CN111686239A - 抗真菌化合物的应用 - Google Patents
抗真菌化合物的应用 Download PDFInfo
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- CN111686239A CN111686239A CN201910182059.XA CN201910182059A CN111686239A CN 111686239 A CN111686239 A CN 111686239A CN 201910182059 A CN201910182059 A CN 201910182059A CN 111686239 A CN111686239 A CN 111686239A
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- fatty liver
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Abstract
本发明提供了抗真菌化合物在制备治疗和/或预防代谢相关疾病药物或食品中的应用，所述的抗真菌化合物包括卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑。通过本发明的抗真菌药物及其药用盐制备的抑制剂、药物、食品或保健品无毒副作用，治疗效果显著。
Description
技术领域
本发明涉及抗真菌化合物新型治疗技术领域。
背景技术
代谢疾病是由于体内代谢紊乱而发生的疾病的总称。代谢疾病通常是由碳水化合物、脂质、蛋白质、维生素、电解质、水等的失衡而引起的。代谢疾病的实例包括肥胖症、高血糖、高血脂症、动脉硬化症、高血压、非酒精性脂肪性肝病等。随着社会的发展，人们生活水平的不断提高和饮食结构的调整，饮食呈富余化趋势，导致代谢类疾病的发病率不断提高，其中以高血糖以及高血脂最引人关注，目前全世界糖尿病人数为2亿人左右，并以惊人的速度每年递增。中国糖尿病人数为4千万，占世界糖尿病人群总数的1/5。另外，因血脂升高导致的动脉粥样硬化、冠心病等心血管疾病发病率逐年升高，并有年轻化趋势。降血糖、降血脂药物已经成为药物研究的重点之一。
随着微生物组计划的启动，肠道菌群与人体健康的关系受到广泛重视，以肠道菌群变化为切入点探讨代谢综合征的治疗和预防已成为研究热点。研究表明肠道元基因组与人体基因组相互作用，借助于神经递质、代谢产物、免疫信号、甚至基因表达等作用方式，调控许多疾病的发生和发展，如癌症、肥胖、糖尿病、非酒精性脂肪肝、心血管疾病、神经性病变等。肠道菌群是生活在我们机体内的特殊微生物，参与宿主的能量代谢,调控脂类、糖类、蛋白质类物质在肠道中的吸收。当菌群结构失调时，血液里内毒素LPS的浓度会增加，LPS进入循环系统，识别结合蛋白，促进CD14和TLR4的表达和炎症因子的产生，诱导肌肉和脂肪IRS1的丝氨酸磷酸化，继而阻断胰岛素在外周组织的传导，造成胰岛素抵抗。此外，肠道菌群失衡，会产生大量乙酸，激活副交感神经，促进胰岛素分泌，释放饥饿素，使能量摄入失衡，同时肠道fiaf基因表达受到抑制，造成脂肪堆积和肥胖。肠道菌群在代谢综合征的两个核心症状胰岛素抵抗和肥胖的发生发展中都发挥着非常重要的作用，已被证实是代谢综合征的元凶，或者是代谢类疾病的潜伏感染源。
但目前关于肠道菌群对代谢性疾病影响的研究主要集中在肠道细菌上，而肠道中另外一类重要共生者-肠道真菌对代谢性疾病的作用目前尚不清晰，有部分对于人体的研究表明肥胖及脂肪肝患者的肠道真菌发生了改变，但肠道真菌在肥胖、糖尿病、脂肪肝等代谢性疾病中的作用目前并不清楚，肠道真菌的干扰对代谢性疾病的影响尚无研究报道。我们发现卡泊芬净、两性霉素B、氟康唑、伊曲康唑及伏立康唑等抗真菌药物均可以显著改善糖尿病、高血脂、脂肪肝等代谢病疾病，证明了口服抗真菌药物对于代谢性疾病治疗的新用途。
发明内容
本发明提供了抗真菌化合物在制备治疗和/或预防代谢相关疾病药物或食品中的应用，所述的抗真菌化合物包括卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑。
进一步地，所述的代谢性疾病包括肥胖、高血糖、高血脂、非酒精性脂肪性肝病和酒精性脂肪肝病。
