CN118078797A - 桑根酮黄酮在制备抗糖尿病足药物的用途 - Google Patents
桑根酮黄酮在制备抗糖尿病足药物的用途 Download PDFInfo
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- CN118078797A CN118078797A CN202211458452.5A CN202211458452A CN118078797A CN 118078797 A CN118078797 A CN 118078797A CN 202211458452 A CN202211458452 A CN 202211458452A CN 118078797 A CN118078797 A CN 118078797A
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- pharmaceutically acceptable
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- foot
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了桑根酮黄酮在制备抗糖尿病足药物的用途。本发明具体提供了如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种在制备预防和/或治疗糖尿病足的药物的用途。该化合物对糖尿病足诱发的痛觉丧失、伤口愈合和足部肿胀均有显著改善作用,与阳性药物七叶皂苷类和α‑硫辛酸分别相当。
Description
技术领域
本发明涉及生物医药领域,具体涉及桑根酮黄酮在制备抗糖尿病足方面的药物的用途。
背景技术
糖尿病足(diabetic foot)是指糖尿病患者踝关节以远的皮肤及其深层组织破坏,常合并感染和(或)下肢不同程度的动脉闭塞,严重者累及肌肉和骨组织的疾病。具体临床表现多样,主要为:1)神经病变表现:患肢皮肤干而无汗,肢端刺痛、灼痛、麻木、感觉减退或缺失,呈袜套样改变,行走时脚踩棉絮感;2)下肢缺血表现皮肤营养不良、肌肉萎缩,皮肤干燥弹性差,皮温下降,色素沉着,肢端动脉搏动减弱或消失,患者可合并有下肢间歇跛行症状。随着病变进展,可出现静息痛,趾端出现坏疽,足跟或跖趾关节受压部位出现溃疡且愈合困难,部分患者可肢体感染。据统计,全球每20秒就有一例糖尿病患者截肢,糖尿病足溃疡患者每年死亡率高达11%,而截肢患者死亡率更高达22%。我国50岁以上的糖尿病患者首诊的糖尿病足发病率高达8.1%,15年以上的糖尿病患者有50%患神经病变。糖尿病足是糖尿病患者致残、致死的主要原因之一。
糖尿病足发病机制复杂,临床表征多,治疗难度大,根据《中国糖尿病足防治指南》(2019版)的指导意见,针对糖尿病足的药物治疗主要从糖尿病周围神经病变(diabeticperipheral neuropathy,DPN)和糖尿病合并慢性下肢静脉病变(Lower extremityatherosclerotic disease,LEAD)两个角度进行。DPN治疗药物从功能分类主要为:1)抗氧化剂,α-硫辛酸是目前临床应用最广的强抗氧化剂,多项临床研究证实,α-硫辛酸600mg/d静滴3周,可改善神经感觉症状(TSS评分)和神经传导速度,且安全性好;2)改善微循环,前列腺素E1改善DPN以及神经传导速度优于B族维生素及其他改善微循环药物,且安全性较好,主要副作用是胃肠道反应和静脉炎。此外,胰激肽原酶具有改善运动或感觉神经传导速度,抑制血小板聚集,防止血栓形成,改善微循环等作用,在改善DPN症状及体征以及神经传导速度放慢与前列素E1类似;3)营养神经及神经修复,活性维生素B12制剂如甲钴胺可明显改善DPN的临床症状、体征以及神经传导速度,临床上多与前列腺素联用。另一方面,针对LEAD治疗的常用药物根据来源可分为天然药物和合成药物两大类。天然产物如七叶皂苷类、黄酮类(芦丁、地奥司明、橙皮苷等)、香豆素类和生物碱类(己酮可可碱),合成药物包括羟苯磺酸钙、舒洛地特、他汀类和前列腺素类等。天然产物药物黄酮类、七叶皂苷类和香豆素作为静脉活性药物可降低毛细血管通透性、减少炎症介质的释放及改善静脉张力,临床主要用于解除患者下肢沉重、酸胀不适(肿胀感、烧灼感和抽筋现象)、疼痛和水肿等临床表现,且耐受性良好,药物安全性高。己酮可可碱类作为非静脉活性药物可通过减少白细胞激活抑制血小板功能等机制,发挥抗炎作用,临床用于溃疡愈合;合成药物羟苯磺酸钙对慢性下肢静脉病变有治疗作用报道,但缺乏足够研究证据;他汀类药物对糖尿病足溃疡愈合时间有明显缩短的作用,但相关临床研究数据有待扩充;前列腺素类似物可促进淤血性溃疡的愈合和改善慢性下肢静脉病变的症状,且安全性高,但当前临床数据同样存在不够丰富的情况。一些大分子药物在治疗LEAD导致的淤血性溃疡也有应用,如重组人角质细胞生长因子-2(repifermin)局部使用可使75%的创面愈合。总之,糖尿病足药物种类繁复,但都处于对单一临床表征进行针对性治疗,缺乏针对性的特效药物。
