CN114053255A - 甲磺酸苦柯胺b在制备治疗脓毒症休克药物中的应用 - Google Patents
甲磺酸苦柯胺b在制备治疗脓毒症休克药物中的应用 Download PDFInfo
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Abstract
本发明提供了甲磺酸苦柯胺B在制备治疗脓毒症休克药物中的应用,属于医药技术领域。本发明通过开展甲磺酸苦柯胺B的IIa期临床试验可知,通过静脉滴注给药,甲磺酸苦柯胺B对于脓毒症休克具有良好的治疗作用,与安慰剂相比,可以显著降低脓毒症休克患者的SOFA评分,改善患者生存质量。
Description
技术领域
本发明涉及医药技术领域,尤其涉及甲磺酸苦柯胺B在制备治疗脓毒症休克药物中的应用。
背景技术
天然产物苦柯胺B(Kukoamine B)是Shinji Funayama等(S.Funayama,G.Zhang&S.Nozoe.Phytochemistry.1995;38:1529-1531)首次从地骨皮中分离提取的生物碱类化合物,化学结构如式1所示:
脓毒症是一种机体对感染的反应失调而导致危及生命的器官功能障碍。苦柯胺B能有效拮抗导致脓毒症的细菌病原体相关分子——内毒素/脂多糖(endotoxin/lipopolysaccharide,LPS)和细菌DNA(CpG DNA),对治疗脓毒症表现出良好活性,且作用明显优于阳性对照药物,因而具有良好的成药前景。
脓毒性休克是指在发生脓毒症的基础上,患者经过充分的液体复苏治疗,包括用一些血管活性药和其他一些配套辅助的措施,都不能纠正的较为顽固的低血压,多数情况下可能会伴有组织器官的灌注不足,血乳酸指标升高至大于2mmol/L,甚至还会伴有一些器官功能的障碍。因此脓毒症休克是指脓毒症合并出现严重的循环障碍和细胞代谢紊乱,其死亡风险较单纯脓毒症显著升高。如何实现脓毒症休克的良好治疗,是目前需要解决的技术问题。
发明内容
本发明的目的在于提供甲磺酸苦柯胺B在制备治疗脓毒症休克药物中的应用,本发明所述甲磺酸苦柯胺B对于脓毒症休克具有良好的治疗作用。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了甲磺酸苦柯胺B在制备治疗脓毒症休克药物中的应用。
优选地,所述治疗脓毒症休克药物包括甲磺酸苦柯胺B和药学上可接受的辅料。
优选地,所述治疗脓毒症休克药物中甲磺酸苦柯胺B的质量分数为1~20%。
优选地,所述药学上可接受的辅料包括甘露醇、盐酸半胱氨酸、依地酸钙钠、右旋糖酐和甘氨酸中的一种或几种。
优选地,所述治疗脓毒症休克药物的剂型包括冻干粉针剂、注射液或无菌粉针剂。
优选地,所述治疗脓毒症休克药物为注射用甲磺酸苦柯胺B。
优选地,所述治疗脓毒症休克药物的给药方式为静脉滴注给药。
本发明提供了甲磺酸苦柯胺B在制备治疗脓毒症休克药物中的应用,本发明通过开展甲磺酸苦柯胺B的IIa期临床试验可知,通过静脉滴注给药,甲磺酸苦柯胺B对于脓毒症休克具有良好的治疗作用,与安慰剂相比,可以显著降低脓毒症休克患者的SOFA评分,改善患者生存质量。
附图说明
图1为实施例2中各剂量组SOFA数值柱状图;
图2为实施例2中各剂量组SOFA数值变化趋势图。
具体实施方式
本发明提供了甲磺酸苦柯胺B在制备治疗脓毒症休克药物中的应用。
在本发明中,所述治疗脓毒症休克药物优选包括甲磺酸苦柯胺B和药学上可接受的辅料。在本发明中,所述治疗脓毒症休克药物中甲磺酸苦柯胺B的质量分数优选为1~20%,进一步优选为1~10%。在本发明中,所述药学上可接受的辅料优选包括甘露醇、盐酸半胱氨酸、依地酸钙钠、右旋糖酐和甘氨酸中的一种或几种。
