Chapter

Miconazole Nitrate: Comprehensive Profile

Authors:
  • King Saud University, College of Pharmacy,
To read the full-text of this research, you can request a copy directly from the author.

Abstract

This chapter focuses on a comprehensive profile of miconazole nitrate. Miconazole base is a white or almost white powder. Miconazole is an imidazole antifungal agent used as miconazole base or miconazole nitrate for the treatment of superficial candidiasis and of skin infections dermatophytosis and pityriasis versicolor. The drug is also given intravenously by infusion for the treatment of disseminated fungal infections. Miconazole nitrate was prepared by Godefori and co‐workers. Slightly soluble in water and is soluble in 9.5 of ethanol. The X‐ray powder diffraction pattern of miconazole is performed using a Simmons XRD‐5000 diffractometer. The mass spectrum of miconazole nitrate is obtained using a Shimadzu PQ‐5000 mass spectrometer. Different methods of analysis are explained in this chapter. Different types of chromatography are also explained in the chapter. Benson and Nahata discussed the chemistry, pharmacology, pharmacokinetics, clinical uses, adverse effects, and drug interactions of miconazole and three other antifungal drugs.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the author.

... Regarding preparation of water-soluble film, it was essential to add propylene glycol as a genuine plasticizer to the macromolecular chains of CMC to produce an elastic film. Propylene glycol is liquid in nature, and any added excess amount would not be entrapped within the film and remained as an unobservable thin layer following dryness of the film (Al-Badr, 1972). The excellent folding and endurance results of the prepared film might be due to using excess amount of propylene glycol. ...
... This effect might be attributed to two reasons: first, the amount of urea used was high compared to the film structure composition. Second, urea is a crystalline substance, which would be expected to increase the rigidity of the film (Al-Badr, 1972;Mady et al., 2018). To simulate the mechanism by which the inserted soluble film produce the antifungal effect, a special model was suggested. ...
Article
Full-text available
Cutaneous mycoses, particularly tinea pedis caused by Trichophyton rubrum, are commonly known infections in humans. They are still considered as a major public health problem worldwide affecting the quality of life due to prolonged period of treatment and development of drug resistance, which leads to recurrence of infections. The objective of our study was to assess the effectiveness of miconazole in the presence and absence of urea, as a penetration enhancer, against T. rubrum and to formulate both of them in a water-soluble film to be applied topically for the purpose of treating tinea pedis caused by this fungus. Drug combination revealed synergism where miconazole minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) (0.5 and 1 mg/L) were considerably declined to 0.001 and 0.004 mg/L, respectively, when combined with 20% urea. This enhanced drug interaction activity against the test strain was explained by the alterations raised on the morphology and ultrastructures observed microscopically. Minimal fungicidal dose of miconazole/urea combination displayed plasmolysis and shrink cytoplasm; however, necrotic cells with punctured walls and degraded cytoplasmic content were observed at high fungicidal dose. Water-soluble films, prepared using increasing values of miconazole MFC and urea, were transparent, smooth, uniform, and flexible. Their physicochemical characters showed homogeneity in weight, thickness, drug content, and folding endurances with normal surface pH values, indicating the reproducibility of the preparation method. The novel simulation model for the film mechanism of action supported the idea and the suggested application method of the new dosage form. Evaluation of these films was carried in vitro using disk diffusion assay as well as in vivo using guinea pig dermatophytosis model. The in vitro assessment revealed an increase in the inhibition zone diameters in a concentration-dependent manner upon using 10 or 20% of urea combined with miconazole. In vivo test showed that combination of 0.004 mg/L miconazole with 20% urea (M + U20) showed the highest efficacy percentage (95.83%), which was statistically superior to the infected untreated control (p < 0.001) in fungal burden reduction as well as improvement in clinical scores (p < 0.001). This work supports the hypothesis and suggests a new promising dosage form for the treatment of T. rubrum infections.
... Also, miconazole nitrate exerted a dose-dependent inhibition on Kv10.1 activity. MN is a drug used to treat fungal infections and can be administered vaginally, orally, or parenterally (Al-Badr, 2005). As well as fluoxetine, MN has been described previously as a HERG-blocker with an IC50 of 2.1 µM (Kikuchi et al., 2005), 11 times more potent than the IC50 described here for Kv10.1. ...
Article
Full-text available
Resting membrane potential is a bioelectric property of all cells. Multiple players govern this property, the ion channels being the most important. Ion channel dysfunction can affect cells’ resting membrane potential and could be associated with numerous diseases. Therefore, the drug discovery focus on ion channels has increased yearly. In addition to patch-clamp, cell-based fluorescent assays have shown a rapid and reliable method for searching new ion channel modulators. Here, we used a cell-based membrane potential assay to search for new blockers of the Kv10.1, a potassium channel strongly associated with cancer progression and a promising target in anticancer therapy. We found that fluoxetine and miconazole can inhibit the Kv10.1 channel in the micromolar range. In contrast, BL-1249 potentiates Kv10.1 currents in a dose-dependent manner, becoming the first molecule described as an activator of the channel. These results demonstrate that cell-based membrane potential assay can accelerate the discovery of new Kv10.1 modulators.
... MN has been widely used in human and veterinary medicine in treatment of super candidiasis and dermal infections, dermatophytosis and pityriasis versicolor through topical (Rochette, 2003;Frymus, 2013), vaginal (Kenechukwu, 2018;Salah, 2018), buccal (Cartagena, 2017;Tejada, 2018), oral (Dimopoulou, 2015) and parenteral (Wade, 1979) administrations. MN is a positively charged compound with 6.7 pKa value and very slightly soluble in water, methanol and alcohol (Al-Badr, 2005; Martindale: The Complete Drug Reference, 2009;Qushawy, 2018). The combination of MN with CHX has been shown to exert synergistic effect against numerous bacteria (Perrins, 2003;Mueller, 2008;Nenoff, 2017). ...
Article
Miconazole nitrate (MN) and chlorhexidine digluconate (CHX) are the commonly used antimicrobials for topical treatment of dermal infections. Combination of antimicrobials has been investigated to enhance the efficacy of the treatment. Gel formulations based on bioadhesive polymers are preferred for delivery of these drugs. Chitosan is a promising bioadhesive polymer due to its penetration enhancing, antimicrobial and tissue healing properties. Yet, most of the gel-based formulations present analytical challenges during testing the drug content. It was aimed to develop an HPLC method for simultaneous determination of MN and CHX in chitosan-based gel formulations. Different solvent combinations were investigated for extraction of drugs from the gels. HPLC conditions such as mobile phase, flow rate, run time, column temperature and wavelength were explored. The method was validated according to ICH guideline Q2(R1). MN and CHX were extracted in solvent composition same with the mobile phase. The method was employed on ACE-C8 column at 40°C by isocratic elution using the mobile phase consisting of methanol:phosphate (75:25 v/v) buffer (containing triethylamine). Flow rate was 1 mL/min. The drugs were detected at 254 nm (CHX) and 230 nm (MN). Linearity was obtained between 5 to 80 μg/mL for both drugs. LOD and LOQ obtained for CHX was 1.61 and 1.06, for MN: 4.87 and 3.21 µg/mL, respectively. A new validated HPLC method was developed for simultaneous determination of CHX and MN in chitosan-based gels, with 98 to 102% recovery, without any interference with the excipients.
