CN113384570A - 咖啡酸甲酯及与三唑类组合物在制备抗真菌产品中的应用 - Google Patents
咖啡酸甲酯及与三唑类组合物在制备抗真菌产品中的应用 Download PDFInfo
- Publication number
- CN113384570A CN113384570A CN202110789898.5A CN202110789898A CN113384570A CN 113384570 A CN113384570 A CN 113384570A CN 202110789898 A CN202110789898 A CN 202110789898A CN 113384570 A CN113384570 A CN 113384570A
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- Prior art keywords
- triazole
- antifungal
- caffeic acid
- methyl ester
- acid methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 230000000843 anti-fungal effect Effects 0.000 title claims abstract description 45
- MAEVSPLUELJOMM-UHFFFAOYSA-N caffeic acid methyl ester Natural products COC(=O)C=CC1=CC=C(O)C=C1O MAEVSPLUELJOMM-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 229940121375 antifungal agent Drugs 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
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- 241000222126 [Candida] glabrata Species 0.000 claims abstract description 17
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- JXRYDOZRPYFBKO-UHFFFAOYSA-N 3,4-dimethoxy-cinnamic acidmethyl ester Natural products COC(=O)C=CC1=CC=C(OC)C(OC)=C1 JXRYDOZRPYFBKO-UHFFFAOYSA-N 0.000 claims description 30
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 27
- 229960004130 itraconazole Drugs 0.000 claims description 27
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 claims description 25
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/36—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids
