CN118078791A - 丁香酸的新用途 - Google Patents
丁香酸的新用途 Download PDFInfo
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Abstract
本发明公开了丁香酸的新用途,属于生物医药技术领域。该药物可预防和/或治疗猫病原体感染,包括疱疹病毒、杯状病毒、细小病毒、轮状病毒、白血病病毒和肠道冠状病毒,制备的药物剂型包括滴鼻剂、冲剂、颗粒剂、滴丸剂和软膏剂。本发明以丁香酸制备的药物具有抗炎镇痛和调节神经系统异常等作用,具有良好的镇痛活性,且安全,可长期使用。
Description
技术领域
本发明属于丁香酸的应用技术领域,具体涉及丁香酸的新用途。
背景技术
丁香酸(Syringic acid,3,5-二甲氧基-4-羟基苯甲酸)是植物体内重要的次生性代谢酚类,主要存在于板蓝根、益母草和石斛等多种药用植物中,具有抗菌、抗氧化和抗内毒素等多种药理作用。丁香酸中含有的活性羟基,具有芳香性和一定的疏水性,位于芳香环3位和5位上的甲氧基使得它具有广泛的药用价值。紫外线照射损伤引起组织细胞中产生过多的活性氧簇(Reactive oxygen species,ROS),导致细胞中的蛋白和脂质被破坏,同时导致细胞来源的NADPH氧化酶(Nicotinamide adenine dinucleotide phosphate oxidase)失衡,引起皮肤癌变。Ha等(Ha SJ,Lee J,Park J,et al.Syringic acid prevents skincarcinogenesis via regulation of NoX and EGFR signaling.Biochem Pharmacol,2018;154:435-445.)发现丁香酸能够作用于Nox/ROS/PTP-k/EGFR轴从而抑制由紫外线损伤引起的皮肤癌。Lu等(Lu CL,Zhu W,Wang DM,et al.Inhibitory Effects of ChemicalCompounds Isolated from the Rhizome of Smilax glabra on Nitric Oxide andTumor 53Necrosis Factor-αProduction in Lipopolysaccharide-Induced RAW264.7Cell.Evid Based Complement Alternat Med,2015;2015:602425.)通过体外脂多糖诱导RAW264.7细胞为模型,发现丁香酸能够明显抑制NO的产生,具有良好的抗炎和抗氧化特性;Pirmr等(Pieme CA,Santosh GK,Tekwu EM,et al.Fruits and barks extracts ofZanthozyllum heitzii a spice from Cameroon induce mitochondrial dependentapoptosis and Go/G1 phase arrest in human leukemia HL-60cells.Biol Res,2014;47(1):54.)发现丁香酸能够抑制人白血病HL-60(急性粒细胞白血病细胞)的增殖,在线粒体膜电位并发损失的同时促进活性氧的产生,导致细胞周期呈现不稳定的状态,从而诱导细胞凋亡,然而目前并未有丁香酸可镇痛以及抑制疱疹病毒、杯状病毒、细小病毒、轮状病毒、白血病病毒和肠道冠状病毒感染的报道。
