CN112957362A - 枸橼酸托法替布在制备治疗免疫检查点抑制剂相关心肌炎的药物上的应用 - Google Patents
枸橼酸托法替布在制备治疗免疫检查点抑制剂相关心肌炎的药物上的应用 Download PDFInfo
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Abstract
本发明涉及一种枸橼酸托法替布在制备治疗免疫检查点抑制剂相关心肌炎的药物上的应用。在施用对于重症型免疫检查点抑制剂相关心肌炎激素冲击的药物同时加用枸橼酸托法替布。与现有技术相比，本发明为重症型免疫抑制剂相关性心肌炎患者带来安全可靠的治疗方案。
Description
技术领域
本发明属于生物医药领域，尤其是涉及一种枸橼酸托法替布在制备治疗免疫检查点抑制剂相关心肌炎的药物上的应用。
背景技术
近年来免疫检查点抑制剂的推广应用为肿瘤治疗带来颠覆性的革新，众多肿瘤患者受益于该项治疗技术。通过抗体抑制免疫检查点的活性，进而提高效应T细胞识别和杀伤肿瘤细胞的能力，最终增强患者免疫系统抗肿瘤水平。然而免疫抑制剂在带来临床获益的同时，对各器官的免疫毒性日益成为患者及医生必须谨慎面对的问题。免疫检查点抑制剂可引起相关心肌炎、肝炎、肌炎等，其中免疫抑制剂相关心肌炎是致死性最高的不良反应。治疗手段有限，病情变化迅速，预后较差是其显著特点。
糖皮质激素是目前治疗免疫抑制剂相关心肌炎的一线推荐药物，对重症型和危重型心肌炎患者推荐静脉注射甲基强的松龙(1g/d)冲击治疗。对于重症型心肌炎患者指南指出在糖皮质激素的基础之上，推荐增加1～3类免疫抑制类药物联合或序贯应用，目前免疫抑制类药物包括：吗替麦考酚酯(MMF)、抗人胸腺细胞免疫球蛋白(ATG)、英夫利昔单抗、阿仑单抗、阿巴西普、静脉注射免疫球蛋白(IVIG)。因为研究样本有限，目前对于上述治疗方案的短期及长期治疗效果并未有明确答案，且上述免疫抑制类药物多作用于单一炎症通路或者因子，导致这些常用的免疫抑制类药物针对个体的治疗效果差异较大。
枸橼酸托法替布是一种新型小分子抑制剂，作用于JAK通路。2012年11月在美国首先批准上市，商品名尚杰/XELJANZ，具体化学结构如下：
枸橼酸托法替布作为泛JAK通路抑制剂，可有效阻断炎症细胞因子风暴中核心的JAK-STAT通路，目前已在众多免疫相关疾病中有效安全使用。
枸橼酸托法替布适用于甲氨蝶呤疗效不足或对其无法耐受的中度至重度活动性类风湿关节炎(RA)成年患者，可与甲氨蝶呤或其他非生物改善病情抗风湿药(DMARD)联合使用。
目前，已经公布的枸橼酸托法替布的相关研究中尚未有将其用于重型免疫检查点抑制剂相关心肌炎的治疗药物。
发明内容
本发明的目的在于提供一种枸橼酸托法替布的新的医药用途，即枸橼酸托法替布在制备治疗免疫检查点抑制剂相关心肌炎的药物上的应用。
本发明的目的可以通过以下技术方案来实现：
本发明首先提供一种枸橼酸托法替布在制备治疗免疫检查点抑制剂相关心肌炎的药物上的应用。
更进一步地，提供所述枸橼酸托法替布在制备治疗激素抵抗型免疫检查点抑制剂相关心肌炎的药物上的应用。
在本发明的一个实施方式中，本发明提供所述的枸橼酸托法替布和激素冲击的药物联合在制备治疗免疫检查点抑制剂相关心肌炎的药物上的应用。
在本发明的一个实施方式中，在提供所述的枸橼酸托法替布和激素冲击的药物联合在制备治疗免疫检查点抑制剂相关心肌炎的药物上的应用时，所述的枸橼酸托法替布与激素冲击的药物的质量比为1：100～200。
在本发明的一个实施方式中，所述的激素冲击的药物选自甲强龙(甲基强的松龙)、氢化可的松、醋酸泼尼松龙等。
本发明还提供一种治疗免疫检查点抑制剂相关心肌炎的药物组合，包括治疗有效量的枸橼酸托法替布和治疗有效量的激素冲击的药物，所述枸橼酸托法替布和激素冲击的药物分别独立存放。
