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Pancreatic ductal adenocarcinoma (PDAC) is characterized by the highest mortality among carcinomas. The pathogenesis of PDAC requires elevated autophagy, inhibition of which using hydroxychloroquine has shown promise. However, current realization is impeded by its suboptimal use and unpredictable toxicity. Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach. Here, using a patient-derived organoid model, we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents, through which econazole (ECON), an antifungal compound, emerged as the top candidate. Further testing in cell-line and xenograft models of PDAC validated this activity, which occurred as a direct consequence of dysfunctional autophagy. More specifically, ECON boosted autophagy initiation but blocked lysosome biogenesis. RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3 (ATF3). Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1 (ID-1) led to inactivation of the AKT/mammalian target of rapamycin (mTOR) pathway, thus giving rise to autophagosome accumulation in PDAC cells. The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis. Furthermore, ECON, as an autophagy inhibitor, exhibited synergistic effects with trametinib on PDAC. This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.
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OBJECTIVE: To optimize the formulation of econazole solid lipid nanoparticles(E-SLN) by combining pseudo-ternary phase diagrams and central composite design-response surface methodology (CCD-RSM). METHODS: Econazole solubility in different solid lipids and the capacity of lipid emulsion were tested. The microemulsion region was obtained by the pseudo-ternary phase diagrams. Then the E-SLN were prepared by microemulsion method. Drug/lipid (X1), lipid/surfactant (X2) and surfactant/cosurfactant (X3) were taken as individual factors, the encapsulation efficiency (Y1), particle size (Y2), Zeta potential (Y3) were taken as the dependent factors. The possible optimum formulation was predicted by CCD-RSM and validated. RESULTS: Econazole could be dissolved in tripalmitic acid glyceride (TAG), monostearic acid glyceride, stearic acid and lauric acid glyceride. TAG had a good capacity of emulsion. The optimized formulation was econazole 0.06 g, glyceryl palmitate 0.48 g, Tween-80 1.194 g, glycerol 0.274 g and added water to 30 mL by CCD-RSM. According to the optimized formulation, the encapsulation efficiency, particle size and Zeta potential were (94.06±1.54)%, (18.88±0.38)nm and (3.53±0.01)mV, respectively. The deviation was less than 5%. CONCLUSION: The stable and ultra-small size E-SLN with high encapsulation efficiency could be obtained by combining pseudo-ternary phase diagrams and CCD-RSM.
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Background/Objective: The aim of the study was to prepare a nanoemulsion (NE)-enriched hydrogel of econazolenitrate (EC) for a topical broad-spectrum antimycotic application. EC is classified as a Biopharmaceutical ClassificationSystem Class IV (low permeability, low solubility) drug. Nanotechnology is one of the most important approaches toimprove drugs solubility and permeability.Methods: Depending on solubility study of EC in NE components which include oils (peppermint oil, eucalyptus oil,and olive oil), surfactants (Tween 40, Brij 35, and Ceto stearyl alcohol), and co-surfactants (Propylene glycol, PEG400, and Glycerol); peppermint oil was selected as the oil phase. Tween 40 and propylene glycol were selected asthe surfactant and co-surfactant, respectively. Deionized water was used as an aqueous phase. A phase diagram wasprepared with a 5:1 weight ratio of tween 40 to propylene glycol. One percent of EC was loaded into the selectedNE system and combined with hydrogel consisting of carbopol 934 or HPMC as gelling polymer at three differentpercentages. Evaluation and in vitro release of the product were done.Results: NE Formula (F10) which is composed of 10% w/w of each the oil and surfactant mixture was selected asoptimum NE which shows a particle size of 80.57 nm and acceptable viscosity and pH (5.65). Formula (G6) which iscomposed of NE (F10) combined with hydrogel 3.5% HPMC shows satisfactory physical properties with the completeand prolonged release over 8 hours.Conclusion: The results suggest that the prepared NE-enriched hydrogel can be considered as a promising deliverysystem for class IV antifungal drug
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La piel es un órgano apropiado para administrar principios activos con el fin de obtener efectos locales o sistémicos. Las formulaciones de uso tópico más comunes son: lociones, emulsiones, suspensiones, cremas, pomadas; las cuales deben reunir determinadas condiciones para ser aplicadas sobre la piel. El objetivo del presente trabajo es seleccionar una emulsión preparada con la técnica de formación de cristales líquidos compuesta de ácido esteárico, vaselina líquida, trietanolamina, propilparabeno, metilparabeno y agua, a la que se le incorpora un ingrediente farmacéutico activo liposoluble: econazol. El econazol, principio activo cuya vía de administración es la tópica y su acción es local, es una sustancia soluble en aceites, que se aloja en la fracción liposoluble de los cristales líquidos y en la fase interna de la emulsión sin que se modifique el perfil reológico ni la estabilidad de los sistemas. Se estudió además del HLB y de sus comportamientos reológicos, la presencia de cristales líquidos con luz polarizada, la existencia de gotas secundarias con luz común y la estabilidad de los sistemas por centrifugación y estrés térmico a temperaturas de 40 ºC. Los valores obtenidos en los estudios realizados, demostraron que la emulsión lograda presenta un perfil reológico y las condiciones de estabilidad adecuadas para ser utilizada como crema medicinal.