... Miconazole nitrate is usually applied twice daily as a 2% cream, lotion, or powder in the treatment of fungal infections of the skin, including candidiasis, dermatophytosis, and pityriasis Versicolor. [4][5] Various novel approaches were studied to improve the solubility and drug permeation through the skin such as liposomes, [6] niosomes, [7][8] solid lipid nanoparticles, [9] microemulsion. [10] Proniosomes are either anhydrous free-flowing formulations or liquid crystals with a jelly-like consistency of water-soluble carrier coated with suitable noisomeforming surfactants. ...
Article
Full-text available
Proniosomal gel formulations of miconazole nitrate (MCZ) were prepared by using combinations of different grades of (non-ionic surfactant) span, cholesterol, and lecithin by coacervation phase separation method. Developed 10 proniosomal gel formulations were characterized for particle size, shape, % entrapment efficiency, drug content, in vitro drug permeation, scanning electron microscopy (SEM), DSC, stability study. The fourier transform infrared spectroscopy (FTIR) studies confirmed the compatibility of the drug with excipients. The results showed that all the formulations were pale yellow to pale brown in color, pH was is in the range of 5.60 to 7.20, and encapsulation efficiency was found is in the range of 83 to 91.25% and particle size in between 5.81 ± 0.2 to 07.52 ± 0.07. Among the ten formulations MF2, MF3, MF5, MF6, and MF8 showed maximum drug release in a controlled manner at 12 hours of study and developed into carbopol proniosomal topical gel and evaluated for ex-vivo drug permeation. Formulationoptimized formulation C5MF8 showed higher drug permeation 74.19 ± 0.16% at 12 hr. with a flux valueof 6.829 ± 0.12 μg/cm2 /hr. The permeability coefficient of 0.341 ±0.08 cm2 /hrs., higher correlation coefficient R2 0.9944 for zero-order drug release kinetic model, and follows zero-order release kinetics. Among the 5 formulations, optimized carbopol proniosomal topical gel formulation C5MF8 drug release and in-vitro antifungal activity was compared with marketed formulation cream.C5MF8 showed sustain drug release and zone of inhibition value was very near to marketed preparation. Hence it was concluded that developed carbopol proniosomal topical gel had the potential to act as a controlled release drug carrier,which sustains the drug release for many hours and exhibit good antifungal activity
... However, propylene glycol was found to have a negative effect on the weight of the medicated films. This could be explained by the study of Al-Badr (1972), who reported that miconazole was soluble in propylene glycol and hence this led to a reduction in the actual drug concentration in the medicated films. ...
Article
Full-text available
A growing concern about Candida albicans is the emergence of high incidence of resistance against antifungal agents, which requires searching for new medications or improving the response to the existing members. The objective of this work was to evaluate the effectiveness of the miconazole in the absence and presence of urea, as a penetration enhancer, against C. albicans. In addition to, formulating both of them in a polymer film to be used topically for treatment of mouth fungal white patches caused by C. albicans. A synergistic effect was recorded between this imidazole and urea against the test strain. Miconazole MIC (32 mg/L) was dramatically reduced to 0.0625 mg/L following combination with urea. Transmission electron microscopy explained the mechanisms of action mediated by the test agents. Minimal fungicidal dose of miconazole combined with urea showed early apoptotic cells with condensed chromatin and small blebs. Cytoplasmic leakage and necrosis in some cells was observed at high fungicidal dose. Buccal bioadhesive films were prepared using increasing values of the drug MIC and urea. The physicochemical characters of the prepared films including; film weight, thickness, swelling index, drug content, folding endurance, surface pH, bioadhesion force and time and drug release kinetics, were studied. Microbiological evaluation of all prepared films showed an increase in the inhibition zone diameters for films containing increasing concentrations of both miconazole and urea in a concentration-dependent manner (30-40 mm) compared to miconazole alone (18 mm). Based on our results, the prepared films are promising for buccal administration of miconazole/urea showing synergistic effect for treatment of C. albicans infection.
... Due to the presence of an imidazole cycle, MNZ is a basic compound (pKa 6.77), and due to the presence of the aromatic rings it is a liphophilic substance (log P 5.86); MNZ has a water solubility 0,7μg/mL at 25 o C [4]. ...
Article
Full-text available
Objective : Miconazole, an imidazole antifungal derivative, is a very hydrophobic compound, a major drawback in obtaining topical pharmaceutical formulations with optimal bioavailability. Cyclodextrins (CDs) may increase local drug delivery by enhancing the drug release and/or permeation. The aim of the study is the characterization of inclusion complexes between miconazole and different CD derivatives. Methods : Several CD derivatives were tested in the experiments. The binary systems between miconazole and different CDs were prepared in 1:1 molar ratios by physical-mixture and kneading methods. Differential scanning calorimetry (DSC) and Fourier transformed-infrared spectroscopy (FT-IR) methods were used to characterize solid state interactions between miconazole and CDs in their binary systems. Results : The FT-IR analysis suggests the formation of a new solid phase, indicating a molecular interaction between the components. The DSC analysis sustains the hypothesis of formation of partial inclusion complexes between miconazole nitrate and CD. Conclusion : The thermic behaviour of the complexes depends both on the preparation method and the composition of the products.
... However, propylene glycol was found to have a negative effect on the weight of the medicated films. This could be explained by the study of Al-Badr (1972), who reported that miconazole was soluble in propylene glycol and hence this led to a reduction in the actual drug concentration in the medicated films. ...
Article
Full-text available
A growing concern about Candida albicans is the emergence of high incidence of resistance against antifungal agents, which requires searching for new medications or improving the response to the existing members. The objective of this work was to evaluate the effectiveness of the miconazole in the absence and presence of urea, as a penetration enhancer, against C. albicans. In addition to, formulating both of them in a polymer film to be used topically for treatment of mouth fungal white patches caused by C. albicans. A synergistic effect was recorded between this imidazole and urea against the test strain. Miconazole MIC (32 mg/L) was dramatically reduced to 0.0625 mg/L following combination with urea. Transmission electron microscopy explained the mechanisms of action mediated by the test agents. Minimal fungicidal dose of miconazole combined with urea showed early apoptotic cells with condensed chromatin and small blebs. Cytoplasmic leakage and necrosis in some cells was observed at high fungicidal dose. Buccal bioadhesive films were prepared using increasing values of the drug MIC and urea. The physicochemical characters of the prepared films including; film weight, thickness, swelling index, drug content, folding endurance, surface pH, bioadhesion force and time and drug release kinetics, were studied. Microbiological evaluation of all prepared films showed an increase in the inhibition zone diameters for films containing increasing concentrations of both miconazole and urea in a concentration-dependent manner (30–40 mm) compared to miconazole alone (18 mm). Based on our results, the prepared films are promising for buccal administration of miconazole/urea showing synergistic effect for treatment of C. albicans infection.