在本发明的一个实施方式中，在治疗免疫检查点抑制剂相关心肌炎的药物组合中，配合一次使用的剂量中，所述的枸橼酸托法替布与激素冲击的药物的质量比为1：100～200。
在本发明的一个实施方式中，在治疗免疫检查点抑制剂相关心肌炎的药物组合中，所述的激素冲击的药物选自甲强龙(甲基强的松龙)、氢化可的松、醋酸泼尼松龙等。
本发明还提供一种治疗免疫检查点抑制剂相关心肌炎的药盒，包括治疗有效量的枸橼酸托法替布和治疗有效量的激素冲击的药物，所述枸橼酸托法替布和激素冲击的药物分别独立存放，还包括使用说明书，所述使用说明书上注明：将枸橼酸托法替布和激素冲击的药物联合施用，用于治疗免疫检查点抑制剂相关心肌炎。
所述使用说明书上还注明：施用激素冲击的药物500mg-1000mg冲击3天，然后激素按照如下剂量进行减量240mg*3d，120mg*3d，80mg*3d，60mg*3d，40mg*3d，后续改为口服激素冲击的药物，每周减量5mg，2-3月停药；枸橼酸托法替布在激素冲击的同时即加用，用量为5mg bid，在激素完成撤退后继续巩固治疗2-4周。
免疫检查点抑制剂相关心肌炎发病机制不清，与常见病毒性心肌炎、细菌性、寄生虫性、过敏性心肌炎病理机制存在显著差异，且免疫检查点抑制剂相关心肌炎临床风险程度及预后与上述心肌炎存在较大差异。目前研究提示自身免疫性淋巴细胞系统过度激活及识别错误，以及炎症因子风暴在免疫检查点抑制剂相关心肌炎发病机制中起重要作用。对于重型免疫检查点抑制剂相关心肌炎，自身免疫通路的过度激活以及广泛的炎症因子风暴在疾病的进展中起关键调控节点作用，然而目前常规抗炎及免疫抑制药物并不能提供较为理想的治疗效果。
枸橼酸托法替布作为第一种泛JAK通路抑制剂，可有效阻断JAK-STAT通路，托法替布对JAK1、JAK2、JAK3、TYK2均有抑制作用，而上述分子在细胞炎症反应中发挥重要作用。但在心肌炎症，特别是免疫检查点抑制剂相关心肌炎中未曾有应用尝试。
免疫检查点抑制剂相关心肌炎发病机制虽然仍不甚清楚，但自身免疫的过度激活以及炎症因子风暴在其中发挥重要作用，因此本发明将托法替布用于免疫检查点抑制剂引起的相关心肌炎可有效阻断相关炎症因子风暴同时抑制过度激活的自身免疫机制，进而对于免疫检查点抑制剂引起的相关心肌炎有很好的疗效。
与现有技术相比，本发明具有以下优点：对于重症型免疫检查点抑制剂相关心肌炎患者给予大剂量激素冲击(500mg-1000mg)起始冲击，同时加用枸橼酸托法替布(可选择的药品可以为尚杰)5mg bid，有效治愈了重症型免疫检查点抑制剂引起的相关心肌炎，安全可靠。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
实施例1
患者女性63岁胃癌4期，使用卡瑞利珠单抗200mg 3周期后出现胸闷、乏力、眼睑下垂症状，cTnT 0.348ng/ml BNP 745.2pg/ml CK 499U/L CKMM 442U/L CKMB 57U/L ALT188U/L AST 65U/L心超示左室整体收缩活动减弱，心脏磁共振提示心肌炎症，考虑患者为重型免疫抑制剂相关性心肌炎患者，施用泼尼松龙500mg冲击3天，然后泼尼松龙按照如下剂量进行减量240mg*3d，120mg*3d，80mg*3d，60mg*3d，40mg*3d，后续改为口服泼尼松龙，每周减量5mg，3月停药。枸橼酸托法替布在激素冲击的同时即加用，用量为5mg bid，在激素完成撤退后继续巩固治疗2周。随访患者心脏标志物及肝酶、肌酶稳步下降，末次随访cTnT0.023ng/ml BNP 171.4pg/ml CK 32U/L CKMM 29U/L CKMB 3U/L ALT 24U/L AST 26U/L，上述心脏损伤标志物及肝功能指标基本恢复正常。
实施例2
