CN118236380A - 盐酸布那唑嗪在防治肠缺血再灌注损伤中的应用 - Google Patents
盐酸布那唑嗪在防治肠缺血再灌注损伤中的应用 Download PDFInfo
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Abstract
本发明属于生物技术领域,具体涉及盐酸布那唑嗪在防治肠缺血再灌注损伤中的应用。所述盐酸布那唑嗪为盐酸布那唑嗪溶液;所述盐酸布那唑嗪通过减轻肠缺血再灌注损伤、抑制肠外脏器的损伤、增加模型动物的生存时间、抑制缺血再灌注诱导的氧化应激、凋亡和促进上皮细胞增殖的方式防治肠缺血再灌注损伤。发明人经实验证实,布那唑嗪可有效减轻肠缺血再灌注损伤,同时抑制肠外脏器的损伤,明显增加模型动物的生存时间,抑制缺血再灌注诱导的氧化应激、凋亡和促进上皮细胞增殖的能力,为治疗肠缺血再灌注损伤的新药筛选提供了基础。
Description
技术领域
本发明属于生物技术领域,具体涉及盐酸布那唑嗪在防治肠缺血再灌注损伤中的应用。
背景技术
肠缺血再灌注损伤(Ischemia/Reperfusion,I/R)是一种在多种临床情况如创伤、休克、感染、肠梗阻和体外循环中常见的状况。尽管急性肠缺血在及早治疗下可逆,但血流再灌注会进一步加重肠组织损伤。不仅如此,肠组织损伤会导致肠屏障通透性增加,大量的细菌、内毒素、炎症因子等释放入血,导致肠外器官的损伤甚至衰竭。
在缺血期间,肠组织因缺乏氧和营养而开始受损。细胞的线粒体功能障碍,导致细胞能量减少,从而影响细胞稳态。此外,缺血还会导致细胞内钙浓度升高、酸中毒、自由基生成增加以及炎性介质的释放。尽管缺血本身会导致细胞损伤,但真正的伤害往往发生在血流恢复时,即再灌注阶段。当血流恢复时,大量的反应性氧和氮种类产生,引发氧化应激,从而损伤细胞结构和功能。此外,激活的中性粒细胞会聚集到缺血组织,释放炎性因子和蛋白酶,进一步加重组织损伤。这种反应性氧和氮种类的产生与中性粒细胞的活化共同导致血管通透性增加,形成水肿。再灌注损伤也影响肠黏膜屏障,可能导致细菌和毒素渗入循环,引发全身性感染或多器官功能衰竭。因此,研究肠I/R损伤的机制并寻找可能的治疗策略至关重要。
为了研究肠I/R损伤的机制,科学家们开发了多种动物模型。最常见的方法是通过夹闭肠系膜上动脉或其分支来诱导缺血,随后放开动脉夹来恢复血流。通过这种方法,可以模拟人体中的肠缺血和再灌注过程。在治疗上,科研人员已经探索了多种潜在的策略,如自由基清除剂、抗炎药、钙通道拮抗剂和线粒体保护剂等。其中,一些已经在实验动物中显示出对肠I/R损伤有保护作用。当前,由于临床表现的模糊性和缺乏早期特异性的生物标志物,对肠I/R损伤的早期诊断仍然具有挑战性。虽然如肠脂肪酸结合蛋白(I-FABP)和平滑肌蛋白(SM22)被认为是检测肠损伤的标志物,但它们在特异性和灵敏度上仍存在限制。因此,寻找更为特异和敏感的肠损伤标志物变得至关重要。
总的来说,肠缺血再灌注损伤是一个复杂的疾病,涉及多种细胞和分子的相互作用,理解其机制并找到有效的治疗策略是当前研究的焦点。
发明内容
本发明的目的在于提供一种盐酸布那唑嗪在防治肠缺血再灌注损伤中的应用,有效改善肠缺血再灌注损伤指标,提升预后。
本发明的目的是通过如下技术方案实现的:
本发明提供了一种盐酸布那唑嗪在防治肠缺血再灌注损伤中的应用。
进一步的,所述盐酸布那唑嗪为盐酸布那唑嗪溶液。
进一步的,所述盐酸布那唑嗪通过减轻肠缺血再灌注损伤、抑制肠外脏器的损伤、增加模型动物的生存时间、抑制缺血再灌注诱导的氧化应激、凋亡和促进上皮细胞增殖的方式防治肠缺血再灌注损伤。
本发明还提供了一种盐酸布那唑嗪在制备防治肠缺血再灌注损伤的药物中的应用。
进一步的,所述盐酸布那唑嗪可加入药学可接受的辅料制备成包括注射剂、胶囊剂、片剂、颗粒剂、混悬剂、乳剂、喷雾剂、散剂、脂质体、口服液、滴丸在内的任一剂型。
进一步的,所述药物的给药方式包括肌肉注射、皮下注射、静脉注射、口服给药、舌下含服、病灶内或脑内或植入的递送、喷雾给药中的一种或几种。
本发明的有益效果是:发明人经实验证实,布那唑嗪可有效减轻肠缺血再灌注损伤,同时抑制肠外脏器的损伤,明显增加模型动物的生存时间,抑制缺血再灌注诱导的氧化应激、凋亡和促进上皮细胞增殖的能力,为治疗肠缺血再灌注损伤的新药筛选提供了基础。
附图说明
图1为实施例1中在体实验验证盐酸布那唑嗪防治肠缺血再灌注损伤的实验结果图,其中图A为不同模型小鼠中小肠损伤的HE病理评分;图B为不同模型小鼠的生存率;图C为不同模型小鼠血浆中的内毒素水平。
具体实施方式
本发明中所采用的盐酸布那唑嗪的具体产品信息如下:
产品名称:盐酸布那唑嗪
分子式:C19H28ClN5O3
分子量:409.91
