CRYSTAL GROWTH & DESIGN
·
2020
·
IF 4.089
Xin Chen,Duanxiu Li,Zongwu Deng,Hailu Zhang
Ketoconazole (KTZ) is an imidazole derivative that is used to treat a wide variety of fungal infections and other human diseases. As a class II compound in the biopharmaceutics classification system, KTZ has low aqueous solubility. To improve this disadvantage, five phenolic acids were employed to form cocrystals with KTZ. The antifungal and anti-inflammatory activity of the phenolic acids may bring an enhanced therapeutic effect and reduce the risk of hepatotoxicity at the same time. The structural information on these five crystalline samples and KTZ were fully disclosed by single-crystal X-ray diffraction. In addition to a previously reported carboxylic acid···imidazole N interaction, hydroxyl···imidazole N hydrogen bonding also appears in the KTZ cocrystals as a main supramolecular heterosynthon. The short strong hydrogen bonds were observed in two cocrystal structures, which contain slightly longer carboxylic O–H length. 15N solid-state NMR also provided valuable clues for the confirmation of the molecular/ionization states. The dissolution tests revealed that all the newly obtained cocrystals exhibit significantly improved solubility compared to KTZ.
研究领域:
药学
·
化学
✓ 已验证
DOI
高影响因子
JOURNAL OF ALLOYS AND COMPOUNDS
·
2018
·
IF 3.779
Y.W. Liu,Y. Chen,X.H. Chen,Z.N. Yang,Y. Xie,Z. Zhang
The inhibition effect of ketoconazole (KCZ) on Q235 mild steel corrosion in 1.0 M HCl solution was studied using weight loss, electrochemical impedance spectroscopy (EIS), electrochemical noise (EN), scanning electron microscope (SEM) and energy dispersive X-ray detector (EDX). Results reveal that the inhibition efficiency increases with increasing the KCZ inhibitor concentration and the adsorption behavior of ketoconazole onto Q235 mild steel follows the Langmuir adsorption isotherm with negative value of Δ G a d s 0 , suggesting a spontaneous adsorption process . It is also found that the type of adsorption of KCZ on the mild steel surface belongs to chemisorption . New parameter of corrosion active energy C AE proposed from EN measurements which representing the electrode reaction speed exhibited the same variation trend with the corrosion rate.
研究领域:
材料科学
·
电化学
·
腐蚀科学
✓ 已验证
产品关联
DOI
高影响因子
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
·
2019
·
IF 2.367
Dan Lou,Xiao Cui,Su-Su Bao,Wei Sun,Wen-He Pan,Meng-Chun Chen,Yao-Yao Dong,Guo-Xin Hu,Rui-Jie Chen,Zhe Wang
We investigated the effect of azole antifungal drugs (ketoconazole, voriconazole, and itraconazole) on the pharmacokinetics of apatinib in rats. The rats in ketoconazole, voriconazole, and itraconazole groups received single-dose apatinib 30 mg/kg after the oral administration of ketoconazole, voriconazole, and itraconazole, respectively. Co-administration of ketoconazole or voriconazole significantly increased the apatinib Cmax and AUC(0–t) and decreased the clearance. Co-administration of itraconazole did not significantly affect the pharmacokinetics parameters of apatinib. It could be concluded that both ketoconazole and voriconazole significantly increase the exposure of apatinib, and affect the pharmacokinetics of apatinib in rat. Apatinib can be co-administered with itraconazole, but ketoconazole and voriconazole should be avoided if possible or be underwent therapeutic drug monitoring of apatinib. A further clinical study should be conducted to investigate the inhibitory effect of azole antifungal drugs on the apatinib plasma concentration.
研究领域:
药理学
·
临床医学
✓ 已验证
DOI
高影响因子
JOURNAL DE MYCOLOGIE MEDICALE
·
2025
·
IF 1.8
Zhaowei Jin,Danqing Wu,Yangnan Chen,Yanqiu Long,Yan Liu,Zhiyun Zheng,Shuangying Gui,Yuzhe Huang,Ning He
Ketoconazole (KCZ), an imidazole antifungal drug, is constrained by its low solubility and poor stability, restricting its effective absorption and bioavailability. This study introduces a KCZ-loaded microsponge based film coating agent (KCZ-MSF), designed to enhance the transdermal absorption and bioavailability of KCZ. The KCZ-MS was prepared by emulsion solvent evaporation method and the composition of the prescription was optimized by Box-Behnken design (BBD). Moreover, characterization of the optimized KCZ-MS was conducted using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). The film coating agent's preparation was further optimized through orthogonal experiments, converting the optimized KCZ-MS into a film coating agent suitable for topical skin application. The KCZ-MS showed a spherical porous structure with a mean particle size of 22.42 ± 8.45 μm, a drug loading efficiency of 20.74%, entrapment efficiency of 92.12%, and good compatibility between the drug and excipients. The optimized KCZ-MSF displayed good physical properties. In vitro transdermal experiments revealed that the skin retention of KCZ-MSF surpassed that of commercially available KCZ cream at 6, 12, and 24 h. The pharmacokinetic experiment results indicate that the area under the curve ( AUC 0-24 ) of KCZ-MSF 420.71 ± 21.77 μg/(g·h) is 2.05 times that of KCZ film coating agent (KCZ-F) and 1.29 times that of commercially available ketoconazole cream. Therefore, KCZ-MSF presents a more promising platform for the treatment of superficial skin fungal infections.
