CN114949067B - 花椒油在制备预防和/或治疗高尿酸血症药物中的应用 - Google Patents
花椒油在制备预防和/或治疗高尿酸血症药物中的应用 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/75—Rutaceae (Rue family)
- A61K36/758—Zanthoxylum, e.g. pricklyash
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- A61P19/00—Drugs for skeletal disorders
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Abstract
本发明属于医药技术领域,公开了一种花椒油在制备预防和/或治疗高尿酸血症药物中的应用。本发明采用花椒提取的花椒油抑制黄嘌呤氧化酶活性,将花椒油在制备预防和/或治疗高尿酸血症药物,及高尿酸血症导致的痛风、尿酸性肾结石、痛风石或高尿酸性肾损害药物中应用,为预防和治疗高尿酸血症提供新的药物选择。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种花椒油在制备预防和/或治疗高尿酸血症药物中的应用。
背景技术
高尿酸血症(Hyperuricaemia,HUA)是嘌呤代谢障碍引起的代谢性疾病,在正常嘌呤饮食状态下,非同日两次空腹血尿酸水平男性高于420umol/L,女性高于360umo/L。荟萃分析显示:HUA患病具有呈逐年上升、年轻化、男性高于女性、沿海高于内陆等特点,其中20-30岁男性发病率最高。在HUA高流行的同时,大量的研究证据凸显了HUA的危害。HUA是痛风发生的最重要的生化基础和最直接病因,但是大多数HUA并不发展为痛风,只有尿酸盐结晶在机体组织中沉积造成损害才出现痛风。HUA是2型糖尿病发生发展的独立危险因素,2型糖尿病发病风险随着血尿酸水平的升高而增加。HUA是高血压发病的独立危险因素,血尿酸与肾动脉性高血压相关,尤其是使用利尿剂者。HUA可参考预测心血管及全因死亡,是预测心血管事件发生的独立危险因素,更是心力衰竭、缺血性卒中发生及死亡的独立危险因素。HUA可导致急性尿酸性肾病、慢性尿酸性肾病和肾结石,增加发生肾功能衰竭的风险。总之,HUA是一种常见的慢性非传染性疾病,与痛风之间密不可分,并且是代谢性疾病(糖尿病、代谢综合征、高脂血症等)、慢性肾病、心血管疾病、脑卒中等多种疾病的独立危险因素。
目前,在临床上有多种药物(如别嘌醇、苯溴马隆)应用于HUA的治疗,但是均难以治愈而且药物长期使用会出现多种不良反应,如损害肝肾功能、停药反应等。
发明内容
本发明的目的在于克服现有技术的不足之处而提供一种花椒油在制备预防和/或治疗高尿酸血症药物中的应用。
为实现上述目的,本发明采取的技术方案如下:
第一方面,本发明将花椒油在制备预防和/或治疗高尿酸血症药物中应用。
第二方面,本发明将花椒油在制备预防和/或治疗高尿酸血症导致的痛风、尿酸性肾结石、痛风石或高尿酸性肾损害药物中应用。
作为本发明所述应用的优选实施方式,所述药物为黄嘌呤氧化酶抑制剂。
作为本发明所述应用的优选实施方式,所述药物包括花椒油和/或其药学上可接受的盐或辅料。优选的,所述辅料为载体、稀释剂、赋形剂、辅助剂中的任意一种。
作为本发明所述应用的优选实施方式,所述花椒油由花椒萃取制得。
优选的,所述萃取的方法包括以下步骤:
(1)取花椒,粉碎过筛,加入有机溶剂,浸泡,过滤得滤液;
(2)将所得滤液回流,得回流滤液;
(3)将所得回流滤液去除水分,回收所述有机溶剂,得纯滤液;
(4)将所得纯滤液干燥、浓缩、冷却,即得。
进一步的,所述步骤(1)中,所述花椒与所述有机溶剂的固液比为(0.5~ 2)g:3ml;所述有机溶剂为无水乙醚或石油醚。
进一步的,所述步骤(2)中,所述回流的温度为50℃~65℃,时间为0.5h~ 2h。