在本发明中,所述治疗脓毒症休克药物的剂型优选包括冻干粉针剂、注射液或无菌粉针剂。
在本发明中,所述治疗脓毒症休克药物为注射用甲磺酸苦柯胺B。
在本发明中,所述治疗脓毒症休克药物的给药方式为静脉滴注给药。
甲磺酸苦柯胺B为苦柯胺B的甲磺酸盐,申请号为201010156503.X的专利中公开了苦柯胺A和苦柯胺B用于制备预防和治疗脓毒症及自身免疫性疾病的药物的用途,其作用机理为拮抗导致脓毒症和自身免疫性疾病发病的关键因素细菌内毒素(LPS)和细菌非甲基化DNA(CpGDNA),并通过小鼠检测了苦柯胺A和苦柯胺B对于试验动物体内LPS和CpGDNA的拮抗作用。通过上述动物试验结果可知,苦柯胺A和苦柯胺B可以拮抗脓毒症发生过程中的关键致病因素LPS和CpGDNA,可以推定苦柯胺A和苦柯胺B能够用于脓毒症的治疗,但是并未进一步说明苦柯胺B可以用于脓毒症发病过程中的具体阶段。
脓毒性休克是指在发生脓毒症的基础上,患者经过大量积极的液体复苏治疗,包括用一些血管活性药和其他一些配套辅助的措施,都不能纠正的较为顽固的低血压,多数情况下可能会伴有组织器官的灌注不足,血乳酸指标升高至大于2mmol/L,甚至还会伴有一些器官功能的障碍,其死亡风险较单纯脓毒症显著升高。下面就脓毒症以及脓毒性休克的区别进行详细说明。1991年美国胸科医师学会(American college ofchestphysicians,ACCP)和美国危重病学会(society ofcritical care medicine,SCCM)召开联席会议,发布脓毒症-1版定义:定义脓毒症为感染引起的全身性反应;定义严重脓毒症为脓毒症伴有器官功能障碍、组织低灌注或脓毒症介导的低血压;定义脓毒性休克为严重脓毒症的一种,脓毒症伴有低血压,表现为经充分液体复苏仍不能纠正的灌注异常或器官功能障碍。根据脓毒症-1定义,在感染的基础上符合2条及以上全身炎症反应综合征(systemicinflammatory response syndrome,SIRS)诊断标准的患者即可诊断为脓毒症,SIRS诊断标准包括:
①体温>38℃或<36℃;
②心率>90次/min;
③呼吸>20次/min或PaCO2<32mmHg(1mmHg=0.133kPa);
④白细胞计数>12×109/L或<4×109/L,或幼稚细胞>10%。
该定义、诊断标准虽然得到了学术界的广泛认同,但是在医疗实践中也发现了很多问题,SIRS标准特异性差。
2001年,ACCP、SCCM联合欧洲危重病医学会(European society of intensivecare medicine,ESICM)、美国胸科学会以及外科感染学会召开国际脓毒症定义会议,并达成共识(即脓毒症-2),其认为尚无足够的证据对脓毒症原有相关定义进行修改,但是新增了脓毒症诊断要点:存在已经确定或高度怀疑的感染,并具备全身一般情况、炎性参数、血流动力学参数、器官功能不全参数、组织灌注参数5个方面24项诊断指标;脓毒性休克被定义为脓毒症所致低血压,虽经液体复苏后仍无法逆转。脓毒症所致组织灌注不足定义为感染引起的低血压、高乳酸血症或少尿。此版诊断要点过于复杂,可操作性差,致使其未能在临床广泛应用,很多医师继续使用“感染+SIRS”作为诊断标准。
2016年,第45届美国重症医学年会发布了脓毒症-3新定义。此版定义和诊断标准的修订是SCCM和ESICM共同召集,由来自脓毒症病理学、临床试验以及流行病学等领域的19位专家组成的第3次国际共识定义特别专家组,通过会议讨论、Delphi法、电子病历数据分析以及投票等方式共同完成。此次会议定义:
脓毒症为针对感染的宿主反应失调引起的致命性器官功能障碍,诊断标准为感染引起的序贯性器官功能衰竭评价(sequential organ failure assessment,SOFA)评分(表1)急性改变≥2分,即“脓毒症=感染+SOFA≥2”。
定义脓毒性休克为感染导致的循环衰竭和细胞代谢异常,是脓毒症的一个亚型,诊断标准为在脓毒症和充分液体复苏的基础上,使用血管升压药才能使平均动脉压维持在65mmHg以上,并且血乳酸水平≥2mmol/L,见表1。
另外,专家组认为脓毒症患者的病死率高达10%,已属于一个非常严重的状态,故判定“严重脓毒症”这个术语是重复多余的,在脓毒症-3中取消严重脓毒症这个定义。
表1SOFA评分(脓毒症相关)
注:表1中SOFA:序贯性器官功能衰竭评价;FiO2:吸入氧浓度;PaO2:氧分压;GCS评分:格拉斯哥昏迷量表评分;MAP:平均动脉压;a:至少监测1h的儿茶酚胺剂量[μg/kg·min]。
脓毒症-3定义强调感染导致宿主产生内稳态失衡,存在潜在致命风险,指出脓毒症可引起器官功能障碍,提示其病理生理机制较之前的认识更为复杂。在脓毒症-3的诊断标准中增加器官功能障碍评分,去除SIRS诊断标准,强调评估患者器官衰竭的程度与脓毒症治疗的关系,即脓毒症=感染+SOFA≥2。
由上述脓毒症和脓毒症休克的定义和诊断标准可知,二者存在明显的区别,并非一种疾病。脓毒症休克是比脓毒症更加凶险的疾病,其死亡率远高于脓毒症。其中,脓毒症休克与脓毒症治疗的最明显差异是脓毒症休克治疗中需要持续给药升压药物,例如去甲肾上腺素、多巴酚丁胺、多巴胺等,用于维持患者血压。
采用盲肠结扎穿孔术(cecal ligation andpuncture,CLP)建立的动物模型是目前研究脓毒症应用最广泛的一种模型。CLP模型由Wichterman等改良并推广应用,至今已有30多年。2009年,Rittirsch等将方法步骤标准化,其CLP造模方法是:氯胺酮(80~100mg/kg)和甲苯噻嗪(5~15mg/kg)腹腔注射麻醉小鼠,然后在其腹壁正中切口,轻轻拉出盲肠,避免碰伤肠系膜血管,并轻轻地挤压盲肠上端粪便,使盲肠末梢充盈,分离肠系膜表面血管;用无菌4号丝线在盲瓣与盲肠中点进行结扎,并用21G无菌针头在结扎部位与盲肠顶端的中点处贯通穿刺盲肠壁,造成穿孔;轻轻挤压盲肠,挤出少许内容物以确保穿孔通畅,将挤出的内容物擦净,然后把盲肠推回腹腔,关闭腹腔,逐层缝合;手术后用生理盐水进行液体复苏(37℃,5mL/100g)并应用丁丙诺啡(0.05mg/kg)止痛。与其他模型相比,CLP模型模仿临床脓毒症的特点,剖腹术引起组织创伤,远端盲肠结扎引起组织坏死,穿孔后混有细菌的肠内容物持续漏入腹腔引起感染,从而诱发腹膜炎,导致肠道细菌移位,从而激活免疫系统,最终出现呼吸、循环等系统衰竭,多器官功能障碍综合征,直至死亡。CLP模型与临床发生极为贴近,但也有自身的不足,其存在的主要问题是不同研究团队采用相同实验方法建立的CLP模型所得到的病死率存在较大差异,而此模型结果的不均一性直接影响以CLP为基础的各项研究的可靠性。
虽然CLP模型在病理生理和免疫系统中可阐述脓毒症的发生、发展,并取得一定研究成果,但这些成果却不能很好地转化为临床应用;一些在动物实验中显示出很好疗效的药物,在临床试验性治疗中并未取得预期的结果,如IL-2阻断剂、类固醇等在临床试验中相继失败,有的甚至显示出有害作用。动物实验与临床试验出现如此强烈的差异,首先是脓毒症的发病机制一直没有明确,其次是CLP模型不能充分模仿出临床脓毒症的复杂变化。
