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The enantiomeric separation of seven imidazole antifungals was first systematically examined on a derivative polysaccharide chiral stationary phase (CSP), i.e. Chiralcel OD-RH in the reversed phase mode. The influence of the type and content of the organic modifier, the pH of buffer solution, type and concentration of buffer salt, and column temperature on enantiomeric separation were evaluated and optimized. The maximum resolution values for flutrimazole, econazole, miconazole, butoconazole, isoconazole, sulconazole, and climbazole were 2.36, 1.55, 0.89, 1.51, 0.96, 1.13, and 2.30. For a better understanding of the chiral recognition mechanism, detailed computational simulations of Chiralcel OD-RH interaction with seven pairs of enantiomers were carried out using the molecular docking software AutoDock. The various interactions affecting enantiomeric separation were confirmed in detail from the the molecular level. The modeling data were in agreement with the chromatographic results concerning enantioselectivity. It was found that the enantiomeric separation of imidazole analytes on Chiralcel OD-RH was the result of a mixture of hydrogen bonds, π–π, hydrophobic, dipole–dipole, and some special interactions. The docking results showed good agreement with our experimental results.

Background: Sulconazole (SCZ) is a broad-spectrum transdermally administered anti-fungicidal agent. However, the therapeutic effect of SCZ is generally limited by its poor water solubility. This present study aimed to develop and evaluate sulconazole-loaded nanoemulsions (SCZ-NEs) for enhancement of the transdermal permeation and antifungal activity. Methods: A spontaneous titration method was applied to prepare the SCZ-NEs. And the optimized formulation of SCZ-NEs was screened by central composite design (CCD). In addition, the characteristics of the SCZ-NEs were evaluated, including particle size, zeta potential, drug loading (DL%) and encapsulation efficiency (EE%). The morphology of SCZ-NEs was observed by transmission electron microscopy (TEM). Franz diffusion cells were used to evaluate the transdermal permeability of the SCZ-NEs. The antifungal activity of the SCZ-NEs was measured by a zone of inhibition (ZOI) test. Results: The optimized SCZ-NEs possessed a moderate particle size of 52.3±3.8 nm, zeta potential of 23.3±1.2 mV, DL% of 0.47±0.05% and EE% of 87.1±3.2%. The ex vivo skin permeation study verified that the cumulative permeability (Qn) and penetration rate (Js) of the optimized SCZ-NEs were about 1.7-fold higher than that of a commercial reference, miconazole (MCZ) cream and 3-fold higher than that of SCZ-DMSO solution. The optimized SCZ-NEs exhibited zone of inhibition (ZOI) values of 23.5±2.4 and 20.4±2.5 mm against C. albicans and T. rubrum, which were larger compared with these of the MCZ cream and SCZ-DMSO solution. Conclusion: SCZ-NEs were effectively developed to overcome the poor solubility of SCZ, promote SCZ permeation through the skin and improve its antifungal activity. Thus, the SCZ-NEs are a promising percutaneous administration for skin fungal infections induced by C. albicans and T. rubrum.

Glioblastoma (GBM) is a uniformly lethal disease driven by glioma stem cells (GSCs). Here, we use a chemical biology approach to unveil previously unknown GBM dependencies. By studying sulconazole (SN) with anti-GSC properties, we find that SN disrupts biotin distribution to the carboxylases and histones. Transcriptomic and metabolomic analyses of SN-treated GSCs reveal metabolic alterations that are characteristic of biotin-deficient cells, including intracellular cholesterol depletion, impairment of oxidative phosphorylation, and energetic crisis. Furthermore, SN treatment reduces histone biotinylation, histone acetylation, and expression of superenhancer-associated GSC critical genes, which are also observed when biotin distribution is genetically disrupted by holocarboxylase synthetase (HLCS) depletion. HLCS silencing impaired GSC tumorigenicity in an orthotopic xenograft brain tumor model. In GBM, high HLCS expression robustly indicates a poor prognosis. Thus, the dependency of GBM on biotin distribution suggests that the rational cotargeting of biotin-dependent metabolism and epigenetic pathways may be explored for GSC eradication. National Research Foundation (NRF) National University of Singapore (NUS), Temasek Laboratories Published version This work was supported by the National Research Foundation Fellowship NRF-NRFF2017-01 (D.S.T.O.), National University of Singapore (NUS) start-up grant (D.S.T.O. and M.J.K.), NUS President’s Assistant Professorship (D.S.T.O.), and NUS Research Scholarships (M.J.Y.A., B.W.L.L., Y.H.C., and R.T.M.). S.K. and C.S.V. thank A*STAR and NSCC for support.

Due to the remarkable enantioselective performances of polysaccharide derivatives, immobilized cellulose-based columns have high enantioseparation ability, which can be applied under various mobile phase conditions. In the present work, a cellulose-derived chiral stationary phase (CSP), namely Chiralpak IC was evaluated for enantioseparation of eight imidazole antifungal drugs (miconazole, econazole, isoconazole, sulconazole, butoconazole, fenticonazole, sertaconazole, and ketoconazole) in three mobile phase modes: normal-phase mode, polar organic mode and reversed-phase mode. The factors that affected the enantioseparation were investigated and optimized. Results indicated that the Chiralpak IC column possessed good enantioselectivity in three modes, with all analytes being successfully resolved. In addition, the mechanism of enantioseparation was preliminarily discussed based on the molecular structures and retention behavior of the enantiomers.

