协同氟康唑抗耐药白念珠菌化合物的设计合成及活性研究

目的 基于前期研究的胡椒乙胺和咖啡酸类化合物分别具有协同氟康唑(FCZ)抗耐药真菌的作用,将两类化合物结构片段通过适当的连接子连接,设计合成新型化合物,研究其体外抗耐药真菌活性。方法 以胡椒乙胺为起始原料,与叔丁氧羰基保护的氨基酸缩合,随后脱保护基,再与咖啡酸缩合,形成目标化合物。对4个中间体和9个目标化合物进行体外协同FCZ抗耐药白念珠菌作用评价。结果 9个目标化合物均具有协同FCZ(8.0μg/ml)抗耐药白念珠菌活性,MIC₈₀为0.5~2.0μg/ml;其中, 3b、3f、3g、3i等化合物的MIC₈₀均为0.5μg/ml,与对照化合物7b和5相当。结论 将胡椒乙胺和咖啡酸通过4-哌啶甲酸(3b)、缬氨酸(3g)、亮氨酸(3f)、异亮氨酸(3i)连接,可以获得协同FCZ抗耐药真菌的高活性化合物。     

吡喃鎓衍生物N2的体外抗真菌活性研究

目的 研究N2系列化合物的抗真菌作用。方法 利用微量液基稀释法考察化合物N2系列化合物的体外抗真菌活性；在菌丝和被膜诱导条件下考察N2化合物对白念珠菌菌丝和被膜形成的抑制效果。结果 N2化合物对临床常见条件致病真菌白念珠菌有明显抗真菌活性；N2化合物可以明显抑制白念珠菌菌丝生长和被膜的形成；N2化合物可以通过损伤白念珠菌细胞膜和细胞壁发挥杀菌作用。结论 N2化合物具有较为广泛的抗真菌谱，能起到明显的体外抗真菌效果，对真菌菌丝和生物被膜的形成均有明显的抑制作用，可以认为N2化合物具有抗真菌潜力，可作为先导化合物，指导进一步改造。筛选获得了具有抗真菌活性的N2化合物，为抗真菌药物研发和解决真菌耐药问题提供新思路。     

米诺环素对白念珠菌抗菌活性的实验室研究

目的 探究米诺环素在白念珠菌感染中的体外抗菌活性.方法 用K-B纸片扩散法对临床标本分离出的白念珠菌进行抗菌药物包括米诺环素的药敏试验,观察并记录所有药敏试验中,米诺环素的敏感程度及敏感率.结果 发现32种抗菌药物中只有米诺环素对自念珠菌有抑菌环,有抑菌环并且直径14mm以上的占41%.结论 米诺环素在体外具有抗真菌药的活性.     

14种中草药体外抗白念珠菌作用研究

目的探讨14种中草药对白念珠菌的抗菌作用。方法将黄连、黄柏、虎杖、丁香、石榴皮、七叶一枝花、五倍子、白头翁、仙鹤草、连翘、金银花、苦参、蛇床子、诃子等14味中药材制备成醇浸膏,采用倍比稀释法,将醇浸膏分别稀释成1 000.00,500.00,250.00,125.00,62.50,31.25 mg.mL-1的溶液,采用平板打孔法和平板稀释法分别测定14种中草药体外抗白念珠菌的效果。结果黄连的最小抑菌浓度为6.25 mg.mL-1,黄柏、虎杖的最小抑菌浓度为25.00mg.mL-1,丁香、石榴皮、七叶一枝花、五倍子的最小抑菌浓度为50.00 mg.mL-1。未见其他药物体外对白念珠菌有明显抑制作用。结论黄连醇浸膏体外对白念珠菌有明显抑制作用,虎杖、黄柏、丁香、石榴皮、七叶一枝花、五倍子的醇浸膏体外对白念珠菌有一定的抑菌作用。     

蜂胶抗肿瘤活性成分的研究

采用溶媒萃取法和硅胶柱层析法从蜂胶中获得了两种具有抗肿瘤活性的组分PPLCC和PPLSE,体外抗肿瘤细胞人肝癌细胞(HepG2)和人口腔癌细胞(KB)试验表明,浓度为50μg/ml的PPLCC和PPLSE对HepG2细胞的抑制率分别达87.4%和35.1%,IC50分别为17.5μg/ml和1151.2μg/ml;对KB细胞的抑制率分别为84.9%和59.8%,IC50分别为21.0μg/ml和33.6μg/ml。结果表明,蜂胶可作为抗肿瘤活性物质的天然来源。     

