CN110575451A - 四乙酰灯盏乙素苷元在治疗和预防脓毒症药物中的应用 - Google Patents
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Abstract
本发明公开了四乙酰灯盏乙素苷元(I)在治疗和预防脓毒症药物中的应用。通过实验证明，四乙酰灯盏乙素苷元对脓毒症模型小鼠的生存保护作用，能降低脓毒症模型小鼠血清IL‑1β和IL‑6水平。四乙酰灯盏乙素苷元可能通过调节IL‑1β及IL‑6的表达抑制炎症而发挥对脓毒症的保护作用。四乙酰灯盏乙素苷元具有治疗和预防脓毒症药物应用前景。
Description
技术领域
本发明属于医药技术领域，具体涉及四乙酰灯盏乙素苷元在治疗和预防脓毒症药物中的应用。
背景技术
脓毒症是指由感染诱发的全身炎症反应，可以导致休克、多器官功能障碍综合征(MODS)，甚至死亡。全球估计有1800万例，其发生率为：3/1000，并以每年1.5%的速度增加。脓毒症患者总体医院病死率为28.6%，而严重脓毒症和脓毒症休克患者病死率分别为25%-30%和40%-70%，全球每天死亡1400万人。脓毒症患者治疗耗资巨大，占ICU消费的40%。目前脓毒症已成为非心脏重症监护病房的患者死亡的主要原因。
本病可归属于中医学伤寒、温病的范畴，其发病机制为病原微生物活化的巨噬细胞、中性粒细胞和内皮细胞等释放大量的炎性介质、超氧阴离子等，引起内皮细胞损伤、凝血功能紊乱等，造成微循环的障碍，并最终导致多器官功能不全。促炎和抗炎、致病和兔疫、失衡和代偿等贯穿于整个发病过程。传统西药的单靶点治疗太过局限，中医学在治疗脓毒症方面积累了丰富的经验，活血化淤、凉血化淤等药物被广泛应用于临床，该类药物可畅通络中气血、减少毒邪的蕴积、改善各脏腑的温煦濡养对防治脓毒症具有极其重要的意义。因此，在中医药的基础上开发预防和治疗脓毒症的药物具有应用前景。
灯盏花是菊科植物短葶飞蓬[Erigeron breviscapus (Vant.) Hand.-mazz]的干燥全草，又名灯盏细辛、东菊，主要分布于我国西南地区，尤以云南较多。首载于《滇南本草》，《中国药典》1977年版一部曾予收载。灯盏花性寒、微苦、甘温辛，具有微寒解毒、祛风除湿、活血化瘀、通经活络、消炎止痛的功效，其中灯盏乙素是其主要药效成分。灯盏乙素具有扩张血管、降低血液黏滞度、改善微循环、防治血栓形成的作用。研究发现其对大鼠胰腺、心肌、脑组织等缺血再灌注损伤有保护作，对LPS所致脓毒症模型大鼠有一定的保护作用。
灯盏花素水溶性差，水中溶解度仅为0.16 mg/mL，脂溶性差，pH 4.2的PBS中logP为- 2.56，Beagle犬口服绝对生物利用度仅（0.40±0.19）%，而家犬静注消除半衰期短仅为（52±29）min，其理化性质和体内行为限制了其临床应用。目前上市的有普通片剂、颗粒剂、注射剂、注射粉针剂等，因此开发灯盏花素新剂型，提高其口服生物利用度或延长其体内半衰期，有着巨大的市场价值。近几年来，灯盏花素新剂型的研制越趋越热，已公开的发明专利多达59项，涉及注射剂、脂质体、磷脂复合物、口腔速崩片、舌下片、缓释微丸、渗透泵控释制剂、环糊精包合物、滴丸、自乳化剂等。此外，对灯盏乙素进行化学结构修饰以改善其理化性质，从而提高其生物利用度。我们在对灯盏乙素进行结构修饰过程中，意外发现其中四乙酰灯盏乙素苷元对脓毒症具有良好的治疗效果。