更进一步地，所述的非酒精性脂肪性肝病包括：单纯脂肪性病变的脂肪性肝病、非酒精性脂肪肝炎的脂肪性肝病、肝纤维化的脂肪性肝病。
通过本发明的抗真菌化合物及其药用盐制备的抑制剂、药物、食品或保健品无毒副作用，治疗效果显著。
附图说明
图1是非酒精性脂肪性肝病的肝脏观察和组织病理切片图。
图2是红色胶原纤维形成网状结构图。
图3是酒精性脂肪性肝病的肝脏观察和组织病理切片图。
具体实施方式
发明人经过广泛而深入的研究和实验，发现抗真菌药物卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑具有预防和治疗代谢相关疾病(包括肥胖、高血糖、高血脂、非酒精性脂肪性肝病)的作用，将含有卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑的单一化合物或组合物饲喂实验对象，发现均能够抑制体重增加，降低血糖，降低血脂、改善非酒精性脂肪性肝病、缓解非酒精性脂肪肝炎及肝纤维化症状，有效减轻糖尿病及肥胖等代谢性疾病病症。在此基础上完成本发明。
本发明提供了抗真菌药物在治疗和预防代谢相关疾病方面的用途。受试动物摄入高脂肪的食物，卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑均具有抑制该受试动物体重增加的能力。根据本发明的一个优选例，经卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑来治疗的被喂以可导致肥胖的高脂肪食物的C57BL/6J小鼠以及肥胖模型ob/ob小鼠，与未受治疗的对照组相比，可保持体重无任何增加，且有助于血糖、血脂下降，非酒精性脂肪性肝病症状的改善。因此，所述化合物能够用以预防和治疗肥胖及由肥胖引起的疾病如糖尿病、非酒精性脂肪性肝病等。
本发明还提供了一种组合物，优选地，为药物组合物。所述组合物包括有效量的卡泊芬净、两性霉素B、氟康唑、伊曲康唑、伏立康唑及其组合。
本发明药物组合物可以以药物片剂，针剂或胶囊的任一种形式给药，所述药物制剂包括赋形剂、药物允许的媒介和载体，这些物质可根据给药途径进行选择。本发明中的药物制剂可进一步包含辅助的活性组分。
乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖、淀粉、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、细结晶纤维素、聚乙烯吡咯烷酮(PVP)、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁或矿物油等都可用作本发明中药物组合物的载体、赋形剂或稀释剂等。
此外，本发明的药物组合物可进一步包括润滑剂、润湿剂、乳化剂、悬乳液稳定剂、防腐剂、甜味剂和香料等。本发明的药物组合物可通过多种公知的方法以肠衣制剂生产，以便于药物组合物的活性成分即微生物能顺利通过胃而不被胃酸所破坏。
本发明的组合物可制成肠衣片供口服使用。本申请中的术语-“肠衣”包括所有常规药物允许使用的包衣，这些包衣不被胃酸降解，但在小肠中能充分分解并快速释放出本发明的微生物。本发明的肠衣能在合成胃酸如pH＝1的HCl溶液中36-38℃维持2小时以上，并优选在合成肠液如pH＝7.0的缓冲液中在1.0小时内分解。
本发明的肠衣以每片约16-30mg进行包衣，较佳地16-25mg，更佳地16-20mg进行包衣。本发明中肠衣厚度为5-100μm，理想的厚度为20-80μm.肠衣成分自己公开知晓的常规聚合物。
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。
实施例1
抗真菌化合物对肥胖、糖尿病模型小鼠ob/ob血糖、血脂及体重影响
材料：被测化合物为卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)，每种药物选择三个灌胃剂量，分别为10mg/kg、50mg/kg、100mg/kg体重，频率为每日一次。