A diastereoselective α-sulfenylation of chiral α-aryl/alkyl N- tert-butanesulfinyl imidates has been developed. Suitable sulfur electrophiles can be used as sulfenylating reagents to intercept aza-enolates generated from imidate deprotonation, giving α-thiofunctionalized imidates in good yields with high diastereocontrol. This protocol for C-S bond formation can efficiently synthesize enantioenriched 1,2-sulfanyl amine derivatives such as sulconazole.

Sulconazole has been reported to degrade into sulconazole sulfoxide via sulfur oxidation; however, structural characterization data was lacking and the potential formation of an N-oxide or sulfone could not be excluded. To clarify the degradation pathways and incorporate the impurity profile of sulconazole into the United States Pharmacopeia–National Formulary (USP–NF) monographs, a multifaceted approach was utilized to confirm the identity of the degradant. The approach combines stress testing of sulconazole nitrate, chemical synthesis of the degradant via a hydrogen peroxide-mediated oxidation reaction, semi-preparative HPLC purification, and structural elucidation by LC–MS/MS and NMR spectroscopy. Structural determination was primarily based on the comparison of spectroscopic data of sulconazole and the oxidative degradant. The mass spectrometric data have revealed a McLafferty-type rearrangement as the characteristic fragmentation pathway for alkyl sulfoxides with a β-hydrogen atom, and was used to distinguish the sulfoxide from N-oxide or sulfone derivatives. Moreover, the generated sulconazole sulfoxide was utilized as reference material for compendial procedure development and validation, which provides support for USP monograph modernization. Keywords: Sulconazole nitrate, Sulconazole sulfoxide, Forced degradation, Structural characterization, LC–MS/MS

Four amino acid chiral ionic liquids were evaluated in dual systems with hydroxypropyl-beta-cyclodextrin to investigate the enantioseparation by CE of a group of seven drugs as model compounds (duloxetine, verapamil, terbutaline, econazole, sulconazole, metoprolol, and nadolol). The use of two of these chiral ionic liquids (tetramethylammonium L-Lysine ([TMA][L-Lys]) and tetramethylammonium L-glutamic acid ([TMA][L-Glu]) as modifiers in CE is reported for the first time in this work whereas tetrabutylammonium L-lysine [TBA][L-Lys]) and tetrabutylammonium L-glutamic acid ([TBA][L-Glu]) were employed previously in CE although very scarcely. The effect of the nature and the concentration of each ionic liquid added to the separation buffer containing the neutral cyclodextrin on the enantiomeric resolution and the migration time obtained for each drug, was investigated. A synergistic effect was observed when combining each chiral ionic liquid with hydroxypropyl-beta-cyclodextrin in the case of the five compounds for which the cyclodextrin showed enantiomeric discrimination power when used as sole chiral selector (duloxetine, verapamil, terbutaline, econazole, sulconazole). Buffer concentration and pH, temperature and separation voltage were varied in order to optimize the enantiomeric separation of these five compounds using dual systems giving rise to resolutions ranging from 1.1 to 6.6. (C) 2019 Elsevier B.V. All rights reserved.

Background: Sulconazole (SCZ) is a broad-spectrum transdermally administered anti-fungicidal agent. However, the therapeutic effect of SCZ is generally limited by its poor water solubility. This present study aimed to develop and evaluate sulconazole-loaded nanoemulsions (SCZ-NEs) for enhancement of the transdermal permeation and antifungal activity. Methods: A spontaneous titration method was applied to prepare the SCZ-NEs. And the optimized formulation of SCZ-NEs was screened by central composite design (CCD). In addition, the characteristics of the SCZ-NEs were evaluated, including particle size, zeta potential, drug loading (DL%) and encapsulation efficiency (EE%). The morphology of SCZ-NEs was observed by transmission electron microscopy (TEM). Franz diffusion cells were used to evaluate the transdermal permeability of the SCZ-NEs. The antifungal activity of the SCZ-NEs was measured by a zone of inhibition (ZOI) test. Results: The optimized SCZ-NEs possessed a moderate particle size of 52.3±3.8 nm, zeta potential of 23.3±1.2 mV, DL% of 0.47±0.05% and EE% of 87.1±3.2%. The ex vivo skin permeation study verified that the cumulative permeability (Qn) and penetration rate (Js) of the optimized SCZ-NEs were about 1.7-fold higher than that of a commercial reference, miconazole (MCZ) cream and 3-fold higher than that of SCZ-DMSO solution. The optimized SCZ-NEs exhibited zone of inhibition (ZOI) values of 23.5±2.4 and 20.4±2.5 mm against C. albicans and T. rubrum, which were larger compared with these of the MCZ cream and SCZ-DMSO solution. Conclusion: SCZ-NEs were effectively developed to overcome the poor solubility of SCZ, promote SCZ permeation through the skin and improve its antifungal activity. Thus, the SCZ-NEs are a promising percutaneous administration for skin fungal infections induced by C. albicans and T. rubrum.