本剂为缓释剂型。制剂特点:药片由多个盐酸布那唑嗪的可持续释放颗粒与赋形剂压制而成。每个颗粒都裹有疏水膜。口服后药片迅速在胃内分解,使缓释颗粒弥散开来,将活性成分缓慢持续释放到胃肠道。口服吸收良好,未发现受饮食影响。相对生物利用度81.1%。血药浓度峰值10ng/ml,有效血药浓度(4~5ng/ml)可维持12~14小时。T1/2约为12小时,主要在肝脏中代谢。
本发明中盐酸布那唑嗪的制备方法如下:
方法1:4-氨基-2-氯-6,7-二甲氧基喹唑啉和1-甲酰基高哌嗪,在丁醇中回流;生成的化合物(I)在9%盐酸中回流,得化合物(Ⅱ),收率80.4%。再和丁酰氯在丙酮中反应,得布那唑嗪。
方法2:2-氨基-4,5-二甲氧基苯腈、化合物(Ⅲ)和甲醇钠,在二甲亚砜中回流,得布那唑嗪。
其中,布那唑嗪可加入药学可接受的辅料,制成下列之一的剂型:注射剂、胶囊剂、片剂、颗粒剂、混悬剂、乳剂、喷雾剂、散剂、脂质体、口服液、滴丸,优选剂型为注射剂。
布那唑嗪的给药方式为肌肉注射、皮下注射、静脉注射、口服给药、舌下含服、病灶内或脑内或植入的递送、喷雾给药中的一种或几种,优选为口服,肌肉、皮下或静脉注射。
实施例1在体实验验证盐酸布那唑嗪溶液减轻肠缺血再灌注损伤
在动物水平上,给予盐酸布那唑嗪溶液灌胃预处理,利用C57BL/6J小鼠建立肠缺血再灌注损伤(I/R)模型,检测小鼠生存率;肠组织的HE病理损伤、肠屏障通透性、血清内毒素(LPS)水平,证实盐酸布那唑嗪溶液可以减轻肠缺血再灌注损伤(I/R)。
1.肠缺血再灌注损伤模型的建立:
为建立肠I/R模型,C57BL/6J小鼠在手术前12小时禁食,允许自由饮水。使用4%异氟烷进行全身麻醉,维持手术麻醉浓度为1.5%。在手术台上将小鼠固定于仰卧位,腹部进行剃毛并用75%乙醇消毒。通过腹部正中线开腹1-3cm,并逐层进入腹腔。继而,夹闭肠系膜上动脉阻断血流1小时。随后恢复血供并确保腹腔内无出血,逐层缝合腹腔。每次操作都伴随37℃生理盐水0.5ml皮下注射。经过2小时再灌注,取下腔静脉血和各肠段组织。假手术组(Sham)的操作与I/R组相同,但不进行动脉夹闭。
2.实验分组:
本实验采用24只6-8周大的C57BL/6J小鼠,并随机分为四组:Sham组、I/R组、Bunazosin+I/R组和Bunazosin+Sham组:
(1)Sham组:除了不进行肠系膜夹闭阻断血供和取出动脉夹再灌注操作,其余小鼠所有的操作步骤均同I/R保持一致;
(2)I/R组:对小鼠建立肠I/R模型;
(3)盐酸布那唑嗪溶液+肠缺血再灌注损伤模型组(Bunazosin+I/R):预先给小鼠灌胃10mg/kg的盐酸布那唑嗪溶液,60分钟后对小鼠建立肠I/R模型;
(4)盐酸布那唑嗪溶液+肠缺血再灌注损伤模型组(Bunazosin+I/R):预先给小鼠灌胃10mg/kg的盐酸布那唑嗪溶液,60分钟后对小鼠建立肠I/R模型。
3.检测指标与技术方法:
(1)观察并记录小鼠7天生存情况。
(2)肠组织损伤评估:a.苏木精和伊红(H&E)染色小肠段,光镜下观察小肠组织形态学变化并拍照,由对实验分组不知情的病理学专家根据肠损伤评分标准对组织损伤进行评估。b.肠屏障通透性检测:1)异硫氰酸荧光素标记的葡聚糖(FITC-dextran)检测肠道通透性:以0.6mg/kg剂量于检测前4小时灌胃处理小鼠,用酶标仪(485nm、530nm)检测外周血中FITC的含量;2)检测血浆中的内毒素(LPS)水平:根据ELISA试剂盒说明书提供的步骤检测。c.RT-PCR检测肠组织中炎症因子的mRNA表达水平。
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围。
Claims (6)
1.盐酸布那唑嗪在防治肠缺血再灌注损伤中的应用。
2.如权利要求1所述的应用,其特征在于,所述盐酸布那唑嗪为盐酸布那唑嗪溶液。
3.如权利要求1所述的应用,其特征在于,所述盐酸布那唑嗪通过减轻肠缺血再灌注损伤、抑制肠外脏器的损伤、增加模型动物的生存时间、抑制缺血再灌注诱导的氧化应激、凋亡和促进上皮细胞增殖的方式防治肠缺血再灌注损伤。
4.盐酸布那唑嗪在制备防治肠缺血再灌注损伤的药物中的应用。
5.如权利要求4所述的应用,其特征在于,所述盐酸布那唑嗪可加入药学可接受的辅料制备成包括注射剂、胶囊剂、片剂、颗粒剂、混悬剂、乳剂、喷雾剂、散剂、脂质体、口服液、滴丸在内的任一剂型。
6.如权利要求4所述的应用,其特征在于,所述药物的给药方式包括肌肉注射、皮下注射、静脉注射、口服给药、舌下含服、病灶内或脑内或植入的递送、喷雾给药中的一种或几种。
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