EPSCC),(6)胃肠胰神经内分泌肿瘤(GEP-NET):a.前肠NET(胃、近端十二指肠、胸腺、肺和支气管),b.胰腺NET,c.中肠GEP-NET(从十二指肠第二部分的远端一半到横结肠的近端三分之二),阑尾NET,e.后肠NET,(7)肝胆NET,(8)肾上腺肿瘤和肾上腺髓质肿瘤,(9),(10)嗜铬细胞瘤,(11)外周神经系统NET:a.神经鞘瘤,b.副神经节瘤成神经细胞瘤,(12)乳腺NET,(13)生殖泌尿道NET:a.尿路类癌瘤和神经内分泌癌,b.卵巢NET,c.宫颈NET,d.前列腺NET,e.睾丸NET,(14)皮肤梅克尔细胞癌(小梁癌),(15)遗传性NET:a.多发性内分泌腺瘤1型(MEN1)和2型(MEN2),b.希佩尔林道(Von Hippel-Lindau)(VHL)病,c.1型和2型神经纤维瘤病,d.神经鞘瘤病(Schwanomatosis),e.结节性硬化,f.卡尼综合征(LAMB或NAME综合征)。
B.中枢神经系统肿瘤
(1)脑肿瘤和脊柱肿瘤:a.转移性脑肿瘤,b,毛细胞性星形细胞瘤,c.胶质瘤,d.多形性成胶质细胞瘤(GBM),e.少突神经胶质瘤,f.室管膜瘤,g.成神经管细胞瘤,h.脑膜肿瘤,i.脑膜瘤,j.转移性脑膜炎癌病。
C.口咽肿瘤:
良性肿瘤:嗜酸性肉芽肿,纤维瘤,颗粒细胞肿瘤,角化棘皮瘤,平滑肌瘤,骨软骨瘤,脂肪瘤,神经纤维瘤,乳头状瘤,尖锐湿疣,疣状黄瘤,化脓性肉芽肿,横纹肌瘤,牙源性肿瘤,癌前病变,白血病,红细胞增多,红白血病,恶性肿瘤,鳞状细胞癌,疣状癌,小唾液腺癌,淋巴瘤。
D.喉癌
鼻旁窦和鼻腔癌,鼻咽癌,畸胎瘤,腺癌,腺样囊性癌,粘液表皮样癌,唾液腺癌,甲状腺癌:a.乳头状甲状腺癌,b.具有乳头状核特征的非侵入性滤泡性甲状腺肿瘤,c.滤泡性甲状腺癌,c.低分化甲状腺癌,d.间变性甲状腺癌,e.甲状腺淋巴瘤,f.鳞状细胞甲状腺癌,g.甲状腺肉瘤,h.许特尔细胞癌。
E.皮肤癌
基底细胞癌,鳞状细胞癌,恶性黑素瘤,卡波西肉瘤,
F.血管系统癌症
血管肉瘤,上皮样血管内皮瘤,血管外皮细胞瘤,淋巴管肉瘤,卡波西样血管内皮瘤(KHE),婴儿血管瘤,先天性血管瘤,成血管细胞瘤,化脓性肉芽肿,丛状血管瘤,血管球瘤。
G.肌肉和骨肿瘤
平滑肌瘤,平滑肌肉瘤,恶性潜能不确定的平滑肌肿瘤(STUMP),转移性肿瘤,骨肉瘤,软骨肉瘤,尤因氏肉瘤,纤维肉瘤,未分化多形性肉瘤,畸胎瘤,骨瘤,骨样骨瘤,骨软骨瘤,成骨细胞瘤,软骨瘤,骨巨细胞瘤,动脉瘤性骨囊肿。
H.乳腺癌
转移性肿瘤,浸润性导管癌,浸润性小叶癌,小管癌,粘液性(胶质)癌,具有髓样特征的癌,浸润性乳头状癌,乳腺淋巴瘤,乳腺肉瘤。
I.肺肿瘤
转移性肿瘤,支气管平滑肌瘤,原发性肺癌:a.小细胞肺癌(SCLC),b.非小细胞肺癌(NSCLC),c.胸膜肺母细胞瘤,d.肺淋巴瘤,e.肺肉瘤,f.纵隔肿瘤,g.胸膜肿瘤,h.恶性间皮瘤,j.胸膜肉瘤,k.胸膜血管肉瘤,l.胸膜促结缔组织增生性小圆细胞肿瘤(胸膜DSRCT),m.胸膜滑膜肉瘤,n.胸膜孤立性纤维性肿瘤(胸膜SFT),o.胸膜平滑肌肿瘤,p.胸膜癌,q.胸膜粘液表皮样癌,r.胸膜假间皮瘤腺癌,s.胸膜钙化纤维性假瘤。