- A01N37/38—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a singly bound oxygen or sulfur atom attached to the same carbon skeleton, this oxygen or sulfur atom not being a member of a carboxylic group or of a thio analogue, or of a derivative thereof, e.g. hydroxy-carboxylic acids having at least one oxygen or sulfur atom attached to an aromatic ring system
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/37—Esters of carboxylic acids
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Abstract
本公开属于抗真菌药物联合用药技术领域,具体提供咖啡酸甲酯及与三唑类组合物在制备抗真菌产品中的应用。具体提供咖啡酸甲酯在制备抗真菌药物中的应用,所述真菌为非白色念珠菌,优选为光滑念珠菌或克柔念珠菌或二者混合菌。解决现有技术中抗真菌药物主要采用三唑类药物,导致耐药率不断上升的问题。
Description
技术领域
本公开属于抗真菌药物联合用药技术领域,具体提供咖啡酸甲酯及与三唑类组合物在制备抗真菌产品中的应用。
背景技术
这里的陈述仅提供与本公开有关的背景信息,而不必然构成现有技术。
近年来,真菌感染在临床上呈现出逐年上升的态势,可在各个不同年龄段发生,而且不合理用药产生的真菌耐药现象越来越突出,尤其真菌对唑类药物耐药率更是高达65%,其中念珠菌是呼吸系统、血流感染、消化系统、泌尿系统真菌感染的常见分离菌。资料显示,非白色念珠菌耐药的问题尤其突出。目前临床可用的抗真菌药物品种有限,且大多价格昂贵、毒副作用明显,使得非抗真菌药物与抗真菌药物的联合应用研究备受关注。
三唑类抗真菌药物,相比于两性霉素B和5-氟胞嘧啶等抗真菌药物,抗菌活性更强、毒性更低、生物利用度高,其中氟康唑安全、有效且价格低廉,在临床上使用广泛,因此在抗真菌感染治疗中应用非常广泛,然而发明人发现,近年来也因其大量使用而导致真菌对三唑类药物的耐药率不断上升。
咖啡酸甲酯(Methyl Caffeate,MC)是从天然菊科、毛茛科等植物中提取后经氧化而成的酯类衍生物。近年来有研究表明,咖啡酸甲酯具有多种药理作用。
发明内容
针对现有技术中抗真菌药物主要采用三唑类药物,导致耐药率不断上升的问题。
本公开一个或一些实施方式中,提供咖啡酸甲酯在制备抗真菌药物中的应用。
本公开一个或一些实施方式中,提供一种抗真菌药物组合物,包括咖啡酸甲酯和三唑类药物。
本公开一个或一些实施方式中,提供咖啡酸甲酯在制备抗真菌产品中的应用。
本公开一个或一些实施方式中,提供上述抗真菌药物组合物在制备消炎洗护用品中的应用。
上述技术方案中的一个或一些技术方案具有如下优点或有益效果:
1)咖啡酸甲酯作为一种天然产物,现有技术中针对咖啡酸甲酯治药理作用的研究较多,但未见将咖啡酸甲酯与三唑类抗真菌药物联合应用于抗真菌治疗的报道。本公开首次提出咖啡酸甲酯与三唑类抗真菌药物联合用于抗真菌治疗,且研究结果表明低剂量的咖啡酸甲酯便能够显著降低三唑类药物的用量,有望成为一种效果良好的复合制剂。
2)本公开证明了咖啡酸甲酯与三唑类药物对耐药型非白色念珠菌的特异性抑制作用有望为将来的临床治疗提供新的治疗方式,避免了由于非白色念珠菌耐药程度的提高,导致三唑类药物滥用,研究表明咖啡酸甲酯与三唑类药物联合对耐药型非白色念珠菌具有良好的抑制效果,低剂量的咖啡酸甲酯可使三唑类药物对耐药的非白色念珠菌的MIC降低4-128倍,有效提升真菌对药物的敏感性,减少药物治疗用量,降低机体耐药概率。对于非白色念珠菌耐药的机制也提供了相应的研究材料,具有重要的意义。
具体实施方式