脓毒症的致病因素多种多样,革兰氏阴性和革兰氏阳性细菌、病毒和真菌感染等均可诱发,但CLP模型模仿的是临床穿孔性腹膜炎引发的脓毒症,为多种微生物混合的肠道细菌;临床脓毒症患者年龄大都在50岁以上,而实验大鼠的一般年龄是2~3个月,相当于人的10岁,Turnbull等证实了CLP模型中年龄与病死率的相关性;同时发现,临床脓毒症的治疗时间都是在发病后,而实验室的治疗时间大都是在CLP模型前;临床脓毒症患者检测手段多种多样,而同样的检测手段在动物模型中的应用却少之又少。
综上所述,药物对应CLP模型动物的治疗作用,并不能完全准确用于人体脓毒症治疗的预测和评价,更不能用于人体脓毒症休克治疗的预测和评价。目前并没有公认的用于评价脓毒症休克的动物疾病模型。
下面将结合本发明中的实施例,对本发明中的技术方案进行清楚、完整地描述。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,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,都属于本发明保护的范围。
实施例1
本实施例制备注射用甲磺酸苦柯胺B,所述注射用甲磺酸苦柯胺B的单位制剂处方组成如表2所示:
表2注射用甲磺酸苦柯胺B的单位制剂处方组成
所述注射用甲磺酸苦柯胺B的制备工艺如下:
1)在相对湿度≤30%的条件下,按表2中处方量称取原料药(即甲磺酸苦柯胺B)以及盐酸半胱氨酸、依地酸钙钠、甘露醇和药用炭备用;
2)向配液A罐按重量计注入处方量100%注射用水,并降温至≤40℃,称出20%注射用水(记为第一注射用水)备用,所述配液A罐中保留80%注射用水;
3)从配液A罐中取适量注射用水分别溶解所述原料药、盐酸半胱氨酸、依地酸钙钠以及甘露醇,分别将溶解后的盐酸半胱氨酸、依地酸钙钠以及甘露醇加入至配液A罐中,各物料在配液A罐中混合10min后加入溶解后的原料药;
4)向配液A罐中加入所述第一注射用水至标示量的100%,然后加入所述药用炭,在搅拌条件下吸附20min;
5)将所述配液A罐中溶液过0.45μm微孔滤膜滤过,入配液B罐,得到中间体料液;
6)检测所述中间体料液的性状、甲磺酸苦柯胺B含量、细菌内毒素以及酸度值;
7)所述中间体料液检测合格后,将所得药液过串联0.22μm+0.22μm微孔滤膜(水膜),按调整后的装量灌装(差异限度±0.03mL);
8)在表3中操作条件下对药液进行冷冻干燥;
9)将冷冻干燥后的物料依次压塞(真空)、出箱和压铝盖,得到注射用甲磺酸苦柯胺B。
表3冷冻干燥的操作条件
实施例2
本实施例为随机、双盲、安慰剂对照的临床试验,旨在评价甲磺酸苦柯胺B多次静脉滴注给药在脓毒症患者体内的安全性、耐受性、有效性及药代动力学特征,具体如下:
研究分组:
研究分为预试验和正式试验两部分。
预试验:设2个组,分别为试验药0.06mg/kg组和安慰剂组,共8例,为随机双盲设计,试验药:安慰剂=6:2;给药后留取血样用于检测血药浓度、LPS以及有关药效指标,检测结果为正式试验提供调整依据。
正式试验:计划设3个组,分别为试验药0.12mg/kg、试验药0.24mg/kg组以及安慰剂组;每组12例,受试者按照1:1:1的比例随机分配至各治疗组。
研究分48小时的筛选/基线期、7天的治疗期及末次给药后24小时的随访期。给药后28天随访受试者的生存状态(可通过电话进行)。
受试者入组后首次给药后、给药期间以及最后一次给药后进行药代动力学采血。
所有受试者均进行药效学指标采血,送实验室进行检测。
研究终点:
本试验的主要观察终点为:安全性指标(不良事件及体格检查、生命体征、实验室检查等出现异常情况)和药代动力学参数指标。
本试验的次要终点事件主要为:比较不同剂量组受试者给药后的血浆内毒素、脓毒症相关标记物以及器官功能相对于基线的变化情况。
