Preparation of liposomal fluconazole gel and in vitro transdermal delivery

Aim Liposomal fluconazole gel was prepared and its properties were studied. Methods The fluconazole liposomes were prepared by film dispersion method. Their shapes and sizes were observed by transmission electronic microscope and particle size analyzer, respectively. The skin permeation of liposomal gel was studied on rat skin by permeation cell. Results The entrapment efficiency of flueonazole liposomes was 47.68%. The fluconazole liposomes were oval or round in shape, and their average diameter was 250 ± 8 nm. The accumulative skin permeation of liposomal fluconazole gel （25.27%） was lower than that of non-liposomal fluconazole gel （36.72%）, but fluconazole retained in rat skin of liposomal gel （162 ± 15 μg·cm^-2） was higher than that of nonliposomal gel （48 ± 6μg·cm^-2）. Conclusion Liposomal fluconazole gel can significantly increase the deposited amounts of fluconazole in rat skin and it may be beneficial for topical use.

Solid-state characterization and impurities determination of fluconazol generic products marketed in Morocco

In this paper, we report the results of quality control based in pbysicochemical characteriza- tion and impurities determination of three samples of fluconazole drug substances marketed in Morocco. These samples were supplied by different pharmaceuticals companies. The sample A, as the discovered product, was supplied by Pfizer, while samples B and C （generics）, were manufactured by two different Indian industries. Solid-state characterization of the three samples was realized with different physicochemical methods as： X-ray powder diffraction, Fourier-transformation infrared spectroscopy, differential scanning calorimetry. High performance liquid chromatography was used to quantify the impurities in the different samples. The results from the physicochemical methods cited above, showed difference in polymorph structure of the three drug substances. Sample A consisted in pure polymorph II1, sample B consisted in pure polymorph I1, sample C consisted in a mixture of fluconazole Form Ili, form II and the monohydrate. This result was confirmed by differential scanning calorimetry. Also it was demonstrated that solvents used during the re-crystallization step were among the origins of these differences in the structure form. On the other hand, the result of the stability study under humidity and temperature showed that fluconazole polymorphic transformation could be owed to the no compliance with the conditions of storage. The HPLC analysis of these compounds showed the presence of specific

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.

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 THE CELL SURFACE PROTEINS OF THE EPITHELIAL CELLS

This paper presented the effects of systemic fluconazole therapy via intravenous (IV) and oral (PO) administrations on the adhesion of Candida albicans (C. albicans) to the buccal epithelial cells (BEC) from five treated patients with three candidosis, one mucormycosis and one sporotrichosis and at the same time.an analysis of the cell surface proteins involving candidal adherent receptor in the BEC of the patients in the course of 7 days were exposed to ￣3H-leucine radiolabeled C. albicans for in vitro candidal adherent assay.and the BEC from first intake day and the last intake day of the patients were extracted by dithiothreitol (DTT)-iodoacetamide treatment for SDSPAGE. These results indicate that the systemic fluconazole therapy results in the inhibitory effect of candidal adhesion to BEC of treated patients to prevent them from oral candidosis for a prolonged time, which is based on the absent surface protein (35 KDa) of the BEC.

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.

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.

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.

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.

1岁患儿热水烫伤继发阿萨希丝孢酵母菌皮肤感染1例

患儿,男,1岁,热水烫伤后继发皮肤感染,微生物检查提示罕见菌阿萨希丝孢酵母菌感染,且对文献推荐的首选药物伏立康唑表现为剂量依赖性敏感。根据患儿个体情况,选择使用氟康唑72 mg/d静脉滴注及藻酸银敷料联合治疗7 d后,取得了满意的效果。

比较3种微量肉汤稀释法检测念珠菌对氟康唑的敏感度

目的比较3种肉汤稀释药敏检测方法检测念珠菌对氟康唑敏感度的检测能力。方法收集河北医科大学第二医院临床分离的念珠菌84株,采取经典微量肉汤稀释法、ATB FUNGUS 3方法和Yeast One真菌药敏板方法检测念珠菌对氟康唑的敏感度。结果84株念珠菌中,白念珠菌26株,热带念珠菌34株,光滑念珠菌22株以及近平滑念珠菌2株。以经典微量肉汤稀释法为参考方法,ATB FUNGUS 3方法的敏感度为87.5%,特异度为100.0%;基本一致性为95.2%,分类一致性为92.9%;假耐药率为7.1%,假敏感率为0。Yeast One方法的敏感度为100.0%,特异度为94.4%;基本一致性和分类一致性均为97.6%,假敏感率和假耐药率均为0。结论Yeast One真菌药敏板方法检测氟康唑对念珠菌活性优于ATB FUNGUS 3方法。

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.