Two analytical methodologies based on the combined use of hydroxypropyl-beta-cyclodextrin and two different amino acid-based chiral ionic liquids (tetrabutylammonium-L-lysine or tetrabutylammonium-L-glutamic acid) in electrokinetic chromatography were developed in this work to perform the enantios-elective determination of econazole and sulconazole in pharmaceutical formulations. The influence of different experimental variables such as buffer concentration, applied voltage, nature and concentration of the ionic liquid, temperature and injection time, on the enantiomeric separation was investigated. The combination of hydroxypropyl-beta-cyclodextrin and tetrabutylammonium-L-lysine under the optimized conditions enabled to achieve the enantiomeric determination of both drugs with high enantiomeric resolution (3.5 for econazole and 2.4 for sulconazole). The analytical characteristics of the developed methodologies were evaluated in terms of linearity, precision, LOD, LOQ and recovery showing good performance for the determination of both drugs which were successfully quantitated in pharmaceutical formulations. This work reports the first analytical methodology enabling the enantiomeric determination of sulconazole in pharmaceutical formulations.

Objectives Sulconazole is a broad spectrum antifungal agent of the imidazole class used against dermatophytes and other fungi to treat skin infections. The aim of the present work was to formulate and evaluate a microemulsion-based topical sulconazole gel. Materials and methods Microemulsion formulation of sulconazole nitrate was prepared by using oil, surfactant, cosurfactant and water at different ratios. This was then subjected to clarity and particle size analysis, a centrifugation test, a dilution test, and freeze thawing. Results The zeta potential of formulation F1 was -41.3 and stable. The pH of the microemulsion formulation was within the range of pH of skin. F1 showed a higher percentage amount of drug as compared with the other formulations. The viscosity showed that F1 was optimum. The freezing and thawing results showed there was no phase separation and the formulation was stable. In vitro drug release showed that the drug release from the microemulsion of F1 was higher when compared to the other formulations. It revealed F1 had the highest drug content of 95.88±0.3% and % cumulative drug release was 88.75% release in 8 h. The in vivo skin irritation study on rats confirmed that formulation was nontoxic and nonirritant. Conclusion The present study confirmed the safety of the formulated sulconazole loaded microemulsion gel for topical application.

In this paper, two spiral structure CILs, 1-butyl-3-methylimidazolium(T-4)-bis[(2S)-2-(hydroxy-κO)-3-methyl-butanoato-κO]borate(BMIm+BLHvB-) and 1-butyl-3-methylimidazolium (T-4)-bis[(αS)-α-(hydroxy-κO)-4-methyl-benzeneacetato-κO]borate (BMIm+BSMB-)were applied to evaluate their potential synergistic effect with dextrin for CE enantiomeric separation. The established dextrin-based synergistic system with CILs as additives showed good separation performance towards four tested drugs, including duloxetine, ketoconazole, sulconazole and citalopram. It was also observed that significantly improved separation and selectivity for tested analytes were achieved in CILs/dextrin synergistic system compared to single dextrin system. Primary parameters, such as the concentration of CIL, dextrin concentration, buffer pH and applied voltage, were systematically investigated to optimize the enantiomeric separation with BMIm+BLHvB-/dextrin as model system. Finally, the method of Statistical Product and Service Solutions (SPSS) was exploited to further elucidate the influence of experimental parameters on the synergistic effect.

It has been reported that chiral dual system is able to improve the enantioseparation of enantiomers in many cases. Currently, the dual systems involved in CE chiral separation are mostly dual CDs systems, and the polysaccharides-based chiral dual system was reported in only one paper. To the best of our knowledge, the use of chondroitin sulfate C (CSC)-based dual system for enantiomeric separation has not been reported previously. Herein, four CSC-based chiral dual systems, namely CSC/glycogen, CSC/chondroitin sulfate A (CSA), CSC/hydroxypropyl-β-CD (HP-β-CD), as well as CSC/β-CD (β-CD), were evaluated for the first time for their enantioseparation capability by CE in this paper. During the course of the work, the influences of chiral selector concentration and buffer pH values on enantioseparation in dual systems were systematically investigated. Under the optimized conditions, the dual system consisting of CSC and glycogen exhibited better separations toward nefopam, duloxetine, sulconazole, atenolol, laudanosine, and cetirizine enantiomers compared to the single CSC or glycogen system. The combination of CSC and HP-β-CD improved the separation of amlodipine and chlorphenamine enantiomers. However, no synergistic effect was observed in the CSC/CSA and CSC/β-CD systems.

The seven azole compounds, econazole nitrate, sulconazole nitrate, miconazole nitrate, thiabendazole, epoxiconazole, propiconazole, and tebuconazole, were applied to wool fabrics at 3.0% on mass of wool and the protection from wool-digesting Tineola bisselliella (common clothes moth) larvae was assessed in bioassays. Econazole nitrate gave the greatest protection according to Wools of New Zealand Test Method 25, easily passing the bioassay. Other good results with sulconazole and epoxiconazole led to further bioassays being performed with Australian carpet beetle larvae Anthrenocerus australis. Propiconazole provided the most effective protection of wool from this species, with a concentration of approximately 0.4% on mass of wool predicted to give adequate insect resistance. A combination of propiconazole and isoniazid was trialed against Anthrenocerus australis, without any synergistic effect. The antiprotozoal compound pentamidine isethionate had no measurable effect on Anthrenocerus australis larvae, but provided a moderate anti-feeding effect on Tineola bisselliella. Antimicrobial compounds could affect the digestive process of wool-digesting insects either directly or by their effects on any gut flora and/or fauna. Azoles are antifungal compounds, and are likely to disrupt the insect utilisation of cholesterol by inhibiting the cytochrome P450 enzymes. Propiconazole was trialed as a dyebath-applied insect-proofing agent on piece-dyed carpet, showing inefficient uptake onto wool, but good fastness to carpet shampooing and light exposure.