研究领域:
药剂学
·
皮肤科学
·
药物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2015
·
IF 3.85
Junxiu Che,Zushuai Wu,Weiyan Shao,Penghao Guo,Yuanyuan Lin,Wenhui Pan,Weidong Zeng,Guoguang Zhang,Chuanbin Wu,Yuehong Xu
The objective was to develop a ternary skin targeting system for ketoconazole (KET) using a combined strategy of microemulsion (ME) and cyclodextrin (HP-β-CD), i.e., KET-CD-ME, which exploits both virtues of cyclodextrin complex and ME to obtain the synergetic effect. KET-CD-ME was formulated using Labrafil M 1944 CS as oil phase, Solutol HS 15 as surfactant, Transcutol P as cosurfactant , and HP-β-CD solution as aqueous phase. The formulation of KET-CD-ME was optimized and the optimal formulation was characterized in terms of particle size, size distribution, pH value, and viscosity. Long term stability experiment showed that HP-β-CD could increase the physical stability of ternary system and KET chemical stability. Percutaneous permeation of KET from KET-CD-ME in vitro through rat skin was investigated in comparison with KET microemulsion (KET-ME), KET HP-β-CD inclusion solution (KET-CD), KET aqueous suspension, and commercial KET cream; the results showed that the combination of ME with HP-β-CD exhibited significantly synergistic effect on KET deposition within the skin (29.38 ± 1.79 μg/cm 2 ) and a slightly synergistic effect on KET penetration through the skin (11.3 μg/cm 2 /h). The enhancement of the combination on skin deposition was further visualized by confocal laser scanning microscope (CLSM). In vitro sensitivity against Candida parapsilosis test indicated that KET-CD-ME enhanced KET antifungal activity mainly owing to the solubilization of HP-β-CD on KET in the ternary system. Moreover, the interactions between HP-β-CD and KET in the ternary system were elucidated through microScale thermophoresis (MST) and 2D 1 H NMR spectroscopy . The profiles from MST confirmed the host–guest interactions of HP-β-CD with KET in the ternary system and a deep insight into the interactions between KET and HP-β-CD were obtained by means of 2D 1 H NMR spectroscopy . The results indicate that the ternary system of ME combination with HP-β-CD may be a promising approach for skin targeting delivery of KET.
研究领域:
药剂学
·
皮肤病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2016
·
IF 3.902
Baolin Wang,Hongxia Zheng,Ming-Wei Chang,Zeeshan Ahmad,Jing-Song Li
Hollow magnetic fibers for trigger based drug release were synthesized using one-step co-axial electrospinning (COX-ES). This was achieved by encapsulating the antifungal active ‘ketoconazole’ (KCZ) and iron oxide (Fe 3 O 4 ) nanoparticles (NPs) in composite form within the core shell polymeric matrix material (polycaprolactone, PCL) during the COX-ES process. Dimethyl silicone oil was used as the inner core (liquid) of co-flowing solutions, which subsequently perfused out of the two-phase electrospun microstructures to form hollow fibers. Resulting drug-loaded magnetic hollow fibers were characterized using optical microscopy, scanning electron microscopy and Fourier Transform Infra-Red. The tensile strength and magnetization properties of composite fibers were also assessed. KCZ drug concentration in electrospinning solutions strongly influenced resulting fiber morphology, drug loading efficiency and release. Expedited drug release during a slow-sustained phase was demonstrated through the application of an auxiliary magnetic field. Variations in tensile strength (∼1.3–6.3 MPa) were due to composite fiber components compromising polymer chain integrity. In-vitro cell studies (using human cervical carcinoma cell lines) demonstrated fiber biocompatibility. The present study demonstrates the potential application of magnetic hollow fibers for controlled treatment of fungal infections and antimicrobial indications.
