A stepwise optimization strategy to formulate in situ gelling formulations comprising fluconazole-hydroxypropyl-beta-cyclodextrin complex loaded niosomal vesicles and Eudragit nanoparticles for enhanced antifungal activity and prolonged ocular delivery

Fungal keratitis and endopthalmitis are serious eye diseases.Fluconazole(FL)is indicated for their treatment,but suffers from poor topical ocular availability.This study was intended to improve and prolong its ocular availability.FL niosomal vesicles were prepared using span 60.Also,polymeric nanoparticles were prepared using cationic Eudragit RS100 and Eudragit RL100.The investigated particles had adequate entrapment efficiency(EE%),nanoscale particle size and high zeta potential.Subsequently,formulations were optimized using full factorial design.FL-HP-β-CD complex was encapsulated in selected Eudragit nanoprticles(FL-CD-ERS1)and niosmal vesicles.The niosomes were further coated with cationic and bioadhesive chitosan(FL-CD-Nios-ch).EE%for FL-CD-ERS1 and FL-CD-Niosch formulations were 76.4%and 61.7%;particle sizes were 151.1 and 392 nm;also,they exhibited satisfactory zeta potential+40.1 and+28.5 m V.In situ gels were prepared by poloxamer P407,HPMC and chitosan and evaluated for gelling capacity,rheological behavior and gelling temperature.To increase the precorneal residence time,free drug and selected nano-formulations were incorporated in the selected in situ gel.Release study revealed sustained release within 24 h.Permeation through excised rabbits corneas demonstrated enhanced drug flux and large AUC0-6 h in comparison to plain drug.Corneal permeation of selected formulations labeled with Rhodamine B was visualized by Confocal laser microscopy.Histopathological study and in vivo tolerance test evidenced safety.In vivo susceptibility test using Candida albicans depicted enhanced growth inhibition and sustained effect.In this study the adopted stepwise optimization strategy combined cylodextrin complexation,drug nano-encapsulation and loading within thermosenstive in situ gel.Finally,the developed innovated formulations displayed boosted corneal permeation,enhanced antifungal activity and prolonged action.

Combined Application of 5% Natamycin and 0.2% Fluconazole for the Treatment of Fungal Keratitis

Purpose: To observe the clinical efficacy of combined use of 5% natamycin and 0.2% fluconazole for the treatment of fungal keratitis. Methods:A total of 65 cases diagnosed with fungal keratitis by direct smear and/or fungus culture from January 2010 to January 2013 were enrolled in this study.The duration from the onset of symptoms to admission to our ophthalmic center ranged from 9 to 90 d (mean 29.5 ±19.1 d) in the severe group, which significantly differed from the 7 to 36 d (mean 16.6±7.1 d) in the non-severe group (P<0.01). All cases were divided into non-severe and severe groups based on the degree of corneal inflammation. All cases were treated with topical use of 5% natamycin and 0.2% fluconazole once per hour. The same clinical and examination protocols were adopted for both groups. Results:In the non-severe group,23 of the 24 patients (95.8%) were healed, and 1 (4.2%) showed treatment effica cy. In the severe group,12 of 41 patients (29.3%) were healed, 11(26.8%) showed clinical efficacy, and 18(43.9%) showed no efficacy. The patients between two groups significantly differed in terms of efficacy (P<0.01). Conclusion:Combined use of 5% natamycin and 0.2% fluconazole is efficacious in treating fungal keratitis, especially mild or moderate infections.

Treatment of pulmonary coccidioidomycosis after successful hepatitis C therapy in a patient with fluconazole induced hepatotoxicity

A patient with hepatitis C infection and cavitary pul- monary coccidioidomycosis is reported. Treatment of hepatitis C was associated with resolution of flucona- zole-induced hepatotoxicity. Successful treatment of he- patitis C enabled the patient to tolerate increaseing doses of fluconazole. This case highlights that hepatic toxicity of fluconazole can improve after successful treatment of hepatitis C.

