Effect Of Miconazole Research Articles

Miconazole and terbinafine induced reactive oxygen species accumulation and topical toxicity in human keratinocytes

There are an estimated 1 billion cases of superficial fungal infection globally. Fungal pathogens form biofilms within wounds and delay the wound healing process. Miconazole and terbinafine are commonly used to treat fungal infections. They induce the accumulation of reactive oxygen species (ROS) in fungi, resulting in the death of fungal cells. ROS are highly reactive molecules, such as oxygen (O2), superoxide anion (O2•−), hydrogen peroxide (H2O2) and hydroxyl radicals (•OH). Although ROS generation is useful for killing pathogenic fungi, it is cytotoxic to human keratinocytes. To the best of our knowledge, the effect of miconazole and terbinafine on HaCaT cells has not been studied with respect to intracellular ROS stimulation. We hypothesized that miconazole and terbinafine have anti-wound healing effects on skin cells when used in antifungal treatment because they generate ROS in fungal cells. We used sulforhodamine B protein staining to investigate cytotoxicity and 2′,7′-dichlorofluorescein diacetate to determine ROS accumulation at the 50% inhibitory concentrations of miconazole and terbinafine in HaCaT cells. Our preliminary results showed that topical treatment with miconazole and terbinafine induced cytotoxic responses, with miconazole showing higher cytotoxicity than terbinafine. Both the treatments stimulated ROS in keratinocytes, which may induce oxidative stress and cell death. This suggests a negative correlation between intracellular ROS accumulation in keratinocytes treated with miconazole or terbinafine and the healing of fungi-infected skin wounds.

Miconazole triggers various forms of cell death in human breast cancer MDA-MB-231 cells.

In recent years, "drug repurposing" has become an important approach and focus of studies on anti-tumor drug research and development (R&D). As one of the first-generation broad-spectrum imidazole anti-fungal drugs, miconazole (MCZ) exhibits anti-tumor effects in addition to its anti-fungal effect. However, no report has focused on examining the effect of MCZ on the proliferation and cell-death of human breast cancer MDA-MB-231 cells. MCZ significantly inhibited the proliferation of MDA-MB-231 cells in a concentration- and time-dependent manner. We also observed that MCZ induced both apoptosis and necroptosis in MDA-MB-231 cells. Transmission electron microscopy showed submicroscopic structures in these cells, which correspond to necrotic features, in addition to the characteristic features of apoptosis. Pretreatment of cells with z-VAD-fmk, an apoptosis inhibitor or Nec-1, a necroptosis inhibitor, significantly increased their viability compared with MCZ treatment. The initial mechanism of MCZ-mediated cell death in human breast cancer MDA-MB-231 cells involves an increase in the Bax/Bcl-2 ratio, downregulation of apoptosis induced by Akt and p-Akt-473, a simultaneous upregulation of the receptor-interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) protein expression, and ROS production to induce necroptosis. Our results suggest that MCZ may be a potential lead compound for the development of anti-breast cancer drugs.

Direct stimulation of adenylyl cyclase 9 by the fungicide imidazole miconazole.

In mammals, nine genes encode trans-membrane adenylyl cyclase (tmAC) isoforms that synthesize the intracellular messenger compound cAMP from ATP. As cAMP is produced in virtually all types of cell, isoform-selective modulators of tmAC would have major research and therapeutic potential. This study investigated the effects of fungicide imidazoles previously shown to suppress cAMP production in various tissues on the activities of tmAC isoforms AC1, 2, or 9 stably expressed in human embryonic kidney 293 cells. Intact cells, as well as crude membranes, were exposed to various imidazoles or known stimulators of tmAC and the ensuing changes in the production of cAMP analyzed. In crude membranes, the activity of AC9 in the presence of GDP-β-S was enhanced by miconazole with an EC50 of ~ 8μM, while AC1 and AC2 were inhibited with an IC50 of ~ 20μM. Clotrimazole (10-100μM) was an inhibitor of all the ACs tested. Substrate saturation analysis indicated that miconazole increased the Vmax of AC9 by 3-fold while having no effect on the Km. In intact cells, the effect of miconazole on cAMP production through AC9 was additive with that of isoproterenol. The stimulation of cAMP production by miconazole was inhibited by Ca2+, and this could be prevented by the calcineurin blocker FK506. In sum, activation of AC9 by miconazole is through a mechanism distinct from that of forskolin, activated G proteins, or the COOH-terminal mediated autoinhibition. However, it is subject to the AC9 isoform-specific inhibition by Ca2+/calcineurin. Differential modulation of mammalian tmAC paralogs appears to be achievable by an imidazole with phenylated side chains. Optimization of the lead compound and exploration of the underlying mechanism(s) of action in more detail could exploit this further.