J.胃肠道肿瘤
(1)库肯勃氏(Krukenberg)瘤(转移肿瘤):(2)食管癌,a.鳞状细胞癌(ESCC),b.食管腺癌(EAC),c.巴雷特食管,d.胃癌,e.胃腺癌,f.印戒细胞癌,g.胃淋巴瘤,h.结外边缘区B细胞淋巴瘤(MALT淋巴瘤),(2)类癌瘤:a.十二指肠腺癌,b.增生,c.类癌瘤,(3)腹膜假性粘液瘤:a.结肠直肠肿瘤(4)结肠直肠息肉:a.腺瘤,b.增生,c.幼年型,d.无蒂锯齿状腺瘤,e.传统锯齿状腺瘤,f.Peutz-Jeghers综合征,(5)Cronkhite-Canada综合征,(6)息肉病综合征:a.幼年型MUTYH相关的家族性腺瘤性和锯齿状息肉病,(7)腺癌,(8)家族性腺瘤性息肉病,(10)遗传性非息肉性结肠直肠癌,(11)肛门肿瘤:鳞状细胞癌,(12)肝癌,(13)转移性肿瘤,(14)肝细胞癌,(15)肝母细胞瘤,(16)肝细胞腺瘤,(17)海绵状血管瘤,(18)局灶性结节性增生,(19)结节性再生性增生,(20)胆囊癌,(21)胆管癌,(22)Klatskin肿瘤,(23)胆囊腺癌,(24)胰腺癌,(25)外分泌肿瘤:a.腺癌,b.胰腺导管腺癌,(26)囊性肿瘤:a.浆液性微囊性腺瘤,b.导管内乳头状黏液性肿瘤,c.黏液性囊性肿瘤,d.实性假乳头状瘤胰母细胞瘤,(27)内分泌PanNET:a.MALT淋巴瘤,b.腹膜肿瘤,(28)转移性腹膜炎癌病。
K.泌尿生殖道癌症
(1)肾肿瘤:a.转移肿瘤,b.肾细胞癌(RCC):b1.透明细胞RCC,b2.乳头状RCC,b.嫌色性RCC,b4.收集管RCC,c.透明细胞肉瘤,d.中胚层肾瘤,e.维尔姆氏肿瘤(肾母细胞瘤),f.肾嗜酸细胞瘤,g.囊性肾瘤,h.血管肌脂瘤,i.后肾腺瘤,j.肾髓质纤维瘤,(2)输尿管癌:a.移行细胞癌,b.输尿管肿瘤,(3)膀胱肿瘤:a.转移性肿瘤,b.乳头状移行细胞癌,c.非乳头状移行细胞癌,d.鳞状细胞癌,e.腺癌,f.肉瘤,g.小细胞癌,(4)卵巢肿瘤,a.卵巢恶性肿瘤:a1.上皮癌,a2.生殖细胞癌,a3.基质癌,b.良性:b1.上皮表面肿瘤,b2.基质肿瘤,b3.生殖细胞肿瘤,(5)子宫肿瘤:a.子宫纤维瘤或平滑肌瘤,(6)子宫颈肿瘤:a.宫颈癌,a1.鳞状细胞癌,a2.腺癌,a3.腺鳞癌,a4.小细胞癌,a5.神经内分泌瘤,a6.玻璃状细胞癌,a7.腺泡腺癌,b.宫颈上皮内瘤变,(7)睾丸肿瘤:a.生殖细胞肿瘤:a1.小管内生殖细胞瘤形成,a2.精原细胞瘤,a3.精母细胞肿瘤,a4.胚胎癌,a5.卵黄囊肿瘤,b.滋养层肿瘤:b1.绒毛膜癌,b2.单相绒毛膜癌,b3.胎盘部位滋养层肿瘤,b4.囊性滋养细胞肿瘤,c.畸胎瘤:c1.皮样囊肿,c2.表皮样囊肿,c3.单胚层畸胎瘤(类癌瘤),c4.原始神经外胚层肿瘤(PNET),c5.肾母细胞瘤样肿瘤,c6.畸胎瘤伴躯体型恶性肿瘤,d.