Article
Full-text available
The present study aimed to develop miconazole nitrate solid lipid nanoparticle (SLN) loaded polymeric microneedle (MN) patches (SPs) via the vacuum micromolding approach. The SLNs were fabricated through melt emulsification of stearic acid using Tween 80. SPs were prepared using chitosan, gelatin (as base materials) and polyethylene glycol 400 (as a plasticizer). The prepared formulations were evaluated for various physicochemical parameters, including particle size, polydispersity index, encapsulation efficiency, loading capacity (in the case of SLNs), folding endurance, % swelling and insertion ability (in the case of SPs). Scanning electron microscopy and differential scanning calorimetry (DSC) studies were carried out for morphological and thermal analysis, respectively. Phase analysis was carried out via X-ray diffraction (XRD). In vitro tensile strength, drug release, anti-biofilm activity and in vivo anti-biofilm activity were studied to assess the efficiency of the SLN loaded polymeric formulation. Miconazole nitrate containing SLNs appeared as smooth-surfaced aggregates and displayed a particle diameter of ∼224 nm, polydispersity index of ∼0.32, encapsulation efficiency of ∼88.88% and loading capacity of ∼8.88%. SPs exhibited evenly aligned, uniform-surfaced, sharp-tipped projections, with an acceptable folding endurance of ∼300 and % swelling of ∼359%. DSC and XRD results confirmed the incorporation of the drug within the solidified lipid matrix as an amorphous solid. The miconazole nitrate lipidic nanoparticle containing polymeric formulation exhibited a tensile strength ∼1.35 times lower than the pure drug loaded counterpart. During in vitro studies, SPs released ∼94% miconazole nitrate within 150 minutes and reduced the mass of the Candida albicans (C. albicans) biofilm by ∼79%. After 10 days of treatment with SPs, C. albicans infected wounds were healed, confirming that the prepared formulations can be used for the management of fungal biofilms.
Article
Effective antifungal therapy for the treatment of fungal keratitis requires a high drug concentration at the corneal surface. However, the use of natural β-cyclodextrin (βCD) in the preparation of aqueous eye drop formulations for treating fungal keratitis is limited by its low aqueous solubility. Here, we synthesized water-soluble anionic βCD derivatives capable of forming water-soluble complexes and evaluated the solubility, cytotoxicity, and antifungal efficacy of drug prepared using the βCD derivative. To achieve this, a citric acid crosslinked βCD (polyCTR-βCD) was successfully synthesized, and the aqueous solubilities of selected antifungal drugs, including voriconazole, miconazole (MCZ), itraconazole, and amphotericin B, in polyCTR-βCD and analogous βCD solutions were evaluated. Among the drugs tested, complexation of MCZ with polyCTR-βCD (MCZ/polyCTR-βCD) increased MCZ aqueous solubility by 95-fold compared with that of MCZ/βCD. The inclusion complex formation of MCZ/βCD and MCZ/polyCTR-βCD was confirmed by spectroscopic techniques. Additionally, the nanoaggregates of saturated MCZ/polyCTR-βCD and MCZ/βCD solutions were observed using dynamic light scattering and transmission electron microscopy. Moreover, MCZ/polyCTR-βCD solution exhibited good mucoadhesion, sustained drug release, and high drug permeation of porcine cornea ex vivo. Hen's Egg test-chorioallantoic membrane assay and cell viability study using Statens Seruminstitut Rabbit Cornea cell line showed that both MCZ/polyCTR-βCD and MCZ/βCD exhibited no signs of irritation and non-toxic to cell line. Additionally, antifungal activity evaluation demonstrated that all isolated fungi, including Candida albicans, Aspergillus flavus, and Fusarium solani, were susceptible to MCZ/polyCTR-βCD. Overall, the results showed that polyCTR-βCD could be a promising nanocarrier for the ocular delivery of MCZ.
Article
Full-text available
A green and simple method was proposed for the synthesis of silver nanoparticles (Ag-NPs) using Piper cubeba seed extract as a reducing agent for the first time. The prepared Ag-NPs were characterized using different spectroscopic and microscopic techniques. The obtained Ag-NPs showed an emission band at 320 nm when excited at 280 nm and exhibited strong green fluorescence under UV-light. The produced Ag-NPs were used as fluorescent nanosensors for the spectrofluorimetric determination of ornidazole (ONZ) and miconazole nitrate (MIZ) based on their quantitative quenching of Ag-NPs native fluorescence. The current study introduces the first spectrofluorimetric method for the determination of the studied drugs using Ag-NPs without the need for any pre-derivatization steps. Since the studied drugs don't exhibit native fluorescent properties, the importance of the proposed study is magnified. The proposed method displayed a linear relationship between the fluorescence quenching and the concentrations of the studied drugs over the range of 5.0–80.0 µM and 20.0–100.0 µM with limits of detection (LOD) of 0.35 µM and 1.43 µM for ONZ and MIZ, respectively. The proposed method was applied for the determination of ONZ and MIZ in different dosage forms and human plasma samples with high % recoveries and low % RSD values. The developed method was validated according to ICH guidelines. Moreover, the synthesized Ag-NPs demonstrated significant antimicrobial activities against three different bacterial strains and one candida species. Therefore, the proposed method may hold potential applications in the antimicrobial therapy and related mechanism research.
Article
Full-text available
The retention behavior of bifonazole, clotrimazole, fenticonazole, fluconazole, ketoconazole, miconazole, metronidazole, and itraconazole, widely used antimycotic drugs have been determined by TLC by use of the binary mobile phases acetone-n-hexane, methanol-toluene, and methyl ethyl ketone-toluene containing different amounts of organic modifier. Hydrophobicity was established from the linear relationships between the solute R-M values and the concentration of organic modifier. Calculated values of R-M(0) and C-0 were considered for application in QSAR studies of the antimycotics.
Article
Full-text available
A simple and rapid densitometric method has been developed for simultaneous determination of betamethasone valerate and miconazole nitrate in cream preparations. After extraction of the analyte with 96 % ethanol, the extracts were spotted on pre–coated silica gel plates, which were eluted two times with a mixture of chloroform–acetone–glacial acetic acid, 34+4+3 (v/v/v). Quantitative evaluation was performed by measuring the absorbance reflectance of the analyte spots at λ = 233 nm. The densitometric method is selective, precise, and accurate, and can be used for routine analysis of the cream preparations in pharmaceutical industry quality control laboratories.
Article
Full-text available
An alternative synthesis for the preparation of miconazole, enilconazole and econazole is described. The process involves the intermolecular insertion of a carbenoid species to imidazole from α- diazoketones with copper acetylacetonate as the key reaction of the synthesis route.