Ob/ob小鼠购自中国医学科学院北京协和医学院动物研究所，温度20-24摄氏度，恒湿50-60％，光照12小时(8:00-20:00)，隔音，自由摄食、饮水，适应环境一周后进行实验。血糖试纸(罗氏公司)、血糖仪(罗氏公司)、血清总胆固醇TC试剂盒(批号20131112)，低密度脂蛋白LDL-C试剂盒(批号20140114)，高密度脂蛋白HDL-C试剂盒(批号20140413)，甘油三酯TG试剂盒(批号20131226)购自南京建成生物工程研究所。
方法：雄性C57小鼠6-8周，体重30-32，10只，作为正常对照组(1)，雄性ob/ob小鼠6-8周，体重38-42，测定空腹血糖，依据血糖值和体重情况平均分组：(2)模型对照组，(3)Cas 10mg/kg，(4)Cas 50mg/kg，(5)Cas 100mg/kg，(6)Amp 10mg/kg，(7)Amp 50mg/kg，(8)Amp 100mg/kg，(9)FCZ 10mg/kg，(10)FCZ 50mg/kg，(11)FCZ 100mg/kg，(12)ICZ 10mg/kg，(13)ICZ 50mg/kg，(14)ICZ 100mg/kg，(15)VCZ 10mg/kg，(16)VCZ 50mg/kg，(17)VCZ100mg/kg，每组8只，连续给药5周。模型对照组给予等量的水。对照组和模型组给予等量的生理盐水。末次给药后，取血，4摄氏度3000rpm离心，测定血清总胆固醇TC，低密度脂蛋白LDL-C，甘油三酯TG。
结果：与对照组和模型组比较，卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)在不同剂量下均可以剂量依赖的显著控制体重，从第1周起即可降低自由饮食血糖及禁食(4小时)血糖，改善小鼠血脂情况，结果见表1-4。
表1抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对高血糖小鼠ob/ob的体重影响
表2抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对高血糖小鼠ob/ob的自由饮食血糖影响
表3抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对高血糖小鼠ob/ob的禁食血糖影响
表4抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对高血糖小鼠ob/ob的血脂影响
实施例2
抗真菌化合物对非酒精性脂肪性肝病的影响
材料：被测化合物为卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)，剂量选定为有效剂量50mg/kg，频率为每日一次。
雄性SPF级Wister大鼠60只，体重180-220g，购自维通利华实验动物中心。温度20-24摄氏度，恒湿50-60％，光照12小时(8:00-20:00)，隔音，自由摄食、饮水，适应环境一周后进行实验。血清总胆固醇TC试剂盒(批号20131112)，低密度脂蛋白LDL-C试剂盒(批号20140114)，高密度脂蛋白HDL-C试剂盒(批号20140413)，甘油三酯TG试剂盒(批号20131226)，谷草转氨酶ALT试剂盒(批号20131006)购自南京建成生物工程研究所。
方法：雄性SPF级Wister大鼠随机分组：(1)正常组；(2)模型对照组；(3)Cas 50mg/kg；(4)Amp 50mg/kg；(5)FCZ 50mg/kg；(6)ICZ 50mg/kg；(7)ICZ 100mg/kg；(8)VCZ 50mg/kg，每组10只。正常组大鼠标准饲料喂养，其余组大鼠每天喂食胆碱缺乏饲料(高脂饲料)，检测大鼠摄食量及体重。胆碱缺乏饲料喂养会诱发肝脏细胞变性、肝炎及肝损伤，同时血脂水平升高并诱发胰岛素抵抗，是常用的啮齿类动物脂肪肝的造模方法。
高脂饮食喂养8周后，给药组开始给药，连续给药4周。正常组和模型对照组给予等量的水。给药四周后，麻醉处死大鼠，取肝组织和血。
测定指标：1)肝脏指数。
2)测定血清总胆固醇、高密度脂蛋白、低密度脂蛋白及甘油三酯含量。
3)测定谷丙转氨酶、谷草转氨酶、羟脯氨酸含量，利用elisa试剂盒检测肝炎及肝纤维化TGFβ1及TNFα含量。
4)肝脏组织切片：末次给药后，麻醉处死，冰上取肝脏，并迅速放入福尔马林中固定，准备组织切片。