Miconazole stimulates post-ischemic neurogenesis and promotes functional restoration in rats

Miconazole, a frequently used antifungal drug, has been identified with new functions to promote oligodendrocyte progenitor cells differentiation and to enhance remyelination. However, the neuroregenerative and therapeutic benefit of miconazole on ischemic stroke model have not been tested. In the present study, the effects of miconazole on a rat model of transient middle cerebral artery occlusion were evaluated. Rats received miconazole (10 mg/kg) or saline by intravenous administration for 7 days after stroke. A battery of neurobehavioral assessments, including rotarod test, open-field test, neurological severity score and novel object recognition task were evaluated. The results revealed a significant functional improvement in miconazole-treated rats compared with vehicle-treated control. Animals were sacrificed at 7 and 28 days after stroke. Double immunofluorescence staining for NeuN+/BrdU+, DCX+/BrdU+ and Nestin+/BrdU+ cells indicated miconazole significantly promoted neurogenesis. Western blotting analysis revealed miconazole upregulated the protein expression of brain derived neurotrophic factor, myocyte enhancer factor 2D, synaptophysin, and postsynaptic density protein 95, while downregulated the expression of cyclin-dependent kinase 5. Taken together, miconazole promoted functional recovery on ischemic stroke model via stimulating post-ischemic neurogenesis.

Translational suppression of HIF-1α by miconazole through the mTOR signaling pathway.

Miconazole is an imidazole antifungal agent that has amply been used in the treatment of superficial mycosis. Preliminary data indicate that miconazole may also induce anticancer effects. As yet, however, little is known about the therapeutic efficacy of miconazole on cancer and the putative mechanism(s) involved. Here, we show that miconazole suppresses hypoxia inducible factor-1α (HIF-1α) protein translation in different cancer-derived cells. The effect of miconazole on HIF-1α expression was examined by Western blotting and reverse transcriptase polymerase chain reaction assays in human U87MG and MCF-7 glioma and breast cancer-derived cell lines, respectively. The transcriptional activity of the HIF-1 complex was confirmed using a luciferase assay. To assess whether angiogenic factors are increased under hypoxic conditions in these cells, vascular endothelial growth factor (VEGF) levels were measured by ELISA. Metabolic labeling was performed to examine HIF-1α protein translation and global protein synthesis. The role of the mammalian target of rapamycin (mTOR) signaling pathway was examined to determine translation regulation of HIF-1α after miconazole treatment. Miconazole was found to suppress HIF-1α protein expression through post-transcriptional regulation in U87MG and MCF-7 cells. The suppressive effect of HIF-1α protein synthesis was found to be due to inhibition of mTOR. Miconazole significantly inhibited the transcriptional activity of the HIF-1 complex and the expression of its target VEGF. Moreover, miconazole was found to suppress global protein synthesis by inducing phosphorylation of the translation initiation factor 2α (eIF2α). Our data indicate that miconazole plays a role in translational suppression of HIF-1α. We suggest that miconazole may represent a novel therapeutic option for the treatment of cancer.

Antifungal Miconazole Induces Cardiotoxicity Via Inhibition of APE/Ref-1-Related Pathway in Rat Neonatal Cardiomyocytes

Effects of miconazole, an azole antifungal, have not been fully determined in cardiomyocytes. We therefore identified the transcriptome in neonatal rat cardiomyocytes responding to miconazole using DNA microarray analysis and selected a gene and investigated its role in cardiomyocytes. Miconazole dose-dependently increased the levels of superoxide (O(2)(-)) and apoptosis in cardiomyocytes; these increases were inhibited by treatment with antioxidants. The DNA microarray revealed that 4163 genes were upregulated and 4829 genes downregulated by more than threefold in miconazole-treated cardiomyocytes compared with the vehicle-treated control. Moreover, redox homeostasis-, oxidative stress-, and reactive oxygen species (ROS)-related categories of genes were strongly affected by miconazole treatment. Among genes overlapped in all these categories, apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1), a redox-related gene, was prominent and was diminished in the miconazole-treated group. Changes in the O(2)(-) production and apoptosis induction in response to miconazole were inhibited in cardiomyocytes transfected with adenoviral APE/Ref-1. Overexpression of APE/Ref-1 reversed the reduction in beating frequency induced by miconazole. Our results demonstrate that miconazole may induce rat cardiotoxicity via a ROS-mediated pathway, which is initiated by the inhibition of APE/Ref-1 expression. This possible new adverse event in cardiomyocyte function caused by miconazole may provide a basis for the development of novel antifungal agents.