Article
Full-text available
A radial diffusion bioassay for miconazole, which employs Candida stellatoidea as the indicator organism, is described. Results from three patients treated with the drug are presented.
Article
The ultraviolet spectrophotometry for quantitative determination of miconazole nitrate in liniment has been developed. Miconazole nitrate was analyzed at 272 nm, the average recovery, was 99.76%, RSD was 0.3% (n = 5). The results showed that the method can be used for the determination of miconazole nitrate in liniment.
Chapter
The objective of this work was to compare the intravenous pharmacokinetic of miconazole in sheep after its administration in a polyoxyl 35 castor oil/lactic acid mixture, a 100 mM HP-ßCD — 50 mM lactic acid solution and a 50 mM SBE7-ßCD — 50 mM lactic acid solution.
Article
We tested toxicity of the antifungal agents amphotericin B, clotrimazole, griseofulvin, haloprogin, miconazole, nystatin, and tolnaftate to larval horn flies, each of which appeared to be potentially useful in bovine fetal medium. The toxicity of ethanol, methanol, dimethylsulfoxide (DMSO) and dimethylformamide (DMF) were also evaluated. DMSO and DMF were incompatible with horn fly larvae at all concentrations tested. Methanol and ethanol were each tolerated to about 2% (vol/wt), but exhibited increasing toxic effects at higher concentrations. Ethanol supplementation up to 2% had a positive effect on larval growth and survival. A combination of streptomycin, nystatin and ethanol was found to be compatible with use in horn fly larval bioassays.
Article
Simple method for gas-chromatographic identification of 7, among 9 used, antimycotic compounds, derivatives of imidazole has been elaborated. The conditions have been established for quantitative determination of selected compounds of this group present in substances and such pharmaceuticals as ointments and creams. The column, packed with UCW-98 on Chromosorb WAW, and flame-ionisation detector were used. The statistical data indicate satisfactory precision of the method, both in the determination of imidazole derivatives in substances and in preparations.
Article
A simple and accurate pH-metric method is described for the determination of two sparingly soluble in water antifungal drugs: ketoconazole and miconazole. Cetyltrimethylammonium bromide and sodium dodecylsulfate micelles have been used to solubilize these compounds. The application of the proposed method to the analysis of pharmaceutical preparations of the related species gave satisfactory results. Simplicity and the absence of harmful organic solvents in this method makes it possible to be used in routine analyses.
Article
In this paper, two new spectrophotometric methods were used for the simultaneous determination of metronidazole and miconazole nitrate in their binary mixture. In the first method, derivative spectrophotometry, dA/dλ values were measured at 328.6 and 230.8 nm for metronidazole and miconazole nitrate, respectively, in the first derivative spectra of their combination. The relative standard deviation of the method was found to be 0.21% for metronidazole and 0.50% for miconazole nitrate. In the other method, the absorbency ratio method, the quantification of metronidazole and miconazole nitrate was performed by using the absorbencies read at 310.4, 280.6 and 272.0 nm in the zero-order spectra of their mixture. The relative standard deviation of the method was found to be 0.67 and 0.85% for metronidazole and miconazole nitrate, respectively. These two methods have been successfully applied to an ovule containing only these drugs.
Article
Synopsis Miconazole 1 is an imidazole antifungal drug which has recently become available for systemic use. Its antifungal activity has been well studied and it is active in vitro against a wide range of fungi. Published and unpublished reports of the use of miconazole in conditions such as systemic or mucocutaneous candidosis, coccidioidomycosis, fungal meningitis, and paracoccidioidomycosis (which seems especially responsive) have often been encouraging, particularly in view of the serious, refractory nature of the conditions treated, but in most areas of use experience is limited. There are few effective drugs available for treating most systemic fungal infections, and if further studies confirm the encouraging results often seen to date, miconazole will be an important addition to the limited choices available for such conditions. Antimicrobial Activity Miconazole has useful in vitro activity against a wide range of dermatophytes (e.g. Trichophyton mentagrophytes, Epidermophyton floccosum), yeasts (e.g. Candida albicans, Pityrosporum orbiculare and pachydermatis, Cryptococcus neoformans) and actinomycetes (e.g. Streptomyces madurae, Nocardia asteroides), as well as some Gram-positive and anaerobic bacteria (e.g. Staphylococcus aureus, Streptococcus faecalis, Bacteroides fragilis). Like the closely related compound, econazole, it has no useful activity against Gram-negative rods. Candida albicans is moderately sensitive, most strains being inhibited by a miconazole concentration of 0.5 to 4µg/ml. Coccidioides immitis is also moderately sensitive. The causative organism of South American blastomycosis (Paracoccidioides brasiliensis), a serious endemic disease in parts of Central and South America, is highly sensitive in vitro, the minimum inhibitory concentration being about 0.001µg/ml. In in vivo studies, intramuscular miconazole markedly increased the survival rate of rats with experimental systemic candidosis compared with placebo controls, and increased survival of mice infected with Coccidioides immitis. However, subcutaneous and intraperitoneal administration were ineffective in treating mice infected with Cryptococcus neoformans. ‘Higher’ oral doses (160mg/kg/day) were effective in treating cutaneous dermatophyte infections in guinea pigs, and oral doses of 1.5 to 3g daily markedly reduced colony counts in asymptomatic volunteers with C. albicans in their sputum. The mode of antimicrobial action of miconazole may involve an effect on cell membranes or, according to more recent studies, miconazole may result in the accumulation of toxic reactive peroxide compounds within the microbial cell. Pharmacokinetic Studies Miconazole is only partially absorbed from the gastrointestinal tract, oral bioavailability being about 25 to 30%. After intravenous infusion of 522mg over 15 minutes in patients, peak plasma concentrations of 2 to 9µg/ml occurred, declining to 0.1 to 0.2µg/ml at 8 hours. Miconazole is widely distributed to body tissues. It readily penetrates into infected joints and into vitreous humour, but penetration into cerebrospinal fluid and sputum is variable and relatively low, CSF concentrations varying from less than 3% to about 50% of plasma concentrations. About 90% of the drug is bound to plasma proteins. The apparent volume of distribution in man is about 1400L. Miconazole is extensively metabolised, less than 1% being excreted in the urine unchanged. The elimination half-life in volunteers or patients is about 20 to 25 hours. Neither renal impairment nor haemodialysis appear to affect the elimination of miconazole, but plasma concentrations are higher in patients with impaired renal function receiving the same dose as patients with normal renal function, due to a decreased distribution volume in renal impairment. Clinical Use Much of the clinical experience with miconazole has been reported