病毒性疾病是在兽医临床上对动物危害最为严重的疾病之一,特别是一些高致病性病毒性疾病的流行,往往给饲主带来巨大的经济和精神上的损失。动物的病毒病通常传染快,致病率和致死率高,严重危害动物的健康和生命。而且,一些病毒还能够通过动物传染给人类,给人类的生命安全带来威胁。
新时代养宠人群不断增加,宠物被赋予更多情感角色,健康、快乐养宠形成趋势。而猫常见的病毒有猫瘟、猫疱疹、猫腹水、猫杯状等。猫瘟又称猫泛白细胞减少症或猫传染性肠炎,是一种高度接触性的传染病毒性疾病,主要发生于一岁以内的幼猫;感染的途径通常多见在疫苗接种不全或未接种的猫咪身上,尤以3~5月龄的幼猫最容易得猫瘟;而母猫如果在怀孕期感染,则会造成死胎、流产和初生小猫出现神经症状,由于市面上已经研发有猫瘟血清,只要及时送医,其治愈率还是较为客观的。猫疱疹病毒是一种大型的病毒,具有封套及双股的DNA,于细胞核内进行增殖,并形成核内包涵体,猫疱疹病毒于酸性下极度不稳定,对热、乙醚、氯仿、福尔马林和酚非常敏感,因此在干燥的环境中一般存活不超过12h,在环境中显得相当脆弱,一般的消毒剂即能进行有效的消毒;猫疱疹病毒的传染途径主要是通过飞沫传播,会导致急性上呼吸道感染,如结膜炎、流口水、鼻炎等,该病毒对于幼猫而言,其严重性还是较大的,会有一定的死亡率,但对成猫而言一般不会致死。猫腹水,也称为猫腹腔积水,虽然不是病毒,但一般都是由病毒引起的,包括感染冠状病毒、患有腹膜炎、肝肾疾病等,这些原因导致血浆渗透压降低、淋巴管堵塞等,最终使腹腔内的水分增多并出现积水,其症状的治疗非常麻烦,需要综合多种方法,包括抽取腹水缓解腹腔压力、使用利尿剂等。猫杯状病毒是一种高度接触性的病毒性传染病,主要侵害几周龄内的幼猫的上呼吸道,通常感染后的潜伏期为2~3天,能经鼻、口和眼分泌物传播,感染初期,猫咪会发热至39.5-40.5℃,出现精神沉郁、浆液性和粘液性鼻漏、结膜炎、口腔炎和支气管炎等症状,伴有双相热。猫咪感染轮状病毒以后常常发生呕吐、腹泻和精神不振等症状,轮状病毒发病突然,会引起猫咪腹泻、排黄绿色稀便和粘液,时间可持续一周左右,严重者,会有出血性肠炎、粪便带血、心跳加快和体温下降等情况,且可导致死亡。猫白血病是猫常见的非创伤性致死疾病,是由猫白血病病毒和猫肉瘤病毒引起的恶性肿瘤性传染病。主要特征是恶性淋巴肿瘤、骨髓性白血病以及变性性胸腺萎缩和非再生性贫血等,其中对猫最严重的是恶性淋巴肿瘤;幼猫易感性高,随年龄增长易感性降低。
目前针对这类型病都是以接种疫苗预防为主,但是疫苗接种不能完全免疫,存在一定免疫失败率。而且这些病症可垂直传播,同时病毒存在变异风险,疫苗对新出现的病毒的效用需要评估,且耗费较大。
发明内容
针对现有技术存在的上述问题,本发明所要解决的技术问题在于提供丁香酸在镇痛和抗病毒感染中的新用途,该丁香酸制备的药物具有抗炎镇痛、调节神经系统异常和改善病毒感染症状等作用,对猫病原体感染具有优异的预防和/或治疗的作用。
为了解决上述问题,本发明所采用的技术方案如下:
丁香酸在制备用于抗病毒感染的药物中的应用。
所述的应用,所述病毒为疱疹病毒、杯状病毒、细小病毒、轮状病毒、白血病病毒和肠道冠状病毒。
丁香酸在制备用于治疗由疱疹病毒引起的病毒性鼻支气管炎的药物中的应用。
丁香酸在制备用于镇痛的药物中的应用。
丁香酸在制备预防和/或治疗猫鼻支的药物中的应用。