此外,给药后28天将进行一次随访,以评估受试者的生存状况。
研究人群:成年脓毒症患者(包括脓毒症休克患者)。
受试者数量:44例(其中脓毒症休克患者28例)。
研究中心数量:大约10个。
患者基础治疗及研究药物使用情况:
入组后患者在常规治疗的基础上加载使用KB,其中脓毒症休克患者在常规使用血管升压药维持血压的同时加载使用KB或使用安慰剂。
给药途径:静脉滴注。
治疗分组:
预试验:随机双盲,共8例,A组:D组为6:2;A组:0.06mg/kg,D组:安慰剂;
正式试验:随机双盲,每组12例,B组:C组:D组为1:1:1;B组:0.12mg/kg,C组:0.24mg/kg,D组:安慰剂;
给药途径:静脉滴注;
给药方式:D1-D7(第一天到第七天):静脉滴注60min±3min,Q8h;首次给药开始时间可以安排在9AM、5PM或1AM,共计给药21次。
入选标准:
1、年龄≥18周岁且≤75周岁,性别不限;
2、确诊或可疑的细菌感染;
3、出现感染相关的器官功能衰竭不超过48小时;器官功能衰竭定义为循环、呼吸、肾脏、肝脏、凝血和中枢神经系统中至少一个器官或系统的序贯性器官功能衰竭评分(SOFA)≥3分(即筛选期任意时间点新出现的SOFA评分≥3分);
4、入选至给予试验药物之间的时间间隔不超过8小时;
5、育龄女性尿妊娠试验阴性;
6、育龄患者近半年内无育儿计划且同意在研究期间采取有效措施避孕;
7、患者或法定代理人签署知情同意。
上述为本实验脓毒症患者的入选标准。根据脓毒症休克的定义,脓毒症休克患者为在脓毒症入选标准的基础上,需要血管升压药物治疗以维持血压的脓毒症患者,在本实验中共计28例,随机分布在各个分组中。
排除标准:
1、妊娠期或哺乳期女性,或不能采取有效措施避孕者;
2、因基础疾病导致患者预期生存时间少于28天,如终末期恶性肿瘤,入组前30天内发生心跳骤停,终末期肺病等;
3、患者存在以下慢性器官功能不全或免疫功能抑制(根据APACHE II评分的慢性健康评分评估):
a)心脏:纽约心脏病协会心功能IV级;
b)呼吸:慢性阻塞性、梗阻性或血管性肺疾病导致活动重度受限,即不能上楼或不能做家务;或明确的慢性低氧、CO2潴留、继发性真红细胞增多症、重度肺动脉高压(>40mmHg)或呼吸机依赖;
c)肾脏:接受长期透析治疗;
d)肝脏:活检证实的肝硬化及明确的门脉高压;既往因门脉高压引起的上消化道出血;或既往发生肝功能衰竭/肝性脑病/肝昏迷;
e)免疫功能抑制:接受的治疗措施影响感染抵抗力(如免疫功能抑制治疗,化疗,放疗,长期或近期使用大剂量激素),或罹患疾病影响感染抵抗力(如白血病、淋巴瘤和AIDS);
4、实体器官或骨髓移植;
5、植物生存状态;
6、入组前4周内出现以下情况:
a)急性肺栓塞;
b)输血反应;
c)急性冠脉综合征;
7、确诊或高度疑似病毒性肝炎活动期、活动期肺结核;
8、心动过缓的患者(心率每分钟低于60次);
9、筛选前24小时内,接受过全血/红细胞输注,或重度贫血(血红蛋白小于7.0g/dL);
10、既往24小时内存在未控制的出血(临床判断需要输血支持者);
11、大面积烧伤或化学灼伤(III度烧伤面积>30%BSA);
12、经过充分液体复苏及血管活性药物治疗后平均动脉压<65mmHg;
13、急性骨髓造血抑制,如表现为粒细胞缺乏(ANC<500/mm3);
14、对试验药物有效成分或其辅料过敏;
15、患者正在使用的药物可能严重影响试验用药的代谢;
16、患者和(或)法定代理人签署不抢救预嘱(DNR),或决定撤除生命支持治疗(withdraw)或限制生命支持治疗强度(withhold)并签署相关知情同意书;