枸橼酸托法替布作为治疗激素抵抗型免疫检查点抑制剂相关心肌炎的药物的应用
1.1实验对象与分组
将11例重症激素抵抗型免疫检查点抑制剂相关心肌炎患者(诊断标准参照免疫检查点抑制剂相关心肌炎监测与管理中国专家共识(2020版)分为治疗组8例和观察组3例，两组在性别、年龄、病情等一般临床资料比较，差异无显著性(p>0.05)，具有可比性。
1.2治疗方法
观察组给予指南推荐常规激素治疗方案：给予甲泼尼龙500mg*3d，240mg*3d，120mg*3d，80mg*3d，60mg*3d，40mg*3d，后续改为口服泼尼松龙，每周减量5mg，2-3月停药。
治疗组则在上述治疗方案上加用枸橼酸托法替布片，每日2次，每次5mg。在激素完成撤退后继续巩固治疗2-4周。随访半年。
1.3观察指标及方法
有效：存活。无效：死亡。
1.4统计学方法
采用SPSS13.0进行统计学处理，采用t检验计数资料，p<0.05为差异有统计学意义。
2、结果
2.1两组疗效比较
两组患者经治疗后，治疗组生存5例、死亡3例，其中死于心肌炎进展1例，死于肺部感染导致的感染性休克2例，总有效率62.5％；观察组3例患者均死亡；治疗组总有效率显著高于对照组，(p<0.05)。
Claims (10)
1.一种枸橼酸托法替布在制备治疗免疫检查点抑制剂相关心肌炎的药物上的应用。
2.根据权利要求1所述的应用，其特征在于，所述枸橼酸托法替布在制备治疗激素抵抗型免疫检查点抑制剂相关心肌炎的药物上的应用。
3.根据权利要求1或2所述的应用，其特征在于，所述的枸橼酸托法替布和激素冲击的药物联合在制备治疗免疫检查点抑制剂相关心肌炎的药物上的应用。
4.根据权利要求3所述的应用，其特征在于，所述的枸橼酸托法替布与激素冲击的药物的质量比为1：100～200。
5.根据权利要求3所述的应用，其特征在于，所述的激素冲击的药物选自甲强龙、氢化可的松、醋酸泼尼松龙。
6.一种治疗免疫检查点抑制剂相关心肌炎的药物组合，其特征在于，包括治疗有效量的枸橼酸托法替布和治疗有效量的激素冲击的药物，所述枸橼酸托法替布和激素冲击的药物分别独立存放。
7.根据权利要求6所述的一种治疗免疫检查点抑制剂相关心肌炎的药物组合，其特征在于，配合一次使用的剂量中，所述的枸橼酸托法替布与激素冲击的药物的质量比为1：100～200。
8.根据权利要求6所述的一种治疗免疫检查点抑制剂相关心肌炎的药物组合，其特征在于，所述的激素冲击的药物选自甲强龙、氢化可的松、醋酸泼尼松龙。
9.一种治疗免疫检查点抑制剂相关心肌炎的药盒，其特征在于，包括治疗有效量的枸橼酸托法替布和治疗有效量的激素冲击的药物，所述枸橼酸托法替布和激素冲击的药物分别独立存放，还包括使用说明书，所述使用说明书上注明：将枸橼酸托法替布和激素冲击的药物联合施用，用于治疗免疫检查点抑制剂相关心肌炎。
10.根据权利要求9所述一种治疗免疫检查点抑制剂相关心肌炎的药盒，其特征在于，所述使用说明书上还注明：施用激素冲击的药物500mg-1000mg冲击3天，然后激素冲击的药物按照如下剂量进行减量240mg*3d，120mg*3d，80mg*3d，60mg*3d，40mg*3d，后续改为口服激素冲击的药物，每周减量5mg，2-3月停药；枸橼酸托法替布在激素冲击的同时即加用，用量为5mg bid，在激素完成撤退后继续巩固治疗2-4周。
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| CN106902120A (zh) * | 2015-12-22 | 2017-06-30 | 江苏万邦生化医药股份有限公司 | 枸橼酸托法替布在老年退行性心瓣膜病辅助治疗药物中的应用 |
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