Various chiral selectors have been utilized successfully in capillary electrophoresis (CE); however, the number of polysaccharides used as chiral selectors is still small and the mechanism of enantiorecognition has not been fully elucidated. Chondroitin sulfate D (CSD) and chondroitin sulfate E (CSE), belonging to the group of glycosaminoglycans, are linear, sulfated polysaccharides with large mass. In this paper, they were investigated for the first time for their potential as chiral selectors by CE. The effect of buffer composition and pH, chiral selector concentration, and applied voltage were systematically examined and optimized. A variety of drug enantiomers were resolved in the buffer pH range of 2.8-3.4 using 20 mM Tris/H3PO4 buffer with 5.0 % CSD or CSE and 20 kV applied voltage. A central composite design was used to validate the optimized separation parameters and satisfactory uniformity was obtained. As observed, CSE allowed satisfactory separation of the enantiomers of amlodipine, laudanosine, nefopam, sulconazole, and tryptophan methyl ester, as well as partial resolution of citalopram, duloxetine, and propranolol under the optimized conditions. CSD allowed partial or nearly baseline separation of amlodipine, laudanosine, nefopam, and sulconazole. The results indicated that CSE has a better enantiorecognition capability than CSD toward the tested drugs.

The enantioseparation of 10 basic drugs was evaluated in NACE systems using heptakis(2-O-methyl-3-O-acetyl-6-O-sulfo)-β-CD (HMAS-β-CD). For this purpose, a D-optimal design with 21 experimental points was applied. Four antifungal agents (econazole, isoconazole, miconazole, sulconazole), three local anesthetics (bupivacaine, mepivacaine and prilocaine), two sympathomimetics (salbutamol and terbutaline) and one β-blocker (carvedilol) were selected as basic model analytes. The influence on the enantiomeric resolution of anionic CD and BGE anion concentrations as well as the BGE anion nature was investigated. For all studied analytes, the enantiomeric resolution was shown to be significantly influenced by the CD concentration. Based on the observed results, a generic NACE system was recommended, namely 20mM HMAS-β-CD and 10mM ammonium camphor SO(3)(-) in methanol acidified with 0.75 M formic acid. Moreover, this NACE system was compared to previous conditions with heptakis(2,3-di-O-methyl-6-O-sulfo)-β-CD (HDMS-β-CD) or heptakis(2,3-di-O-acetyl-6-O-sulfo)-β-CD (HDAS-β-CD). Finally, two generic systems using either HDAS-β-CD or HMAS-β-CD were proposed and evaluated for the enantioseparation of ketamine and norketamine after incubation of ketamine in phenobarbital-induced male rat liver microsomes systems.

The chiral separations of four racemic imidazole antifungal drugs namely econazole, miconazole, isoconazole and sulconazole were achieved on AmyCoat RP column (150 × 4.6 mm, 3.0 μm particle size). The mobile phases used were different combinations of water and acetonitrile. Besides, few drops of diethylamine and acetic acid were added to optimize chiral separation of sulconazole. The flow rates of mobile phases were 1.00 and 1.5 mL min−1 with detection at 225 nm. The values of capacity, separation and resolution factors were 0.53–2.10, 1.45–1.98 and 1.29–1.97, respectively. Attempts have been made to describe chiral recognition mechanism at supra-molecular level. The reported chiral LC method is simple, fast and reproducible, and can be used for the resolution of these molecules in biological matrices.

Summary. Trichophyton rubrum and Trichophyton interdigitale have been grown in liquid culture in the presence of sulconazole. The antigenic activity of detergent extracts of intact organisms was analysed following SDS-PAGE and the probing of Western blots with homologous antisera raised in rabbits and with sera from patients with dermatophyte infections. Differences in protein-band patterns were noted; some bands present in control samples were absent in azole-treated samples and vice versa. These differences were reflected in antigenic band patterns, especially among components of approximate molecular weight of 30–40, 50–60 and 92–100 kDa. Zusammenfassung. Trichophyton rubrum and Trichophyton interdigitale wurden in Gegenwart von Sulconazol in Flussigkulturen angezuchtet. Der Antigenbestand in Detergens-Extrakten der intakten Organismen wurde nach SDS-PAGE in Westernblots unter Verwendung homologer Seren von Kaninchen und von Dermatophytose-Patienten untersucht. Es wurden Unterschiede in den Proteinbanden gefunden. Einige Banden zeigten sich in den Kontrollproben, fehlten aber in den Sulconazol-behandelten Ansatzen und umgekehrt. Diese Differenzen zeigten sich in Antigenbanden mit Molekulargewichten von 30-40, 50-60 und 92-100 kDa.