The skin is the appropiate organ to administrate active principles in orden to obtain local or systemic effects. Formulations for topical use most common are: lotions, emulsions, suspensions, creams, ointments, which must gather certain conditions to be applied to the skin. In this work, the objective is to select an emulsion prepared by a technique of liquid crystals formation composed by stearic acid, mineral oil, triethanolamine, propylparaben, methylparaben and water. To this formula we incorporated a pharmaceutical active liposoluble ingredient: econazole. Econazole, a principle active with topical administration and local action, is a substance soluble in oils, which stays in the liposoluble fraction of the liquid crystals and in their internal phase of the emulsion without modifying their rheological profile not even the stability of systems. Besides the HLB of the systems and their rheological behaviour we also study the presence of liquid crystals with polarized light, the existence of secondary drops with common light and systems stability by centrifugation, thermal stress and temperatures of 40 °C. The values obtained from the studies made, demonstrated that the emulsion achieved present a rheological profile and stability conditions suitable for medicinal use cream.
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Background Econazole nitrate is not effective as an antifungal eyedrop because of its poor intraocular permeability,therefore changing the formulation of econazole nitrate to improve its intraocular permeability become a critical point in the treatment of intraocular fungal infection. Objective The present study was to observe the penetration of 0.5％ econazole nitrate nanoparticles in the corneas and aqueous humors following its topicaladministration. Methods Econazole nitrate nanoparticles were prepared by quasi-emulsion solvent diffusion.Characteristics and size of nanoparticles were examined with transmission electron microscope and laser scatteringmethod,respectively.Econazole nitrate nanoparticles drops (0.5％ )was topically administered in 27 New Zealandwhite rabbits bilaterally,and aqueous humor and corneas were obtained after the application of the eye drops for 5,15,30,45,60,90,120,180,240 minutes respectively to detect the concentration of econazole nitrate with highperformance liquid chromatography (HPLC). The pharmacokinetic parameters were calculated with 3 p97pharmacokinetic computer software.The use of the animals followed the Regulation for the Administration of AffairsConcerning Experimental Animals by State Science and Technology Commission. Results The diameter of thenanoparticles was 50 nm with the round shape and encapsulation efficiency was 96.0％.Econazole nitrate nanoparticlesat the concentration of 0.5％ could be rapidly separated with other elements by HPLC with a lowest quantitativeconcentration of 0.1 mg/L.The mean recovery rates of econazole nitrate nanoparticles were 98.09％ in cornea and 99.66％ in aqueous humor,respectively after topical administration.The peak levels of econazole nitrate nanoparticles in cornea and aqueous humor were achieved at 5 minutes after application ( cornea:40.620 μg/g± 7.756 μg/g;aqueous humor:0.504 mg/L±0.153 mg/L),and its half-life( t1/2 )in cornea and aqueous humor was 23.5 minutes and 18.6 minutes,respectively. Conclusions Econazole nitrate nanoparticles at 0.5％ concentration can remain a feasible bioavailability in ocular tissue and therapeutic level in cornea and aqueous humor.
