CN115089592B - 多重酪氨酸激酶在制备抑制肠道病毒71型嗜神经性病毒药物中的应用 - Google Patents
多重酪氨酸激酶在制备抑制肠道病毒71型嗜神经性病毒药物中的应用 Download PDFInfo
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Abstract
本发明提供了一种多重酪氨酸激酶抑制剂(SU14813)在制备抑制肠道病毒71型嗜神经性病毒(EV‑A71)药物中的应用。本发明还包括相应的SU14813药物组合、使用方法、SU14813试剂盒等。本发明的研究表明,SU14813能够有效的抑制肠道病毒71型嗜神经性病毒的活性,SU14813治疗后RD细胞的病毒减少,并且SU14813对RD细胞中EV‑A71抑制作用呈现剂量依赖性。本发明从已上市药品中筛选具有抗EV‑A71病毒活性的药物,将节约药物筛选过程中有关药物代谢、药物安全和毒理等方面的研究费用,降低药物研发的风险,为EV‑A71感染疾病的对症治疗和新药开发提供新的思路和途径。
Description
技术领域
本发明属于生物医药领域,涉及肠道病毒71型嗜神经性病毒的一种新型抑制剂。具体而言,本发明涉及多重酪氨酸激酶(SU14813)在制备抑制肠道病毒71型嗜神经性病毒药物中的应用。
背景技术
肠道病毒71型(Enterovirus A71,EV-A71)为嗜神经性病毒,属于小RNA病毒科肠道病毒属,是引起手足口病、咽峡炎、疱疹的主要病原体之一。手足口病是全球性疾病,在我国各地全年均有发生,发病率为每10万人37.01~205.06例,病死率为每10万人6.46~51.00例;在手足口病的实验室病原学诊断结果中,EV-A71阳性比例占44%,重症病例中EV-A71阳性占74%,死亡病例中占93%;EV-A71感染导致的手足口病常见于婴幼儿,是如今造成中国儿童死亡的重要原因。预防EV-A71感染最有效的方法是对适龄儿童接种EV-A71疫苗;尽管目前已有疫苗上市,但尚缺乏有效的免疫持久性研究数据,其免疫效力和持续时间仍有待于进一步验证。
目前,临床上尚缺乏特效的抗EV-A71感染药物,抗EV-A71药物的研究多处于基础实验阶段,高效抗病毒药物的缺乏仍是一个亟待解决的问题。由于新药开发耗时长、费用高、风险大,从已上市药品中筛选具有抗EV-A71病毒活性的药物,将节约药物筛选过程中有关药物代谢、药物安全和毒理等方面的研究费用,降低药物研发的风险,为EV-A71感染疾病的对症治疗和新药开发提供新的思路和途径。
发明内容
本发明要解决的技术问题是提供一种多重酪氨酸激酶在制备抑制肠道病毒71型嗜神经性病毒药物中的应用,以提供一种新的抗EV-A71病毒活性的药物。
一方面,本发明提供了SU14813在制备抑制病毒药物中的应用,所述的病毒是肠道病毒71型嗜神经性病毒EV-A71。
较好的,所述的药物是抑制EV-A71病毒活性的药物。
进一步的,所述的药物是降低EV-A71病毒活力、病毒载量或者VP1蛋白表达量的药物。
SU14813是一种多靶点受体酪氨酸激酶抑制剂,它对VEGFR-1,VEGFR-2,PDGFR-β和KIT的IC50值分别为2,50,4,15nM。SU14813以剂量和时间依赖的方式抑制异种移植肿瘤中的VEGFR-2,PDGFR-beta和FLT3磷酸化。体内靶标抑制所需的浓度估计为100至200ng/mL。SU14813与多西紫杉醇联合治疗显著增强了对原发性肿瘤生长的抑制,延长荷瘤小鼠的存活。
表1不同实验动物依据体表面积的等效剂量转换表(数据来源于FDA指南)
小鼠 | 大鼠 | 兔 | 豚鼠 | 仓鼠 | 狗 | |
重量(kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
体表面积(m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km系数 | 3 | 6 | 12 | 8 | 5 | 20 |