进一步的,所述步骤(3)中,所述回收的温度为60℃~75℃。
优选的,所述去除水分时添加无水硫酸钠;所述无水硫酸钠与所述回流滤液的质量体积比为(0.5~1)g:10ml。
进一步的,所述步骤(4)中,所述干燥的温度为50℃~70℃。
与现有技术相比,本发明的有益效果为:
本发明采用花椒提取的花椒油抑制黄嘌呤氧化酶活性,降低血尿酸水平,同时具有肾保护作用,具有良好的预防和治疗高尿酸血症前景,为预防和治疗高尿酸血症提供新的药物选择。
附图说明
图1为花椒油对高尿酸小鼠尿酸和肾功能的影响;
其中,A为花椒油能够降低氧嗪酸钾诱导的高尿酸小鼠血清尿酸水平;B 为花椒油能够降低小鼠血清黄嘌呤氧化酶的活性。C、D为花椒油可以保护和改善小鼠肾功能,降低血清肌酐和尿素氮的水平;
图2为各组大鼠的体重变化及进食摄水量比较;
其中,A为各组大鼠的体重变化;B、C为各组大鼠干预第3周时的进食和摄水量比较;
图3为花椒油对UOX-/-大鼠尿酸和肾功能的影响;
其中,A为花椒油降低UOX-/-大鼠的血尿酸水平;B、C、D为花椒油具有肾功能保护作用,降低UOX-/-大鼠的血肌酐、尿素氮和胱抑素C的水平;
图中,*P<0.05,**P<0.01,***P<0.001。
具体实施方式
为更好地说明本发明的目的、技术方案和优点,下面将结合具体实施例对本发明作进一步说明。本领域技术人员应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明。
实施例中所用的试验方法如无特殊说明,均为常规方法;所用的材料等,如无特殊说明,均可从商业途径得到。
所用的试剂、耗材和仪器如下:
氧嗪酸钾(毕得医药科技有限公司,中国);
别嘌醇(上海阿拉丁有限公司,中国);
羧甲基纤维素钠(上海阿拉丁有限公司,中国);
吐温-80(上海阿拉丁有限公司,中国);
尿酸检测试剂盒(DIUA-250,博世生物技术有限公司,美国);
黄嘌呤氧化酶测试盒(A002-1-1,南京建成生物工程研究所,中国);
肌酐试剂盒(C011-2-1,南京建成生物工程研究所,中国);
尿素氮试剂盒(C013-2-1,南京建成生物工程研究所,中国);
Cysc Elisa检测试剂盒(江苏博深公司,中国);
全自动生化分析仪(Beckman公司,美国)。
实施例1:花椒油的制备方法
具体花椒油的制备方法如下:
将适量花椒进行干燥并粉碎,过40目筛,得到花椒粉末,称取适量花椒粉末,按固液比约1:3(g:ml)加入无水乙醚,浸泡32h,过滤,滤液回流1.5h,温度为55-60℃;向滤液中加入无水硫酸钠,无水硫酸钠与所述滤液的质量体积比为0.8g:10ml,以除去滤液中的水分;将滤液全部转移至抽提瓶内,在68℃水浴温度下回收乙醚;将抽提瓶置于通风处放置30min(使瓶内乙醚浓度降低,防止产生爆炸),然后放入鼓风干燥箱中干燥浓缩,温度为60℃,时间为2h;取出抽提瓶放于干燥器内冷却0.5h,得到花椒油。
实施例2:花椒油对氧嗪酸钾诱导的高尿酸小鼠尿酸代谢的影响
将40只昆明鼠(22-27g),随机分为对照组(CTR组,n=10)、模型组(MOD 组,n=10)、花椒油组(ZanO组,n=10)和别嘌醇组(ALP组,n=10),适应性饲养1周,饲养条件为饲养温度为22℃-26℃,相对湿度为60±10%,每12h 交替照明,自由进食摄水。
适应性饲养结束后,(1)药物预处理3天:ZanO组和ALP组分别灌胃实施例1制备的花椒油(300mg/kg)、别嘌醇混悬液(20mg/kg),连续给药3天, CTR组和MOD组灌胃等体积的4%吐温-80;(2)氧嗪酸钾诱导小鼠高尿酸模型:在花椒油和别嘌醇灌胃1小时后,MOD组、ZanO组和ALP组腹腔注射氧嗪酸钾混悬液(PO 300mg/kg),CTR组腹腔注射等体积的0.5%CMC-Na,连续干预7天。最后一次给药前8小时进行禁食不禁水,最后一次腹腔注射PO 1h 后去眼球取血。血液室温静置60min后,在4℃低温环境下,4000rpm离心10min,收集上清,-80℃保存。测定血清中尿酸、黄嘌呤氧化酶活性和血清肌酐、尿素氮水平。