Evaluation of Dosages Regimen of Fluconazole in Patients of Candidemia with Gender by PK/PD and Mote Carlo Simulation

Candidemia is one of the four most common nosocomial blood infections and is the most common hospital-acquired fungemia in a recent multi-institutional study from the US. The mortality of Candidemia can be up to 50%. Fluconazole is a triazole derivative widely used for the treatment of invasive candidiasis. It was recommended as first-line drugs for the treatment and prevention of mycoses. In our study, we aimed to optimise the dosage of fluconazole with gender against Candida spp. based on pharmacokinetic/pharmacodynamics (PK/PD) analysis. We collected the published data about pharmacokinetic parameters of fluconazole and the MIC distribution of Candida spp. on fluconazole. We decided to evaluate the gender between males and females with the pharmacokinetics of fluconazole. Using probability of target attainment (PTA) and cumulative fraction of response (CFR) as indexes, crystal ball software 11.1.2.4 was used for Monte Carlo simulation of different dosage regimens of different males and females. For C. albicans, C. tropicalis and C. lusitaniae, when doses of regimen are 100 mg IV, 200 mg IV and MIC was lower than 1 g/ml, PTA was higher than 90%. For C. tropicalis, each dosing regimen and MIC was less than 2 g/ml. PTA was higher than 90%. As C. glabrata, C. parapsilosis, C. krusei, C. guilliermondii for PTA with more than 90%, MIC of fluconazole 200 mg were less than 32 g/ml, 64 g/ml and 64 g/ml, respectively. For the different dosage regimens 100 mg IV and 200 mg IV of fluconazole for Candida spp., it is desirable that fluconazole dosage regimens take into account both the gender of the patient.

Simple,Inexpensive and Ecologically Friendly Derivative Spectrophotometric Fluconazole Assay from Nail Lacquer Formulations

Nail lacquers represent new drug form specifically designed to treat infected nail plate. They are complex organic solutions with specific assaying problems due to the high content of the polymer and plasticizer. Furthermore, there is a lack of assaying methods of active substances from this type of formulations in scientific literature. We developed derivative UV-spectrophotometric method for determination of fluconazole content in antifungal nail lacquer formulations. The method was validated for specificity, linearity, precision (repeatability), intermediate precision and accuracy (recovery). The method is specific, linear in the range of 99.53 - 497.65 μg/ml, precise and showed good recovery (98.79% - 101.77% from all six developed formulations). Besides, it is inexpensive, simple and nontoxic, i.e. ecologically acceptable. This method can be used for assaying fluconazole from this type of formulations.

氟西汀单独使用及联用氟康唑对白念珠菌的影响研究

目的探讨氟西汀单独使用及联用氟康唑对白念珠菌的抑制作用。方法采用白念珠菌标准株、白念珠菌临床分离株和白念珠菌耐药株进行实验,分别制备相应菌株的浮游状态和生物膜状态。XTT减低法检测氟西汀对白念珠菌的作用,改良时间-杀菌曲线测定氟西汀对白念珠菌生物膜的药效学性能,扫描电镜观察氟西汀处理后白念珠菌生物膜的形态变化,棋盘稀释法检测氟西汀与氟康唑联用对生物膜状态白念珠菌的影响。结果氟西汀对3种生物膜状态的白念珠菌均有抑制作用,抑制生物膜状态白念株菌标准株和氟康唑耐药株_(50)%活性的最低药物浓度(sessile minimal inhibitory concentration 50%,SMIC_(50))为32μg/mL,对生物膜状态白念珠菌临床株的SMIC_(50)为64μg/mL。改良时间-杀菌曲线显示在氟西汀浓度为1×SMIC_(50)和2×SMIC_(50)时,3种白念珠菌生物膜活性均较对照组显著下降。扫描电镜观察显示,氟西汀处理后白念珠菌生物膜较无药物处理时菌丝数量减少,形态发生皱缩。棋盘稀释法显示氟西汀与氟康唑联用时对生物膜状态的白念珠菌标准株表现出协同作用,对其余两种菌株表现出无关或拮抗作用。结论氟西汀单独使用对不同种类生物膜状态的白念珠菌均有较好的抑制作用,联用氟康唑对生物膜状态白念珠菌标准株有协同抑制作用。