叶内型肺隔离症合并肺隐球菌病1例并文献复习

报道1例52岁男性叶内型肺隔离症合并肺隐球菌病患者,因咳嗽、咳痰和胸闷入院,胸部CT显示右下肺脊柱旁有1个椭圆形肿块,左下肺有1个结节。CT引导下经皮肺活检证实右下肺肿块为肺隔离症,左下肺结节为隐球菌感染。行电视辅助外科胸腔镜手术切除肺隔离叶,通过口服氟康唑治疗患者左下肺隐球菌结节。术后3年定期随访,增强CT示左下肺隐球菌结节消失,右下肺隔离症术后良好。该文总结了1例肺隔离症合并隐球菌病的临床表现、治疗及转归,旨在提高临床医师对该病的认识。

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例肺隐球菌病患者抗感染治疗的药学分析

目的:分析1例隐球菌感染患者的诊疗过程,为隐球菌病患者的救治提供参考。方法与结果:患者因“肺炎”被收入医院呼吸与危重症医学科治疗,在急诊时予祛痰、抗感染等治疗;入院第5天,根据患者血清隐球菌荚膜抗原检查、肺部CT影像学结果和炎症指标结果,支持诊断为肺隐球菌病,予加用氟康唑氯化钠注射液抗感染治疗,临床药师通过对肺隐球菌病患者抗感染治疗的分析,结合患者临床症状、用药调整、病情转归情况与查阅相关文献,考虑患者身体质量指数为28为肥胖,为保证体内达到有效血药浓度,负荷氟康唑剂量可给到0.84 g,建议予患者经静脉滴注氟康唑氯化钠注射液(400 mg,q12h);入院第7天,患者临床症状较前改善,减少给药频率予氟康唑氯化钠注射液(0.4 g,q24h)抗感染治疗;入院第13天,患者肺部CT提示炎症较前进展,继续予抗感染;入院第17天,患者整体状况尚可,准予出院。结论:临床药师在参与隐球菌抗感染用药治疗过程中,通过积极开展药学监护和用药教育,结合患者实际情况,充分考虑其基础疾病(糖尿病)对感染和自身抵抗力影响和患者自身体质情况,兼顾药物不良反应与相互作用,制定个体化用药方案,获得了制定肺隐球菌病治疗方案的宝贵经验。

1例胃间质瘤合并椎体白假丝酵母感染患者抗真菌治疗的药学监护

目的:分析医院1例胃间质瘤合并椎体白假丝酵母感染患者抗真菌治疗的药学监护过程,为抗菌药物的合理选用和伊马替尼的用药安全提供参考。方法与结果:该患者(男,64岁)因“腰疼”入院,当前因胃间质瘤而长期使用伊马替尼;门诊胸腰段MR检查提示可能存在椎体感染性病变,遂经验性给予头孢哌酮-舒巴坦钠治疗;入院第5天,胸椎穿刺液检查回报白假丝酵母,遂改用卡泊芬净治疗;3 d后,根据药敏结果,将卡泊芬净调整为氟康唑;但又3 d后,患者腰背部疼痛加重,超敏C反应蛋白水平再次升高,医生与药师讨论后,又调整为卡泊芬净;入院第30天,行胸椎病灶刮除术;入院第46天,患者病情明显好转,感染指标明显下降,药师会诊后,考虑与伊马替尼的药物相互作用,建议换用氟康唑口服序贯治疗。结论:对于病因不明的感染患者,临床药师应协助医生及早明确病原菌,以开展针对性治疗,并根据抗感染治疗效果及时调整治疗方案,同时还应关注与其他药物的相互作用,以保证患者的用药安全。

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。