下面将对本公开实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本公开的一部分实施例,而不是全部实施例。基于本公开的实施例,本领域技术人员在没有做出创造性劳动前提下所获得的所有其它实施例,都属于本公开保护的范围。
正如背景技术所介绍的,非白色念珠菌是一种常见的院内血流感染真菌,是死亡率很高的致病菌。目前临床常用的抗真菌药物品种有限,其中三唑类药物具有较强的抗菌活性、较低的毒性及生物利用度,在抗真菌感染治疗中有着广泛的应用。然而近些年来的大量使用导致真菌对三唑类药物的耐药率不断上升,抗耐药真菌的治疗具有重要意义。咖啡酸甲酯作为一种天然产物,对其药理作用的研究较多。发明人针对咖啡酸甲酯与三唑类药物的联合应用展开了研究,研究表明咖啡酸甲酯能够显著降低三唑类药物的最小抑菌浓度,针对耐药型的非白色念珠菌具有良好的抑制效果,在耐药型非白色念珠菌的抑制作用中表现出协同作用,为耐药型真菌感染的治疗提供了新的治疗思路。
本公开一个或一些实施方式中,提供咖啡酸甲酯在制备抗真菌药物中的应用。咖啡酸甲酯是一种化学物质,分子式是C10H10O4,分子量为194.184。现有技术中对于咖啡酸酯类及其衍生物有所研究,尤其是针对咖啡酸苯乙酯。
本公开通过实验验证了咖啡酸甲酯具有抗真菌活性,尤其具备抗非白色念珠菌活性,现有技术中的咖啡酸酯类,大多具备抗白色念珠菌活性,如咖啡酸乙酯、咖啡酸丙酯、咖啡酸丁酯均具备抗白色念珠菌活性,但现有技术中从未研究过咖啡酸酯类化合物在非白色念珠菌中的抗菌性能,因此,本专利针对非白色念珠菌的进行研究。
目前,现有技术中尚无咖啡酸酯类与其它药物联用抗菌的记载,本公开主要创造性之一在于,针对咖啡酸甲酯与三唑类抗真菌药物联用对抗非白色念珠菌的研究。
优选的,所述真菌为非白色念珠菌,非白色念珠菌包括近平滑念珠菌、热带念珠菌、光滑念珠菌和克柔念珠菌等,人体感染非白色念珠菌主要表现为肺部真菌感染、皮肤红肿痛痒等症状,目前临床常用三唑类药物治疗非白色念珠菌感染,但随着三唑类药物的使用,非白色念珠菌的耐药性逐渐提高。且三唑类药物由于体内代谢时间长、毒性小作为抗真菌药物被广泛使用。抗真菌治疗过程中,伴随着耐药株的出现,往往需要不断提高抗真菌药物的用量,加重肝肾负担,不利于治疗的继续进行。应当理解的是,由于本公开通过实验证实了咖啡酸甲酯具有抗非白色念珠菌活性,因此,咖啡酸甲酯应当可以治疗多种因非白色念珠菌导致的疾病。
优选为光滑念珠菌或克柔念珠菌或二者混合菌。
优选的,所述真菌为敏感型非白色念珠菌,敏感含义为按照《临床和实验室标准协会》M27-A3(Clinical and Laboratory Standards Institute M27-A3)菌株对三唑类药物敏感;
优选的,所述真菌为耐药型非白色念珠菌,耐药含义为按照《临床和实验室标准协会》M27-A3(Clinical and Laboratory Standards Institute M27-A3)菌株对三唑类药物具有耐药性;
本公开一个或一些实施方式中,提供一种抗真菌药物组合物,包括咖啡酸甲酯和三唑类药物。两者的联用对耐药型的非白色念珠菌表现出协同作用,咖啡酸甲酯加入可以显著的降低三唑类药物的最小抑菌浓度。但对于敏感型非白色念珠菌,咖啡酸甲酯与三唑类药物显示无关作用,实现同等抑制效果,咖啡酸甲酯的加入对三唑类药物的用量无影响。该研究结果表明咖啡酸甲酯与三唑类抗真菌药物的联用有望应用于临床耐药真菌的治疗,可以显著降低三唑类药物的用量,有望成为一种针对耐药型菌株的复合制剂,降低药物不良反应,减少耐药真菌的进一步出现。
所述三唑类药物包括氟康唑、伊曲康唑、伏立康唑、泊沙康唑等,三唑类药物抗菌谱广,大多对于深部感染或浅部感染均有效,抗菌种类重合较多,因此,虽然本公开仅进行了咖啡酸甲酯与伊曲康唑、伏立康唑联用实验,但应当理解的是,咖啡酸甲酯可以与多种三唑类药物联用。
优选的,所述抗真菌药物组合物剂型选自口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液,用于胃肠外注射的无菌溶液、悬浮液或乳液,用于外用的软膏、乳膏或凝胶剂,或者用于直肠给药的栓剂。