本发明所述的桑根酮型黄酮是具有式I所示化学结构:是本申请人从黑桑(Morusnigra Linn.)中提取分离得到,化学名为(5a R,10a S)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯呋喃[3,2-b][1]苯并吡喃-11-酮,俗名桑根醇F(sanggenol F,SGF),在下文中名代号为SGF。目前关于该化合物的用途报道较少,主要有提高胰岛素敏感性、治疗糖尿病和高脂血症。但是本发明人经过大量研究发现,在糖尿病晚期模型小鼠中测试空腹血糖,SGF并无明显的降血糖活性;至今更未见SGF用于抗糖尿病足的用途。
发明内容
本发明所要解决的技术问题是克服现有技术中缺乏有效治疗糖尿病足的药物的缺陷,提供一种桑根酮黄酮SGF在制备糖尿病足方面的药物的用途。本发明将所述药物SGF用于糖尿病足的预防和/或治疗,其对db/db2型糖尿病小鼠糖尿病足模型小鼠,在痛觉丧失、伤口愈合和足部肿胀均有显著改善作用,与阳性药物七叶皂苷类和α-硫辛酸分别相当,这表明通过SGF对于糖尿病足具有明显的改善作用。
本发明是通过以下方法来解决上述技术问题的:
本发明提供一种如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种在制备预防和/或治疗糖尿病足的药物的用途;
所述如式Ⅰ所示的化合物,为桑根酮型黄酮,又名桑根醇F(sanggenol F,SGF)。
所述的药物中,活性成分包括所述的如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种。
在本发明的某一实施方案中,所述的用途中,所述的药物以如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种作为唯一活性成分。
在本发明的某一实施方案中,所述的糖尿病足包括感觉减退或缺失、下肢缺血、足部畸形、周围动脉病变、下肢血管病变、足部疼痛、足部坏疽、足部溃疡、足部创伤和足部肿胀中的一种或多种;所述的用途包括改善神经感觉症状、减轻疼痛、促进伤口愈合和减轻肿胀中的一种或多种。
本发明所述的药物中,所述的如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种的含量为治疗有效量。
本发明所述的药物能以各种途径给予患者包括但不限于口服、透皮、肌肉、皮下和静脉注射。
本发明所述的药物的剂型不限,只要是使所述的活性成分有效地到达体内的剂型都可以,包括但不限于:片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂等;优选口服剂型,如:胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等。
本发明所述药物中,除了含有所述的活性成分之外,还可含有少量的且不影响活性成分的次要成分和/或药学上可接受的载体以及各种制剂所必要的辅料等;例如,所述药物为口服剂型时,可含有常用的赋形剂,诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂,必要时可对片剂进行包衣。适宜的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂;适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物,例如羟基乙酸淀粉钠;适宜的润滑剂包括,例如硬脂酸镁;适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
本发明还提供了一种如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种在制造用于改善糖尿病足和/或预防糖尿病足的保健食品的用途。
所述的保健食品中,活性成分包括所述的如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种。
在本发明的某一实施方案中,所述的用途中,所述的保健食品以如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种作为唯一活性成分。
在本发明的某一实施方案中,所述的用途为如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体在制造用于改善糖尿病足和/或预防糖尿病足的保健食品的用途。
本发明所述的保健食品中,所述的如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种的含量为满足保健食品基本的调节功能即可。
本发明中所述术语的定义如下:
术语“药学上可接受的盐”指所述化合物与药学上可接受的无机酸或有机酸所形成的盐,所述的无机酸包括但不限于:盐酸、氢溴酸、磷酸、硝酸、硫酸;所述的有机酸包括但不限于:甲酸、乙酸、丙酸、丁二酸、1,5-萘二磺酸、亚细亚酸、草酸、酒石酸、乳酸、水杨酸、苯甲酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、对甲苯磺酸、柠檬酸,以及氨基酸;所述“药学上可接受的”是指适用于人而无过度不良副反应(如毒性、刺激和变态反应),即有合理的效益/风险比的物质。
术语“互变异构体”指因分子中某一原子在两个位置迅速移动而产生的官能团异构体,例如:烯醇与相应的酮。
术语“立体异构体”指由分子中原子在空间上排列方式不同所产生的异构体,例如:顺反异构体、对映异构体、构象异构体等。
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的化合物的量。治疗有效量将根据化合物、疾病种类、疾病的严重度、患者的年龄等变化,但可由本领域技术人员视情况调整。
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质;溶剂合物中的溶剂分子可以有序或非有序排列的形式存在;所述的溶剂包括但不限于:水、甲醇、乙醇等,较佳地为水。
术语“治疗”指治疗性疗法。涉及具体病症时,治疗指:(1)缓解疾病或者病症的一种或多种生物学表现,(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现,(3)改善与病症相关的一种或多种症状、影响或副作用,或者与病症或其治疗相关的一种或多种症状、影响或副作用,或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“预防”是指获得或发生疾病或障碍的风险降低(即导致可能暴露于导致疾病试剂或疾病发作前易感疾病的受试者中未发生疾病的临床症状的至少一种)。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
1.SGF对糖尿病足诱发的痛觉丧失,伤口愈合和足部肿胀均有显著改善作用。
2.SGF在足肿胀,伤口愈合和痛觉丧失的临床表征的治疗效果与两个阳性药物分别相当,显示出多症状改善优势。
附图说明
图1为受试物对糖尿病足动物的伤口的影响
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1:SGF的制备和结构鉴定
1.1SGF的制备
1)提取:取黑桑茎枝8kg,加90%乙醇回流提取,90%乙醇用量为药材量的10(v/m)倍,提取2次,每次1小时,将提取液过滤后合并,干燥,得提取物浸膏820g。
2)柱层析:将得到的提取物浸膏,进行AB-8大孔吸附树脂层析,分别用水、40%乙醇水溶液、95%乙醇水溶液洗脱,每个梯度洗脱溶剂量为3倍柱体积(v/v)(即溶剂使用体积为大孔吸附树脂装柱体积的3倍),收集95%乙醇水溶液洗脱部位,浓缩得到粗提物104g。
粗提物80g进行柱硅胶分离,流动相石油醚:乙酸乙酯(10:1→7:1→5:1→2:1→1:1)梯度洗脱,每个比例12L,得到组分Rr.1–15。第4个组分(6.2g),经凝胶柱层析分离,流动相二氯甲烷-甲醇(1:1)等度洗脱,共洗脱1.2L,得到6个组分,Fr.4A–Fr.4F。
3)将上述组分Fr.4E经HPLC制备(色谱柱型号:XBridge BEH C18,5μm,20×250mm;进样量:200μL;柱温:25℃;固定相为C18键合硅胶;流动相为58%乙腈水溶液,检测波长210nm,流速10mL/min;制备液相为LC3050N型高效液相色谱仪),得到桑根酮黄酮化合物(tR=17.4min):(5aR,10a S)-5a,10a-二氢-1,3,8,10a-四羟基-2,5a-二(3-甲基-2-丁烯基)-11H-苯呋喃[3,2-b][1]苯并吡喃-11-酮,俗名桑根醇F(sanggenol F)。
1.2经测试分析得到:分子式为C25H26O7;
1H-NMR(400MHz,氘代丙酮):δH 11.91(1H,br s,OH-5),7.35(1H,d,J=8.0Hz,H-6'),6.51(1H,dd,J=8.0/2.0Hz,H-5'),6.39(1H,d,J=2.0Hz,H-3'),5.93(1H,s,H-8),5.24(1H,br t,J=7.2Hz,H-15),5.17(1H,br t,J=7.2Hz,H-10),3.22(2H,br d,J=7.2Hz,H-14),3.10(1H,br dd,J=14.8/8.8Hz,H-9a),2.77(1H,br dd,J=14.8/6.4Hz,H-9b),1.73(3H,br s,H-18),1.62(3H,br s,H-17),1.61(3H,br s,H-13),1.51(3H,br s,H-12).