去甲泽拉木醛的体外抗真菌作用研究

目的 研究去甲泽拉木醛的体外抗真菌作用。方法 采用微量液基稀释法测定去甲泽拉木醛与氟康唑单独应用于23株真菌的最低抑菌浓度(MIC),以棋盘式微量液基稀释法测定两药联合抗耐药白念珠菌的协同指数(FICI),判断两药联合抗菌效果;并通过纸片扩散实验直观验证两药联合的协同作用。最后通过CCK-8法测定去甲泽拉木醛的细胞毒性。结果 去甲泽拉木醛单用时呈现广谱的抗真菌作用,MIC范围为4~32 g/L。两药联用时,可将氟康唑的有效浓度从大于64 g/L降至0.25 g/L,FICI值介于0.129~0.254之间,两药表现出协同抗耐药白念珠菌作用。CCK-8结果显示,去甲泽拉木醛在高于MIC值4倍浓度下才展示出细胞毒性。结论 去甲泽拉木醛表现出较好的抗真菌作用,与氟康唑联合时有很好的协同效果,且毒性较低。

Evaluation of the disc diffusion method with a comparison study for fluconazole susceptibility of Candida strains

To performance susceptibility testing of antifungal agents Due to the increasing number of resistant strains, susceptibility testing of antifungal agents is gaining importance Methods We compared the results of standard macrotube dilution reference method with two different microdilution methods, as well as the disc diffusion method in order to test the susceptibility of 150 Candida strains to fluconazole Results Overall correlation between microdilution and macrodilution methods was 86% It was 91% between the Minimal Inhibitory Concentrations obtained from macrodilution and disc diffusion zone diameters Conclusion The disc diffusion test was evaluated as a low-cost, reproducible, and efficient way of assessing the in vitro susceptibility of Candida strains to fluconazole

1例氟康唑和沙利度胺致皮肌炎合并肺部感染的药学监护

目的探讨临床药师在皮肌炎合并肺部感染治疗中的药学监护作用。方法临床药师参与1例皮肌炎合并肺部感染的药物治疗,分析患者出现药品不良反应的原因,并提供药学监护。结果患者出现四肢及口唇发麻后,临床药师建议停用可疑药品沙利度胺,医师采纳;患者四肢及口唇发麻未见明显改善,临床药师再次建议停用可疑药品氟康唑,患者四肢及口唇发麻症状改善。结论临床药师参与治疗方案的制订,提供药学服务,有助于提高患者的治疗效果,促进合理用药。同时,在药学查房过程中,密切监测使用沙利度胺的患者,一旦出现药源性周围神经炎,应立即减量或停用可疑药物。

表没食子儿茶素没食子酸酯与氟康唑联用抗耐药白色念珠菌的协同作用及机制

目的探讨表没食子儿茶素没食子酸酯(epigallocatechin gallate,EGCG)与氟康唑(fluconazole,FLC)联用对耐药白色念珠菌(Candida albicans,CA)的协同抗感染效果及作用机制。方法选用6株耐药CA,通过棋盘微量稀释试验,利用部分抑菌浓度指数(fractional inhibitory concentration index,FICI)评价联合作用的抗耐药CA作用;及利用荧光显微镜观察两药联用对菌丝生长的影响。结果通过FICI评价法,证实了EGCG与氟康唑联用具有协同抗耐药CA作用,且二者的协同作用可能与抑制菌丝生长有关。结论EGCG与FLC联用具有协同抗耐药CA的作用,且协同作用机制可能与抑制菌丝生长有关。

1例罕见的限制性马拉色菌致血流感染患者的临床诊疗分析

目的:分析1例罕见的限制性马拉色菌致血流感染患者的临床诊疗过程,为临床此类罕见感染疾病的诊治提供参考。方法与结果:该患者2周前被猫抓伤后反复发热,入院后仍持续发热,检查显示血清白细胞计数和降钙素原均正常,仅C反应蛋白升高,结合患者的临床症状,临床排除了呼吸道和尿路的感染,且未发现其他明显的感染灶,临床先经验性予阿奇霉素;2 d后,真菌D-葡聚糖检查结果异常(222.53 pg/mL);临床药师会诊发现,患者近期存在糖尿病血糖控制不佳且有服用糖皮质激素的情况,因而可能免疫功能较差,综合患者前期检查结果,怀疑患者的发热可能是由猫抓伤致真菌侵入血液所致的血流感染引起的,遂建议加用氟康唑进行抗真菌治疗;第2天,患者体温明显回落,且第3天患者血标本的二代测序结果为限制性马拉色菌(序列数为29),基本印证了临床药师的判定;最后,患者在用氟康唑治疗10 d后出院。结论:对于不明原因发热的患者,临床医生和药师应充分结合患者的临床表现和各种检查结果,以及经验性抗感染治疗的反馈,以准确判断患者的感染部位和可能病原菌,从而更有针对性、更有效地为患者开展治疗。

