CN114425051A - 硫辛酸在制备治疗脓毒症和/或脓毒性休克的药物中的应用 - Google Patents
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Abstract
本发明属于生物医药技术领域，本发明提供了硫辛酸在制备治疗脓毒症和/或脓毒性休克的药物中的应用。氧化应激是脓毒症发病的重要机制，抑制氧化应激可有效改善脓毒症动物模型和脓毒症患者临床试验中的氧化应激。硫辛酸及其代谢产物是体内天然的生物抗氧化剂，通过捕捉体内自由基抑制体内过度的炎症，进而保护器官功能，降低脓毒症病死率，改善患者预后。
Description
技术领域
本发明属于生物医药技术领域，具体涉及硫辛酸在制备治疗脓毒症和/或脓毒性休克的药物中的应用。
背景技术
脓毒症(Sepsis)是机体对感染的反应失调而导致危及生命的器官功能障碍，脓毒性休克(Septic shock)是指脓毒症合并出现严重的循环障碍和细胞代谢紊乱，是感染、烧/创伤、休克等急危重患者的严重并发症。
目前脓毒症无特效药，针对其病理生理学机制的干预显得更为重要，是提高患者生存率的关键。脓毒症作为一种临床综合征，核心是全身炎症反应综合征(Systematicinflammatory reaction syndrome,SIRS)，其病理生理学机制涉及分子、细胞和器官多个水平。
既往研究表明，作为内源性抗氧化的必需营养素，高剂量维生素C可减轻氧化应激和炎症、改善血管升压素合成、增强免疫细胞功能、改善血管内功能和表观免疫修饰、增强抗菌防御能力。目前已知维生素C减轻氧化应激水平保护器官功能的机制包括：抑制烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶和诱导型一氧化氮(NO)合酶的激活、增加四氢生物蝶呤(FH4)、防止氧化磷酸化解偶联、减少超氧化物和过氧亚硝酸盐的形成以及直接清除超氧化物。维生素C可通过维持环鸟苷酸磷酸酶和封闭蛋白磷酸化来保护内皮屏障，并防止细胞凋亡，恢复血管对血管收缩剂的反应，减少脓毒症休克患者血管活性药物应用时间，有效预防进行性的器官功能障碍，降低患者病死率。维生素C还可减少表面P选择素表达的血小板聚集，防止吞噬细胞氧化损伤。多项临床试验证明了维生素C的安全性，最近的两项研究显示了改善死亡率和缩短住院时间的有希望的数据(参见【FowlerAA,3rd,SyedAA,KnowlsonS,Sculthorpe R,Farthing D,DeWilde C,Farthing CA,Larus TL,Martin E,Brophy DFet al:Phase I safety trial of intravenous ascorbic acid in patients withsevere sepsis.J TranslMed 2014,12:32】和【
H,Chalker E:Vitamin C CanShorten the Length of Stay in the ICU:A Meta-Analysis.Nutrients 2019,11(4).】)。
但是维生素C作为脓毒症的治疗药物仍然具有局限性。首先，单一维生素C治疗脓毒症的作用不确切，多个临床研究采用的是抗氧化剂鸡尾酒疗法。其次，需要静脉内大剂量补充维生素C(最低3g/d，为推荐剂量的30倍)来恢复正常的血清值，会导致代谢性酸中毒，干扰血糖监测值等已知和其他未知不利结局。目前的脓毒症治疗指南也不支持对危重病人给予高剂量维生素C。
硫辛酸为B族维生素，是丙酮酸脱氢酶系和α-酮戊二酸脱氢酶系的辅酶，离体试验显示硫辛酸可以降低神经组织的脂质氧化，可抑制蛋白质糖基化作用，抑制醛糖还原酶。在体内，硫辛酸具有抗氧化作用，参与谷胱甘肽及辅酶Q10等抗氧化剂再循环。硫辛酸作为抗氧化剂，具有捕捉消除自由基、螯合金属离子、再生(还原)其他的抗氧化剂的作用。硫辛酸兼具脂溶性水溶性，比维生素C(仅水溶性)、维生素E(仅脂溶性)抗氧化能力更强，具有超强的清理氧自由基作用。动物研究表明硫辛酸在体内可发挥强有力的抗氧化作用。硫辛酸作为一种生物抗氧化剂，临床方面也得到了广泛应用，尤其是在治疗糖尿病方面。同时，它也用于治疗老年性心血管疾病、认知障碍、神经肌肉疾病等，并且是一些炎症信号通路的调节因子。硫辛酸还可以是抑制大脑脂质过氧化，研究表明硫辛酸有助于提高急性脑梗死患者的疗效。硫辛酸对动脉粥样硬化等多种心血管疾病具有较好的预防和治疗作用，对病毒性心肌炎的炎症反应也是抑制作用。