例如,依据体表面积折算法,将化合物用于小鼠的剂量20mg/kg换算成大鼠的剂量,需要将20mg/kg乘以小鼠的Km系数(3),再除以大鼠的Km系数(6),得到化合物用于大鼠的等效剂量为10mg/kg。
表2SU14813的基本数据
分子量 | 442.48 |
分子式 | C23H27FN4O4 |
CAS号 | 627908-92-3 |
纯度 | >98% |
溶解性(25℃) | DMSO≥30mg/mL |
储存和运输条件 | 固体粉末:-20℃冷藏长期储存,常温运输及临时存放 |
SU14813(多重酪氨酸激酶)是一种多受体tyrosine kinase的抑制剂,SU14813具有强大的抗血管生成和抗肿瘤活性(Patyna S等.Mol Cancer Ther.SU14813:a novelmultiple receptor tyrosine kinase inhibitor with potent antiangiogenic andantitumor activity.)。目前,SU14813主要是作为一种抗肿瘤药物在临床应用。实验用的SU14813可以从MCE、美国APExBIO中文官网、上海芮晖等单位购得。SU14813的结构式如下:
另一方面,本发明提供了一种抑制体外细胞中EV-A71病毒的方法,所述的方法包括以下步骤:
获得含有EV-A71病毒的体外培养细胞;和/或在含有EV-A71病毒的体外培养细胞的培养环境中添加SU14813,并孵育。
较好的,加入的SU14813并使之在体外培养细胞的培养环境中均匀分布,SU14813在体外培养细胞的培养环境中的终浓度不少于0.5μM,通常为1-25μM,更好的是5-10μM,例如,0.8、1.0、1.3、2.5、3.0、5.0、7.0、8.0、10.0、12.5、15.0、18.0、20.0、22.5、25μM,等等。
较好的,加入的SU14813并使之在体外培养细胞的培养环境中均匀分布,孵育的时间不少于8小时;更好的,孵育的时间不少于12小时。在本发明的一个实施例中,SU14813加入体外培养细胞的培养环境中后孵育的时间不少于24小时。
本发明中,获得含有EV-A71病毒的体外培养细胞可以通过常规方法获得,例如将病毒颗粒置于细胞的培养环境中,或者在细胞中表达EV-A71病毒或者其核心组分。在本发明的一个实施例中,所述的细胞是体外培养的RD细胞。
再一方面,本发明提供了一种SU14813药物组合物,所述的偶联物含有SU14813和
a)与标记物连接的载体,或者
b)与固体连接的衔接体。
可选的,本发明提供一种SU14813组合物,其包含肠道病毒71型嗜神经性病毒抑制剂或其任何药学上可接受的盐,酯或前药。药学上可接受的盐,酯或前药包括但不限于:硫酸盐,二甲基异山梨醇,20-80,环糊精(例如/>),角鲨烯,第二种丙二醇,聚乙二醇(最好是低分子量,例如PEG400),聚山梨酯,泊洛沙姆,聚氧基和它们的组合。
再一方面,本发明提供了一种SU14813抑制EV-A71病毒的试剂盒,该试剂盒含有以SU14813为有效成分、辅以药学上可接受的辅料的抗EV-A71病毒药物和盛放药物的容器。
再一方面,本发明提供了一种抑制VP1蛋白的方法,该方法包括以下步骤:
A)获取VP1蛋白或者产生VP1蛋白的细胞;
B)获取含有SU14813成分的药剂;
C)将含有SU14813成分的药剂与产生VP1蛋白的细胞或者VP1蛋白接触。
本发明中,用于治疗的药物不仅会因所选的特定抑制剂而异,而且还取决于使用途径,需要哪种治疗方法以及患者的年龄、体重和状况,最终将由主治医师决定。一般而言,合适的剂量可以在约0.005的范围内至每天约30mg/kg体重,最好在0.05的范围内到10mg/kg/天。所需剂量可以方便地以单剂量或以适当的间隔(例如两次,20次)分次服用每天三,四或更多剂。根据治疗需要和/或预防,所需剂量也可以是,例如,每次两天,每三天一次,甚至每周一次。该组合物方便地以单位剂型给药;优选地,单位剂量。对于含有0.5至1500mg,方便地1至1000mg,最多25的示例每单位剂型方便地含有5至700mg活性成分。