13C-NMR(100MHz,氘代丙酮):188.2(C-4),166.6(C-7),162.7(C-5),161.6(C-8a),161.3(C-2′),161.2(C-4′),136.5(C-11),131.4(C-16),125.6(C-6′),123.3(C-15),121.4(C-1′),118.7d(C-10),109.7d(C-5′),109.1(C-6),102.6(C-3),100.2(C-4a),99.5(C-3′),95.3(C-8),91.9(C-2),31.8(C-9),25.9(C-13),25.8(C-17),21.5(C-14),18.1(C-12),17.8(C-18)。
实施例2:SGF对糖尿病足模型小鼠体重影响
2.1实验方法
2.1.1研究动物及实验分组
SPF级db/db2型糖尿病小鼠60只,16周龄,随机血糖≥16.7nmol/L,体重50±5g;SPF级C57小鼠4只,16周龄,体重27±2g,常州卡文斯实验动物有限公司提供,室温22~25℃、湿度60%~70%、昼夜循环12h自由进食。动物随机分为8组,正常组为C57小鼠,db/db小鼠分别分为阴性对照组、模型组、α-硫辛酸组、七叶皂苷钠组、SGF(20mg/kg)组、SGF(2mg/kg)组和SGF(0.2mg/kg)组,每组10只。α-硫辛酸组和七叶皂苷钠组动物于造模后第二天腹腔注射给药2mg/kg,SGF各组分别按剂量造模后第二天腹腔注射给药。
2.1.2模型构建
小鼠适应性饲养后,异氟烷麻醉保留自主呼吸,俯卧位固定,待角膜反射消失后,手术剪在左后肢背部剪除全层皮肤,深达筋膜层,形成直径约6mm的圆形切割伤创面,造成皮肤溃疡模型。
2.1.3样品配制
1)SGF注射液(0.4mg/ml)的注射液
精密称量8mg SGF,溶解于800μL的DMSO溶液中,加入1.2mL的PEG400混匀,注射用生理盐水定容至20ml即得。
2)七叶皂苷(0.2mg/ml)注射液
精密称量4mg七叶皂苷,溶解于800μL的DMSO溶液中,加入1.2mL的PEG400混匀,注射用生理盐水定容至20ml即得。
3)α-硫辛酸(0.2mg/ml)注射液
精密称量4mgα-硫辛酸,溶解于800μL的DMSO溶液中,加入1.2mL的PEG400混匀,注射用生理盐水定容至20ml即得。
2.2体重考察
分别于造模后第1、3、5、7、9和11天对db/db小鼠进行称重。见表1所示,正常组C57小鼠体重均匀在26g左右,对照组db/db小鼠体重升高至53g左右,体重显著升高(p<0.01)。其余各组动物体重平稳。
表1受试物对糖尿病足动物体重的影响(n=10,)
##,p<0.01vs正常组
实施例3:SGF对糖尿病足模型小鼠机械痛阈的影响
3.1实验方法同实例2项下2.1
3.2机械痛阈考察
分别于造模后第1、3、5、7、9和11天进行机械痛考察,Von-frey电子测痛仪考察机械痛阈痛阈。小鼠置于网状平面适应5min后,打开Von-frey电子测痛仪,连接压力传感器,将硬质塑料探针安装于手柄上,垂直角度逐渐给小鼠左侧后足足底加压,记录小鼠出现缩足反应时的最大用力,即为机械痛阈阈值。
3.2结果
结果如表2所示,正常组C57小鼠的机械痛阈在1.5g左右,模型组db/db小鼠的机械痛阈升高至5.6左右,与正常组比较,表现出显著性差异(p<0.01)。各给药组db/db小鼠的机械痛阈均表现出不同程度降低。以不同受试物为组间处理因素,以Day-1、Day-3、Day-5、Day-7、Day-9和Day-11时间点为重复测量变量,进行重复测量的方差分析。组间效应方差分析结果发现,与模型组相比,在α=0.05检验水准下,时间因素的6个多元检验统计量七叶皂苷(2mg/kg)组,α-硫辛酸(2mg/kg)组,SGF(0.2,2和20mg/kg)组p值均低于0.05。