研究领域:
材料科学
·
药学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
MATERIALS LETTERS
·
2017
·
IF 2.572
Baolin Wang,Meidi Wang,Ming-Wei Chang,Zesshan Ahmad,Jie Huang,Jing-song Li
Multi-compartment fibers with well-defined regions and functional media hosting potential provide co-encapsulation opportunities for a variety of bio-molecules, drugs and even nutrients. In this research, fibers possessing multiple compartments were prepared using the single-step electrospinning method and a modified non-concentric multi-needle. Polyvinyl pyrrolidone (PVP) was used as the fiber shell material, while ketoconazole (KCZ, model drug) and Sudan Red (model probe) were encapsulated as two separate segments running along the fiber length. Multi-compartment fiber morphology and structure were examined using optical and electron microscopy. The effect of flow rate on fiber morphology was also investigated and the release of encapsulated KCZ and Sudan Red was examined using UV spectroscopy. The results present an efficient and promising method to engineer multi-compartment fibers in a single step for several biomedical applications in lieu .
研究领域:
材料科学
·
生物医学工程
✓ 已验证
DOI
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2017
·
IF 4.164
Peizong Deng,Fangfang Teng,Feilong Zhou,Zhimei Song,Ning Meng,Na Liu,Runliang Feng
Ketoconazole is a hydrophobic broad-spectrum antifungal agent for skin infection therapy. In order to develop topical formulation of ketoconazole for improving its selective skin deposition and water-solubility, ketoconazole-loaded Y-shaped monomethoxy poly(ethylene glycol)-block-poly(ɛ-caprolactone) micelles were prepared through thin-film hydration method with high entrapment efficiency (96.1 ± 0.76%) and small particle (about 58.66 nm). The drug-loaded micelles showed comparative in vitro antimicrobial activity with KET cream. In e x in vivo skin deposition and permeation study, ketoconazole-loaded micelles provided skin accumulation higher than marketed ketoconazole cream without obvious permeation in the whole period. Fluorescence microscopy study and histopathological study demonstrated the copolymeric micelles' penetrating into skin in depth due to its capability of weakening the barrier function of stratum corneum. In vivo skin deposition parameters further confirmed high skin deposition of drug-loaded micelles (AUC (0-t) = 396.16 μg·h/cm 2 ) over marketed ketoconazole cream (AUC (0-t) = 250.03 μg·h/cm 2 ). Meanwhile, in vivo pharmacokinetic parameters proved that ketoconazole-loaded micelles reduced ketoconazole's distribution in blood in comparison with the cream (AUC (0-t) = 93,028.00 μg·h/L vs AUC (0-t) = 151,714.00 μg·h/L), meaning lower possibility of its systemic unwanted effects in the skin fungal infection treatment. The results suggested that the copolymeric micelles can be adopted for specific delivering ketoconazole into skin for fungal infection cure.
研究领域:
药剂学
·
皮肤病学
·
生物材料学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CHROMATOGRAPHIC SCIENCE
·
2015
·Vol. 54
·期 3
·361-366
·
IF 1.363
Tian Tingting,Yang Min,Zhao Zhongxi,Luan Yuxia,Tang Xuan,Zhu Meihua,Liu Yan
In this work, a stability-indicating high-performance liquid chromatography (HPLC) method was developed and validated for the simultaneous analysis of ketoconazole (KCZ) and beauvericin (BEA) as well as their degradation products in the combination tablets. KCZ is a synthetic broad-spectrum antifungal agent with the risk of hepatoxicity. However, it was found that the combined use of KCZ and BEA in their low dose had not only maintained the antifungal activity of KCZ but also significantly reduced the liver toxicity. The method development was started from forced degradation studies including acidic, basic, oxidative, thermal and photolytic degradations in the solution mixtures of KCZ and BEA. The forced degradation study results indicate that hydrolysis and oxidation were the major degradation pathways for KCZ while BEA mainly decomposed under basic hydrolytic condition. The newly developed HPLC method was validated according to the International Conference on Harmonization (ICH) guidelines with respect to specificity, linearity, precision, accuracy, limits of detection and quantification and robustness. The method validation results indicate that the new HPLC method could be successfully applied in the simultaneous detection and quantitation of KCZ and BEA and their degradation products. For example, the accuracy and the precision of the method were determined by a recovery study at 80, 100 and 120% of the tablet dosage levels. The recovery was found to be 99.6–100.2 for both analytes with a relative standard deviation of no more than 1.2% (n = 5) at any concentration level. This new method can be used for further development of various KCZ and BEA combination drug products.