本发明的SU14813组合物通常将通过口服给药,肠胃外,静脉内,肌内,皮下或其他注射剂途径,颊,直肠,阴道,经皮和/或鼻腔途径和/或通过以药学上可接受的剂型吸入。取决于待治疗的疾病和患者以及给药途径,组合物可以不同的剂量给药。药物组合物包括但不限于那些合适的药物组合物用于口腔,直肠,鼻腔,局部(包括颊和舌下),透皮,阴道或肠胃外(包括肌肉内,皮下和静脉内)给药或以适合于通过以下方式给药的形式吸入或吹入。
该SU14813组合物在适当的情况下可以是方便地以离散的剂量单位显示,可以通过药学领域众所周知的任何方法。制药业适合口服的组合物方便地列为独立包装的单位,例如胶囊,扁囊剂或药片,每个都包含一个预定量的活性物质。口服片剂和胶囊可能含有常规药物赋形剂,例如粘合剂,填充剂,润滑剂,崩解剂或润湿剂。可以根据方法对片剂进行包衣本领域已知的。可以将组合物配制成用于肠胃外给药的形式(例如通过注射(例如推注或连续输注),并且可以是小剂量安瓿瓶中的单位剂型形式输注或添加了防腐剂的多剂量容器中。组合物可采用悬浮液,溶液或油性或水性介质中的乳化液,可能含有配方剂例如悬浮剂,稳定剂和/或分散剂。
SU14813的存储液可以按照如下方式配置。
以下数据基于产品分子量,对于特殊产品,请参照COA中的储备液配制条件和说明进行操作。
表3SU14813的存储液配置示例
浓度s | 1mg | 5mg | 10mg |
1mM | 2.26mL | 11.2999mL | 22.5999mL |
5mM | 0.452mL | 2.26mL | 4.52mL |
10mM | 0.226mL | 1.13mL | 2.26mL |
提供以下示例以说明本发明并不局限于此,并且不应认为是对本发明的限制。以下是组合物的许多非限制性实例包含稳定的无定形杂化纳米颗粒的例子。缩写的意义如下:
“I”代表病毒抑制剂SU14813;“P”代表聚合物稳定和形成基质的组分;“S”代表增溶剂;
“I+P”代表SU14813抑制剂与聚合物稳定和形成基质的组分的物理混合物,即无需进一步处理;
“I+S”代表SU14813抑制剂与增溶剂的物理混合物;
“I+P+S”代表SU14813抑制剂的物理混合物,聚合物稳定和形成基质的组分和增溶剂;
“I/P”代表具有SU14813抑制剂的稳定,无定形杂化纳米颗粒以及聚合物稳定和形成基质的组分;
“I/P+S”代表稳定的无定形杂化纳米粒子,具有15抑制剂和聚合物稳定和形成基质的组分以及添加单独的增溶剂;
“I/P/S”表示稳定,无定形的杂化纳米粒子,具有抑制剂,聚合物稳定和形成基质的组分以及增溶剂。
如本发明所用,术语“组合物”旨在涵盖包含指定量的指定成分的产品,以及直接或间接地由指定量的指定成分的组合产生的任何产品。
术语“治疗”是指逆转,减轻,抑制或减缓这些术语适用的疾病,病症或病状或此类疾病,病症或病状的一种或多种症状的进展。
除非另有说明,否则成分的所有百分比均为每体积重量(w/v),除非另有说明,否则w/v百分比是指最终组合物的重量百分比。
如本发明所使用的,被定义为“大约”每个特定值的,与量,重量等有关的所有数值为正负10%。例如,短语“约5%w/v”应理解为“4.5%至5.5%w/v”。因此,权利要求的范围涵盖在要求保护的值的10%以内的量。
术语“药学上可接受的”描述了不是生物学上或其他方面不期望的材料,即,不会引起不可接受水平的不期望的生物学作用或以有害的方式相互作用的材料。
如本发明所用,术语“有效量”是指足以影响期望的生物学作用,例如有益结果的量,包括但不限于预防,减少,减轻或消除疾病或病症的体征或症状。因此,药物组合物或方法的每种活性成分的总量足以显示有意义的受试者益处。因此,“有效量”将取决于其被施用的环境。有效量可以一种或多种预防或治疗性给药方式给药。
术语“前药”是指化合物,包括本发明化合物的单体和二聚体,其具有可裂解的基团并在生理条件下变为在体内具有药物活性的化合物。
如本发明所用,“盐”是指保留母体化合物的生物学效力和性质并且在所施用的剂量下对生物学无害或以其他方式无害的那些盐。本发明化合物的盐可以由无机或有机酸或碱制备。