Fungicidal activity of miconazole against Candida spp. biofilms

Although azole antifungals are considered to be fungistatic, miconazole has fungicidal activity against planktonic Candida albicans cells, presumably associated with the induction of reactive oxygen species (ROS) production. Only few data are available concerning the effect of miconazole against sessile C. albicans cells. In the present study, the fungicidal activity of miconazole against in vitro-grown mature Candida biofilms, and its relationship with the induction of ROS and ROS-dependent apoptosis were examined. The effect of miconazole on mature biofilms formed by 10 C. albicans strains and 5 strains from other Candida species was evaluated by plate counting and measuring the level of ROS induction. MIC tests were performed in the absence and presence of ascorbic acid, a quencher of ROS. The apoptotic population in C. albicans cells was determined using annexin-Cy3. Miconazole showed a significant fungicidal effect against all mature Candida biofilms tested and caused elevated ROS levels, both in planktonic and sessile cells. Addition of ascorbic acid drastically reduced these levels. While ROS quenching decreased the susceptibility to miconazole of planktonic cells of most Candida strains, no reduced fungicidal activity of miconazole against biofilms was observed. Miconazole did not cause a significant increase in apoptosis. ROS levels increased in all Candida biofilms upon addition of miconazole. However, ROS induction was not the only factor that underlies its fungicidal activity, as quenching of ROS did not lead to an enhanced survival of biofilm cells. ROS-induced apoptosis was not observed in C. albicans cells after miconazole treatment.

Effect of Miconazole and Terbinafine on Artemisinin Content of Shooty Teratoma of Artemisia annua

The effects produced by the addition of sterol synthesis inhibitors on the artemisinin content of the transgenic organ culture (A. tumefaciens ATCC 33970 or 15955) of Artemisia annua are presented. The transgenic tissue produced 3-4 fold higher levels of artemisinin 0.84% (56.3 mg/L) within a short culture period compared with field grown plants (0.23%). The addition of the sterol synthesis inhibitors, miconazole and terbinafine, to these transgenic cultures resulted in enhanced artemisinin content up to 1.15% and 1.44%, respectively. Further enhancement of artemisinin content was achieved by varying the addition time of the sterol synthesis inhibitor to the cultures. The best artemisinin content (2.62%) was observed after terbinafine (10 mg/L) addition on the sixteenth day of the culture period.

Effect of miconazole, an antifungal agent, on allene oxide synthase: Inhibition, kinetics, and binding

We investigated the inhibition of allene oxide synthase (AOS), a key enzyme in jasmonic acid biosynthesis, by miconazole. Kinetic analysis indicated that miconazole was a mixed-type inhibitor of AOS with a K i value of approximately 8.4 ± 0.2 μM. Analysis of the interactions between miconazole and AOS by optical difference spectroscopy revealed that miconazole binding induces type II binding spectra with a K d value of approximately 6.0 ± 0.2 μM.

Inhibition of Protein Kinase Cβ Protects against Diabetes-Induced Impairment in Arachidonic Acid Dilation of Small Coronary Arteries

To test the hypothesis that protein kinase C (PKC)beta-induced reactive oxygen species (ROS) underlie the vascular dysfunction in diabetes, we examined the effects of (S)-13[(dimethylamino)-methyl]-10,11-14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadi-azacyclohexadecene-1,3(2H)-dione (LY333531; LY), a specific PKCbeta inhibitor, on arachidonic acid (AA)-mediated dilation in small coronary arteries from streptozotocin-induced diabetic rats. This study was designed to determine whether diabetes impairs AA-induced vasodilation of small coronary arteries and whether this defect could be blunted by dietary treatment with LY. Coronary diameter was measured using videomicroscopy in isolated pressurized vessels. In controls, AA dose dependently dilated coronary arteries, with 1 muM producing 54.7 +/- 3.1% and 30 microM producing 72.0 +/- 3.0% dilation (n = 9). In diabetic rats, 1 microM AA only produced 31.4 +/- 3.8% (n = 8; p < 0.01 versus control) and 30 microM 43.8 +/- 3.7% dilation (n = 8; p < 0.001 versus control). Nitroprusside-mediated vasodilations were similar in control and diabetic rats. In contrast, in diabetic rats receiving LY, AA-mediated coronary dilations were normal. In controls, AA-mediated vasodilation was inhibited by miconazole (an inhibitor of cytochrome P450 epoxygenase) and by iberiotoxin (IBTX, an inhibitor of the large conductance Ca(2+)-activated K(+) channel), but miconazole and IBTX had no effects in diabetic vessels. In diabetic rats receiving LY, the effects of miconazole and IBTX were similar to control. Superoxide dismutase restored responses to AA in diabetic vessels but had no effect in vessels from control or diabetic rats on LY. These results suggest that AA-mediated vasodilation in rat coronary arteries are impaired in diabetic rats due to increases in generation of ROS. LY protects against these defects in diabetes through inhibition of PKCbeta-mediated production of ROS.