17、近3个月内参加过临床干预试验;
18、受试者为研究人员或其直系亲属,或可能存在不当知情同意的患者;主治医生认为不宜参加本试验的患者。
评估安排:
筛选期:
签署知情同意书后开始,入选前48小时内完成。筛选期将进行下列检查:1)评估受试者的合格性;2)签署知情同意书;3)进行筛选和基线评估;4)进行随机入组并分配试验用药。
给药期:
第1天(首次给药日为D1)至第7天(D7)。给药方式为静脉滴注,持续60min±3min。受试者首次给药安排在D1,给药前和给药后进行药代动力学采血;末次给药安排在D7,末3次给药前以及末次给药后进行药代动力学采血。
末次安全随访:
末次给药后24小时,进行末次安全性访视。
生存随访:
给药后28天(D29);如果患者已出院,可电话随访受试者的生存状态。
有效性实验结果:
研究结果表明,治疗组患者各组器官功能分析总分随着治疗呈现下降趋势,其中脓毒症休克患者的SOFA评分结果见表4、图1以及图2。结果显示,与基线期相比,0.06mg/kg、0.12mg/kg和0.24mg/kg组第七天的SOFA总分较基线变化值与安慰剂比较有明显的差异,较安慰剂组△SOFA评分降低了2.25分、4.55分以及2.75分,这说明甲磺酸苦柯胺B对于脓毒症休克患者具有治疗作用,且具有显著的临床意义。
表4各剂量组的SOFA评分结果
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (7)
1.甲磺酸苦柯胺B在制备治疗脓毒症休克药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述治疗脓毒症休克药物包括甲磺酸苦柯胺B和药学上可接受的辅料。
3.根据权利要求2所述的应用,其特征在于,所述治疗脓毒症休克药物中甲磺酸苦柯胺B的质量分数为1~20%。
4.根据权利要求2所述的应用,其特征在于,所述药学上可接受的辅料包括甘露醇、盐酸半胱氨酸、依地酸钙钠、右旋糖酐和甘氨酸中的一种或几种。
5.根据权利要求1所述的应用,其特征在于,所述治疗脓毒症休克药物的剂型包括冻干粉针剂、注射液或无菌粉针剂。
6.根据权利要求1所述的应用,其特征在于,所述治疗脓毒症休克药物为注射用甲磺酸苦柯胺B。
7.根据权利要求1所述的应用,其特征在于,所述治疗脓毒症休克药物的给药方式为静脉滴注给药。
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Citations (2)
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CN101829075A (zh) * | 2010-04-27 | 2010-09-15 | 中国人民解放军第三军医大学第一附属医院 | 苦柯胺a和苦柯胺b的用途 |
CN106580892A (zh) * | 2016-12-21 | 2017-04-26 | 天津红日药业股份有限公司 | 一种苦柯胺b注射用组合物 |
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CN101829075A (zh) * | 2010-04-27 | 2010-09-15 | 中国人民解放军第三军医大学第一附属医院 | 苦柯胺a和苦柯胺b的用途 |
CN106580892A (zh) * | 2016-12-21 | 2017-04-26 | 天津红日药业股份有限公司 | 一种苦柯胺b注射用组合物 |
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