氟康唑联合克霉唑阴道片在霉菌性阴道炎治疗中的疗效评价

目的分析氟康唑联合克霉唑阴道片治疗霉菌性阴道炎的临床效果。方法选取86例霉菌性阴道炎患者,根据治疗方法不同分为对照组与研究组,每组43例。对照组开展克霉唑阴道片治疗,研究组开展氟康唑联合克霉唑阴道片治疗。比较两组患者的治疗效果、不良反应发生情况、疾病症状消失时间及炎症因子指标。结果研究组患者治疗总有效率97.67%较对照组81.40%更高(P<0.05)。对照组不良反应发生率11.63%与研究组9.30%比较,差异无统计学意义(P>0.05)。研究组患者的外阴瘙痒、白带异常、腰腹酸痛、尿频、尿痛症状消失时间均较对照组更短(P<0.05)。治疗后,两组患者肿瘤坏死因子-α(TNF-α)、超敏C反应蛋白(hs-CRP)、白介素-4(IL-4)及白介素-6(IL-6)指标均较治疗前下降,且研究组患者较对照组更低(P<0.05)。结论氟康唑联合克霉唑阴道片应用于霉菌性阴道炎治疗中,可提升治疗效果,促进疾病症状消失,并改善患者的炎症因子,值得临床推广。

氟康唑胶囊联合雪莲抑霉菌洗液治疗霉菌性阴道炎的效果分析

目的探讨霉菌性阴道炎采用氟康唑胶囊联合雪莲抑霉菌洗液治疗效果。方法选择60例霉菌性阴道炎患者为研究对象,采用随机数字表法分为研究组和对照组,每组30例。对照组给予氟康唑胶囊治疗,研究组给予氟康唑胶囊联合雪莲抑霉菌洗液治疗。比较两组治疗效果、症状缓解情况、不良反应发生率。结果治疗后,研究组总有效率高于对照组(P<0.05);研究组白带异常、阴道充血及外阴瘙痒等症状评分均低于对照组(P<0.05);研究组不良反应发生率低于对照组,但两组比较差异无统计学意义(P>0.05)。结论霉菌性阴道炎采用氟康唑胶囊联合雪莲抑霉菌洗液治疗效果较好,能改善患者临床病症,促进患者恢复,且安全性高,值得临床推广与应用。

Relationship between antifungal resistance of fluconazole resistant Candida albicans and mutations in ERG11 gene

Background The cytochrome P450 lanosterol 14a-demethylase （Ergllp） encoded by ERG11 gene is the primary target for azole antifungals. Changes in azole affinity of this enzyme caused by amino acid substitutions have been reported as a mechanism of azole antifungal resistance. This study aimed to investigate the relationship between amino acid substitutions in Erg11 p from fluconazole resistant Candida a/bicans （C. albicans） isolates and their cross-resistance to azoles. Methods Mutations in ERG11 gene were screened in 10 clinical isolates of fluconazole resistant C. albicans strains. DNA sequence of ERG11 was determined by PCR based DNA sequencing. Results In the 10 isolates, 19 types of amino acid substitutions were found, of which 10 substitutions （F72S, F103L, F1451, F198L, G206D, G227D, N349S, F416S, F422L and T482A） have not been reported previously. Mutations in ERG11 gene were detected in 9 isolates of fluconazole resistant C. albicans, but were not detected in 1 isolate. Conclusions Although no definite correlation was found between the type of amino acid substitutions in Ergllp and the phenotype of cross-resistance to azoles, the substitutions F72S, F1451 and G227D in our study may be highly associated with resistance to azoles because of their special location in Erg11p.

Extractive Spectrophotometric Determination of Fluconazole by Ion-pair Complex Formation with Bromocresol Green

An extraction-spectrophotometric method for the determination of trace amounts of fluconazole was described. Fluconazole was effectively extracted as a 1 ： 1 ion-pair complex with bromocresole green （BCG） at pH 3.0 into chloroform, followed by spectrophotometric determination at 420 nm. Beer＇s law was obeyed over the range of 4-50 μg.mL^-1 of fluconazole with a detection limit of 3.7 μg.mL^-1 . The method is simple, rapid and sensitive. The procedure was applied to the determination of fluconazole in pharmaceutical preparations as well as its recovery from a blood serum sample.

