CN103599102B - Nitrosporeusines A在治疗急性肾衰药物中的应用 - Google Patents
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Abstract
本发明涉及Nitrosporeusines A的新医药用途，即Nitrosporeusines A在制备治疗急性肾衰药物中的应用，在制备抗急性肾衰药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于急性肾衰抑制活性强，具备突出的实质性特点，同时用于抗急性肾衰显然具有显著的进步。
Description
技术领域
本发明涉及化合物Nitrosporeusines A的新用途，尤其涉及Nitrosporeusines A在制备治疗急性肾衰药物中的应用。
背景技术
急性肾功能衰竭（Acute Renal Failure，ARF）是由多种原因引起的临床综合征，可见于临床各科病人，发病率高且往往带来严重后果，其特点为短期内（数小时至数天）神功能急剧下降，临床表现为急性少尿（尿量<400mLPd）或无尿（尿量<100mLPd），体内氮质代谢产物排出产生障碍，迅速出现氮质血症，水及电解质、酸碱平衡紊乱，并引起全身各系统相应功能失调。引起急性肾衰的主要因素是肾血流量的急剧减少，以及由于肾组织缺血引起的氧化应激和细胞损伤，最终导致肾脏组织结构的破坏和功能的恶化。目前临床上尚无公认的治疗急性肾衰有效的药物，仅能通过纠正水电解质平衡，纠正酸中毒等对症治疗措施改善症状，后期还需要通过血液透析维持机体机能。在改善肾脏血流灌注障碍和减轻肾组织损伤方面有明显疗效的临床药物少见。
本发明涉及的化合物Nitrosporeusines A是一个2013年发表（Aigang Yang，et al.,Nitrosporeusines A and B,Unprecedented Thioester-Bearing Alkaloids from the Arctic Streptomyces nitrosporeus.Organic Letters，2013，15(20):5366–5369.）的新化合物，该化合物拥有全新的骨架类型，发现其能抗H1N1（Aigang Yang，et al.,Nitrosporeusines A and B,Unprecedented Thioester-Bearing Alkaloids from the Arctic Streptomyces nitrosporeus.Organic Letters，2013，15(20):5366–5369.），本发明涉及的Nitrosporeusines A在制备治疗急性肾衰药物中的用途属于首次公开。
发明内容
本发明的目的在于根据现有Nitrosporeusines A研究中未发现其具有抗急性肾衰活性的报道的现状，提供了Nitrosporeusines A在制备抗急性肾衰药物中的应用。
通过我们的研究发现，Nitrosporeusines A能够改善急性肾衰时的无尿或少尿症状，保护肾脏的功能。
所述化合物Nitrosporeusines A,结构如式（Ⅰ）所示：
式（Ⅰ）
本发明涉及的Nitrosporeusines A在制备抗急性肾衰药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于急性肾衰抑制活性强，具备突出的实质性特点，同时用于抗急性肾衰显然具有显著的进步。
具体实施方式
以下通过实施例对本发明作进一步详细的说明，但本发明的保护范围不受具体实施例的任何限制，而是由权利要求加以限定。
本发明所涉及化合物Nitrosporeusines A的制备方法参见文献（Aigang Yang，et al.,Nitrosporeusines A and B,Unprecedented Thioester-Bearing Alkaloids from the Arctic Streptomyces nitrosporeus.Organic Letters，2013，15(20):5366–5369.），按照上述方法制备化合物Nitrosporeusines A。
实施例1：本发明所涉及化合物Nitrosporeusines A片剂的制备：
取5克化合物Nitrosporeusines A,加入糊精195克，混匀，常规压片制成1000片。
实施例2：本发明所涉及化合物Nitrosporeusines A胶囊剂的制备：
取5克化合物Nitrosporeusines A，加入淀粉195克，混匀，装胶囊制成1000粒。
下面通过药效学实验来进一步说明其药物活性。
实验例1：Nitrosporeusines A对急性肾衰大鼠的治疗作用
（一）实验方法：采用肌肉注射甘油致急性肾功能衰竭大鼠动物模型。选用180～220g健康雄性SD大鼠60只，南京医科大学实验动物中心，随机分为5组：假手术组（肌肉注射生理盐水）；模型组（肌肉注射甘油）；Nitrosporeusines AⅠ组（0.3mg/Kg））；Nitrosporeusines A Ⅱ组（0.6mg/Kg））；Nitrosporeusines AⅢ组（1.2mg/Kg）），各组大鼠在甘油造模后立即尾静脉注射生理盐水或Nitrosporeusines A，12和24小时后再给药一次。
（二）观察指标：60只大鼠末次给予Nitrosporeusines A或生理盐水后放入代谢笼收集24小时尿，留尿后6小时用4%水合氯醛腹腔注射麻醉，采用激光多普勒血流仪测定造模后及治疗后双侧肾脏血流量，取平均值作为单只动物肾血流量；取血制备血清，测定血BUN和 Cre；取肾脏，制备10%肾皮质匀浆，测定肾皮质匀浆MDA、GSH、NO（均按试剂盒说明书操作）。
（三）实验结果
1.Nitrosporeusines A可增加急性肾衰小鼠肾血流量
表1Nitrosporeusines A对急性肾衰小鼠肾血流量的影响
*P<0.05与急性肾衰模型组对比
2.Nitrosporeusines A对急性肾衰小鼠肾功能具保护作用
模型组大鼠较假手术组大鼠24小时尿量显著减少，分别为4.57±0.74ml和11.82±2.36ml；中、高剂量Nitrosporeusines A组24小时尿量显著高于模型组（P<0.05），三个药物治疗组的尿量具有剂量依赖性，分别为Ⅰ组5.48±0.87ml，Ⅱ组7.82±1.32ml，Ⅲ组9.68±1.50ml。说明Nitrosporeusines A能改善急性肾衰大鼠的少尿症状。急性肾衰大鼠静脉注射生理盐水24小时后，血清BUN为25.53±1.62mmol/L，Cre为168.56±13.01umol/L，明显高于假手术组，说明模型组动物肾功能损害严重。中、高剂量Nitrosporeusines A能剂量依赖性地改善急性肾衰大鼠的肾功能（P<0.05）。见表2。
表2各试验组大鼠肾功能指标比较
*P<0.05与急性肾衰模型组对比
结论：Nitrosporeusines A能够改善急性肾衰时的无尿或少尿症状，保护肾脏的功能,可以用来制备抗急性肾衰药物。
Claims (1)
1.Nitrosporeusines A在制备治疗急性肾衰药物中的应用，所述化合物Nitrosporeusines A结构如式(Ⅰ)所示：
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