优选的,所述三唑类药物为伊曲康唑或伏立康唑;
优选的,所述三唑类药物为伊曲康唑,所述伊曲康唑的最小抑菌浓度为1μg/mL,咖啡酸甲酯的最小抑菌浓度为2μg/mL;
或,所述三唑类药物为伏立康唑,所述伏立康唑的最小抑菌浓度为2μg/mL,咖啡酸甲酯的最小抑菌浓度为0.25μg/mL。
优选的,咖啡酸甲酯在体外的抑菌浓度为32~0.5μg/mL;优选的,所述体外环境为细胞悬液。
优选的,所述三唑类药物为伊曲康唑,所述伊曲康唑在体外的抑菌浓度为128~0.25μg/mL,
或,所述三唑类药物为伏立康唑,所述伏立康唑在的抑菌浓度为16~0.125μg/mL。
由于本公开只进行了体外抑菌实验,因此,在此限定体外抑菌浓度,本领域技术人员可以在此实验基础上进行动物或人体实验,由此换算成动物体或人体服用剂量,也应当在本公开保护的范围之内。
优选的,所述真菌为耐药型克柔念珠菌,所述伊曲康唑用药剂量在1μg/mL以上、咖啡酸甲酯的浓度在2μg/mL以上。
高于上述浓度范围,可能会导致副作用,所述副作用包括,皮肤红肿、头晕恶心,呕吐、血压升高等。低于上述浓度范围,可能无法起到对应的抗菌作用。
在一些实施方式中,如症状为轻度小型感染,低于上述范围下限的剂量水平可能已经是足够的。
在其它实施方式中,如重度大型感染,可能需要高于上述范围上限的剂量水平。
优选的,所述真菌为非白色念珠菌,优选为光滑念珠菌或克柔念珠菌或二者混合菌;
或,所述真菌为耐药型非白色念珠菌,耐药含义为对三唑类药物具有耐药性。
优选的,还包括其它活性成分,所述其他活性成分包括中成药及化学实体药物;其中,所述中成药包括白令胶囊、丹七软胶囊、血府逐瘀口服液、至灵菌丝胶囊、六味地黄丸;所述化学实体药物包括但不限于强的松、钙尔奇、雷贝拉唑、美卓乐、尼达尼布、吡非尼酮。
通常情况下,中成药或其它化学实体药物对于本公开所述的药物组合物具有辅助吸收等作用。
本公开一个或一些实施方式中,提供咖啡酸甲酯在制备抗真菌产品中的应用,优选的,所述抗真菌产品包括毛巾、家纺、内衣。
本公开一个或一些实施方式中,提供上述抗真菌药物组合物在制备消炎洗护用品中的应用,优选的,所述消炎洗护用品包括沐浴露、洗面奶、洗发水、男女性私处护理液、泡脚水。
实施例1咖啡酸甲酯与三唑类联合抗真菌作用测定
1.材料
1.1药品与试剂
咖啡酸甲酯(Methyl Caffeate,MC),大连美仑生物技术有限公司;
伊曲康唑(itraconazole,ITR),大连美仑生物技术有限公司;
伏立康唑(voriconazole,VRC),大连美仑生物技术有限公司;
科玛嘉念珠菌显色培养基,郑州博赛生物工程有限公司;
TTC-沙保罗培养基,青岛高科技园海博生物技术有限公司;
酵母膏,北京奥博星生物技术有限责任公司;
蛋白胨,北京奥博星生物技术有限责任公司;
葡萄糖,国药集团化学试剂有限公司;
琼脂粉,北京鼎国昌盛生物技术有限责任公司;
PBS磷酸盐缓冲剂,北京鼎国昌盛生物技术有限责任公司;
氢氧化钠,国营山东单县有机化工厂,批号940420;
磷酸二氢钾,上海新宝精细化工厂,批号200602132。
RPMI 1640原料药粉,美国GIBCO公司;
二甲基亚砜,北京鼎国昌盛生物技术有限责任公司。
药物溶液:来氟米特、伊曲康唑及伏立康唑分别用二甲基亚砜溶解,配成2560μg/mL的储备液,过滤分装。所有药液于-20℃冰箱保存,备用。
PBS缓冲液:称取12gPBS磷酸盐缓冲剂至1L容量瓶,加入蒸馏水搅拌使其完全溶解,再加蒸溜水至刻度线,分装到试剂瓶后在121℃下高压灭菌30min,冷却后放4℃冰箱保存。
酵母浸膏-蛋白胨-葡萄糖琼脂培养基:葡萄糖10g,蛋白胨10g,酵母膏5g,琼脂粉10g,加水溶解在500mL锥形瓶中,充分搅拌均匀后121℃灭菌30min,冷却后4℃冰箱保存备用。