所述的应用,所述药物由丁香酸、药学上允许的任意一种辅料或药物赋形剂和药用载体制备而成。
所述丁香酸的给药量为1~1000mg/kg体重。
所述的应用,所述药物的剂型为滴鼻剂、冲剂、颗粒剂、滴丸剂和软膏剂。
所述的应用,所述滴鼻剂的制备方法为:将丁香酸与丙二醇混合,备用;把卡波姆放入生理盐水中溶解,溶解完成后加入水溶性氮酮,搅拌均匀,再加入丁香酸与丙二醇的混合溶液,调节pH为6~8,定容,灭菌,制备得到丁香酸滴鼻液。
所述的应用,所述药物的给药形式为口服给药、黏膜给药和皮肤给药。
有益效果:相比于现有技术,本发明的优点为:
(1)病毒感染一般伴随着发热、精神不振等感染症状,本发明的丁香酸药物具有抗炎镇痛、调节神经系统异常和改善疱疹病毒、杯状病毒、细小病毒、轮状病毒、白血病病毒和肠道冠状病毒的感染症状的作用,恢复病毒感染至阴性。
(2)丁香酸能显著减少醋酸所致的小鼠扭体次数,高剂量组与阿司匹林作用相当,具有良好的镇痛活性。
(3)丁香酸能显著小鼠耳廓肿胀度,具有良好的抗炎活性。
(4)丁香酸施药于感染猫鼻支的猫,能改善症状,恢复至阴性感染,对猫鼻支具有显著的疗效。
(5)丁香酸以谷氨酸受体2为作用靶标,其对突触可塑性、神经系统发育、疼痛感知等多种生命活动的调控均有调节作用。
(6)本发明的丁香酸药物安全,可长期使用。
附图说明
图1为本发明不同剂量丁香酸镇痛作用研究结果(平均±SD);
图2为本发明不同剂量丁香酸对耳廓肿胀度的影响研究结果。
具体实施方式
下面结合具体实施例对本发明进一步进行描述。
本发明丁香酸来源于市售或采用现有技术制备获得。
实施例1
丁香酸滴鼻剂的制备方法如下所示:
精密称取丁香酸,加丙二醇配制成200mg/mL的丁香酸溶液,为溶液A,备用。精密称取卡波姆0.1g,加入50mL生理盐水于40℃水浴锅溶解,在室温放置数小时直至肉眼观察卡波姆溶液无白芯,溶胀完成,为溶液B。在溶液B中加入水溶性氮酮1mL搅拌充分,然后加入5mL溶液A再次充分混匀,磷酸盐缓冲液调节pH值至6.4~7.4,定容至100mL,高压灭菌20min,得到丁香酸滴鼻剂样品溶液。
实施例2
丁香酸镇痛作用研究(醋酸扭体实验)
将雌性小鼠随机分为5个组,每组10只。各组小鼠分别以生理盐水(对照组Control),阿司匹林(30mg/kg,阳性对照组APC,生理盐水溶解),低(20mg/kg,L)、中(40mg/kg,M)、高(60mg/kg,H)剂量的丁香酸生理盐水混悬剂进行灌胃处理。在给药30min后,腹腔注射0.6%醋酸溶液0.2mL。观察记录注射醋酸溶液后15min内小鼠出现的扭体反应的次数,扭体反应包括腹部内凹、躯干与后肢伸张和臀部高起。抑制率按以下公式计算:
抑制率=(对照组扭体次数–给药组扭体次数)/对照组扭体次×100%。
结果如图1所示。
图1为本发明不同剂量丁香酸镇痛作用研究结果(平均±SD),由图可知,与对照组比较,阿司匹林和不同剂量丁香酸均能显著减少醋酸所致的小鼠扭体次数(P<0.05),且呈剂量依赖性。在高和中两个剂量下,丁香酸的抑制活性分别为66.3%和51.5%),表现出了很好的抑制活性,抑制率均大于50%,但仅高剂量组与阿司匹林组无显著性差异。可见丁香酸具有较好的镇痛作用活性。
实施例3
丁香酸抗炎作用研究(小鼠耳廓肿胀实验)
本研究采用小鼠耳廓肿胀实验制备非特异性动物炎症模型并进行相关指标的测定,从而验证丁香酸的功能。