但是，目前没有关于将硫辛酸用于治疗脓毒症和/或脓毒性休克的报道。
发明内容
有鉴于此，本发明的目的在于提供硫辛酸在制备治疗脓毒症和/或脓毒性休克的药物中的应用。
本发明提供了硫辛酸在制备治疗脓毒症和/或脓毒性休克的药物中的应用。
优选的，所述药物的剂型包括注射剂。
优选的，所述硫辛酸包括硫辛酸注射液。
优选的，所述硫辛酸注射液购自于亚宝药业集团股份有限公司。
优选的，所述药物中硫辛酸注射液的浓度为300mg/12mL。
优选的，所述药物中硫辛酸注射液的浓度为12mg/5mL。
优选的，所述药物还包括药学上可接受的辅料；所述辅料包括生理盐水。
优选的，所述硫辛酸为所述药物中的唯一活性成分。
优选的，所述药物包括成人用药。
本发明提供了硫辛酸在制备治疗脓毒症和/或脓毒性休克的药物中的应用。氧化应激是Sepsis发病的重要机制，抑制氧化应激可有效改善脓毒症动物模型和脓毒症患者临床试验中的氧化应激。硫辛酸及其代谢产物是体内天然的生物抗氧化剂，通过捕捉体内自由基抑制体内过度的炎症，进而保护器官功能，降低Sepsis病死率，改善患者预后。
具体实施方式
本发明提供了硫辛酸在制备治疗脓毒症和/或脓毒性休克的药物中的应用。
在本发明中，所述药物的剂型优选的包括注射剂。
在本发明中，所述硫辛酸优选的包括硫辛酸注射液。在本发明中，所述硫辛酸注射液优选的购自于亚宝药业集团股份有限公司，300mg/支，有效成分为硫辛酸300mg，每支12mL。
在本发明中，所述药物优选的还包括药学上可接受的辅料。在本发明中，所述辅料优选的包括生理盐水。
在本发明中，所述硫辛酸优选为所述药物中的唯一活性成分。
在本发明中，所述药物优选的包括成人用药。
在本发明中，所述药物优选的采用以下方法制备：将硫辛酸注射液和生理盐水混合。
在本发明中，所述药物的使用方法优选为静脉滴注，优选的是将硫辛酸注射液，加入到生理盐水中，用铝铂纸包裹避光，静脉滴注；所述静脉滴注的时间优选为30min，所述静脉滴注的频率为每天1次，每次静脉滴注硫辛酸注射液的剂量优选为600mg、生理盐水的用量优选为250mL；所述药物的使用时间优选为7d。
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。
实施例1
1.样本量估计
本研究以28天全因病死率为主要疗效指标，通过大型ICU流行病学调查，对照组28天全因病死率为38.2％，硫辛酸注射液治疗组相对对照组的相对风险降低值(Relativerisk reduction，RRR)约为0.33，预计治疗组28天全因病死率为22.9％，采用单侧检验，α＝0.025，β＝0.2(功效＝80％)，界值Δ＝0，采用优效检验(低优)，治疗组与对照组按1：1比例分配病例，每组样本量为160例，考虑脱落因素，增加约10％的样本量，即治疗组和对照组各176例，共352例。
2.病例分组
本研究计划入组受试者352例。受试者来源于申报单位和合作单位ICU病房，并且按照Sepsis-3标准已被确诊为脓毒症患者，进入筛选。符合入组标准的受试者将按1:1随机分配至硫辛酸组和安慰剂组，并进行相应的治疗和访视观察。硫辛酸组使用硫辛酸注射液治疗。
安慰剂组：予以常规方案治疗同时给予安慰剂，占比入组总人数的1/2；硫辛酸组：在常规治疗联合硫辛酸治疗，占比入组总人数的1/2。
3.随机化
为尽量减少各个医院之间在患者来源方面的差异，研究中心进行计算机生成的区组随机化(区组大小＝8)。在完成所有数据分析前，不将随机化方法和区组大小揭盲。入选患者的临床医师不参与收集数据。入选的患者被随机化中心通过电话验证按照1:1的比例随机分配到每家医院，每个区组中有4名患者接受药物治疗(硫辛酸组)，另外4名患者作为对照(安慰剂组)。向研究者隐藏患者分配顺序。为防止提前知晓治疗分配和破坏分配顺序，在揭开唯一的参与号码与分配组别前，填写病例报告表(CRF)中的试验输入表，并签署知情同意书，此后不得更改和删除此唯一号码。
4.研究中心