实验结果，与正常对照组比较，模型组肝指数显著升高，给予抗真菌药后各组能显著降低非酒精性脂肪性肝病大鼠的肝指数。同时模型组的TC、LDL-C、TG均显著升高，HDL-C显著降低，提示本模型造成明显的血脂紊乱，与模型组相比，给予五种抗真菌药物后均可降低非酒精性脂肪性肝病大鼠的血脂，同时还能改善肝功能，降低血浆ALT的含量，降低非酒精性脂肪肝炎指标TNFα及肝纤维化指标TGFβ1水平。
表5抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对非酒精性肝脏脂肪性病变的影响
表6抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对非酒精性肝炎及肝纤维化的影响
结合解剖时对肝脏大体的肉眼观察和组织病理切片的油红染色发现(图1)，模型组大鼠肝细胞内均有大量大小不等的脂肪空泡，形成脂肪肝，同时，天狼猩红染色发现模型组大鼠肝脏纤维化情况明显，红色胶原纤维形成网状结构(图2)。而卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)组中大鼠肝细胞内的甘油三酯脂滴及肝脏纤维化情况基本消失。
结果表明卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)均可以有效防治由于肥胖引起的的非酒精性脂肪性肝病。
实施例3
抗真菌化合物对酒精性脂肪性肝病的影响
材料：被测化合物为卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)，剂量选定为有效剂量50mg/kg，频率为每日一次。
C57BL/6J(9weeks，♂，SPF级)小鼠随机分成7组，每组12只，分组情况如下：(1)正常对照组Lieber-DeCarli对照液体饲料喂养(给予与给药组相同剂量的蒸馏水)；(2)模型组Lieber-DeCarli酒精液体饲料喂养(给予与给药组相同剂量的蒸馏水)；(3)卡泊芬净(Cas)50mg/kg剂量组Lieber-DeCarli酒精液体饲料喂养；(4)两性霉素B(Amp)50mg/kg剂量组Lieber-DeCarli酒精液体饲料喂养；(5)氟康唑(FCZ)50mg/kg剂量组Lieber-DeCarli酒精液体饲料喂养；(6)伊曲康唑(ICZ)50mg/kg剂量组Lieber-DeCarli酒精液体饲料喂养；(7)伏立康唑(VCZ)50mg/kg剂量组Lieber-DeCarli酒精液体饲料喂养；连续给药4周。正常组和模型对照组给予等量的水。给药四周后，麻醉处死大鼠，取肝组织和血。
测定指标：1)肝脏指数。
2)测定血清总胆固醇、高密度脂蛋白、低密度脂蛋白及甘油三酯含量。
3)测定谷丙转氨酶、谷草转氨酶、羟脯氨酸含量，利用elisa试剂盒检测肝炎及肝纤维化TGFβ1及TNFα含量。
4)肝脏组织切片：末次给药后，麻醉处死，冰上取肝脏，并迅速放入福尔马林中固定，准备组织切片。
实验结果，与正常对照组比较，给予液体酒精饲料组小鼠肝指数显著升高，给予抗真菌药后各组能显著降低酒精性脂肪性肝病小鼠的肝指数。同时模型组的TC、LDL-C、TG均显著升高，HDL-C显著降低，提示本模型造成明显的血脂紊乱，与模型组相比，给予五种抗真菌药物后均可降低酒精性脂肪性肝病小鼠的血脂，同时还能改善肝功能，降低血浆ALT的含量，降低非酒精性脂肪肝炎指标TNFα及肝纤维化指标TGFβ1水平。
表5抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对酒精性肝脏脂肪性病变的影响
表6抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)对酒精性肝炎及肝纤维化的影响
结合解剖时对肝脏大体的肉眼观察和组织病理切片的油红染色发现(图3)，模型组小鼠肝细胞内均有大量大小不等的脂肪空泡，形成脂肪肝。而卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)组中大鼠肝细胞内的甘油三酯脂滴基本消失。
结果表明卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)均可以有效防治由于酒精诱导的酒精性脂肪性肝病。
实施例4
抗真菌化合物与代谢性疾病治疗药物组合物对高血糖小鼠ob/ob血糖、体重、血脂及肝功能的影响