发明内容
本发明的目的在于提供四乙酰灯盏乙素苷元(I)在治疗和预防脓毒症药物中的应用。
本发明的目的是这样实现的：
四乙酰灯盏乙素苷元(I)在治疗和预防脓毒症药物中的应用。
脓毒症是指脓毒症及其相关疾病，如急性肺损伤、急性肝损伤、急性肾损伤、内毒素血症和脓毒症休克等。
一种治疗和预防脓毒症药物，包括四乙酰灯盏乙素苷元(I)。
剂型为口服剂型或静脉注射剂。
本发明优点：
1、本发明提供实验研究证明了四乙酰灯盏乙素苷元(I)能降低脓毒症模型小鼠的死亡率，具有较强的生存保护作用；
2、本发明提供了四乙酰灯盏乙素苷元(I)的应用，即四乙酰灯盏乙素苷元(I)在制备治疗脓毒症药物上的应用，并且四乙酰灯盏乙素苷元能降低脓毒症模型小鼠体内的炎性因子水平。
附图说明
图1为本发明四乙酰灯盏乙素苷元(I)的化学结构式；
图2为CLP模型结扎部位及示意图；
图3为四乙酰灯盏乙素对脓毒症小鼠的生存保护作用；
图4为四乙酰灯盏乙素苷元对脓毒症小鼠的血清IL-1β水平的影响；
图5为四乙酰灯盏乙素苷元对脓毒症小鼠的血清IL-6水平的影响。
具体实施方式
下面对本发明作进一步的说明，但不以任何方式对本发明加以限制，基于本发明所作的任何变换，均属于本发明的保护范围。
四乙酰灯盏乙素苷元(I)在制备治疗和预防脓毒症药物中的应用。
脓毒症是指脓毒症及其相关疾病，如急性肺损伤、急性肝损伤、急性肾损伤、内毒素血症和脓毒症休克等。
一种治疗和预防脓毒症药物，包含四乙酰灯盏乙素苷元(I)。
剂型为口服剂型或静脉注射剂。
实施例1：
四乙酰灯盏乙素苷元对脓毒症模型小鼠的生存保护作用
1. 实验动物
SPF级ICR小鼠，全雄，体重18～22g，分组时体重差异不超过平均体重的10%。饲养于IVC动物实验室，温度20～25℃（日温差≤3℃），湿度40%～70%，照明12h:12h明暗交替，照度150～300lx，噪音≤60dB。
2. 实验材料
器械：镊子、剪刀、持针器、4号线，针，5ml及1ml注射器，穿刺针（21g）；
试剂：碘、75%酒精棉球、4%水合氯醛、生理盐水。
3. 分组、脓毒症小鼠模型复制、给药及指标测定
适应性饲养5d后，将ICR小鼠随机分为4组，分别为假手术组（6只）、模型组（12只）、地塞米松2mg/kg组(6只)、四乙酰灯盏乙素苷元100mg/kg组(6只)，于造模1h后给药一次，参照文献[Daniel Rittirsch, Markus S Huber-Lang, Michael A Flierl, Peter A Ward.Immunodesign of experimental sepsis by cecal ligation and puncture[J]. NATUREPROTOCOLS, 2009, 4(1):31-36.]中的方法，每鼠腹腔注射4%的水合氯醛麻醉，注射体积为10ml/kg（或者2%水合氯醛 20ml/kg）麻醉。麻醉后背位固定小鼠，电动剃须刀将其腹部备皮并依次用碘酒和酒精消毒。于腹中线处剖开腹腔，创口长度约为1cm，钝性分离肌肉，找出盲肠，游离盲肠及部分肠系膜，4号丝线在距盲肠盲端2/3长度处环行结扎（图2中虚线位置）（盲肠穿孔之前，轻轻推盲肠内容向着远侧盲肠），21g号针在结扎部位中部处贯通穿刺（穿刺方向为从肠系膜到系膜；穿刺时，轻轻吸任何截留的空气或气体，图2中箭头指向）。挤出粪便少许，将肠系膜和盲肠回纳入腹腔，逐层缝合关腹。术后立即皮下注射37℃生理盐水5ml/100g（补充术中液体丢失）和0.05mg/kg丁基原啡因（用于术后镇痛，每6h一次，持续2天）；同时每只小鼠肌注青霉素2*104U以预防切口感染。空白组不进行任何处理；假手术组不进行盲肠部位的结扎和穿孔，其余操作等同模型组。