初定为9家中心，分别是茂名市人民医院、广东省人民医院、广东医科大学附属医院、广州医科大学附属第二医院、湛江中心人民医院、惠州市中心医院、中山小榄人民医院、惠州市第三人民医院、云浮市人民医院。
5.研究药物
硫辛酸注射液(亚宝药业集团股份有限公司)600mg，加入到生理盐水250ml，用铝铂纸包裹避光，静脉滴注，时间约30min，每天1次，使用7天。
治疗期
两组均依据美国重症医学会(SCCM)/欧洲危重病医学会(ESICM)制定的Sepsis-3的脓毒症指南常规治疗。研究对象被分入安慰剂组或硫辛酸组按相应治疗方案治疗。其中安慰剂组：予以安慰剂生理盐水250ml，用铝铂纸包裹避光，静脉滴注，时间约30分钟；硫辛酸组，在常规治疗的基础上应用硫辛酸注射液治疗硫辛酸注射液(亚宝药业集团股份有限公司)600mg，加入到生理盐水250ml，用铝铂纸包裹避光，静脉滴注，时间约30分钟。
目前已入组硫辛酸组11人，对照组10人，初步试验结果参见表1，表1的结果显示硫辛酸组患者炎症水平、死亡率、急性肾功能损害发生率较安慰组有下降趋势。
表1硫辛酸注射液组和对照组结局
尽管上述实施例对本发明做出了详尽的描述，但它仅仅是本发明一部分实施例而不是全部实施例，人们还可以根据本实施例在不经创造性前提下获得其他实施例，这些实施例都属于本发明保护范围。
Claims (8)
1.硫辛酸在制备治疗脓毒症和/或脓毒性休克的药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述药物的剂型包括注射剂。
3.根据权利要求2所述的应用，其特征在于，所述硫辛酸包括硫辛酸注射液。
4.根据权利要求3所述的应用，其特征在于，所述硫辛酸注射液购自于亚宝药业集团股份有限公司。
5.根据权利要求3或4所述的应用，其特征在于，所述药物中硫辛酸注射液的浓度为300mg/12mL。
6.根据权利要求1～4中任意一项所述的应用，其特征在于，所述药物还包括药学上可接受的辅料；所述辅料包括生理盐水。
7.根据权利要求1～4中任意一项所述的应用，其特征在于，所述硫辛酸为所述药物中的唯一活性成分。
8.根据权利要求1～4中任意一项所述的应用，其特征在于，所述药物包括成人用药。
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| CN1207683A (zh) * | 1995-12-14 | 1999-02-10 | M·B·巴拉佐夫斯基 | 细胞因子和造血因子内源性产生的增强剂及其使用方法 |
| CN1802102A (zh) * | 2003-02-05 | 2006-07-12 | 努特里奇亚有限公司 | 用于预防和/或治疗脓毒症的肠内组合物 |
| CN1882348A (zh) * | 2003-09-19 | 2006-12-20 | 努特里奇亚有限公司 | 碳水化合物组合物及其在制备用于治疗或预防肺部炎症或急性呼吸窘迫综合征的药物中的应用 |
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| CN1207683A (zh) * | 1995-12-14 | 1999-02-10 | M·B·巴拉佐夫斯基 | 细胞因子和造血因子内源性产生的增强剂及其使用方法 |
| US6165979A (en) * | 1995-12-14 | 2000-12-26 | Novelos Therapeutics, Inc. | Cytokine and hemopoietic factor endogenous production enhancer and methods of use thereof |
| CN1802102A (zh) * | 2003-02-05 | 2006-07-12 | 努特里奇亚有限公司 | 用于预防和/或治疗脓毒症的肠内组合物 |
| CN1882348A (zh) * | 2003-09-19 | 2006-12-20 | 努特里奇亚有限公司 | 碳水化合物组合物及其在制备用于治疗或预防肺部炎症或急性呼吸窘迫综合征的药物中的应用 |
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