性索-性腺基质肿瘤:d1.间质细胞肿瘤,d2.足细胞肿瘤,d3.富脂质变体,d4.硬化变体,d5.大细胞钙化变体,d6.Peutz-Jeghers综合征中的小管内足细胞瘤形成,d7.颗粒细胞肿瘤,d8.成年型,d9.幼年型,d10.纤维瘤组,d11.腺瘤,d12.纤维瘤,d13.不完全分化的肿瘤,d14.混合型肿瘤,e.混合型生殖细胞和性索/性腺基质肿瘤:e1.性腺母细胞瘤,e2.生殖细胞-性索/性腺基质肿瘤,未分类的,f.睾丸杂瘤:f1.淋巴瘤:f1a.原发性睾丸弥漫性大B细胞淋巴瘤,f1b.睾丸套细胞淋巴瘤,f1c.睾丸结外边缘区B细胞淋巴瘤,f1d.结外NK/T细胞淋巴瘤,睾丸鼻型,f1e.睾丸外周T细胞淋巴瘤,f1f.睾丸激活素受体样激酶-1阴性间变性大细胞淋巴瘤,f1g.小儿型睾丸滤泡性淋巴瘤,f2.类癌瘤,f3.卵巢上皮型肿瘤:f3a.交界性恶性肿瘤的浆液性肿瘤,f3b.浆液性癌,f3c.分化良好的子宫内膜样肿瘤,f3d.粘液性囊腺瘤,f3e.粘液性囊腺癌,f3f.Brenner肿瘤,f4.肾母细胞瘤,f5.副神经节瘤造血肿瘤,g.造血系统肿瘤,h.集合导管和膜层的肿瘤:h1.腺瘤,h2.癌,i.副睾丸结构的肿瘤:i1.腺瘤性肿瘤,i2.恶性和良性间皮瘤,i3.附睾腺癌,i4.附睾乳头状囊腺瘤,i5.黑质神经外胚层肿瘤,i6.促结缔组织增生性小圆细胞肿瘤,j.精索和睾丸附件间充质肿瘤:j1.脂肪瘤,j2.脂肪肉瘤,j3.横纹肌肉瘤,j4.侵袭性血管粘液瘤,j5.血管肌纤维母细胞瘤样肿瘤(参见粘液瘤),j6.纤维瘤病,j7.纤维瘤,j8.孤立性纤维性肿瘤,j9.其他,k.睾丸继发性肿瘤,(8)尿道癌:a.移行细胞癌,b.鳞状细胞癌,c.腺癌,d.黑素瘤,e.前列腺肿瘤,f.转移性前列腺肿瘤,g.良性前列腺增生,i.前列腺癌,(9)阴茎肿瘤:a.包茎,b.阴茎癌。
L.腹膜后肿瘤
(1)实体瘤:a.转移肿瘤,b.纤维瘤、纤维肉瘤、恶性纤维组织细胞瘤,c.脂肪瘤、脂肪肉瘤,d.平滑肌瘤、平滑肌肉瘤,e.硬纤维瘤,即神经节细胞瘤、节细胞神经母细胞瘤、神经鞘瘤、神经纤维瘤,g.性腺外生殖细胞肿瘤,h.淋巴瘤,i.淋巴结病;(2)囊性肿瘤:a.囊性淋巴管瘤,b.囊性畸胎瘤,c.囊腺瘤、囊腺癌,d.囊性间皮瘤,即表皮样囊肿,f.Tarlov囊肿(周围神经囊肿)。
11.创伤和创伤后综合征
(1)创伤性蛛网膜下腔出血,(2)头部损伤,包括重度创伤性头部损伤,(3)创伤性脑损伤后的脑缺血,(4)多发伤状况,(5)创伤性癫痫发作。
12.肺、肾、心脏、肝等器官移植后的炎症。
(1)器官移植后的急性免疫反应,(2)宿主的慢性器官组织排斥反应,(3)器官移植后的纤维化。
Claims (32)
1.哺乳动物P2X7受体(P2X7R)拮抗剂用于治疗哺乳动物患者的过度炎症综合征的用途,通过靶向初级淋巴结向所述患者施用所述P2X7R拮抗剂直至所述拮抗剂在所述靶向淋巴结中的浓度高于所述拮抗剂在所述哺乳动物中的最大可耐受血浆水平。