in the form of individual case studies or reports of small series of patients. Methods of evaluation of treatment results, and duration of follow-up, often varied among reports or were not clearly stated. Most patients who have received miconazole to date have been seriously ill or dying, and many either did not respond to, or did not tolerate, previous treatment with amphotericin B or flucytosine. Nevertheless, further well designed studies are needed before the relative effectiveness of miconazole, as compared with other systemic antifungal drugs, can be stated with any certainty. In patients with systemic or mucocutaneous candidosis, the overall response rates appear encouraging, about 80 to 90% of patients showing some improvement. The largest experience is in candidal septicaemia, and gastrointestinal, mucocutaneous and bronchopulmonary candidosis, with a small number of patients with genitourinary candidosis also reported in the literature. The response rate in patients with chronic, severe coccidioidomycosis has varied somewhat between studies, 30% of a very small series of patients with severe disseminated disease responding and about 40 to 60% of patients with chronic pulmonary, skin and soft tissue, or musculoskeletal involvement. Many patients had been unsuccessfully treated with amphotericin B. The duration of follow-up was often not clear, but as with amphotericin B relapses occurred frequently after an initial response (about 25 to 50% of responders), and many patients received more than 1 treatment course of miconazole. The response rate in patients with paracoccidioidomycosis (South American blastomycosis) has been high (85 to 100%). This serious condition, endemic in some areas, may prove to be an important area of use. Encouragingly, when miconazole was administered orally* for 2 years (1.5g daily) following an adequate intravenous regimen, relapse did not occur. Indeed, oral therapy alone has been successful in some patients. However, the period of follow-up must be extended to confirm the absence of relapses. A small number of patients with fungal meningitis, usually due to Coccidioides immitis or Cryptococcus neoformans, have been treated. All of these patients were seriously ill or moribund when miconazole therapy was begun. Although the response in some of these small series has been impressive (about 60% of patients), further well designed and reported studies are needed to expand the clinical experience. Many of these patients received intrathecal as well as intravenous treatment, but it has not been clearly shown that intrathecal administration improves the response. Small numbers of patients with other fungal conditions, such as pulmonary or musculoskeletal cryptococcosis, North American blastomycosis, aspergillosis, histoplasmosis, Petriellidium boydii infections etc. have been treated with miconazole with varying degrees of success, but again further data are needed before clear statements about the response rates in such conditions can be made. In the only controlled study available, oral miconazole (2g daily) was more effective than a placebo in preventing development of mycotic infections in cancer patients undergoing intensive cytotoxic drug therapy. Side Effects In data collated by the manufacturer from published and unpublished reports in the USA, the most frequent side effects were phlebitis (28%), pruritus, nausea (both about 20%), fever or chills, rash (both about 10%), vomiting and anaemia (6 to 7%). However, in a relatively large individual series of patients in the USA the incidence of some such reactions was higher, and hyponatraemia also occurred frequently (50%), especially in patients with meningitis. Other reversible haematological abnormalities (decreased haematocrit and thrombocytosis, leucopenia, erythrocyte aggregation on blood smears), possibly related to the carrier solution (a polyethoxylated castor oil; ‘Cremophor EL’), have also occurred. Reversible hyperlipidaemia also appears to be due to the carrier solution. Allergic reactions have occurred rarely. Interestingly, the incidence of some adverse reactions was lower in studies conducted outside the USA, probably due to the generally lower doses used in non-USA studies or to formulation differences. Dosage and Administration Miconazole should be administered by intravenous infusion, each dose diluted in at least 200ml of 0.9% sodium chloride or 5% dextrose and infused over 30 to 60 minutes. The recommended daily dose, which may be given in 3 equal infusions 8-hourly, is 1.8 to 3.6g in coccidioidomycosis, 1.2 to 2.4g in cryptococcosis, 0.6 to 1.8g in candidosis and 0.2 to 1.2g in paracoccidioidomycosis. Children should receive about 20 to 40mg/kg daily, not exceeding 15mg/kg in a single infusion. An initial dose of 200mg should be given under observation in all patients. In the treatment of lower urinary tract infections, direct instillation into the bladder is necessary (200mg miconazole daily in an appropriate volume). In fungal meningitis, daily administration of the undiluted injection solution of miconazole (20mg per dose) by the various intrathecal routes is recommended by the manufacturer, in addition to intravenous therapy.
Article
近年, 高度の医療に伴う抗細菌性広域抗生物質, 副腎皮質ホルモン, 抗腫瘍剤, 免疫抑制剤などが広く使用されるようになってから世界的に真菌症の増加が指摘されており, なかでも内臓真菌症が opportunistic infection として著増してきていることは周知のとおりである.治療に関して細菌感染症の化学療法が長足の進歩をとげたのに比較して, 内臓真菌症の化学療法は著しく立ち遅れているといわざるをえず, 開発されてから約30年が経過した amphotericin B (AMPH) が, その強い毒性にも拘らず使用されており,“古い薬”, そして“新らしい治療”といわれているように, 今日でも第1選択剤として使用されているのが現況である.近年開発されたイミダゾール系の miconazole (MCZ), ketoconazole (KCZ) は諸外国では市販されているが, 本邦では未だ市販されておらず, 臨床経験も少なく, その評価は未だ確立されておらず今後の問題であるが, 我々の経験した臨床治験成績ではまずまずの感触をえている. Flucytosine (5-FC) は単独では内臓真菌症の治療には適切でなく, AMPHとの併用で使用すべき薬剤である.新らしい抗真菌剤の開発もすすめられているが, なお今後の検討をまたねばならないのが現況である. このためにも現有の数少ない抗真菌剤を有効に使用する工夫や研究が重要な課題である.
Article
When 30 mg/ml aqueous hydrogenated castor oil consisting of 60 oxyethylene group (HCO-60) solutions were shaken under fluorescent light of about 500 lux in a water bath at 30°C or 60°C, hydroperoxide, formaldehyde, and formic acid were formed. An aqueous solution containing 10 mg/ml miconazole (MCZ), 100 mg/ml HCO-60, and 1 mg/ml lactic acid was sealed in ampoules and stored at various temperatures for 8d. At 40°C or above, the concentration of MCZ decreased accompanied by a decrease in pH and formaldehyde formation. However, in the presence of nitrogen, no degradation was observed. The degradation of MCZ was also observed in the presence of iron(II) ion and hydrogen peroxide. Degradation of MCZ and HCO-60 was prevented by the addition of hydroxy radical scavengers, especially potassium iodide and thiourea. These results indicate that hydroxy radicals generated by autoxidation of HCO-60 degraded MCZ.
Article
Miconazole (MCZ) serum concentration was measured by high-performance liquid chromatography (HPLC). We assessed whether the internal standard method produced on intra-assay error, and found that the method gave more precise and more reproducible results than absolute calibration curve method. With 0.5μg/ml of MCZ, the coefficient of variation produced by that method was 3.41%, whereas that of the absolute calibration curve method was 5.20%. The concentrations of absolute calibration curve method showed higher values than the internal standard method. This indicated that the internal standard method was far more precise in measuring the MCZ serum concentrations than was the absolute calibration curve method.