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To investigate the synergistic effect of tetrandrine (TET) to the anti-Trichophyton mentagrophytes activity of econazole (ECZ) in vivo,animal model of dermatophytosis in guinea pig was established by inoculating Trichophyton mentagrophytes conidia.These 40 infected animals were divided into 4 groups randomly and from Day 5 after inoculation,they were treated with the following formulations once per day for successive 14 days: 1% econazole and 1% tetrandrine compound cream (1%ECZ+1%TET group),1% econazole cream (1%ECZ group),1%TET cream (1%TET group) and matrix cream (matrix group).The alterations in the skin lesions and the pathological changes were observed.From the 4~(th) day of drugs applying,the tendency of lesion score about 1%ECZ+1%TET group continued to decline.On the 14~(th) day of drugs applying,the lesion score decreased to 0.75.There was a similarity between 1%ECZ+1%TET group and 1%ECZ group in tendency of lesion score,but more reduction was appeared in 1%ECZ+1%TET group than in 1%ECZ group (mean 0.75 VS 2.00) with obviously statistical difference (P=0.037).The culture results of skin sections and the pathological changes in 1%ECZ+1%TET group were less than those of other 3 groups.It's predicted that there is a synergistic effect of tetrandrine to the anti-Trichophyton mentagrophytes of econazole in animal model of dermatophytosis in guinea pig.
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OBJECTIVE:To prepare compound sparfloxacin auristillae and to establish its quality control method.METHODS:The auristillae was prepared with glycerin and alcohol as solvents;the contents of econazole and sparfloxacin were determined by UV spectrophotometry with their respective detection wavelengths at360nm and297nm respectively,and the stability of which were determined as well.RESULTS:The linear concentration ranges of econazole and sparfloxacin were2～400?g/ml and0.4～80?g/ml respectively;the average recovery of econazole and sparfloxacin were100.96%(RSD=0.99%)and100.38%(RSD=0.44%)respectively.The expiry date(shelf life)of the finished products was above2years.CON?CLUSION:The preparation is simple in preparation,good in stability;and the quality control method is simple and easy,rapid,accurate and feasible.
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Objective To assess the antimicrobial actitivity of econazole nitrate in comparison with other six antibacterial drugs. Methods The minimal inhibitory concentrations (MICs) of econazole nitrate (Eco), neomycin (Neo), erythromycin (E), penicillin (P), cefotaxime sodium (Cef), ciprofloxacin (Cip) and amikacin (An) to 222 strains of Staphylococcus spp isolated from the lesions of patients with eczema and atopic dermatitis were determined by using the broth dilution method. Results MIC50 values of Eco were similar to Neo, Cip, An and Cef, and lower than those of P and E on methicillin-sensitive Staphylococcus aureus (MSSA); significantly lower than those of the other six antibacterial drugs on methicillin-resistant Staphylococcus aureus (MRSA); similar to An, Cip and P, and lower than those of Neo, Cef and E on methicillin-sensitive and coagulase-negative Staphylococcus (MSCNS); and similar to An, Cip P or Neo, and lower than Cef and E on methicillin-resistant and coagulase negative Staphylococus (MRCNS). Based on the NCCLS standards, the resistance rates of Cip, P and E were very high to either Staphylococcus areus or coagulase-negative Staphylococcus (CNS). The resistance rates of An and Cef of were lower to MSSA, but higher than 50% to MRSA. MIC90 value of Eco was similar to its MIC50, and lower than the MIC value reported in the literature. The MIC90 value of neomycin was muich higher than the MIC50 value of econazole. Conclusion Econazole nitrate has antibacterial activity to both Staphylococcus areus and CNS. MIC90 value of Eco is similar to its MIC50, and no resistance to Eco was found.
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OBJECTIVE:To establish the preparation process and method of quality control of econazole nitrate ear-drops.METHODS:With mixture of glycerin and 75% alcohol as solvent,econazole nitrate ear-drops was prepared and the content of econazole was determined by ultraviolet spectrophotometry.The stability,irritation and in vitro antimicrobial tests were carried out.RESULTS:There was a good linearity of calibration curve of econazole in range of 200～600?g/ml,r=0.9 999,the average recovery was 100.76%,RSD=0.82%(n=5).The in vitro antimycotic MICs of econazole nitrate in ear-drops were 2?g/ml and 4?g/ml against standard and clinically isolated strains of Candida albicans respectively.CONCLUSION:The ear-drops is simple in preparation,effective in antimycotic action,good in stability and slight in irritability,and the method of quality control is simple,rapid and accurate.