Summary: In a double-blind parallel study, forty patients with dermatophytoses, verified by derect examination (KOH) and fungal culture, were treated with either sulconazole nitrate 1% cream or econazole nitrate 1% cream (20 patlents per group) twice daily for four weeks. Every patient had positive KOH and culture findings when admitted to the study; after two weeks of treatment with either medication, these results became negative for all except one member of the sulconazole group. By the end of treatment all patients had negative test results. Signs and symptoms of inflammation responded equally well to both treatments throughout the study. Of the 40 patients admitted to the study, 34 were eligible for post-study evaluation. Six patients were excluded from efficacy analyses: one had experienced an allergic reaction when treated with econazole; one had exhibited eczema following sulconazole treatment; two patients had used additional dermatological products during the post-treatment phase of the study; and two others had returned for the 10-week follow-up relapse check prior to the minimum required time. Six weeks after treatment ended, three of the 16 patients who had been treated successfully with econazole experienced relapses of their fungal infections. However, 18 of the patients who had been treated with sulconazole were still completely clear of all clinical signs of fungal infection and remained KOH and culture negative. Cosmetically, sulconazole was better accepted than was econazole. Zusammenfassung: In einer Doppelblindstudie wurden 40 Patienten mit Dermatophytosen, die durch Nativpraparate und Pilzkultur nachgewiesen waren, entweder mit 1%lger Sulconazolnitrat-oder mit 1%lger Econazolnitratcreme (20 Patienten pro Gruppe) zweimal taglich uber vier Wochen behandelt. Alle Patienten hatten zu Beginn der Untersuchung positive Ergebnisse im Nativpraparat und in der Kultur. Nach zweiwochiger Behandlung mit einem der beiden Praparate wurden diese Ergebnisse fur alle Patienten negativ mit Ausnahme eines Patienten in der Sulconazol-Gruppe. Nach Abschlus der Behandlung waren samtliche mykologischen Untersuchungsergebnisse negativ. Objektive und subjektive Symptome der Entziundung sprachen ebenso auf beide Behandlungsformen an. Von den ursprunglichen 40 Patienten konnten die Ergebnisse von 34 nach Abschlus der Behandlung ausgewertet werden. 6 Patienten musten von der Bewertung ausgeschlossen werden. Von diesen hatte ein Patient unter Econazol-Behandlung eine allergische Reaktion entwickelt. Ein Patient zeigte ein Ekzem infolge der Sulconazol-Behandlung. Zwei Patienten wendeten wahrend der Nachbehandliungsphase andere dermatologische Produkte an. Schlieslich erschienen zwei Patienten vor Ablauf der festgesetzten Nachuntersuchungszeit. 6 Wochen nach Abschlus der Behandlung zeigten drei der erfolgreich mit Econazol behandelten Patienten einen Ruckfall ihrer Pilzinfektion. Dagegen waren alle 18 Patienten, die mit Sulconazol behandelt worden waren, zum Zeitpunkt der Nachuntersuchung klinisch und mykologisch frei von Mykosen. Unter kosmetischen Aspekten wurde die Sulconazol-Zubereitung besser akzeptiert als die Econazol-Creme.

Summary: Forty patients with dermatophytoses were treated with either sulconazole nitrate 1% cream (sulconazole) or miconazole nitrate 2% cream (miconazole) twice daily for three weeks. At the start of the randomised double-blind clinical trial, all KOH and culture results were positive, and 75% of the patients were diagnosed as having tinea pedis and 25% as having other cutaneous dermatophytic infections. Follow-up visits occurred at weeks 2 and 3; all patients who were KOH negative and symptom free at week 3 returned at week 9 for a 6-week post-treatment checkup. Thirty-nine patients completed treatment One sulconazole-treated patient experienced a burning sensation the first day and was therefore withdrawn from the study; no other adverse reaction occurred. Within each treatment group, statistically significant improvement of all parameters investigated occurred at weeks 2 and 3 as compared with baseline. Sulconazole, however, proved to be more rapid in onset of therapeutic response than miconazole. At the week-2 visit, statistically significant differences in favor of sulconazole were elicited for erythema (p = 0.01), scaling (p = 0.03), itching (p = 0.03), and overall clinical improvement (p = 0.0229). Separate analysis of the tinea pedis subgroup likewise showed more rapid improvement of erythema, scaling, and itching sulconazole was used; the difference was statistically significant for overall clinical improvement (p = 0.04). At weeks 2 and 3, both groups exhibited statistically significant mycological cure rates as indicated by negative KOH and culture results. The difference in cure rates between the two groups, however, was not statistially significant A positive KOH at week 9 indicated that one miconazole-treated patient had experienced a relapse; all sulconazole-treated patients remained free of infection. Because of its more rapid onset of symptomatic improvement, sulconazole was considered to be clinically superior to miconazole in the treatment of dermatophytoses. Zusammenfassung: Vierzig Patienten mit Dermatophytosen wurden uber 3 Wochen 2mal taglich entweder mit 1% iger Sulconazolnitratcreme oder mit 2% iger Miconazolnitratcreme behandelt. Zu Begjnn der randomisierten klinischen Doppelblindstudie waren alle Nativpraparate und Pilzkulturen positiv. 75% der Patienten hatten eine Tinea pedis, 25% hatten andere Dermatophytosen der Haut. Untersuchungen fanden 2 und 3 Wochen nach Beginn der Behandlung statt. Alle Patienten mit klinischer Abheilung und negativem Nativpraparat nach 3-wochiger Behandlung kamen 9 Wochen nach Behandlungsbeginn nochmals zu einer Untersuchung 6 Wochen nach Therapieende. 39 Patienten fuhrten die Behandlung vollstandig durch. Ein Patient mit Sulconazolbehandlung fuhlte am ersten Tag ein Brennen an der Haut und wurde daher nicht weiterbehandelt. Andere unerwunschte Wirkungen wurden nicht beobachtet. Innerhalb jeder Behandlungsgruppe zeigten sich statistisch signifikante Besserungen bei alien uberpruften Merkmalen beim Vergleich zwischen dem Ausgangsbefund und den Befunden nach 2 und 3 Wochen. Unter Sulconazol setzte der therapeutische Erfolg rascher ein als unter Miconazol. Bei der Untersuchung nach 2 Wochen war ein gunstigerer Effekt des Sulconazol in bezug auf folgende Parameter festzustellen: Rotung (p = 0,01), Schuppung (p = 0,03), Juckreiz (p = 0,03), generelle klinische Besserung (p = 0,0229). Auch in der Untergruppe der Tinea pedis war ein rascheres Ansprechen von Rotung, Schuppung und Juckreiz bemerkbar. Fur die allgemeine klinische Besserung war auch hier der Unterschied statistisch signifikant (p = 0,04). Nach 2 und 3 Wochen zeigten beide Gruppen statistisch signifikante Heilungsraten, wie durch Negativwerden von Nativpraparat und Kulturen nachzuweisen war. Der Unterschied der Heilungsraten zwischen beiden Gruppen war nicht statistisch signifikant. Ein Miconzol-behandelter Patient erlitt nach 9 Wochen mit erneut positivem Nativpraparat ein Rezidiv. Alle Sulconazol-behandelten Patienten blieben erscheinungsfrei. Wegen des rascheren Einsatzes des Therapieerfolges wurde Sulconazol als Praparat gewertet, das in der Therapie von Dermatophytosen dem Miconazal klinisch uberlegen ist.