小鼠耳肿胀模型的制备与测定:各样品组(与实施例2相同的分组)经口给予0.4mL受试样品,模型组给予等体积蒸馏水,受试样品给予30天。末次给药后1h,汲取二甲苯20μL,滴加在小鼠右耳外侧面耳廓的中央,让其自由扩散,30min后将小鼠脱颈椎处死,剪下双耳,用9mm直径打孔器在两耳相同部位打下耳片并称重,以两耳重量之差为耳廓肿胀值,计算耳廓肿胀度,耳廓肿胀度计算方式如下:
耳廓肿胀度(mg)=右耳片重量—左耳片重量
结果如图2所示。
图2为本发明不同剂量丁香酸对耳廓肿胀度的影响研究结果,在高和中两种剂量下,丁香酸表现出了很好的抗炎活性,与模型组有显著性差异(P<0.05)。
实施例4
丁香酸网络药理学作用靶点研究
在中药系统药理学分析平台TCMSP(https://old.tcmsp-e.com/tcmsp.php)以“Syringic acid”对丁香酸进行检索,得到丁香酸的预测靶点谷氨酸受体2(Gl utamatereceptor 2)。
可知,哺乳动物中枢神经系统中含量最高、分布最广的兴奋性神经递质是谷氨酸。谷氨酸受体分为代谢型受体和离子通道型受体两大类,其中离子通道型谷氨酸受体是介导快速兴奋性突触传递的关键受体,分布广泛,类型多样且功能重要。多种脑疾病,都和离子通道型谷氨酸受体受损或功能异常息息相关。丁香酸作用靶点是谷氨酸受体2,故对突触可塑性、神经系统发育、疼痛感知等多种生命活动的调控均有调节作用。
实施例5
丁香酸抗感染治疗验证实验
取经试纸检测诊断为感染有猫鼻支的刚出生3天幼猫3只,随机分为3组(两个药物组、一个阴性组),施药组分别用丁香酸溶液(实施例1制备的滴鼻剂)、丁香酚水混悬溶液(浓度为7.8mg/mL),阴性组用无菌水。
施药方案:将对应药物直接施用至感染的一只或两只眼睛的表面,或入鼻施用。可以每天一次被施用,每次施用4~6滴。施药时分笼饲喂。
施药后第2天,丁香酸给药组体温已经降为正常值,第4天,眼鼻分泌物已明显消退,食欲、体能已经恢复,第7天已经全部恢复正常,第10天采集鼻腔黏液样品进行复检,呈阴性结果。而无菌水和丁香酚给药组分泌物情况无改善,并在第10天采集鼻腔黏液样品进行复检,仍然呈阳性结果。
Claims (10)
1.丁香酸在制备用于抗病毒感染的药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述病毒为疱疹病毒、杯状病毒、细小病毒、轮状病毒、白血病病毒和肠道冠状病毒。
3.丁香酸在制备用于治疗由疱疹病毒引起的病毒性鼻支气管炎的药物中的应用。
4.丁香酸在制备用于镇痛的药物中的应用。
5.丁香酸在制备预防和/或治疗猫鼻支的药物中的应用。
6.根据权利要求5所述的应用,其特征在于,所述药物由丁香酸、药学上允许的任意一种辅料或药物赋形剂和药用载体制备而成。
7.根据权利要求6所述的应用,其特征在于,所述丁香酸的给药量为1~1000mg/kg体重。
8.根据权利要求5所述的应用,其特征在于,所述药物的剂型为滴鼻剂、冲剂、颗粒剂、滴丸剂和软膏剂。
9.根据权利要求8所述的应用,其特征在于,所述滴鼻剂的制备方法为:将丁香酸与丙二醇混合,备用;把卡波姆放入生理盐水中溶解,溶解完成后加入水溶性氮酮,搅拌均匀,再加入丁香酸与丙二醇的混合溶液,调节pH为6~8,定容,灭菌,制备得到丁香酸滴鼻液。
10.根据权利要求5所述的应用,其特征在于,所述药物的给药形式为口服给药、黏膜给药和皮肤给药。
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