二甲双胍是目前临床上首选的降糖药物，主要通过降低肝糖输出，减少肠道对糖的吸收，增加外周血糖的摄取和利用，达到提高胰岛素的敏感性的作用，本发明中抗真菌药物与一线治疗药物组织使用可以显著增强其治疗效果。
材料：被测化合物为卡泊芬净(Cas)、两性霉素B(Amp)、氟康唑(FCZ)、伊曲康唑(ICZ)、伏立康唑(VCZ)的有效剂量50mg/kg以及二甲双胍(100mg/kg)的联合用药。
Ob/ob小鼠购自中国医学科学院北京协和医学院动物研究所，温度20-24摄氏度，恒湿50-60％，光照12小时(8:00-20:00)，隔音，自由摄食、饮水，适应环境一周后进行实验。血糖仪为德国罗氏公司产品。
方法：雄性C57小鼠6-8周，体重30-32，10只，作为正常对照组(1)；
雄性ob/ob小鼠6-8周，体重38-42g，测定空腹血糖，依据血糖值和体重情况平均分组：
(2)模型对照组；
(3)卡泊芬净(Cas)50mg/kg；
(4)两性霉素B(Amp)50mg/kg；
(5)氟康唑(FCZ)50mg/kg；
(6)伊曲康唑(ICZ)50mg/kg；
(7)伏立康唑(VCZ)50mg/kg；
(8)二甲双胍(Met)100mg/kg；
(9)卡泊芬净(Cas)50mg/kg+二甲双胍(Met)100mg/kg；
(10)两性霉素B(Amp)50mg/kg+二甲双胍(Met)100mg/kg；
(11)氟康唑(FCZ)50mg/kg+二甲双胍(Met)100mg/kg；
(12)伊曲康唑(ICZ)50mg/kg+二甲双胍(Met)100mg/kg；
(13)伏立康唑(VCZ)50mg/kg+二甲双胍(Met)100mg/kg；
每组8只，连续给药5周。模型对照组给予等量的水。
抗真菌药物与二甲双胍的组合效果：
测定指标：1)对体重和血糖的影响：给药第7天、14天、21天、28天、35天称量体重并记录，给药后尾尖取血测血糖值(见表5)。
4)末次给药后，麻醉处死，取血，4摄氏度3000rpm离心，测定血清总胆固醇TC，低密度脂蛋白LDL-C，甘油三酯TG，谷丙转氨酶、谷草转氨酶。
实验结果表明抗真菌药物对高血糖小鼠的代谢紊乱的治疗效果在与二甲双胍联用后更为显著，可以用于制备治疗II型糖尿病、降血脂、肥胖的药物或与其它药物合用治疗II型糖尿病、肥胖、高血脂或在治疗过程中/后起辅助作用。
表9抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)与二甲双胍组合物对高血糖小鼠ob/ob血糖与体重的影响
与对照组和模型组比较，抗真菌药及组合物可以显著改善小鼠血脂情况，对小鼠血清ALT也有很好的逆转作用，提示可以保护高血脂造成的肝损伤结果见表10。
表10.抗真菌药物(Cas,Amp,FCZ,ICZ,VCZ)与二甲双胍组合物对高血糖小鼠ob/ob的血脂和肝功能影响
Claims (3)
1.抗真菌化合物及其药用盐在制备预防和/或治疗代谢性疾病药物、保健品或食品中的应用，其特征在于，
所述的抗真菌化合物包括：卡泊芬净、两性霉素、氟康唑、伊曲康唑、伏立康唑。
2.根据权利要求1所述的的应用，其特征在于，
所述的代谢性疾病包括肥胖、高血糖、高血脂、非酒精性脂肪性肝病和酒精性脂肪肝病。
3.根据权利要求2所述的应用，其特征在于，
所述的非酒精性脂肪性肝病包括：单纯脂肪性病变的脂肪性肝病、非酒精性脂肪肝炎的脂肪性肝病、肝纤维化的脂肪性肝病。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117551596A (zh) * | 2024-01-11 | 2024-02-13 | 云南大学 | 一种解除土壤对生防真菌抑菌作用的方法 |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050031544A1 (en) * | 2003-08-07 | 2005-02-10 | Njemanze Philip Chidi | Receptor mediated nanoscale copolymer assemblies for diagnostic imaging and therapeutic management of hyperlipidemia and infectious diseases |