2.根据权利要求1所述的哺乳动物P2X7R拮抗剂的用途,其中,以对应于所述受体的ICx的所述靶向淋巴结中的浓度施用所述拮抗剂,所述ICx高于所述拮抗剂在所述哺乳动物中的最大可耐受血浆水平,其中x≥10,优选≥20,更优选≥30,甚至更优选≥40,最优选约50。
3.根据权利要求1或2所述的哺乳动物P2X7R拮抗剂的用途,其中,所述淋巴结靶向施用选自局部和侵入性施用。
4.根据权利要求3所述的哺乳动物P2X7R拮抗剂的用途,其中,所述施用是局部的,选自经粘膜和经皮。
5.根据权利要求4所述的哺乳动物P2X7R拮抗剂的用途,其中,所述拮抗剂是亲脂性的。
6.根据权利要求5所述的哺乳动物P2X7R拮抗剂的用途,其中,所述亲脂性拮抗剂是游离碱。
7.根据权利要求5或6所述的哺乳动物P2X7R拮抗剂的用途,其中,所述淋巴结靶向施用包含在口腔中经粘膜施用。
8.根据权利要求7所述的哺乳动物P2X7R拮抗剂的用途,其中,所述施用是颊部、舌下、咽或其组合。
9.根据权利要求4至6中任一项所述的哺乳动物P2X7R拮抗剂的用途,其中,所述施用是经皮的并且为乳膏剂、软膏剂或洗剂、贴剂或硬膏剂的形式和/或涉及微针或其组合。
10.根据权利要求3所述的哺乳动物P2X7R拮抗剂的用途,其中,所述施用是侵入性的,选自皮内、皮下或皮下组织。
11.根据权利要求10所述的哺乳动物P2X7R拮抗剂的用途,其中,所述拮抗剂是亲水性的,特别是以水溶性药学上可接受的盐的形式。
12.根据权利要求3所述的哺乳动物P2X7R拮抗剂的用途,其中,所述施用是静脉内的,所述拮抗剂是亲脂性的并且被限制在药物递送系统中,避免在血液中直接释放。
13.根据前述权利要求中任一项所述的哺乳动物P2X7R拮抗剂的用途,其中,所述P2X7R活化由细胞外ATP激活。
14.根据前述权利要求中任一项所述的哺乳动物P2X7R拮抗剂的用途,其中,所述施用是速释剂型或缓释剂型。
15.根据前述权利要求中任一项所述的哺乳动物P2X7R拮抗剂的用途,其中,所述施用包含一次或多次团注施用、或包含连续施用或其组合。
16.根据权利要求15所述的哺乳动物P2X7R拮抗剂的用途,其中,团注剂量对应于在所述拮抗剂的最大可耐受血浆水平下1ml血浆中所含受体拮抗剂的量的至少1000倍,优选至少5000倍,更优选至少10000倍。
17.根据权利要求15或16所述的哺乳动物P2X7R拮抗剂的用途,其中,所述团注每天施用2-10次。
18.根据前述权利要求中任一项所述的哺乳动物P2X7R拮抗剂的用途,其中,在包含至少1w/v%、优选至少5w/v%、最优选至少10w/v%受体拮抗剂的液体介质中施用所述拮抗剂。
19.根据权利要求10和15所述的哺乳动物P2X7R拮抗剂的用途,其中,所述淋巴结靶向施用通过连续皮内、皮下或皮下组织输注。
20.根据权利要求19所述的哺乳动物P2X7R拮抗剂的用途,其中,所述剂量对应于每千克体重每小时所述拮抗剂的IC10值的至少10倍。