通过对同一时间下各组动物机械痛阈进行分析(表3)。与模型组比较,各给药组动物在给药后第7天机械痛阈开始下降,七叶皂苷(2mg/kg)组和SGF(0.2mg/kg)组小鼠在给药后第9和11天的机械痛阈表现出统计学差异;α-硫辛酸(2mg/kg),SGF(2mg/kg)和SGF(20mg/kg)组小鼠在给药后第7,9和11天的机械痛阈表现出统计学差异(p<0.05,p<0.01)。在实验终点(Day-11),七叶皂苷(2mg/kg)组,α-硫辛酸(2mg/kg),SGF(0.2mg/kg),SGF(2mg/kg)和SGF(20mg/kg)的机械痛阈恢复率分别为50.34%,51.26%,34.10%,46.86%和52.63%。
表2受试物对糖尿病足动物机械痛阈的影响(n=10,)
##,p<0.01vs正常组
*,p<0.05;**,p<0.01vs模型组
表3受试物对糖尿病足动物机械痛阈恢复率(n=10,)
实例4SGF对糖尿病足模型小鼠热痛阈的影响
4.1实验方法同实例2项下2.1
4.2热痛阈考察
造模后第11天(末次给药后)进行热痛痛阈,热痛采用鼠尾光照测痛仪测定。小鼠禁闭在长方形塑料盒,只露出鼠尾。鼠尾平放置于鼠尾光照测痛仪加热点,温度设置为35℃,记录小鼠鼠尾受热后甩尾反应潜伏时间。
4.3实验结果
结果图表4所示,正常组动物的热痛反应时间为0.4秒左右。与对照组比较,阴性对照组和模型组的热痛反应时间提高至6秒左右。与模型组比较,末次给药后七叶皂苷(2mg/kg)组,α-硫辛酸(2mg/kg)组,SGF(20mg/kg)组,SGF(2mg/kg)组和SGF(0.2mg/kg)组对糖尿病足小鼠的热痛反应时间均表现出不同程度的减少。与模型组比较,各给药组均表现出统计学差异(p<0.05)。
表4受试物对糖尿病足动物热痛痛阈的影响(n=10,)
##,p<0.01vs正常组;*,p<0.05vs模型组
实例5SGF对糖尿病足模型小鼠伤口愈合的影响
5.1实验方法同实例2项下2.1
5.2描图法考察溃疡伤口面积
分别于造模后第1、3、5、7、9和11天对动物创面进行拍照并描记伤口,使用Image-Pro Plus 6.0软件计算伤口面积,考察伤口愈合程度。
5.3结果
结果如表5和图1所示,模型组小鼠造模后第3天伤口闭合,创面维持至第7天开始收缩恢复。与模型组比较,各给药组在第5天开始创面表现出不同程度缩小。以不同受试物为组间处理因素,以Day-1、Day-3、Day-5、Day-7、Day-9和Day-11时间点为重复测量变量,进行重复测量的方差分析。组间效应方差分析结果发现,与模型组相比,在α=0.05检验水准下,时间因素的6个多元检验统计量七叶皂苷(2mg/kg)组和SGF(20mg/kg)组p值低于0.05。
通过对同一时间下各组动物伤口面积进行分析。与模型组比较,七叶皂苷(2mg/kg),SGF(0.2mg/kg),SGF(2mg/kg)和SGF(20mg/kg)组动物在给药后第9天伤口开始明显收缩,并在第11天SGF(2mg/kg)和SGF(20mg/kg)组动物的伤口面积表现出统计学差异(p<0.05)。
表5受试物对糖尿病足动物伤口面积的影响(n=10,)
##,p<0.01vs正常组;*,p<0.05vs模型组
实例6SGF对糖尿病足模型小鼠患肢足容积的影响
6.1实验方法同实例2项下2.1
6.2排水法考察患肢足容积
分别于造模后第1、3、5、7、9和11天采用大小鼠足趾肿胀测量仪测定动物足容积。
6.3结果
结果如表6所示,模型组小鼠造模后第1天足底开始肿胀,第5天足底肿胀开始放缓。与模型组比较,各给药组在第5天开始足底肿胀表现出不同程度减轻。以不同受试物为组间处理因素,以Day-1、Day-3、Day-5、Day-7、Day-9和Day-11时间点为重复测量变量,进行重复测量的方差分析。组间效应方差分析结果发现,与模型组相比,在α=0.05检验水准下,时间因素的6个多元检验统计量七叶皂苷(2mg/kg)组和SGF(20mg/kg)组p值低于0.05。
通过对同一时间下各组动物足容积进行分析。与模型组比较,七叶皂苷(2mg/kg)组动物在给药后第3天足底肿胀开始显著减轻,SGF(2mg/kg)和SGF(20mg/kg)组动物在给药后第7天足底肿胀开始显著减轻,在第11天七叶皂苷(2mg/kg)和SGF(20mg/kg)组动物的足底容积表现出统计学差异(p<0.05)。
表6受试物对糖尿病足动物足容积的影响(n=10,)/>
##,p<0.01vs正常组;*,p<0.05vs模型组