本发明的化合物可以以衍生自无机或有机酸或碱的药学上可接受的盐形式使用。短语“药学上可接受的盐”是指在合理的医学判断范围内,适合与人和低等动物的组织接触而没有过度毒性,刺激性,过敏反应等的盐,并且与盐类相当。合理的收益/风险比。药学上可接受的盐是本领域众所周知的。例如,S.M.Berge等1977年在《药物科学》详细描述了药学上可接受的盐。
这些盐可以在本发明化合物的最终分离和纯化过程中原位制备,或者通过使游离碱官能团与合适的有机酸反应而分开制备。代表性的酸加成盐包括但不限于乙酸盐,己二酸盐,藻酸盐,柠檬酸盐,天冬氨酸盐,苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,二葡萄糖酸盐,甘油磷酸酯,半硫酸盐,庚酸盐,己酸盐,富马酸盐,盐酸盐,氢溴酸盐,,2-羟基乙磺酸盐(异硫氰酸盐),乳酸盐,马来酸盐,甲磺酸盐,烟酸盐,2-萘磺酸盐,草酸盐,棕榈酸酯,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,新戊酸酯,丙酸盐,琥珀酸盐,酒石酸盐,硫氰酸盐,碳酸氢盐,磷酸盐,谷氨酸盐对甲苯磺酸盐和十一烷酸盐。另外,碱性含氮基团可以用诸如低级烷基卤化物如甲基,乙基,丙基和丁基氯化物,溴化物和碘化物的季铵化剂进行季铵化。硫酸二烷基酯,如二甲基,二乙基,二丁基和二戊基硫酸盐;长链卤化物,例如癸基,月桂基,肉豆蔻基和硬脂基氯化物,溴化物和碘化物;芳烷基卤化物,例如苄基和苯乙基溴化物等。由此获得水溶性或油溶性或分散性产物。可用于形成药学上可接受的酸加成盐的酸的实例包括诸如盐酸,氢溴酸,苹果酸,硫酸和磷酸的无机酸,以及诸如草酸,苹果酸,马来酸,甲磺酸的有机酸,琥珀酸和柠檬酸。优选的酸加成盐是由甲磺酸,苹果酸和磷酸制备的。
碱性加成盐可以在本发明化合物的最终分离和纯化过程中原位制备,方法是使含羧酸的部分与合适的碱,例如药学上可接受的金属阳离子的氢氧化物,碳酸盐或碳酸氢盐,或与氨或有机伯,仲或叔胺。药学上可接受的盐包括但不限于基于碱金属或碱土金属的阳离子,例如锂,钠,钾,钙,镁和铝的盐等,以及无毒的季铵盐和胺阳离子,包括铵,四甲基铵,四乙基铵甲基铵,二甲基铵,三甲基铵,三乙基铵,二乙基铵和乙基铵等。可用于形成碱加成盐的其他代表性有机胺包括乙二胺,乙醇胺,二乙醇胺,哌啶,哌嗪等。
如本发明所用,术语“酯”由式-OC(O)A表示1或-C(O)OA1,其中A1可以是烷基,环烷基,烯基,环烯基,炔基,环炔基,芳基,杂芳基或其他合适的取代基。
如本发明所用,术语“患者”是指但不限于人或其他动物。
如本发明所用,术语“逐滴”是指将一种溶液递增地添加至另一溶液的任何方法。
本发明的有益效果在于:SU14813对EV-A71具有抗病毒作用,在无毒性浓度下对EV-A71感染的RD细胞均有保护作用,经SU14813治疗后RD细胞的病毒减少,在RD细胞中对EV-A71呈现剂量依赖性抑制。本发明从已上市药品中筛选具有抗EV-A71病毒活性的药物,将节约药物筛选过程中有关药物代谢、药物安全和毒理等方面的研究费用,降低药物研发的风险,为EV-A71感染疾病的对症治疗和新药开发提供新的思路和途径。
附图说明
为了更清楚地说明本申请实施例中的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本申请的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1.实施例1中RD细胞中SU14813的半数细胞毒性浓度CC50;其中,RD细胞用指定浓度的SU14813抑制剂处理,发光细胞活力测定,测量SU14813抑制剂的CC50;
图2.实施例2中SU14813治疗后RD细胞中EV-A71病毒的减少,其中,图2A为细胞裂解物中相对病毒载量(%),图2B为上清液中相对病毒载量(%),图2C为TCID50测定值,图2D为通过蛋白质印迹分析EV-A71的VP1蛋白;
