CN111995610A - 一种尿石素类化合物用于治疗胶质母细胞瘤药物的应用 - Google Patents
一种尿石素类化合物用于治疗胶质母细胞瘤药物的应用 Download PDFInfo
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Abstract
本发明涉及一种尿石素类化合物,其具有如右的结构。所述化合物在体外显示了很强的抗胶质母细胞瘤活性,可配合药用载体,用于制备治疗抗胶质母细胞瘤的各种药物剂型,如胶囊剂、颗粒剂、口服液或者片剂。
Description
技术领域
本发明涉及医药领域,特别是涉及具有抗胶质母细胞瘤作用的一种尿石素类化合物。
背景技术
胶质瘤是中枢神经***最常见的侵袭性肿瘤。胶质母细胞瘤(GBM),也被称为多形性胶质母细胞瘤,是世界卫生组织(WHO)分类的四级胶质瘤,占脑肿瘤的15%,是恶性程度高和高复发的脑肿瘤。胶质母细胞瘤可以从正常细胞发展而来,或者从现有的低级别星形胶质瘤发展而来,中位生存时间为14.6个月。通常情况下,胶质瘤治疗包括手术,手术后使用化疗和放疗,替莫唑胺是目前治疗胶质母细胞瘤的一线化疗药物。然而,只有不到3%-5%的人可以活过5年,目前仍旧缺乏有效的手段来治疗胶质母细胞瘤。因此,寻找治疗胶质母细胞瘤的新药显得尤为迫切。
我们的研究揭示了尿石素类化合物口服制剂具有很强的抗胶质母细胞瘤的作用,可以作为一种治疗胶质母细胞瘤的潜在药物。
发明内容
本发明的目的是提供所述一种尿石素类化合物口服制剂在制备治疗胶质母细胞瘤药物中的应用。
所述尿石素类化合物具有图1所示的结构。
本发明是关于尿石素类化合物尿石素B药物在治疗胶质母细胞瘤中的用途。所述药物是指上述化合物配以医药上可接受的赋形剂,制备的胶囊剂、颗粒剂、口服液或者片剂。
本发明的另一所涉及的尿石素类化合物口服制剂治疗胶质母细胞瘤优于其他制剂。
附图说明
图1 尿石素B结构。
图2 口服尿石素B对胶质母细胞瘤抑制作用。分别在给药0天,7天,14天时生理盐水组(NS)和尿石素B组(UB)的MRI图。
图3 腹腔给药尿石素B对胶质母细胞瘤抑制作用的统计图。分为两组,生理盐水组, 尿石素B组。*p<0.05,表明与生理盐水组比有差异,数据均经单因素方差分析。
图4 口服尿石素B对胶质母细胞瘤抑制作用的统计图。分为两组,生理盐水组, 尿石
素B组。*p<0.05,表明与生理盐水组比有差异,数据均经单因素方差分析。
具体实施方式
实施例1:化合物尿石素类化合物的制备:取鞣花单宁100克,加入1000毫升水室温电动搅拌30天,将提取液离心,离心条件:15000 rpm,10 min,获得尿石素类化合物。
质谱引导的制备液相色谱分离尿石素类化合物,由UPLC谱图可得到正离子模式下的主要的正离子,将要检测的MSD值输入工作站:930,干燥气流速12 L/min,干燥气温度350℃,雾化气压力350 psig,毛细管电压3000 V。平衡:以A相50%,B相50%的比例平衡制备柱,时间约15 min。进样量设置为4.5 mL,通过手动接样收集目标流分,目标流分进入流分收集器。减压真空干燥得到化合物尿石素类化合物。
实施例2:尿石素B的抗原位胶质母细胞瘤作用
小鼠采用C6细胞造模后,第7天用小动物核磁扫描***对小鼠脑部的T2相进行扫描,大部分小鼠左侧尾状核部有异常生物生成,内部有液化现象,周围有水肿,且边界清楚。对核磁图进行筛选,得到12只有肿瘤生长并大小接近的鼠,记录好他们的初始瘤大小,并做好标记。这12只ICR模型鼠中,6只作为阴性对照组,每天灌胃生理盐水0.2 mL,6只作为尿石素B灌胃给药组,给药剂量根据参考文献为40 mg/kg进行实验。给药14天,每隔7天做一次核磁扫描并记录瘤大小。对照组小鼠0-5天时状态良好,无明显活动异常。5天后对照组小鼠有明显的活动减少,体重下降,10天后,对照组有小鼠出现肢体不协调现象。给药组小鼠与对照组小鼠相比,初期出现了食欲不振,之后状态有好转,无肢体不协调及明显的体重下降。直到实验结束未观察到小鼠死亡。
瘤体积的计算公式V=长×宽×(层数-1)×0.5/2 ,0.5是层厚,单位是mm。
抑瘤率%=(1-给药组平均瘤重/阴性对照组平均瘤重)×100%
根据测得的核磁扫描图计算瘤体积大小,并用Graphpad Prism 7进行单因素方差分析,并作图,横坐标为分组,纵坐标为给药前后瘤体积的变化。
实验结果表明尿石素B在腹腔注射和口服给药途径下都对脑胶质瘤具有抑制作用,抑瘤率分别达到了46.91% (见图2,图3)和67.45%(见图4)。而尿石素B口服给药的抑瘤效果优于腹腔给药,且给药后对小鼠的生长状态没有明显的影响,进一步确定了尿石素B的给药方式为口服给药。
实施例3:胶囊剂的制备
取实施例1所得的化合物尿石素类化合物毫克和微粉硅胶280毫克,混匀后过筛,加入适量的硬脂酸镁,混匀,用干法造粒机制粒,过筛,筛取40—80目之间的颗粒,装入胶囊,每粒装0.3克。
实施例4:片剂的制备
取实施例1所得的化合物尿石素类化合物 10克、微粉硅胶42克、无水乳糖38克、氧化硅3克,混合30分钟后,再筛入20克硬脂酸镁,继续混匀,最后用12/32
英寸。
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CN113730583A (zh) * | 2021-08-27 | 2021-12-03 | 武汉大学 | 脂滴作为神经退行性疾病药物靶点的用途 |
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