除空白对照组、假手术组及模型组给予等量溶媒外，其余各组按照表1中给药剂量和方式给予相应浓度的药物。连续给药7天，每天观察动物一般情况，并记录其存活只数。
4. 统计学分析
计量资料以平均数±标准差（X±SD）表示，差异显著性检验若方差齐则采用SNK检验，方差不齐采用Kruskal-Wallis检验；若差异具有统计学意义（P<0.05）则进行组间比较，方差齐时组间比较采用LSD检验，方差不齐时组间比较采用Tamhane’s T2检验。
5. 实验结果
与假手术组相比，模型动物在手术第一天大批死亡，在第四天死亡率为100%；四乙酰灯盏乙素苷元能延长模型小鼠的生存时间、降低其死亡率，具体结果见图3。可见四乙酰灯盏乙素苷元对脓毒症小鼠具有生存保护作用。
6 .结论
本发明提供的四乙酰灯盏乙素苷元，能提高脓毒症模型小鼠生存率，表现出一定的生存保护作用。
实施例2：
四乙酰灯盏乙素苷元对脓毒症模型小鼠炎性因子的影响
实验动物、实验材料和统计学分析与实施例1相同。
1. 分组、脓毒症小鼠模型复制、给药及指标测定
适应性饲养5d后，将ICR小鼠随机分为5组，分别为假手术组（6只）、模型组（12只）、地塞米松2mg/kg组(6只)、四乙酰灯盏乙素苷元50mg/kg组(6只)、四乙酰灯盏乙素苷元100mg/kg组(6只)，于造模1h后给药一次，造模操作同2.1.4项；假手术组不进行盲肠部位的结扎和穿孔，其余操作等同模型组。
除假手术组及模型组给予等量溶媒外，其余各组灌胃给予相应浓度的药物。连续给药7天，末次给药后1h，内眦取血，常温放置30min后，3500rpm离心10min分离血清，采用酶联免疫吸附法（Elisa）法测定血清中IL-1β和IL-6的水平。
2. 四乙酰灯盏乙素苷元对脓毒症小鼠体内炎性因子含量的影响
与假手术组相比，模型动物血清IL-1β和IL-6水平均升高，差异有统计学意义（p<0.05）；四乙酰灯盏乙素苷元连续给药7d，能不同程度降低脓毒症模型小鼠血清IL-1β和IL-6水平，结果见图4和图5。
3. 结论
本发明提供的四乙酰灯盏乙素苷元，能降低脓毒症模型小鼠血清IL-1β和IL-6水平，具有治疗脓毒症的作用。四乙酰灯盏乙素苷元可能通过调节IL-1β及IL-6的表达抑制炎症而发挥对脓毒症的保护作用。
Claims (4)
1.四乙酰灯盏乙素苷元(I)在制备治疗和预防脓毒症药物中的应用
。
2.根据权利要求1所述应用，其特征在于，脓毒症是指脓毒症及其相关疾病，如急性肺损伤、急性肝损伤、急性肾损伤、内毒素血症和脓毒症休克等。
3.一种治疗和预防脓毒症药物，其特征在于包括权利要求1所述的四乙酰灯盏乙素苷元(I)。
4.根据权利要求3所述的药物，其特征在于，剂型为口服剂型或静脉注射剂。
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