21.根据前述权利要求中任一项所述的哺乳动物P2X7R拮抗剂的用途,其中,所述治疗涉及选自以下的疾病的过度炎症综合征:自身免疫疾病和免疫相关疾病,诸如哮喘、变态反应和慢性肺病;治疗引起的免疫相关疾病,诸如化疗;感染性疾病,诸如病毒和细菌感染;心血管疾病和神经血管疾病;神经炎症和神经退行性疾病;癫痫疾病;情感障碍和精神病综合征;纤维化;癌症相关病症;肿瘤假性进展;癌症和赘生物;创伤和创伤后综合征;器官移植后综合征,包括移植器官排斥。
22.根据前述权利要求中任一项所述的哺乳动物P2X7R拮抗剂的用途,其中,所述过度炎症综合征包括呼吸困难。
23.根据权利要求22所述的用于所述的哺乳动物P2X7R拮抗剂的用途,其中,所述呼吸困难与病毒感染、细菌感染、癌症、慢性阻塞性肺病(COPD)、哮喘、变态反应、化疗相关。
24.根据权利要求21至23中任一项所述的哺乳动物P2X7R拮抗剂的用途,其中,所述病毒感染由病毒引起,所述病毒选自:冠状病毒,特别是SARS-CoV-2;流感病毒;埃博拉病毒;呼吸道合胞病毒;人类免疫缺陷病毒。
25.根据前述权利要求中任一项所述的哺乳动物P2X7R拮抗剂的用途,其中,所述P2X7R拮抗剂选自:氨基酰胺衍生物,特别是利多卡因、布比卡因、罗哌卡因和甲哌卡因;抗P2X7R抗体,特别是单克隆抗体;氨基酯衍生物,特别是苯佐卡因和普鲁卡因;金刚烷酰胺衍生物;三唑衍生物;二芳基咪唑烷衍生物;焦谷氨酸酰胺衍生物;吡唑乙酰胺衍生物;二氢二苯并[a,g]喹嗪鎓衍生物;四唑衍生物;酪氨酸基衍生物;吡唑并二氮杂卓衍生物;咪唑衍生物;苯甲酰胺衍生物、KN62类似物和衍生物;金刚烷甲酰胺;芳基碳酰肼;氰基胍;芳基四唑和芳基三唑;PPADS四钠盐;亮蓝G(BBG);氧化ATP(o-ATP);massadine;stylissadine A和B;P2X7R抑制剂C23、C40和C60;[3H]A-804598([3H]2-氰基-1-[(1S)-1-苯基乙基]-3-喹啉-5-基胍);双环杂芳基化合物。
26.根据前述权利要求中任一项所述的哺乳动物P2X7R拮抗剂的用途,其中,所述P2X7R拮抗剂包含利多卡因。
27.根据权利要求26所述的哺乳动物P2X7R拮抗剂的用途,其中,所述治疗包含局部施用游离碱形式的利多卡因。
28.根据权利要求27所述的哺乳动物P2X7R拮抗剂的用途,其中,所述治疗包含在口腔中施用利多卡因碱。
29.根据权利要求28所述的哺乳动物P2X7R拮抗剂的用途,其中,在包含至少2.5w/v%、优选至少5w/v%、更优选至少10w/v%受体拮抗剂的液体介质中施用利多卡因碱。
30.根据权利要求26所述的哺乳动物P2X7R拮抗剂的用途,其中,所述治疗包含侵入性施用水溶性盐形式的利多卡因,特别是盐酸利多卡因。
31.根据权利要求30所述的哺乳动物P2X7R拮抗剂的用途,其中,所述利多卡因盐通过皮内、皮下或皮下组织施用。
32.根据权利要求31所述的哺乳动物P2X7R拮抗剂用途,其中,所述利多卡因盐通过连续皮内、皮下或皮下组织输注施用。
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