Resistant mechanisms of Candida albicans to fluconazole

Objective To detect the resistant mechanisms o f Candida albicans to fluconazole (FCZ) at molecular biology lev el, since the resistance me chanisms of azole antifungal agents have been the focus of attention these years . Methods Thirty two FCZ resistant C.albicans were selected as our test strains (MICs≥64?μg/ml). With 14 α demethylase gene (ERG16 ge ne, target enzyme encoding gene of azoles) as our object, we chose six sets of prim ers from the ERG16 gene to amplify the interested fragments, and conducted South ern blot hybridization, restriction fragment length polymorphism (RFLP), and sin gle strand conformation polymorphism (SSCP) analysis for the fragments which wer e amplified by the six sets of primers, and pre resistant sensitive strains wer e used as controls. Three representative fragments, A66, D66 and E78, were selec ted to be cloned and sequenced. Results The polymerase chain reaction (PCR) amplification showed that s everal tested strains were negative for some primers. However, our Southern blot analysis reminded that their resistance did not result from the lack of targ et enzyme coding gene. SSCP analysis s howed that differences were noted between the resistant and sensitive strains an d inter resistant strains. Statistical analysis showed that the most variable s equence lied in the amplifier of the sixth pair of primer, and all the tested 32 strains showed positive results. In the 11 mutation points we found, five resu lted in amino acid alterations. It is likely that one or more mutational alterations (alone or in combination) might lead to the expression of an enzyme highly resi stant to the inhibitory action of FCZ which in turn is responsible for the FCZ r esistant trait in these strains. Conclusion One or more mutational alterations might lead to the azole r esistant trait in this strains.

Preparation of fluconazole buccal tablet and influence of formulation expedients on its properties

The aim of present study was to prepare buccal tablets of fluconazole for oral candidiasis.The dosage forms were designed to release the drug above the minimum inhibitory concentration for prolonged period of time so as to reduce the frequency of administration and to overcome the side effects of systemic treatment.The buccal tablets were prepared by using Carbopol 71G and Noveon AA-1 by direct compression method.Microcry stalline cellulose was used as the filler and its effect was also studied.The prepared dosage forms were evaluated for physicochemical properties,in vitro release studies and mucoadhesive properties using sheep buccal mucosa as a model tissue.Tablets containing 50% of polymers(Carbopol & Noveon) were found to be the best with moderate swelling along with favorable bioadhesion force,residence time and in vitro drug release.The in vitro drug release studies revealed that drug released for 8 h,which in turn may reduce dosing frequency and improved patient compliance in oral candidiasis patients.

Fluconazole Prophylaxis in Neonates (Non-Systematic) Literature Review

Background: Nosocomial infection remains an important contributing factor for morbidity and mortality in neonates. Coagulase-negative staphylococci have emerged as the predominant pathogens of late onset sepsis. This is followed by staphylococcus aurous, gram negative bacilli, and fungi. Old studies noted that mortality due to candidemia was higher in infants weigh less than 2000 g after being exposed to risk factors. The prophylactic use of fluconazole for the prevention of IC in extremely low birth weight was first reported in 2001. Methods: Current guidelines from Europe and North America that refer to the treatment of fungal infections are included. Literature search was performed using Medline, Scopus and Cochrane Central Register of Controlled Trials through March, 2016. Conclusion: Mortality was not different in early studies. However, recent studies concluded that mortality was reduced in the fluconazole arms. Risk-based approach towards fluconazole prophylaxis seems to be safe and effective.

Synthesis,Crystal Structure and Magnetic Property of a Novel Cu(Ⅱ)-Fluconazole-azide Complex

The title compound formulated as Cu2（C13H11N6OF2）（N3）3CH3OH was synthesized and structurally characterized by elemental analysis,IR and single-crystal X-ray diffraction.In the structure of the complex,the deprotonated fluconazole and azide anion link two copper centers to construct a binuclear SBU and the azide anion exhibits a μ1,1-coordination mode.Each triazole group of fluconazole links two SBUs and the compound exhibits a chain-like architecture with strong antiferromagnetism.

EFFECTS OF SYSTEMIC FLUCONAZOLE THERAPY ON IN VITRO ADHESION OF CANDIDA ALBICANS TO BUCCAL EPITHELIAL CELLS AND CHANGES OF TH

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