CN116966181A - 葡萄糖转运蛋白1抑制剂在制备糖尿病神经病变治疗药物中的应用 - Google Patents
葡萄糖转运蛋白1抑制剂在制备糖尿病神经病变治疗药物中的应用 Download PDFInfo
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Abstract
本发明公开了葡萄糖转运蛋白1抑制剂在制备糖尿病神经病变治疗药物中的应用。本发明通过药效学实验验证了葡萄糖转运蛋白1抑制剂BAY‑876可作为制备治疗糖尿病周围神经病变药物，也可与甲钴胺联合使用作为制备治疗糖尿病周围神经病变药物。
Description
技术领域
本发明属于医药技术领域，具体涉及葡萄糖转运蛋白1抑制剂在制备糖尿病神经病变治疗药物中的应用。
背景技术
糖尿病神经病变是糖尿病最普遍的并发症，影响达50％以上的糖尿病患者。根据受影响的神经，可累及感觉、运动和自主神经及多个器官系统。临床表现腿、脚和手疼痛和麻木；还可能导致消化系统、泌尿道、血管和心脏问题。病变最常损害腿和脚的神经，严重的患者可能致残，加重公共卫生负担。
传统的治疗着重于控制高血糖和神经修复类药物来减缓疾病进展或延迟发作，临床上常用甲钴胺作为神经修复药物。当前的治疗方法中，缺乏有效控制周围神经病变的整体疗法，只能减缓病症并不能阻断病变的进程，因此对能够阻断糖尿病周围神经病变病理进程的新型抗糖尿病周围神经病变药物的发现有着迫切的需求。
BAY-876是一类常见的葡萄糖转运蛋白1(GLUT1)抑制剂，该类抑制剂能有效阻止糖酵解和卵巢癌的生长。目前还没有葡萄糖转运蛋白1抑制剂BAY-876作为药物治疗糖尿病神经病变的相关报道。
发明内容
本发明的目的是提供葡萄糖转运蛋白1抑制剂在制备糖尿病神经病变治疗药物中的应用。
本发明通过药效学实验验证了葡萄糖转运蛋白1抑制剂BAY-876可作为制备治疗糖尿病周围神经病变药物，也可与甲钴胺联合使用作为制备治疗糖尿病周围神经病变药物。
本发明首次公开了葡萄糖转运蛋白1抑制剂BAY-876作为制备治疗糖尿病周围神经病变药物的应用，为糖尿病神经病变的用药提供了新的思路。
附图说明
图1为实施例1中BAY-876大鼠药效学实验结果。
图2为实施例2中BAY-876和甲钴胺联合给药实验结果。
具体实施方式
下面将结合实施例对本发明的优选实施方式进行详细说明。需要理解的是以下实施例的给出仅是为了起到说明的目的，并不是用于对本发明的范围进行限制。本领域的技术人员在不背离本发明的宗旨和精神的情况下，可以对本发明进行各种修改和替换。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
以下实施例中，糖尿病大鼠动物模型建立方法如下：
临用前配制0.1mol/L的柠檬酸钠缓冲液，pH4.2；链脲佐菌素(STZ)溶于柠檬酸钠缓冲液中，制成1％溶液，用0.22μm滤菌器过滤除菌，置于冰上冷却。
SD大鼠，4周龄至6周龄，体重180至200g。禁食12h，按50mg/kg的剂量给予腹腔注射，每日1次，连续2次。
一周后由尾静脉采血测定血糖，以空腹血糖≥16.7mmol/L为标准筛选模型，纳入实验。
实施例1
葡萄糖转运蛋白1抑制剂BAY-876大鼠药效学实验
1、将入选大鼠随机分为4组，每组8只。包括①模型对照组②甲钴胺治疗组③BAY-876低剂量治疗组④BAY-876高剂量治疗组；各组均每日给予10mL/kg灌胃给药，连续给药12周。同时以同龄的8只正常大鼠禁食12h后，腹腔注射等量0.1mol/L pH4.2柠檬酸缓冲液作为正常对照组。
模型组：生理盐水溶液/DMSO溶液(v/v 1000：1)
甲钴胺治疗组：剂量为500μg/kg
BAY-876低剂量组：剂量为250μg/kg
BAY-876高剂量组：剂量为500μg/kg。
2、药物溶液配制：
甲钴胺治疗组：0.5mg甲钴胺片研碎，加蒸馏水制成混悬液，用生理盐水定容至10mL，即剂量为500μg/kg。
BAY-876低剂量组：称取0.5mg BAY-876溶于DMSO溶液，用生理盐水定容至20mL，即剂量为250μg/kg。
BAY-876高剂量组：称取0.5mg BAY-876溶于DMSO溶液，用生理盐水定容至10mL，即剂量为500μg/kg。
3、坐骨神经传导速度检测：给药12周结束，用1％戊巴比妥钠0.4mL/100g腹腔内注射麻醉大鼠，对大鼠下肢的近端与远端进行酒精消毒，切开半膜肌和股二头肌间的皮肤，两肌间行钝性分离，暴露出坐骨神经主干。记录坐骨神经的动作电位，神经刺激电极位于大鼠外踝上方0.3cm处，记录电极位于坐骨神经近心端，测量两极间的距离。刺激每次间隔1分钟，重复3次，取平均值，计算传导速度。检测结果见表1和图1。
表1大鼠坐骨神经传导速度比较(均数±标准差)
由以上结果可知，BAY-876治疗效果与甲钴胺治疗组相当，与模型组存在显著差异。说明葡萄糖转运蛋白1抑制剂BAY-876通过口服给药能够很好的治疗糖尿病周围神经病变，且使用剂量低于甲钴胺。
实施例2
葡萄糖转运蛋白1抑制剂BAY-876和甲钴胺联合给药实验
将造模成功的大鼠分为3组：甲钴胺治疗组(剂量为250μg/kg)、BAY-876组(剂量为250μg/kg)和BAY-876联用甲钴胺组(125μg/kg BAY-876+125μg/kg甲钴胺)。
实验周期为8周和12周，其余按实施例1操作。
给药结束，对大鼠坐骨神经传导速度检测，并进行数据统计分析；通过表2和图2可以看出，BAY-876联用甲钴胺效果显著优于BAY-876或甲钴胺单独给药，并且药效比单独给药提前四周。
表2大鼠坐骨神经传导速度比较(均数±标准差)
由以上结果可知，葡萄糖转运蛋白1抑制剂BAY-876联用甲钴胺具有更好的协同治疗作用。通过实验还证明两药联用，甲钴胺的用药量较单独给药量减少至1/2，并且起效时间快，从而大大降低了用药量和耐药性问题，达到了很好的治疗效果。
综上所述，本发明首次公开了葡萄糖转运蛋白1抑制剂BAY-876作为制备治疗糖尿病性周围神经病变药物的应用；药效学实验数据表明葡萄糖转运蛋白1抑制剂BAY-876是一种高效的糖尿病性周围神经病变药物。
Claims (3)
1.葡萄糖转运蛋白1抑制剂在制备糖尿病神经病变治疗药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述葡萄糖转运蛋白1抑制剂为BAY-876。
3.葡萄糖转运蛋白1抑制剂联用甲钴胺在制备糖尿病神经病变治疗药物中的应用。
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