Sulconazole-β-cyclodextrin water soluble inclusion complex was prepared by freeze drying method in distilled water. The formation of inclusion complex between β-cyclodextrin and sulconazole has been studied in a previous work. Preliminary pharmacological studies concerning the antifungal activity showed that the minimal inhibitory concentrations for 90% of the tested strains decreased. Also, the acute toxicity of the sulconazole-β-cyclodextrin complex is smaller comparing with the pure drug, analyzed alone. These results recommend the described conjugates as future promising therapeutic agents.

Complexation between methyl β-cyclodextrin (Me βCD) and sulconazole nitrate (SULC) was realized both under freeze drying and ultrasonication conditions. The process was carried out in solution and in solid state. In solution, the complexation was evaluated using solubility studies, nuclear magnetic resonance spectroscopy (1H-NMR) and UV–Vis absorption studies. In the solid state, differential scanning calorimetry (DSC), and X-ray diffraction studies were used. Solubility studies indicate the existence of inclusion complexes between SULC and Me βCD. 1H-NMR data showed that the inclusion complexes have different structures, according with the method we used for synthesis: for the freeze dried method the complex is obtained by complexation of dichlorobenzene ring of SULC into inner cavity of CD while for ultrasonication method the complex is obtained by complexation of imidazole graph of SULC into the CD molecule. DSC and X-ray studies bring supplementary information concerning the formation of complex Me βCD–SULC. As a result of the inclusion process into Me βCD, the solubility of SULC increase significant, being 10 times more comparative with the pure drug. We anticipate that these modifications will have a significant impact on the biological effects of the drug, making the SULC–Me βCD complex an appropriate candidate for a new drug delivery system.

Complexation between 5-flucytosine (5-FC), a cytosine analogue with in vitro antifungal and antiyeast activity, and β-cyclodextrins (β-cyclodextrin and hydroxypropyl-β-cyclodextrin) was studied in solution and in solid states. Complexation in solution was evaluated using solubility studies, UV–vis and 1H-NMR. In the solid state, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), FT-IR and X-ray diffraction studies were used. UV–vis, FT-IR and 1H-NMR spectroscopy studies showed that the complex formed occurs by complexation of piridinique base analogue into inner cavity. DSC studies showed the existence of a complex of 5-FC with β-CDs. X-ray studies confirmed the DSC results of the complex existence. Solubility studies showed that the complexed drug is forty times more soluble than free 5-FC, indicating the obtained systems as future, promising drug carriers.

The chiral resolution of four antifungal compounds, three imidazoles (miconazole, econazole and sulconazole) and one triazole (itraconazole) using supercritical fluid chromatography on the amylose-based chiral stationary phase Chiralpak AD, is presented in this work. The influence of pressure, type and percentage of organic modifier and temperature on retention times and resolution was studied. The enantiomeric separation of the three imidazoles was achieved with resolutions higher than two and analysis times lower than 10 min, obtaining the best results using methanol as modifier. However, the analysis time of the triazole was higher than 80 min due to the existence of a high number of functional groups that were able to interact with the chiral stationary phase. In this case, the resolution of the four stereoisomers was achieved only partially with mixtures of ethanol and 2-propanol as modifier. The isoenantioselective temperatures were obtained from the study of the influence of the temperature, they were above the range of temperatures assayed, except for sulconazole using 2-propanol.

This paper describes the modification of Chiralcel OD column properties by adsorption of (+) or (-) camphorsulfonic acids (CSAs) used as additives to the mobile phase. The effects on retention, selectivity and efficiency, of adsorption of (+) and (-) CSAs on a Chiralcel OD column were examined. Racemic anti-histamines, anti-malarial and anti-fungal drugs, namely doxylamine, miconazole, sulconazole, hydroxyzine, homochlorcyclizine, methoxypheniramine, cyclopentolate and ephedrine were investigated as chiral tested compounds. All the studied drugs have an amino nitrogen atom in their structure. Only the enantioseparation of ephedrine enantiomers with CSAs alone was studied on the Nucleosil stationary phase, and these results were compared with the results obtained on the Chiralcel OD phase. A new dynamically generated stationary phase, with very good enantioseparation ability towards the studied compounds, was obtained by the adsorption of (-) CSA on the Chiralcel OD column.