图3.实施例3中SU14813抑制剂在RD细胞中对EV-A71的剂量依赖性抑制,用指定浓度的SU14813抑制剂处理的RD细胞以0.1的MOI接种EV-A71,24小时,以DMSO处理的细胞为100%对照,其中,图3A为细胞裂解物中各指定浓度的SU14813抑制剂处理的RD细胞中相对病毒载量,图3B为上清液中各指定浓度的SU14813抑制剂处理的RD细胞中相对病毒载量,图3C为TCID50测定值,图3D为通过蛋白质印迹分析EV-A71 VP1蛋白。
具体实施方式
下面将对本发明多重酪氨酸激酶在制备抑制肠道病毒71型嗜神经性病毒药物中的应用通过下述实施例进行清楚、完整地描述,显然,所描述的实施例仅仅是本申请一部分实施例,而不是全部的实施例。基于本申请中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本申请保护的范围。
实施例1
SU14813对RD细胞的毒性作用
为了评估SU14813的抗病毒作用,本发明测量了RD细胞中SU14813的50%细胞毒性浓度(CC50),以排除SU14813对RD细胞活力的不利影响。
用指定浓度的SU14813处理RD细胞,使用发光细胞活力试剂测定SU14813的半数细胞毒性浓度(CC50)。相应结果见图1。根据上述实验检测结果计算得出SU14813对RD细胞的CC50为26.35μM。
实施例2
SU14813对EV-A71的抗病毒作用
根据实施例1的细胞毒性结果,我们首先选择10μM作为药物处理RD细胞的浓度,用MOI为0.1的EV-A71感染被DMSO或指定的抑制剂(10μM)处理过的RD细胞,24h后,SU14813对EV-A71的抗病毒效果通过病毒载量,病毒滴度和病毒结构蛋白VP1的表达情况进行对比,相应结果见图2A至图2D:
以EV-A71为100%,SU14813在细胞裂解物(A)和上清液(B)的病毒被收获用于病毒基因拷贝数的量化,如图2A和2B所示,细胞裂解物和上清液中的相对病毒载量分别为5.03225%和14.693%;如图2C所示,通过TCID50测定实验,还确定了抑制剂处理样品的病毒滴度;如图2D,通过蛋白质印迹分析EV-A71 VP1蛋白,GAPDH用作上样对照。数据显示三个独立实验的平均值和SD。*P<0.05;**P<0.01;***P<0.001。****P<0.0001。
以EV-A71为100%,SU14813在细胞裂解物(A)和上清液(B)中病毒基因拷贝数的相对值分别如表1所示。
表1SU14813对EV-A71的抗病毒作用
药物 | 细胞裂解物(相对值%) | 上清液(相对值%) | TCID50/ml |
EV-A71 | 100 | 100 | 5.01×107 |
SU14813 | 5.03225 | 14.693 | 1.41×106 |
根据相应实验检测结果计算得出,SU14813在无毒性浓度下对EV-A71感染的RD细胞有很好的保护作用,即SU14813在RD细胞上对EV-A71都有抑制作用,提示SU14813具有抗EV-A71病毒活性。
实施例3
SU14813可以剂量依赖地抑制EV-A71感染和复制
用MOI为0.1的EV-A71感染被DMSO或指定的抑制剂浓度处理过的RD细胞,24h后,SU14813对EV-A71的抗病毒效果通过病毒载量,病毒滴度和病毒结构蛋白VP1的表达情况进行测定,相应结果见图3。
用指定浓度的SU14813抑制剂处理的RD细胞以0.1的MOI接种EV-A71,24小时,以DMSO处理的细胞为100%对照,使用RT-qPCR分析,如图3A细胞裂解物中随着SU14813浓度增加,从1到25μM,相对病毒载量由约54.3%降至1.6%;如图3B上清液中的相对病毒载量也从50.8%降至3.9%,以及如图3C在TCID50测定值中,DMSO处理的细胞中EV-A71病毒载量为2.82×107/ml,而SU14813浓度为25μM的TCID50测定值为7.88×104,详见表2;如图3D所示,以GAPDH用作上样对照,通过蛋白质印迹分析0、1、5、10、25μM的SU14813处理后细胞中EV-A71 VP1蛋白依次降低,当浓度为25μM时,VP1蛋白几乎检测不到(D)。数据显示三个独立实验的平均值和SD。*P<0.05;**P<0.01;***P<0.001。****P<0.0001。