| US20050049208A1 (en) * | 2003-09-03 | 2005-03-03 | Kaufmann Doug A. | Method of treating and method of preventing diabetes |
| CN101405003A (zh) * | 2006-03-17 | 2009-04-08 | Cv医药有限公司 | 利用a2b腺苷受体拮抗剂预防和治疗肝病的方法 |
| CN101522196A (zh) * | 2006-08-07 | 2009-09-02 | 博士伦公司 | 用组合的分离的糖皮质激素受体激动剂和抗感染剂治疗感染及其后遗症 |
| CN101951936A (zh) * | 2008-02-26 | 2011-01-19 | 康奈尔大学 | 用于防止和治疗急性肾损伤的方法 |
| CN103189374A (zh) * | 2010-08-12 | 2013-07-03 | 杏林制药株式会社 | 非酒精性脂肪肝炎的预防或治疗剂 |
| CN106581680A (zh) * | 2015-10-16 | 2017-04-26 | 山东亨利医药科技有限责任公司 | 一种降低药物吸收受食物影响的药物组合物 |
-
2019
- 2019-03-11 CN CN201910182059.XA patent/CN111686239B/zh active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050031544A1 (en) * | 2003-08-07 | 2005-02-10 | Njemanze Philip Chidi | Receptor mediated nanoscale copolymer assemblies for diagnostic imaging and therapeutic management of hyperlipidemia and infectious diseases |
| US20050049208A1 (en) * | 2003-09-03 | 2005-03-03 | Kaufmann Doug A. | Method of treating and method of preventing diabetes |
| CN101405003A (zh) * | 2006-03-17 | 2009-04-08 | Cv医药有限公司 | 利用a2b腺苷受体拮抗剂预防和治疗肝病的方法 |
| CN101522196A (zh) * | 2006-08-07 | 2009-09-02 | 博士伦公司 | 用组合的分离的糖皮质激素受体激动剂和抗感染剂治疗感染及其后遗症 |
| CN101951936A (zh) * | 2008-02-26 | 2011-01-19 | 康奈尔大学 | 用于防止和治疗急性肾损伤的方法 |
| CN103189374A (zh) * | 2010-08-12 | 2013-07-03 | 杏林制药株式会社 | 非酒精性脂肪肝炎的预防或治疗剂 |
| CN106581680A (zh) * | 2015-10-16 | 2017-04-26 | 山东亨利医药科技有限责任公司 | 一种降低药物吸收受食物影响的药物组合物 |
Non-Patent Citations (1)
| Title |
|---|
| 李同林等: "伏立康唑联合卡泊芬净序贯治疗拟诊侵袭性肺真菌病患者的疗效", 《湖南师范大学学报（医学版）》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117551596A (zh) * | 2024-01-11 | 2024-02-13 | 云南大学 | 一种解除土壤对生防真菌抑菌作用的方法 |
| CN117551596B (zh) * | 2024-01-11 | 2024-03-29 | 云南大学 | 一种解除土壤对生防真菌抑菌作用的方法 |
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