CN107115334A - 一种治疗免疫性流产的药物组合物 - Google Patents
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Abstract
本发明公开了一种治疗免疫性流产的药物组合物，所述药物组合物由一定量的有效药物成分以及药学上常用的载体和辅料组成，其中有效药物成分的结构为：
Description
技术领域
本发明涉及医药领域，具体的说，本发明涉及一种治疗免疫性流产的药物组合物。
背景技术
自然流产是妊娠早期常见的并发症，发生率约占全部妊娠的15-20％，威胁母婴健康和社会稳定。近年来，自然流产率在全球呈现了逐年上升的变化趋势，引起国内外学者的深切关注。由于我国目前的二孩政策，育龄夫妇的数量尤为可观，因此研发抗女性自然流产的药物对于治疗和预防免疫性自然流产来说刻不容缓。
发明内容
本发明的目的在于提供一种治疗免疫性流产的药物组合物。
为了实现本发明的目的，本发明提供一种治疗免疫性流产的药物组合物，所述药物组合物由一定量的有效药物成分以及药学上常用的载体和辅料组成。其中有效药物成分的结构为：
其中
R1独立地选自：H、烷基或卤素；
优选地，R1为F。
更优选地，所述有效药物成分的含量为18-28mg。
更优选地，所述药物组合物可以是任何一种药剂学上所说的剂型
本发明还提供化合物在制备治疗免疫性流产的药物中的用途，所述化合物具有下列结构：
其中
R1独立地选自：H、烷基或卤素；
优选地，R1为F。
从治疗效果上来看，本发明所述的治疗免疫性流产的药物组合物具有抗免疫性自然流产的作用，使用药物之后可以减少孕妇发生自然流产的可能性，是治疗免疫性流产较为满意的药物。从作用机制上来看，本发明药物对于自身免疫性流产的治疗预防具有特异性强，灵敏度高的优越性。
具体实施方式
以下通过实施例对本发明作详细的阐述，测定本发明药物对模型小鼠胎盘组织中关键分子信号转导的影响，从免疫角度揭示本发明药物的作用机制及最后的治疗效果。
实验例1本发明药物的表征
1H NMR(CDCl3,300MHz)δ4.96(s,1H),4.80(s,1H),3.67(s,3H),2.69-2.61(m,1H),2.33-2.24(m,1H),2.11-2.07(m,2H),1.99-1.95(m,2H),1.58-1.34(m,4H)。
实验例2本发明药物对于免疫性流产的治疗效果
分组、造模与给药
将60只雌性BALB/c小鼠随机为6组，每组10只，分别为空白对照组、模型组、阿司匹林组(阳性对照，20mg/mL)和本发明药物低、中、高剂量组(给药剂量分别为10、20、40mg/mL)。除空白对照组外，其余各组小鼠参照文献(Tolomeo T,Rico De Souza A,Roter E,etal.T cells demonstrate a Th1-biased response to native beta2-glycoprot ein Iin a murine model of anti-phospholipid antibody induction[J].Autoimmunity,2009,42(4)：292-295.)中方法以人β2-糖蛋白Ⅰ为免疫原建立抗磷脂抗体(APA)阳性流产小鼠模型：将β2-糖蛋白Ⅰ溶于无菌磷酸盐缓冲液(PBS)中，调整质量浓度为400μg/mL。从实验第1天开始ip人β2-糖蛋白Ⅰ与弗氏完全佐剂(CFA)体积比为1：1的混合液50μL；实验第8天以弗氏不完全佐剂(IFA)代替CFA加强免疫1次，剂量同第1次免疫。于实验第18天，各组♀小鼠与♂小鼠以2：1的比例合笼，自合笼之日起，每天早上8：00和下午14：00分别观察1次，若观察到角化细胞中夹有大量精子和/或见到阴栓则计为妊娠第0.5天。从妊娠第1天起各给药组小鼠均按0.1mL/10g ig给药，空白对照组和模型组小鼠ig等体积蒸馏水，每天1次，连续9d。在妊娠第9.5天时颈椎脱臼法处死小鼠，留取胎盘组织进行相关指标测定。
RT-PCR法测定小鼠胎盘组织Toll样受体4(TLR4)、髓样分化蛋白2(MD2)、髓样分化因子88(MyD88)、核因子(NF-κB)mRNA表达水平
采用Trizol液处理剪碎的胎盘组织并提取总RNA,根据反转录试剂盒说明书进行反转录合成cDNA，以cDNA为模版进行扩增。反应体系：Real-time PCR Master Mix混合液10μL，上、下游引物各0.4μL,cDNA模板2μL，灭菌双蒸水7.2μL，体系共20μL。在基因表达的半定量分析中，以甘油醛-3-磷酸脱氢酶(GAPDH)为内参，通过与GAPDH表达量比较实现待测基因表达量的标准化。反应条件：扩增阶段为95℃5min；95℃15s；60℃60s，共40个循环；溶解曲线阶段为95℃15s；60℃1min；95℃15s。用RT-PCR系统自带软件进行溶解曲线分析，以2-ΔΔCt法(李莎莎，张义军，李洪利，等.非小细胞癌中MTAP蛋白及基因表达水平的检测[J].中国肿瘤杂志，2011,14(2)：151-155.)计算目的基因mRNA的相对表达量。基因引物序列及产物长度见下表。
免疫组化法测定小鼠胎盘组织TLR4、MD2、MyD88、NF-κB蛋白表达水平