Article
The plasma concentration, distrib ution and metabolism of [¹⁴C]miconazole ([¹⁴C])MCZ) were studied after application of [¹⁴C]MCZ gel (10mg/kg of miconazole) to oral mucosa of male rats. 1. After application, the plasma radioactivity reached the maximum level of 1.82μg eq./ml at 2hr, and then declined in a similar manner as after oral administration of [¹⁴C]MCZ. 2. At 1hr after application, high levels of radioactivity were observed in the epidermis of lip, palatum, tongue and buccal mucosa on the enlarged autoradiograms, and the radioactivity was high in the epidermis of buccal mucosa, while low in the buccal muscle. 3. At 1 and/or 6hr after application, the unchanged drug was the main component of radioactivity in the buccal muscle and epidermis of the buccal mucosa, and the minor quantities of other compounds were also detected in each tissue ; oxidative ring-broken form (M8) in both tissues, and Uk3 and Uk10, unknown metabolites in the buccal muscle.
Article
Several reliable methods for bioassay for miconazole in serum or other clinical specimens employing Candida albicans as the indicator organism are described. The well agar plate method with Yeast Morphology Agar was sensitive to 1μg of drug per ml and linear from 1 to equal to or greater than 16μg per ml. The disc agar plate method was much more sensitive, by which 0.06μg of miconazole per disc was quantitatively measurable. The bioautographic method was the most sensitive; the lower limit of the assay was as low as 0.002μg of drug per sample applied. In the latter two methods, Yeast Morphology Agar was used as the assay medium and serum specimens were extracted with cyclohexane or ethyl ether for assay.
Article
A kind of technique of computer extension of perturbation series is presented and used in seeking for the second-order approximation to a large-scale travelling wave solution of the barotropic primitive equations. Numerical experiments show that the second-order approximation keeps major characters of the travelling wave solution and is indeed more exact than the zero-order and the first order approximations.
Article
A spectrophotometric method is described for the assay of some antifungal agents containing an imidazole ring: clotrimazole, econazole, ketoconazole and miconazole. The method is based on the formation of a charge-transfer complex between the drug as n-electron donor and iodine as [sgrave]-acceptor. The product exhibited two absorption maxima at 290 and 377 nm; measurements are made at 290 nm. Beer's law is obeyed in a concentration range of 1-40 μg/ml. The method is rapid, simple and sensitive and can be applied to the analysis of some commercial dosage forms without interference. A detailed investigation of the formed complex was made with respect to its composition, association constant and free energy change.To whom all correspondence should be addressed.
Article
Fourier descriptor (FD) values computed from spectrophotometric measurements were used to compute a purity index. The Fourier Descriptors calculated for a set of absorbencies are independent of concentration and is sensitive to the presence of interferents. Such condition was proven by calculating the FD for pure and degraded benyzylpenicillin. Absorbance data were measured and recorded for twelve different benzenoid compounds. The calculated FD values for these compounds showed significant discrimination between them. Also the reproducibility of FDs was tested by measurement over several successive days and the relative standard deviation obtained was less than 2 %.
Article
Electron capture gas chromatographic assay procedures were developed for quantitating the antifungal agents clotrimazole and miconazole. The procedures were specifically developed for analysis of the drugs in superficial samples of human skin. The analytical methods were sensitive to 5 ng of miconazole and 10 ng clotrimazole per tissue sample.
Article
The purpose of the present study was to compare different calorimetric methods used to determine the glass transition temperature (T(g)) and to evaluate the relaxation behaviour and hence the stability of amorphous drugs below their T(g). Data showed that the values of the activation energy for the transition of a glass to its super-cooled liquid state qualitatively correlate with the values of the mean molecular relaxation time constant of ketoconazole, itraconazole and miconazole, three structurally related drugs. Estimation of the molecular mobility by activation energy calculation indicated that loperamide was more stable than its two building blocks T263 and R731. It was further shown that the most commonly used approach to determine T(g) (T(g (1/2 c(p))) leads to erroneous values when enthalpy recovery is significant. In this case, an alternative method based on enthalpic considerations leads to results in accordance to basic thermodynamics. Estimation of molecular mobility based on activation energy calculations is therefore considered to be a valuable alternative for the method based on measurement of the extent of relaxation. When enthalpy relaxation is important, the use of T(g 1/2c(p)) leads to an overestimation of the T(g).
Article
A high-pressure liquid cliromatographic (HPLC) method is presented for determining clotrimazole, miconazole nitrate and econazole nitrate in various commercial formulations. The analysis was performed on a reversed-phase column (RP 18) under isocratic conditions using a UV detector (230 nm). The described procedure proved to be more specific and versatile than the pharmacopoeia methods.
Article
A rapid and simple colorimetric method is presented for the estimation of organic bases in pharmaceutical preparations. Solid cobalt thiocyanate reagent is used. Many bases form blue coloured ion pairs soluble in dichloromethane.
Article
Retention indices associated with 1318 substances likely to be encountered in toxicological analyses are presented. They are listed in ascending order of retention index for identification purposes and also in alphabetical order of compound name. The 4586 values used in this collection have been extracted from 36 sources, many of which have not been previously published. In many cases, where the quoted retention index is the mean of several determination, the reproducibility and reliability of this value may be assessed.
Article
An abstract is unavailable. This article is available as HTML full text and PDF.
Article
Four azole derivatives showing antimycotic activity (Miconazole, Ketoconazole, Clotrimazole, Fluconazole) in solid phase were exposed to beta irradiation at the dose of 20-200 kGy and then alterations in the physicochemical properties of the above derivatives were studied using the methods: scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis. It was found that the compounds irradiated with sterilising doses (20-50 kGy) showed no significant alterations in their physicochemical properties, while application of doses >50 kGy resulted in small changes in the X-ray diffraction patterns and in the course of DSC curves, including a decrease in the melting points and enthalpy of the process. For Miconazole and Fluconazole, a linear and relatively strong correlation was found (from r =0.9782 to r =0.9003) between the size of the dose of irradiation and the decrease in the melting point and enthalpy value.
Article
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.
Article
A standardtlc procedure was tested for its applicability in the qualitative analysis of several creams. It was found that in creams of known composition the presence of almost all of the active cream components as well as the excipients can be confirmed. An additional eluent, spray reagent, or a liquid extraction clean-up step sometimes appeared to be necessary. If the cream base composition is not known, a ‘fingerprint’ of the various types of excipients is obtained with the described procedure.
Article
A high-performance liqid chromatographic method is reported for the measurement of miconazole in systemic, fungal infectious patients. Pharmacokinetic data are presented for a single patient receiving miconazole therapy. Sample preparation involves protein precipitation by acetonitrile (1:1, vol/vol). Analyses are carried out on a reversed-phae chromatographic system using octadecylsilane stationary phase: a mobile phase consisting of 0.05 M acetate buffer (pH 7.4)acetonitrile (20:80, vol/vol) is used to elaute miconazole is quantified on the basis of ultraviolet absorption at 220 nm. The precision of the method ranged from 3.21% at 0.5 mg/L to 0.85% at 2.0 mg/L. The limit of quantification was established as 0.1 mg/L. Interference from other drugs that are co-adimistered such as amphotericin B, 5-fluorocytosine of ketoconazole and most other comonly encountered drugs was not observed.