RPMI 1640液体培养液:取RPMI 1640(含L-谷氨酰胺,不含碳酸氢钠)粉末2.08g,加入10%葡萄糖溶液40ml(含糖终浓度2%)及MOPS粉6.906g,加蒸馏水至约为200mL,混合均匀后在22℃用1mol/L的NaOH溶液调pH约为7.0±0.1,临用前用0.22μm混合纤维膜过滤灭菌。
1.2仪器
1.3实验菌株
质控菌株:白色念珠菌ATCC10231,山东大学药理教研室惠赠;
实验菌株:光滑念珠菌4株,克柔念珠菌4株;
菌株鉴定:实验用菌株经山东省疾病预防控制中心微生物研究室以标准微生物学方法鉴定。
菌液制备:-20℃下保存的非白色念珠菌(光滑念珠菌和克柔念珠菌)室温下解冻,接种到TTC-沙保罗琼脂培养基上,35℃培养24h,取发育良好的单一菌落再次接种,35℃培养24h,以保证菌株处于生长期。选取若干单个较大菌落,PBS配制成菌悬液,经涡旋器振荡均匀后以中国细菌浊度标准管比浊,调整样品管与标准管浊度一致,此时菌浓度约为1×106CFU/mL,系列稀释即得到工作菌液,并以活菌计数进行浓度验证。
2.内容与方法
2.1咖啡酸甲酯与三唑类联合抗耐药的非白色念珠菌作用测定
根据CLSI M27-A3方案的棋盘法,以RPMI-1640液体培养基稀释药液使其成为4倍工作浓度,筛选咖啡酸甲酯与三唑类联合应用的浓度范围,即咖啡酸甲酯终浓度为32~0.5μg/mL,伊曲康唑的终浓度为128~0.25μg/mL,伏立康唑的终浓度为16~0.125μg/mL。按浓度从低到高的顺序分别吸取三唑类药液50μL,分别加入96孔平板的第2~11列,按浓度从低到高的顺序吸取咖啡酸甲酯药液50μL,分别加入各96孔平板的第G~A行,除第12列外各孔再分别加100μL菌液,其余不足200μL的孔用RPMI-1640培养液补足。其中H1为生长对照,只含菌液不含药物,第12列为空白对照,只含RPMI-1640液体培养基。根据CLSI M27-A3方案的要求,将加入伊曲康唑或伏立康唑的96孔平板置35℃恒温培养箱中培养48h后,用肉眼观察结果并记录最低抑菌浓度。所有实验重复三次。
2.2评价方法与结果判定-Loewe additivity理论
Loewe additivity(LA)理论的基本思想认为药物不可能和它本身发生相互作用,因此将药物单用或联用产生相同药效的浓度(等效位点)进行比较。其分析方法分数抑菌浓度指数法(fractional inhibitory concentration index,FICI),表述如下:
ΣFIC=FICA+FICB=CA/MICA+CB/MICB
MICA和MICB分别是药物A和B单用时的最小抑菌浓度,CA与CB为两药联用时达到相同药效时各自的浓度。FICI>4为拮抗作用,FICI在0.5与4之间为相加或无关作用,FICI≤0.5定义为协同作用。
3.结果
FICI模型的评价指标为FICI值,FICI≤0.5则定义为协同作用。由表1-3可以看出,各组合的FICI值均小于0.5,表现为较强的协同作用。
表1咖啡酸甲酯单用或与伊曲康唑联用对抗非白色念珠菌的作用
aITR:伊曲康唑;MC:咖啡酸甲酯;CG:光滑念珠菌;CK:克柔念珠菌;R:耐药株;S:敏感株;
bMIC值是三次独立实验的平均值,A:伊曲康唑,B:咖啡酸甲酯;
c对FICI值的解释是:FICI≤0.5为协同作用,FICI>4.0为拮抗作用,0.5<FICI≤4.0为无关作用。
从表1中可以看出,咖啡酸甲酯与伊曲康唑联用对耐药型的光滑念珠菌或克柔念珠菌具有协同效果,但是咖啡酸甲酯与伊曲康唑联用对敏感型的光滑念珠菌或克柔念珠菌不具有协同效果。
从表1还可以看出,当菌株为光滑念珠菌CG时,单用相对于联合用药,咖啡酸甲酯与伊曲康唑均对于耐药型菌株的最低抑菌浓度更高,因此,联合用药在降低伊曲康唑用量的同时,也降低了咖啡酸甲酯的用量。
当菌株为克柔念珠菌CK时,规律相同,联合用药可以降低咖啡酸甲酯与伊曲康唑的最低抑菌浓度,显然二者联合用药具有协同性,可以大大降低二者用量。
表2咖啡酸甲酯单用或与伏立康唑联用对抗非白色念珠菌的作用