A total of 56 strains belonging to 4 species of dermatophytes were tested against 10 antifungal drugs by using a modification of the NCCLS (M38-P) standard for filamentous fungi. The minimum inhibitory concentration (MIC) values obtained using the dilution method were compared with the diameters of growth inhibition zones using the disk diffusion method. The antifungals used were itraconazole, fluconazole, ketoconazole, miconazole, sulconazole, oxiconazole, bifonazole, griseofulvin, ciclopiroxolamine, and terbinafine. Relative to the other agents tested. terbinafine possessed the highest antifungal activity against all of the dermatophytes. In contrast, fluconazole was the least active drug. An increase of MIC values was accompanied by a decrease of growth inhibition zone diameter. The disk diffusion method of fungal susceptibility assessment yields data consistent with results obtained front the dilution method. The Study suggests the potential value of the disk diffusion method as a convenient alternative method for testing the susceptibilities of dermatophytes. (C) 2004 Elsevier Inc. All rights reserved.

The chiral resolution of (+/-)-econazole, (+/-)-miconazole and (+/-)-sulconazole on the columns containing different cellulose derivatives namely Chiralcel OD, OJ, OB, OK, OC and OF in normal phase mode has been described. The mobile phase used was hexane-2-propanol-diethylamine (425:74:1, v/v/v). The flow rates of the mobile phase used were 0.50, 1.00 and 1.50 ml/min. The values of the separation factor (alpha) of the resolved enantiomers of econazole, miconazole and sulconazole on chiral phases were ranged from 1.07 to 2.50 while the values of resolution factor (R(s)) varied from 0.17 to 3.90. The chiral recognition mechanisms between the analytes and the chiral selectors are discussed.

Resolution of the enantiomers of (+/-)-econazole, (+/-)-miconazole, and (+/-)-sulconazole has been achieved on different normal-phase chiral amylose columns, Chi-ralpak AD, AS, and AR. The mobile phase used was hexane-2-propanol-diethylamine, 400:99:1 (v/v). The flow rates of the mobile phase used were 0.50 and 1.00 mL min(-1). The alpha values for the resolved enantiomers of econazole, miconazole, and sulconazole on the chiral phases were in the range 1.63 to 1.04; the Rs values varied from 5.68 to 0.32.

Using the results of high performance liquid chromatography (HPLC), this paper investigates the separation and inclusion of a series of weakly polar imidazole derivatives, with hydroxypropylβ -cyclodextrin (HP-β-CD) in the mobile phase over a wide range of column temperatures.These compounds are used for the treatment of onychomycosis. Gibbs Helmholtz parameters (Δ(ΔH) and Δ(ΔS)) of two adjacent imidazole peak on a chromatogram were determined from the graph of the logarithm of the separation factor,α, against the reciprocal of the temperature. A temperature dependent reversal of the elution order between a pair of imidazole derivatives was studied. The results revealed that the main parameter determining interactions between imidazole derivatives and HP-β-CD increased as follows:HP-β-CD ⇔solute hydrogen bonding interaction >HP-β-CD ⇔solute complexation.

Caryophyllene oxide, an oxygenated terpenoid, well known as preservative in food, drugs and cosmetics, has been tested in vitro as an antifungal against dermatophytes. Its antifungal activity has been compared to ciclopiroxolamine and sulconazole, commonly used in onychomycosis treatment and chosen because of their very different chemical structures. So, a new model has been tested, utilizing sheep hoof plates in order to simulate human nails, which are almost unobtainable for in vitro tests. Three protocols were utilized: pre-treatment, simultaneous treatment and post-treatment. Among these, the post-treatment method was the best to simulate antifungal therapy, as it permitted testing and comparing the efficiency of different antifungal drugs.

Polysaccharides such as dextrins, which are mixtures of linear α-(1,4)-linked D-glucose polymers, and dextrans, which are polymers of D-glucose units linked predominantly by α-(1,6) bonds, have been employed as chiral selectors in the capillary electrophoretic (CE) separation of enantiomers. Because these polymers are electrically neutral, the method is applicable to ionic compounds. Among the compounds tested the enantiomers of ibuprofen, naproxen, warfarin and the diltiazem synthetic intermediate 1,1′-binaphthyl-2,2′diyl hydrogen phosphate, which are anionic compounds, were successfully recognized by employing dextran or dextrin under neutral conditions. The enantiomers of basic or cationic drugs such as timepidium, primaquine, sulconazole, trimetoquinol, diltiazem and clentiazem were also successfully separated under acidic conditions. The effects of molecular mass and polysaccharide concentration on enantioselectivity were investigated. High concentrations of these polymers, especially dextrin, led to delayed migration times after repeated injections of the solutes into an uncoated capillary under neutral conditions. Consequently the capillary washing process was found to be very important to obtaining reproducible migration times in the system. A coated capillary was also investigated to overcome this problem. Finally, the method using electrically neutral polysaccharides was applied to the testing of the optical purity of the drug substances.