研究领域:
药学
·
分析化学
✓ 已验证
DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2017
·
IF 2.759
Fangfang Teng,Peizong Deng,Zhimei Song,Feilong Zhou,Runliang Feng
In order to enhance water-solubility and realize controlled release while keeping synergistic effects of ketoconazole and curcumin , drug-loaded methoxy poly (ethylene glycol)-b-poly (ε-caprolactone) micelles were prepared through thin membrane hydration method. Transmission electric microscopy and dynamitic light scattering characterization revealed the formation of ketoconazole- and curcumin-loaded micelles with an average size of 44.70 nm and 39.56 nm, respectively. The drug-loaded micelles endowed the two drugs’ slow controlled release with water-solubility enhanced to 85 and 82000 folds higher than the corresponding raw drugs, respectively. In vitro antifungal activity test, chequerboard test and inhibition zone test indicated that efficacy of ketoconazole-loaded micelles was improved by introduction of curcumin-loaded micelles with a low fractional inhibitory concentration index (0.073). Biofilm formation inhibition assay also demonstrated that participation of curcumin-loaded micelles obviously strengthened the inhibition of fungal biofilms formation induced by ketoconazole-loaded micelles. The high synergistic activity of combinations is encouraging and the MPEG-PCL micelle is a potential drug delivery system for the combination of ketoconazole and curcumin.
研究领域:
药剂学
·
生物医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
XENOBIOTICA
·
2021
·
IF 1.908
Li Guo,Li Zhang,Haiman Xu,Pei Yu,Zhigang Wang,Danyi Lu,Min Chen,Baojian Wu
1. Retrorsine (RTS) is a pyrrolizidine alkaloid (distributed in many medicinal plants) that has significant hepatotoxicity. Here, we aimed to determine the daily variations in RTS hepatotoxicity (chronotoxicity) in mice, and to investigate the role of metabolism in generating RTS chronotoxicity.2. Acute toxicity and pharmacokinetic studies were performed with mice after RTS administration at different times of the day. Hepatotoxicity was assessed by measuring plasma ALT (alanine aminotransferase) and AST (aspartate aminotransferase) levels. mRNA and proteins were determined by qPCR and Western blotting, respectively. Time-dependent in vitro metabolism of RTS was assessed by using mouse liver microsomes.3. We found that RTS toxicity was more severe in the dark phase (zeitgeber time 14 or ZT14 and ZT18) than in the light phase (ZT2 and ZT6). This chronotoxicity was associated with a dosing time difference in the systemic exposures of RTS and a pyrrolic ester metabolite (a cause of hepatotoxicity, measured by the levels of pyrrole-GSH conjugate and pyrrole-protein adducts due to a high chemical reactivity). Moreover, the CYP3A11 (a major enzyme for RTS bioactivation) inhibitor ketoconazole decreased the production of pyrrole-GSH conjugate and abrogated diurnal rhythm in RTS metabolism. In addition, E4bp4 (a circadian regulator of Cyp3a11) ablation abolished the rhythm of CYP3A11 expression and abrogated the dosing time-dependency of RTS toxicity.4. In conclusion, RTS chronotoxicity in mice was attributed to time-varying hepatic metabolism regulated by the circadian clock. Our findings have implications for reducing pyrrolizidine alkaloid-induced toxicity via a chronotherapeutic approach.
研究领域:
药理学
·
毒理学
·
时间生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2023
·
IF 3.5
Qi Luo,Yang Shen,Guohong Zhai,Lin Chen,Furong Ou,Luxi Yi,Danli Yang,Hong Pan,Fuguo Shi
Dictamnine is a representative furan-containing hepatotoxic compound. Administration of dictamnine caused acute liver injury in mice and the metabolic activation of furan to reactive epoxy intermediate was responsible for the hepatotoxicity. This study aimed to characterize the protein adduction by endogenous hepatic aldehydes and investigate its role in dictamnine-induced hepatotoxicity. In the liver sample of dictamnine-treated mice, the protein adduction by five aldehydes was characterized as lysine residue-aldehyde adducts using high-resolution UPLC-Q/Orbitrap MS after exhaustive proteolytic digestion. The levels of protein adduct were increased at 2–3 h after the treatment with dictamnine. The formation of protein adduction increased with increasing doses of dictamnine. Inhibition of the bioactivation by CYP3A inhibitor ketoconazole prevented the protein adduction. Treatment with 2,3-dihydro-dictamnine, an analog of dictamnine that was unable to form the epoxy intermediate, did not lead to an increase in protein adduction. Application of aldehyde dehydrogenase-2 activator ALDA-1 or nucleophilic trapping reagent N -acetyl-L-lysine significantly reduced the protein adduction and attenuated dictamnine-induced liver injury without affecting the bioactivation. In conclusion, the metabolic activation of the furan ring of dictamnine resulted in the protein adduction by multiple hepatic aldehydes and the protein modification played a crucial role in dictamnine-induced liver injury.
研究领域:
药理学
·
毒理学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）