Article
Two different methods have been used to investigate the retention mechanism of a series of imidazole derivatives in reversed-phase liquid chromatography (RPLC) over a range of column temperatures and with different concentrations of hydroxypropyl-β-cyclodextrin (HP-β-CD) in the mobile phase. The first approach was the separate study of each factor affecting the retention mechanism; the second method was the simultaneous variation of all these factors. Changes in Van't Hoff plots as a function of HP-β-CD concentration were examined. Enthalpy and entropy were determined for two physicochemical processes: (i) solute transfer from the mobile phase to the stationary phase, and (ii) solute complexation by HP-β-CD. These thermodynamic data showed that the mechanism of retention of the solute was dependent on the concentration of HP-β-CD in the mobile phase. For a HP-β-CD concentration,C, greater than to 4 mM, from 28°C to a critical temperature,T *, solute retention was entropy-dominated because of inclusion of the solute in the HP-β-CD cavity. AboveT * retention was enthalpy-dominated, because of interaction of the solute with the RP18 stationary phase. At firstT * increased asC was increased up to a critical value,C **; it the remained relatively constant because of auto-association of the HP-β-CD molecules in the mobile phase. Enthalpy-entropy compensation revealed that HP-β-CD-solute complexation had a greater effect on retention than RP18 stationary phase-solute interaction. This confirms that the main parameter determining retention in RPLC is the distribution of the solute in the mobile phase, and that interactions with the stationary phase play a minor role.
Article
Using reversed phase liquid chromatography (RPLC), this paper investigates the enantioselectivity variations, in a series of weak polar R, S-imidazole derivatives, with β-cyclodextrin concentration in the mobile phase over a wide range of column temperatures. These compounds are used for the treatment of onychomycosis. The selectivity data obtained were assessed using a chiral recognition model, based on the formation of complexes between the solute molecule and the cyclodextrin cavity. Gibbs Helmholtz parameters (Δ(ΔH), Δ(ΔS)) between R- and S- enantiomers were determined from the logarithm of the separation factor, α, versus the reciprocal of the temperature plots. The thermodynamic results predicted that the enantioselectivity mechanism was related to both the solute's bulkiness and the asymmetric carbon atom configuration.
Article
A chromatographic approach was proposed to describe the existence of surfactant micelles in a surfactant/hydroorganic phosphate buffer mobile phase. Using this mixture as a mobile phase, a novel mathematical theory is presented to describe the inclusion mechanism of imidazole derivatives in surfactant micelles. Using this model, enthalpy, entropy and the Gibbs free energy were determined for two chromatographic chemical processes: (i) the transfer of the imidazole derivative from the mobile phase to the stationary phase; and (ii) the imidazole derivative inclusion in surfactant micelles. These thermodynamic data indicate that the main parameter determining chromatographic retention is distribution of the imidazole derivatives to micelles of surfactant while the interaction with the stationary phase play a minor role.
Article
Due to the increased number of compromised hosts with fungal infections, doctors have recently started prescribing antifungal agents. In the field of gynecology, however, the choice of which drug to use has been difficult. The efficacies of these drugs depend on their antifungal spectra, potencies and concentrations in tissues. The present study was designed to investigate the pharmacokinetics of miconazole in the exudate of the retroperitoneal space that is formed after radical hysterectomy and pelvic lymphadenectomy. A total of 600 mg of miconazole was administered to the patients for exactly 60 min using an automatic drip-infusion pump. The parameters of the formulas analyzed by the two-compartment model were determined using the least-squares method, and a simulation curve was made. The maximum drug concentration (Cmax) of miconazole in serum was 6.26 mg/l 1 h after drip infusion commencement and the t1/2 in serum was 8.86 h. The value of the area under the time-serum concentration curve (AUC) in serum was 19.13 mg/h per l. The Cmax of miconazole in the exudate of the retroperitoneal space was 0.13 mg/l 2.48 h after the drip infusion was started. The value of AUC in the exudate was 2.52 mg/h per l.
Article
A chemometric methodology was proposed to optimize the migration time, height equivalent to a theoretical plate and separation of a mixture of a series of imidazole compounds by capillary electrophoresis. The optimization process was based on a special polynomial from 9 or 18 preliminary experiments. This method connects a general simplex method to a computer. A simplex two or three optimization-capillary electrophoresis (STO-CE) method has been developed in our laboratory. The most efficient separation was achieved with acetonitrile-phosphate buffer, pH 4.70, (5.30+94.70 (v/v)) with a beta-cyclodextrin concentration in the background electrolyte equal to 5.80 mM and a capillary temperature of 35 degrees C. Similar results were obtained using simple step-wise scanning. The higher relative difference obtained for these values with these two methods (simplex and step-wise scanning) was 5% for the beta-cyclodextrin concentration factor.
Article
Data from this in vivo albino rabbit study suggest that miconazole nitrate may penetrate the ocular compartments better than either natamycin or amphotericin B after intravenous, subconjunctival, or topical administration. The concentrations of miconazole in cornea and in aqueous humor after either topical or subconjunctival administration were very high, and a further threefold increase in the levels was seen if the corneal epithelium had been removed prior to drug therapy. Miconazole was found in the vitreous in some animals after subconjunctival injections of the drug. Intravenous administration produced high concentrations of miconazole in the aqueous humor, which rapidly fell over eight hours. No signs of toxicity or adverse reactions were found in these short-term experiments. Miconazole may be a useful addition in our methods of treating keratomycosis and oculomycosis.
Article
A simple, reliable, and inexpensive assay for quantitation of the imidazole drugs miconazole, RV 40,500, and RV 41,400 was tested. The assay, similar to a Kirby-Bauer test, was sensitive to less than or equal to 0.2 μg of drug per ml and linear from less than or equal to 0.2 to 10.0 μg/ml. Concentration of inoculum and agar depth in test plates was not as critical as the type of medium, amount of inoculum, or type of drug used.
Article
The aim of the study was to investigate the stability of the obtained cures after treatment with 2% miconazole nitrate vaginal cream as well as to evaluate its therapeutic effects and its tolerance. Fifty three females (mean age 26 years) suffering from vaginal candidiasis were included in the study. Those without positive cultures and those who did not return for re-examination or were treated with other antimycotic agents were excluded from the study. All patients in the trial were treated during a first period for their vaginal candidiasis with miconazole nitrate. Those who were cured after two courses of therapy were followed up at monthly intervals until 8 months. Evaluating criteria were the cultures, the microscopic examinations, the subjective symptoms and the objective findings of the investigators. Fifty one patients (96.3%) were cured after one course of treatment (14 days) with miconazole nitrate and the remainig two, after a second course. The effect of the treatment on the subjective complaints as well as on the objective findings of the investigators was very satisfactory and statistically highly significant. Three patients, two on the fifth, one on the sixth month, relapsed during the follow-up period (relapse rate 5.6%). From the relapsed cases two had been treated with oral contraceptives for four months and the third with trichomonacides for a month. It is concluded that miconazole nitrate is an effective and safe anticandidal agent ensuring high cure stability rates in vaginal candidiasis patients.