Since the introduction of clotrimazole cream to the Japanese market in 1979, topical imidazole antimycotics have been used with increasing frequency in the treatment of superficial fungal infections. Topical imidazole antimycotics are in common use today and new imidazole derivatives continue to be developed. In this study, the author discussed allergic contact dermatitis due to topical imidazole antimycotics and cross-reactions among them. Of the 3,049 outpatients who were patch-tested for contact dermatitis at the Department of Dermatology, Nippon Medical School Hospital from January, 1984 to August, 1994, 218 were patch-tested with topical antimycotic agents. Of these 218 cases, 18 were tested with imidazole derivatives and 66 showed positive. Thirty-five were allergic to the active ingredients; 16 were allergic to sulconazole, 11 to croconazole, 3 to tioconazole, 3 to miconazole, one to bifonazole, and one to clotrimazole. The reason why sulconazole induced the most frequent positive reactions is probably that sulconazole was prescribed most frequently at our department during the period. The duration and the total amount of topical imidazole needed until contact dermatitis occurred, were statistically analyzed by t.test. Croconazole needed a significantly shorter duration and smaller quantity than sulconazole. This means that the sensitizing ability of croconazole is stronger than that of sulconazole. Since 21 of the 35 imidazole-allergic cases cross-reacted to other imidazole(s), the imidazole derivatives are considered to cross-react frequently.

The present article reviews the literature (up to 1994) on contact sensitivity to imidazoles and presents the results obtained from 15 patients observed at the Contact Allergy Unit in Leuven. The frequency as well as the cross-reaction patterns described are analyzed. Although allergic contact reactions may have been missed in the past (mainly because of problems with the correct choice of vehicle for patch testing), they seem to be relatively infrequent in view of their widespread use. The imidazole derivatives most frequently reported to be allergens are miconazole, econazole, tioconazole, and isoconazole. As far as cross-reactivity is concerned, statistically significant associations were found in the patient data between miconazole, econazole, and isoconazole; between sulconazole, miconazole, and econazole; and also between isoconazole and tioconazole. Patients sensitive to phenylethyl imidazoles (except ketoconazole) needing antimycotic therapy should be advised to use ketoconazole, clotrimazole, bifonazole, or, perhaps, the new flutrimazole. Clearly, non-imidazole antifungals can also be used.

The enantiomeric resolution of (±)-econazole, (±)-miconazole and (±)-sulconazole was achieved on a Chiralpak WH column. The mobile phase used was hexane-2-propanol-diethylamine (400:99:1,v/v/v). The flow rates of the mobile phase used were 0.50 and 1.00 mL min−1. The values of α of the resolved enantiomers of econazole, miconazole and sulconazole were in the range of 1.68 to 1.23 while the values of Rs varied from 2.42 to 1.10. The resolution of these antifungal agents on Chiralpak WH column is governed by ligand exchange mechanism. Hydrophobic interactions also play an important role for the enantiomeric resoltuion of antifungal agents on the reported CSP.

Several chiral reagents including cyclodextrins (CDs) and derivatives, crown ethers, proteins, chiral surfactants and polymers have been involved in dual selector systems for enantioseparation of a series of chiral compounds by capillary electrophoresis (CE). In comparison to the chiral reagents above-mentioned, there is no report concerning the use of polysaccharides in dual chiral CE system. In this paper we first investigate the enantioselectivity of polysaccharide-based dual selector systems towards some chiral drugs. During our recent work, glycogen belonging to the class of branched polysaccharides has been used as a novel chiral selector in CE. In this study, three glycogen-based dual chiral CE systems have been established for enantiomeric separations of several racemic basic drugs consisting of duloxetine, cetirizine, citalopram, sulconazole, laudanosine, amlodipine, propranolol, atenolol and nefopam. These three dual systems combined glycogen (neutral polysaccharide) with chondroitin sulfate A (CSA, ionic polysaccharide), β-CD and HP-β-CD, respectively. It was found that the dual system of glycogen/CSA exhibited good enantioselective properties toward the tested drugs. More importantly, compared to the single selector systems, synergistic effect was observed when glycogen was used with CSA for most of the analytes. This indicated the enhancement of enantioseparation observed for these analytes in glycogen/CSA system might be due to some favorable interaction effects between glycogen and CSA. Moreover, in order to evaluate the stereoselectivity of glycogen/CSA, the influences of buffer pH and selector concentration on enantioseparation of the studied drugs were also investigated.

The in vitro activity of several new imidazoles, cloconazole, sulconazole, butoconazole, isoconazole and fenticonazole, were compared with those of amphothericin B, flucytosine, and three azoles: econazole, miconazole and ketoconazole against isolates of pathogenic Candida. A total of 186 clinical isolates of 10 species of the genus Candida and two culture collection strains were tested by an agar-dilution technique. Isoconazole was the most active azole, followed by butoconazole and sulconazole. Differences between some of the species in their susceptibility to the antifungal agents were noted. Sulconazole and cloconazole had the highest activity in vitro against 106 isolates of C. albicans. Butoconazole and isoconazole were also very active against isolates of C. albicans, and were the most active azole compounds against 80 isolates of Candida spp.

The highly enantioselective addition of thioacetic acid to nitroalkenes using a new sulfinyl urea organocatalyst is described. The addition of thioacetic acid proceeds in high yields and enantioselectivities for a variety of aromatic and aliphatic nitroalkene substrates. This new method is useful for preparing chiral 1,2-aminothiol derivatives, as demonstrated by the first enantioselective synthesis of the clinically used antifungal drug sulconazole.