表2SU14813可以剂量依赖地抑制EV-A71感染和复制
SU14813 | 细胞裂解物(相对值%) | 上清液(相对值%) | TCID50/ml |
DMSO | 100 | 100 | 2.82×107 |
1 | 54.3421 | 50.7766 | 7.89×106 |
5 | 16.4683 | 26.0881 | 1.41×106 |
10 | 9.12484 | 21.5724 | 5.01×105 |
25 | 1.61593 | 3.8606 | 7.88×104 |
实验结果表明,在一定的浓度范围内,随着SU14813浓度逐渐升高,病毒载量,病毒滴度和病毒结构蛋白VP1的表达逐渐下降,说明SU14813可以剂量依赖地抑制EV-A71的感染和复制。
实施例4
针对EV-A71的抗病毒活性、细胞毒性和选择性指数
本发明除了评估了SU14813对EV-A71感染的CC50(将细胞活力降低50%所需的化合物浓度),也测试了其EC50(达到50%保护免受病毒诱导的细胞致病性所需的化合物浓度),以及对应的选择性指数(Selectivity index,SI,即CC50/EC50)。
实验结果表明,SU14813在RD细胞中表现出较高的细胞毒性(26.35±6.09μM),以1.73±0.18μM的半数最大有效浓度(EC50)有效抑制EV-A71感染,选择性指数SI为15.23,按照CC50/EC50计算。根据上述实验检测结果计算得出,SU14813在RD细胞中抗EV-A71感染的选择性指数为15.23,能够有效的抑制EV-A71病毒活性。
以上所述,仅为本申请的具体实施方式,但本申请的保护范围并不局限于此,任何熟悉本领域技术的技术人员在本申请公开的技术范围内,可轻易想到的变化或替换,都应涵盖在本申请的保护范围之内。因此,本申请的保护范围应以所述权利要求的保护范围为准。
Claims (3)
1.SU14813在制备抑制病毒药物中的应用,所述的病毒是肠道病毒71型嗜神经性病毒EV-A71。
2.根据权利要求1所述的SU14813在制备抑制病毒药物中的应用,其特征在于,所述的药物是抑制EV-A71病毒活性的药物。
3.根据权利要求1所述的SU14813在制备抑制病毒药物中的应用,其特征在于,所述的药物是降低EV-A71病毒活力、病毒载量或者VP1蛋白表达量的药物。
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WO2021257089A1 (en) * | 2020-06-19 | 2021-12-23 | Napo Pharmaceuticals, Inc. | Methods and compositions for treating chemotherapy-induced diarrhea |
CN113827596A (zh) * | 2021-09-06 | 2021-12-24 | 武汉市金银潭医院(武汉市传染病医院) | 拉帕替尼和/或其可药用衍生物在制备抗肠道病毒药物中的应用 |
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WO2021257089A1 (en) * | 2020-06-19 | 2021-12-23 | Napo Pharmaceuticals, Inc. | Methods and compositions for treating chemotherapy-induced diarrhea |
CN113827596A (zh) * | 2021-09-06 | 2021-12-24 | 武汉市金银潭医院(武汉市传染病医院) | 拉帕替尼和/或其可药用衍生物在制备抗肠道病毒药物中的应用 |
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