实例7SGF对糖尿病足模型小鼠空腹血糖的影响
7.1实验方法同实例2项下2.1
7.2分别于造模后1,3,5,7,9,11天测定空腹血糖(FBG)值,测定前所有组小鼠禁食不禁水12h。用割尾法剪去小鼠尾末端约0.5mm长度,之后将已经插入在快速血糖仪上的血糖试纸虹吸约8μL血液,待3s后读取血糖仪上显示的血糖值。
7.3结果
如表7所示,模型组小鼠空腹血糖较正常组明显升高;各给药组空腹血糖水平与模型组无显著性差异,这提示各给药组改善糖尿病足模型小鼠与其降血糖活性无直接关系。值得一提的是,本实验中采用的糖尿病小鼠偏老,对应糖尿病晚期,更加贴合糖尿病足主要发生在糖尿病的晚期的这一临床特征,这也是SGF对模型小鼠空腹血糖无明显作用的主要原因。这也表明,SGF改善糖尿病足功效与其潜在降血糖活性无关,而与其抗炎、改善微循环和神经修复密切相关。
表7受试物对糖尿病足动物空腹血糖的影响(n=10,)/>
##,p<0.01vs正常组;
综上所述,研究实例结果表明,受试物SGF对糖尿病足诱发的痛觉丧失,伤口愈合和足部肿胀均有显著改善作用。对糖尿病足模型小鼠,SGF在足肿胀,伤口愈合和痛觉丧失的临床表征的治疗效果与两个阳性药物分别相当。
最后需要在此指出的是:以上仅是本发明的部分优选实施例,不能理解为对本发明保护范围的限制,本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。
Claims (10)
1.一种如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种在制备预防和/或治疗糖尿病足的药物的用途;
2.如权利要求1所述的用途,其特征在于,所述的药物中,活性成分包括所述的如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种。
3.如权利要求1所述的用途,其特征在于,所述的药物以如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种作为唯一活性成分。
4.如权利要求1所述的用途,其特征在于,所述糖尿病足包括感觉减退或缺失、下肢缺血、足部畸形、周围动脉病变、下肢血管病变、足部疼痛、足部坏疽、足部溃疡、足部创伤和足部肿胀中的一种或多种;
和/或,所述的用途包括改善神经感觉症状、减轻疼痛、促进伤口愈合和减轻肿胀中的一种或多种。
5.如权利要求1所述的用途,其特征在于,本发明所述的药物中,所述的如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种的含量为治疗有效量。
6.如权利要求1-5任一项所述的用途,其特征在于,所述的药物以口服、透皮、肌肉、皮下或静脉注射的途径给予患者。
7.如权利要求1-5任一项所述的用途,其特征在于,所述的药物的剂型为片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂或贴剂;优选为胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂或膏剂。
8.一种如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种在制造用于改善糖尿病足和/或预防糖尿病足的保健食品的用途。
9.如权利要求8所述的用途,其特征在于,所述保健食品的活性成分包括所述的如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种;
可选的,所述的保健食品以如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种作为唯一活性成分。
10.如权利要求8所述的用途,其特征在于,所述的保健食品中,所述的如式I所示的化合物、其溶剂合物、其药学上可接受的盐、其药学上可接受的盐的溶剂合物、其互变异构体和其立体异构体的至少一种的含量为满足保健食品基本的调节功能即可。
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