aVRC:伏立康唑;MC:咖啡酸甲酯;CG:光滑念珠菌;CK:克柔念珠菌;R:耐药株;S:敏感株;
bMIC值是三次独立实验的平均值,A:伏立康唑,B:咖啡酸甲酯;
c对FICI值的解释是:FICI≤0.5为协同作用,FICI>4.0为拮抗作用,0.5<FICI≤4.0为无关作用。
从表2中可以看出,咖啡酸甲酯与伏立康唑联用对耐药型的光滑念珠菌或克柔念珠菌具有协同效果,但是咖啡酸甲酯与伏立康唑联用对敏感型的光滑念珠菌或克柔念珠菌不具有协同效果。
从表2还可以看出,当菌株为光滑念珠菌CG时,单用相对于联合用药,咖啡酸甲酯与伏立康唑均对于耐药型菌株的最低抑菌浓度更高,因此,联合用药在降低伏立康唑用量的同时,也降低了咖啡酸甲酯的用量。
当菌株为克柔念珠菌CK时,规律相同,联合用药可以降低咖啡酸甲酯与伏立康唑的最低抑菌浓度,显然二者联合用药具有协同性,可以大大降低二者用量。
从上述实验及分析来看,发明人在研究过程中,对于多个咖啡酸甲酯的联合用量进行了尝试,结果证明咖啡酸甲酯与三唑类药物联用对耐药型的非白色念珠菌具有协同效果,但是咖啡酸甲酯与三唑类药物联用对敏感型的非白色念珠菌不具有协同效果。
以上所揭露的仅为本公开的优选实施例而已,当然不能以此来限定本公开之权利范围,因此依本公开申请专利范围所作的等同变化,仍属本公开所涵盖的范围。
Claims (10)
1.咖啡酸甲酯在制备抗真菌药物中的应用。
2.如权利要求1所述的应用,其特征在于,所述真菌为非白色念珠菌,优选为光滑念珠菌或克柔念珠菌或二者混合菌。
3.如权利要求1所述的应用,其特征在于,所述真菌为敏感型非白色念珠菌,敏感含义为对三唑类药物敏感;
或,所述真菌为耐药型非白色念珠菌,耐药含义为对三唑类药物具有耐药性;
4.一种抗真菌药物组合物,其特征在于,包括咖啡酸甲酯和三唑类药物。
5.如权利要求4所述的抗真菌药物组合物,其特征在于,所述抗真菌药物组合物剂型选自口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液,用于胃肠外注射的无菌溶液、悬浮液或乳液,用于外用的软膏、乳膏或凝胶剂,或者用于直肠给药的栓剂。
6.如权利要求4所述的抗真菌药物组合物,其特征在于,所述三唑类药物为伊曲康唑或伏立康唑;
优选的,所述三唑类药物为伊曲康唑,所述伊曲康唑的最小抑菌浓度为1μg/mL,咖啡酸甲酯的最小抑菌浓度为2μg/mL;
或,所述三唑类药物为伏立康唑,所述伏立康唑的最小抑菌浓度为2μg/mL,咖啡酸甲酯的最小抑菌浓度为0.25μg/mL
优选的,咖啡酸甲酯在体外的抑菌浓度为32~0.5μg/mL;优选的,所述体外环境为细胞悬液。
优选的,所述三唑类药物为伊曲康唑,所述伊曲康唑在体外的抑菌浓度为128~0.25μg/mL,
或,所述三唑类药物为伏立康唑,所述伏立康唑在的抑菌浓度为16~0.125μg/mL;
优选的,所述真菌为耐药型克柔念珠菌,所述伊曲康唑用药剂量在1μg/mL以上、咖啡酸甲酯的浓度在2μg/mL以上。
7.如权利要求4所述的抗真菌药物组合物,其特征在于,所述真菌为非白色念珠菌,优选为光滑念珠菌或克柔念珠菌或二者混合菌;
或,所述真菌为耐药型非白色念珠菌,耐药含义为对三唑类药物具有耐药性。
8.如权利要求4所述的抗真菌药物组合物,其特征在于,还包括其它活性成分,所述其他活性成分包括中成药及化学实体药物;其中,所述中成药包括白令胶囊、丹七软胶囊、血府逐瘀口服液、至灵菌丝胶囊、六味地黄丸;所述化学实体药物包括但不限于强的松、钙尔奇、雷贝拉唑、美卓乐、尼达尼布、吡非尼酮。
9.咖啡酸甲酯在制备抗真菌产品中的应用,优选的,所述抗真菌产品包括毛巾、家纺、内衣。
10.权利要求4-8任一项所述的抗真菌药物组合物在制备消炎洗护用品中的应用,优选的,所述消炎洗护用品包括沐浴露、洗面奶、洗发水、男女性私处护理液、泡脚水。
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