不同标本类型中分离出白念珠菌对抗真菌药物敏感性分析

目的 探讨从不同类型标本中分离的白念珠菌菌株对常用抗真菌药物的耐药谱，为临床白念珠菌感染性疾病诊断和治疗提供理论和实验依据。方法 用真菌鉴定卡及Rosco真菌药敏纸片对分离出的所有白念珠菌作菌种鉴定和药敏实验，采用μ检验分析从男性生殖道分泌物、女性生殖道分泌物和痰液中分离出白念珠菌的药物敏感特点。结果 从痰液中分离出的白念珠菌对5-氟胞嘧啶、两性霉素B、咪康唑、酮康唑和制霉菌素敏感率分别为97．8％、98．9％、83．1％、87．6％和99．9％；男性尿道分泌物中自念珠菌的敏感率分别是76．1％、81．1％、65．3％、71．6％和86．0％；女性生殖道分泌物中菌株分别是58．4％、71．3％、61．4％、62.4％和86.1％，三组之间具有统计学意义（P〈0．01）。结论 不同标本中分离出的白念珠菌对抗真菌的敏感性有显著性差异。     

含L-4-氧代赖氨酸寡肽的合成及其抗白念珠菌活性

本文运用“违法传送”概念,根据白念珠菌对寡肽的传送特点,设计并合成了十个含L-4-氧代赖氨酸(以下称I-677)的寡肽,以提高I-677的抗白念珠菌活性。体外抗白念珠菌试验表明:I-677-肽(I-677-X₁,I-677-X₁-X₂和I-677-X₁-X₂-Gly,其中X₁,X₂=Met,Leu,Ile,Ala,β-Ala,Gly)较I-677单体摩尔活性提高了2.1～28倍,其摩尔最低抑菌浓度为8.7×10^-8～9.3×10^-9mol/ml,传送肽和赖氨酸分别逆转I-677-肽抗菌活性的实验结果证实了I-677的“违法传送”途径。     

聚乙烯亚胺单独及与三种抗菌药物联用对白念珠菌的体外抗菌活性

目的评估多支链的阳离子高分子聚合物——聚乙烯亚胺(PEI)单独及与三种不同类别的常规抗菌药物(两性霉素B、氟康唑和多黏菌素B)联合使用对白念珠菌(MY7245和MY7238)的两种临床分离物的抗真菌活性。方法通过体外实验测定不同分子质量聚乙烯亚胺单独及与三种不同类别的常规抗菌药物联合使用对两株白念珠菌的最小抑菌浓度和杀灭时间,确定PEI单独及联合使用的体外抗真菌活性。结果分子量在2～745ku范围内的PEI均对这两种白念珠菌产生很好的抗真菌活性,且分子量小的PEI比分子量大的PEI的抗菌作用更显著。与单独作用的PEI相比,分子量较大的PEI与常规药物联合使用时可产生较强的协同作用。在体外致死研究实验中可以看到,PEI-两性霉素B和PEI-氟康唑结合物可以提高抑菌作用,但PEI-多黏菌素B结合物却拮抗抑菌作用。结论PEI单独与联合使用均对白念珠菌产生很好的抗菌效果。     

奥硝唑联用酮康唑体外抗淋球菌和白念珠菌的活性

目的评价奥硝唑与酮康唑体外联合应用对淋球菌和白念珠菌抗菌效应。方法采用棋盘法设计实验，测定不同浓度组合的药物对两种细菌的最低抑菌浓度。结果联合用药对淋球菌FIC指数为0.75，对白念珠菌FIC指数为1.0，表明两药具有相加性。结论奥硝唑与酮康唑联合应用对淋球菌和白念珠菌抗菌活性呈相加作用。     

rmuGM-CSF增强巨噬细胞抗白念珠菌活性研究

目的： 研究重组小鼠粒细胞巨噬细胞集落刺激因子(rmuGM CSF)对巨噬细胞抗白念珠菌活性的调节作用。方法：分别将浓度为100，200，300，400 U·mL 1的rmuGM CSF与小鼠腹腔巨噬细胞共同培养2～5 d，然后测定巨噬细胞的抗白念珠菌活性。结果： rmuGM CSF可增强巨噬细胞的抗白念珠菌活性，作用呈剂量依赖性，且随着与巨噬细胞共培养时间的延长，增强效应不降低。结论： rmuGM CSF能增强巨噬细胞的抗白念珠菌活性，增强效应强而持久。     

In vitro and in vivo anti-Candida activity and toxicology of LY121019

LY121019 (N-p-octyloxybenzoylechinocandin B nucleus) is a semisynthetic antifungal antibiotic that possesses potent anti-Candida activity. The MIC50 and the MIC90 for both LY121019 and amphotericin B were 0.625 and 1.25 micrograms/ml, respectively. Only an 8-fold increase in the MIC against C. albicans occurred during 34-day exposure to subinhibitory concentrations indicating that LY121019 has a low potential for causing resistance development. Scanning electron microscopic studies revealed that LY121019 caused severe damage to the C. albicans cell. The ED50's for LY121019 and amphotericin B administered parenterally to mice were 7.4 and 2.5 mg/kg, respectively. Parenterally administered LY121019 at doses of 6.25 mg/kg significantly reduced the recovery of C. albicans from infected mouse kidneys. Orally administered 50 and 100 mg/kg doses of LY121019 were effective in eliminating C. albicans from the gastrointestinal tract of infected mice. Topical application of 5% LY121019 was as effective as 3% nystatin in the treatment of superficial C. albicans infections. Local administration of LY121019, nystatin, or miconazole was effective against rat vaginal candidiasis. LY121019 was administered intravenously to dogs at doses up to 100 mg/kg/day, 5 days a week for 3 months; all dogs survived. Compound related effects included a histamine-like reaction, increased serum alkaline phosphatase and SGPT, fatty vacuolization of the liver, and some tissue damage at the injection site. The no effect dose in dog was 10 mg/kg. LY121019 had no more than 1/20 the toxicity of amphotericin B in the dog.     