常规制备小鼠胎盘组织石蜡切片。常规脱蜡、脱水，PBS冲洗3次，每次3min；3％双氧水(H2O2)常温孵育15min,PBS冲洗3次，每次3min；3％牛血清白蛋白(BSA)封闭30min后加入相应一抗，湿盒4℃孵育过夜，PBS冲洗3次，每次5min；加入50μL生物素标记的二抗，室温孵育20min，PBS冲洗3次，每次5min；加辣根过氧化物酶标记的链霉素卵白素工作液，室温孵育20min后PBS冲洗3次，每次5min；加入二氨基联苯胺(DAB)显色液，室温下显色2～5min，镜下控制；苏木精复染，常规脱水、透明、封片。阳性产物均定位于细胞浆，以细胞浆着色呈棕褐色为阳性细胞。以计算机图像分析软件(IPP)分析TLR4、MD2、MyD88、NF-κB的积分光密度(IOD)值，以此反映阳性表达的强弱。
统计学方法
采用SPSS 10.0软件进行统计分析。数据以表示，组间比较采用单因素方差分析。P＜0.05表示差异有统计学意义。
各组小鼠胎盘组织TLR4、MD2、MyD88、NF-κB mRNA表达水平测定结果
与空白对照组比较，模型组小鼠胎盘组织TLR4、MD2、MyD88、NF-κB mRNA表达水平均明显升高(P＜0.01)；与模型组比较，阿司匹林组和本发明药物低剂量组小鼠胎盘组织TLR4、MD2、MyD88、NF-κB mRNA表达水平均明显降低(P＜0.01)，本发明药物中剂量组小鼠胎盘组织TLR4、MD2、MyD88mRNA表达水平降低(P＜0.05或P＜0.01)，本发明药物高剂量组上述指标差异均无统计学意义(P>0.05)；与阿司匹林组比较，本发明药物低剂量组小鼠胎盘组织TLR4、MD2、MyD88、NF-κB mRNA表达水平降低更为明显，其中TLR4、MD2mRNA表达水平差异有统计学意义(P＜0.01)，具体结果见下表。
注：与空白对照组比较，**P<0.01；与模型组比较，#P<0.05,##P<0.01；与阿司匹林组比较，ΔΔP<0.01。
各组小鼠胎盘组织TLR4、MD2、MyD88、NF-κB蛋白表达水平测定结果
与空白对照组比较，模型组小鼠胎盘组织TLR4、MD2、MyD88、NF-κB蛋白表达水平明显升高(P＜0.01)；与模型组比较，各给药组小鼠胎盘组织TLR4、MD2、MyD88、NF-κB蛋白表达水平不同程度地降低，除本发明药物高剂量组小鼠胎盘组织MD2、MyD88蛋白表达水平降低不显著外其余各组差异均有统计学意义(P＜0.05或P＜0.01)；与阿司匹林组比较，本发明药物低剂量组小鼠胎盘组织中MD2、MyD88表达水平明显降低(P＜0.05)，具体数据见下表。
注：与空白对照组比较，**P＜0.01；与模型组比较，#P<0.05,##P<0.01；与阿司匹林组比较，ΔP<0.05。
Claims (7)
1.一种治疗免疫性流产的药物组合物，其特征在于，所述药物组合物由一定量的有效药物成分以及药学上常用的载体和辅料组成。
2.根据权利要求1所述的治疗免疫性流产的药物组合物，其特征在于，所述一定量的有效药物成分的结构如下：
其中
R1独立地选自：H、烷基或卤素。
3.根据权利要求2所述的治疗免疫性流产的药物组合物，其特征在于，R1为F。
4.根据权利要求3所述的治疗免疫性流产的药物组合物，其特征在于，所述有效药物成分的含量为18-28mg。
5.根据权利要求4所述的治疗免疫性流产的药物组合物，其特征在于，所述药物组合物可以是任何一种药剂学上所说的剂型。
6.化合物在制备治疗免疫性流产的药物中的用途，其特征在于，所述化合物具有下列结构：
其中
R1独立地选自：H、烷基或卤素。
7.根据权利要求6所述的用途，其特征在于，R1为F。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030004137A1 (en) * | 1997-02-19 | 2003-01-02 | Berlex Laboratories, Inc. | N-heterocyclic derivatives as NOS inhibitors |
| JP2014227401A (ja) * | 2013-05-24 | 2014-12-08 | 大日本住友製薬株式会社 | フェニルアラニン誘導体 |
| CN104640843A (zh) * | 2012-07-19 | 2015-05-20 | 大日本住友制药株式会社 | 1-(环烷基羰基)脯氨酸衍生物 |
| CN106103453A (zh) * | 2014-01-14 | 2016-11-09 | 大日本住友制药株式会社 | 缩合5‑噁唑烷酮衍生物 |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030004137A1 (en) * | 1997-02-19 | 2003-01-02 | Berlex Laboratories, Inc. | N-heterocyclic derivatives as NOS inhibitors |
| CN104640843A (zh) * | 2012-07-19 | 2015-05-20 | 大日本住友制药株式会社 | 1-(环烷基羰基)脯氨酸衍生物 |
| JP2014227401A (ja) * | 2013-05-24 | 2014-12-08 | 大日本住友製薬株式会社 | フェニルアラニン誘導体 |
| CN106103453A (zh) * | 2014-01-14 | 2016-11-09 | 大日本住友制药株式会社 | 缩合5‑噁唑烷酮衍生物 |
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