Article
The stability of amphotericin B, amphotericin B methyl ester, 5-fluorocytosine, and miconazole was assessed under conditions encountered in bioassay and susceptibility testing in vitro. Although the amphotericins were labile as compared with the other drugs, tests should be reliable with all four antimicrobics in view of the rapid action of the polyenes and the relatively slow action of 5-fluorocytosine and miconazole.
Article
Fourteen patients with chronic coccidioidomycosis, many of whom had complicating concurrent diseases and/or had failed to respond to amphotericin therapy, were treated with intravenous miconazole, a synthetic imidazole drug previously shown to be effective in experimental murine coccidioidomycosis. Up to 3.6 g/day was given for up to three months. 7inimal inhibitory concentrations of mycelial and endospore phases of all clinical isolates of C. immitis were less than 2.0 mug/ml. Peak concentrations in the blood of up to 7.5 mug/ml (by assay against C. immitis in vitro) were achieved. Doses above 9 mg/kg or 350 mg/m2 were more efficacious in producing blood levels over 1 mug/ml. Serum protein binding, determined by several methods, was approximately 90 per cent. The disappearance of bioactive drug from blood after infusion has a rapid initial phase (t1/2 approximately 30 minutes) and a final plateau (t1/2 approximately 20 hours). Eight patients had objective evidence of response, three had slight or equivocal responses, two could not be evaluated, and one was a treatment failure. Side effects were generally uncommon, minor and transient except for phlebitis. Infusion into central venous catheters appears to circumvent this problem. Miconazole is a potentially useful drug in the treatment of coccidioidomycosis.
Article
Miconazole2, a synthetic imidazole derivative, is a new topical antifungal agent for use in the local treatment of vaginal, and skin and nail infections due to yeasts and dermatophytes. It is particularly active against Candida spp., Trichophyton spp., Epidermophyton spp., Microsporum spp. and Pityrosporon orbiculare (Malassezia furfur), but also possesses some activity against Gram-positive bacteria. In vaginal candidiasis, miconazole vaginal cream has produced higher cure rates than conventional nystatin vaginal tablets or amphotericin B vaginal cream. There have been no published comparisons with nystatin vaginal cream or foaming vaginal tablets - the nystatin dosage form preferred by some clinicians. The vaginal cream has also achieved a cure where previous nystatin or natamycin therapy had failed. Miconazole has proved equally effective in both Candida and dermatophyte infections of the skin, but as yet there have been no published comparisons with other antifungal agents. However, it has been successfully used in chronic skin infections which had not responded satisfactorily to other agents such as natamycin and pecilocin. Preliminary experience with oral and intravenous miconazole therapy in systemic candidiasis is promising. Miconazole preparations are well accepted and tolerated.
Article
Reversed-phase HPLC on different column packing materials (Hypersil C-18, Spherisorb-CN, Chromspher-B) is used to obtain selective separations of imidazole antimycotic drugs, such as ketoconazole, clotrimazole, tioconazole, bifonazole, isoconazole, econazole, miconazole and fenticonazole. The use of a post-column on-line photochemical reactor is shown to be useful for the enhancement of the sensitivity of the HPLC analysis with UV detection. The proposed HPLC methods are applied to the analysis of commercial dosage forms (creams) with solid-phase extraction (SPE) procedure, using a diol sorbent, being found to be a convenient technique for the sample preparation giving quantitative drug recovery.
Article
A novel analytical screening procedure has been developed, using computer-controlled gas chromatography-mass spectrometry (GC-MS), to detect 120 drugs of interest to road safety. This paper describes GC-MS methodology suitable for use on extracts of biological origin, while extraction procedures will be the subject of a future communication. The method was devised to identify drugs in extracts of blood samples, as part of an investigation into the involvement of drugs, other than alcohol, in road accidents. The method could be adapted to screen for other substances. The method depends on a "macro" program which was written to automate the search of GC-MS data for target drugs. The strategy used was to initially search for each drug in the database by monitoring for a single characteristic ion at the expected retention time. If a peak is found in this first mass chromatogram, a peak for a second characteristic ion is sought within 0.02 min of the first and, if found, the ratio of peak areas calculated. Probable drug identification is based on the simultaneous appearance of peaks for both characteristic ions at the expected retention time and in the correct ratio. If the ratio is outside acceptable limits, a suspected drug (requiring further investigation) is reported. The search macro can use either full mass spectra or, for enhanced sensitivity, data from selected ion monitoring (which requires switching between groups of ions during data acquisition). Quantitative data can be obtained in the usual way by the addition of internal standards.
Article
The stability of miconazole when mixed with peritoneal dialysis (PD) fluid and stored in plastic bags or glass ampuls was determined. Admixtures of miconazole and PD fluid were prepared in 2-L polyvinyl chloride (PVC) bags and in 1-mL glass ampuls to give a nominal initial concentration of 20 mg/mL. Duplicate samples of each solution were assayed in duplicate by high-performance liquid chromatography immediately after preparation and at various intervals up to nine days. All admixtures were stored in ambient light at 20 ± 2°C. A substantial loss of miconazole (greater than 10% of the initial concentration) occurred within four hours for admixtures stored in PVC bags, whereas similar solutions retained more than 90% of their initial miconazole concentration for at least three days when stored in glass ampuls under the same conditions. This suggests that the observed loss of miconazole from the PVC bags was largely due to an interaction with the container, rather than to chemical degradation in solution. About 28% of the miconazole lost from the solution during storage in PVC bags was recovered from the plastic by methanolic extraction. The rapid loss of miconazole when the drug was mixed with PD fluid and stored in PVC bags indicates that such admixtures should be prepared immediately before administration.
Article
Methods based on derivative UV spectrophotometry and high-performance liquid chromatography (HPLC) have been developed for the selective determination of miconazole and econazole in pharmaceutical dosage forms. A solid-phase extraction (SPE) procedure using a diol column gave quantitative drug extraction from formulated creams and provided purified sample solutions suitable for assay by the derivative UV spectrophotometric and HPLC methods. The proposed methods gave comparable accurate results, whereas a conventional UV spectrophotometric method was found to be seriously affected by excipients.
Article
A rapid method has been developed for the determination of miconazole nitrate in creams and suppositories. The sample is dissolved in ethanol, diluted in acetonitrile-water (1 + 1), and injected onto a C18 column. The mobile phase consists of 55% acetonitrile, a triethylammonium phosphate buffer, and an ion-pairing agent. The total run time is less than 4 min, and the active ingredient is determined using absorbance detection at 214 nm. The mean recovery of miconazole from spiked placebo samples was 99.7 +/- 0.7% for the cream samples at the 2% level and 98.8 +/- 0.3% for the suppository samples at the 4% level.