Sodium Tripolyphosphate: an excipient with intrinsic in vitro anti-Candida activity

Sodium Tripolyphosphate (STPP) is a food additive that is being used in the development of micro and nanoparticles as it induces ionic interactions with chitosan molecules. Although the ability of STPP to inhibit the growth of several food contaminants has been reported, studies on its activity against clinical isolates are scarce. Candida spp. are common causative agents of mucocutaneous infections including the vulvovaginal tegument and new therapeutic approaches are needed in order to treat resistant and recurrent cases. The aim of this study was to evaluate in vitro both antifungal (anti-Candida spp.) activity, and cytotoxicity, on human dermal fibroblasts, of STPP solutions. STPP showed an inhibitory species-dependent activity against several Candida spp. strains being particularly active on C. glabrata, followed by C. guilliermondii. In vitro, STPP showed a concentration dependent cytotoxicity. Therefore STPP use, in low concentrations, seems to be interesting in the development of drug delivery systems for the treatment of vulvovaginal candidosis.     

The anti-Candida activity of shikon

Antifungal activity of Shikon, roots of Lithospermum erythrorhizon and Arnebia euchroma was investigated in vitro. The extracts containing the pigments of Ko-shikon or Nan-shikon showed the antifungal activities against Candida albicans. Acetylshikonin, one of these pigments, inhibited the fungal growth at MIC 15.6 micrograms/ml (RPMI24 h) or 3.9 micrograms/ml (YNB24 h).     

Anti-inflammatory activity of propolis

Propolis (bee-glue), known as a folk medicine, is a lipophilic material found in honeybee hives. In the present study on the anti-inflammatory effect of Korean propolis, it was extracted with ethanol, and used as a test material. The LD₅₀ value with the oral administration of ethanolic extract of Korean propolis (EEKP) was higher than 2 g/kg in mice. The oral administration of the propolis extract (100 mg/kg) significantly inhibited the development of hind paw edema induced by carrageenin in rats. The oral pretreatment of the propolis extract markedly inhibited the increase in vascular permeability and the number of writhing induced by acetic acid in mice. Propolis extract, 50 and 100 mg/kg p.o. per day for 7 days, produced a significant inhibitory effect on granuloma and exudate formation in rats. This inhibitory effect was enhanced with the concomitant use of prednisolone (2.5 mg/kg). These results suggest that Korean propolis apparently has a strong anti-inflammatory activity.     

The in vitro properties of a new hydroxypyridone antimycotic rilopirox, with special reference to its anti-Candida activity

In vitro properties of a new hydroxypyridone antimycotic rilopirox (RIL) with special reference to its anti-Candida activities were studied in comparison with the three reference drugs, ciclopirox olamine (CPO), oxiconazole nitrate (OCZ) and isoconazole nitrate (ICZ), using several strains of Candida albicans and Candida glabrata as the test organisms. RIL was potently fungicidal for growing cultures of these Candida strains, whereas all the three reference drugs were slightly fungicidal or fungistatic. Unlike OCZ and ICZ whose anti-Candida activity was decreased by lowering pH or adding serum to culture media, the activity of RIL was scarecely affected by change in pH or serum addition. However, RIL became less potent in the presence of Fe3+ at concentrations of 10(-5) mmol/ml or above. These findings suggest that RIL will be useful as a topical anti-Candida agent.     

口腔白色念珠菌对西吡氯铵含片的体外溶血活性研究

目的用浓缩漱口水法收集的口咽部念珠菌感染患者的白色念珠菌,检测其是否产生溶血性及西吡氯铵是否对白色念珠菌的溶血活性产生影响。方法收集口腔念珠菌感染的患者的白色念珠菌,经培养、分离、纯化和鉴定后,将其接种于血琼脂平板上,加入西吡氯铵,检测其溶血活性。结果未加入西吡氯铵的对照组的白色念珠菌均产生溶血现象,而实验组（加入西吡氯铵）和阳性对照组（加入氟康唑）的溶血现象明显减少,两者之间无显著性差异（P〉0.05）,两者与对照组相比均有显著性差异（P〈0.05）。结论西吡氯铵能降低白色念珠菌的毒性,可以作为临床上治疗口腔白色念珠菌感染的药物。