各组小鼠的尿酸水平如图1中A所示,MOD组的尿酸水平显著高于CTR 组(P<0.05)。与MOD组相比,花椒油可以有效降低小鼠的血清尿酸水平(P <0.05),但其降尿酸的效果不及别嘌醇;如图1中B所示,花椒油可以抑制血清黄嘌呤氧化酶活性(P<0.05),减少尿酸的生成;肾功能方面,如图1中C、 D所示,花椒油对高尿酸小鼠的肾脏具有保护作用,可以降低血清肌酐和尿素氮的水平(P<0.05)。
实施例3:花椒油对UOX基因敲除的自发性高尿酸大鼠尿酸代谢及肾功能的影响
实验SD大鼠购自南京生物医药研究院,该大鼠为使用CRISPR-Cas9系统敲除UOX基因的SD大鼠,将F1代尿酸酶基因敲除杂合子(Uox-/+)大鼠反复交配以获得纯合子UOX基因敲除高尿酸SD大鼠。
将基因鉴定得到的30只8周龄高尿酸SD大鼠(UOX-/-)随机分为高尿酸模型组(MOD组,n=10)、花椒油干预组(ZanO组,n=10)、别嘌醇干预组(ALP组,n=10),将鉴定得到的野生型SD大鼠作为空白对照组(CTR组, n=10)。ZanO组和ALP组分别灌胃花椒油混悬液(200mg/kg)、别嘌醇混悬液(20mg/kg),CTR组和MOD组灌胃等体积的4%吐温-80,连续干预4周,最后一次给药前8小时进行禁食不禁水,最后一次给药1小时后,经腹腔注射 1%戊巴比妥钠溶液麻醉,腹主动脉取血,室温静置60min后,在4℃低温环境下,4000rpm离心10min,收集上清,-80℃保存。利用全自动生化分析仪测定血清尿酸、血清肌酐和血清尿素氮水平,利用Cysc Elisa检测试剂盒检测血清胱抑素C的水平。
(1)花椒油对UOX-/-大鼠的体重及进食摄水量的影响
各组大鼠的体重变化如图2中A所示,各组大鼠的体重5个时间点比较,体重无明显差异;图2中B、C为干预第3周时记录的各组大鼠的每日进食和摄水量,各组大鼠的每日进食量无差异,MOD组、ZanO组和ALP组的摄水量明显多于CTR组(P<0.05),MOD组、ZanO组和ALP组间的摄水量无明显差异。以上数据表明花椒油不影响UOX-/-大鼠的体重、进食和摄水量。
(2)花椒油对UOX-/-大鼠的尿酸和肾功能的影响
干预后各组的尿酸水平如图3中A所示,与CTR组相比,MOD组尿酸水平明显升高,差异有统计学意义(P<0.05);与MOD组相比,花椒油可以降低UOX-/-大鼠的血尿酸水平(P<0.05),但ALP组的尿酸下降更明显;胡椒油具有保护肾功能的疗效,可以有效改善UOX-/-大鼠血肌酐、尿素氮和胱抑素C 的水平,减轻高尿酸血症造成的肾损害。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,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实质和范围。
Claims (2)
1.一种花椒油作为唯一活性成分在制备预防和/或治疗高尿酸血症药物中的应用,其特征在于,所述花椒油提取的方法包括以下步骤:
(1)取花椒,粉碎过筛,加入有机溶剂,浸泡32h,过滤得滤液;向滤液中加入无水硫酸钠,所述无水硫酸钠与所述滤液的质量体积比为0.8g:10ml;
(2)将所得滤液回流,得回流滤液;
(3)将所得回流滤液去除水分,回收所述有机溶剂,得纯滤液;
(4)将所得纯滤液干燥、浓缩、冷却,即得;
所述步骤(1)中,所述花椒与所述有机溶剂的固液比为1g:3ml;所述有机溶剂为无水乙醚;
所述步骤(2)中,所述回流的温度为55℃~65℃,时间为1.5h;
所述步骤(3)中,所述回收的温度为68℃;
所述步骤(4)中,所述干燥的温度为60℃。
2.根据权利要求1所述的应用,其特征在于,所述药物包括花椒油和/或其药学上可接受的盐或辅料。
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