Azoles: Mode of Antifungal Action and Resistance Development. Effect of Miconazole on Endogenous Reactive Oxygen Species Production in Candida albicans

The synthetic class of azole antimycotics constitutes the largest group of antifungal agents currently in clinical use. Widespread use of azoles has led to the rapid development of multiple drug resistance, which poses a major hurdle in antifungal therapy. The generally accepted mode of action of azoles is the inhibition of 14α-lanosterol demethylase, a key enzyme in ergosterol biosynthesis, resulting in depletion of ergosterol and accumulation of toxic 14α-methylated sterols in membranes of susceptible yeast species. For some azoles, their antifungal mode of action is not only characterized by inhibition of ergosterol biosynthesis. Recently, it was shown that generation of reactive oxygen species (ROS) is important for the antifungal activity of miconazole, pointing to an ancillary mode of action for this azole. We further analysed the effect of other azole antifungals on ROS generation in Candida albicans and could demonstrate that only miconazole induces ROS production in C. albicans. Furthermore, we show that the miconazole induced ROS production is probably caused by inhibition of the enzymes implicated in breakdown of peroxide radicals and hydrogen peroxide, i.e. peroxidase and catalase. Interestingly, only miconazole was found to exert its antifungal effect in a fungicidal way. In conclusion, further development of novel azole antimycotics, based on the chemical structure of miconazole and on its related ROS inducing capacity/fungicidal activity would be an interesting approach to address the problem of resistance occurrence. Keywords: azoles, reactive oxygen species, ergosterol, catalase, peroxidase, antifungal

Effect of miconazole on intracellular Ca 2+ levels and proliferation in human osteosarcoma cells

The effect of miconazole, an anti-fungal drug, on cytoplasmic free Ca 2+ concentrations ([Ca 2+] i) in human osteosarcoma cells (MG63) was explored by using the Ca 2+-sensitive dye fura-2. Miconazole acted in a concentration-dependent manner with an EC 50 of 75 μM. The Ca 2+ signal comprised a gradual rise and a sustained elevation. Removal of extracellular Ca 2+ reduced 50% of the signal. In Ca 2+-free medium, the [Ca 2+] i rise induced by 1 μM thapsigargin (an endoplasmic reticulum Ca 2+ pump inhibitor) was completely inhibited by pretreatment with 20 μM miconazole. Pretreatment with thapsigargin partly inhibited miconazole-induced Ca 2+ release. The miconazole-induced Ca 2+ release was not changed by inhibition of phospholipase C with 2 μM U73122. By using tetrazolium as a fluorescent probe, it was shown that 10–100 μM miconazole decreased cell proliferation rate in a concentration-dependent manner. Collectively, this study shows that miconazole induces [Ca 2+] i rises in human osteosarcoma cells via releasing Ca 2+ mainly from the endoplasmic reticulum in a manner independent of phospholipase C activity, and by causing Ca 2+ influx. Furthermore, miconazole may be cytotoxic to the cells at higher concentrations.

Mechanisms of miconazole-induced rise in cytoplasmic calcium concentrations in Madin Darby canine kidney (MDCK) cells

The effect of miconazole on intracellular calcium levels ([Ca 2+] i) in Madin Darby canine kidney (MDCK) cells was studied using fura-2 as the Ca 2+ indicator. Miconazole increased [Ca 2+] i dose-dependently at concentrations of 5–100 μM. The [Ca 2+] i transient consisted of an initial rise, a gradual decay and an elevated plateau (220 s after addition of the drug). Removal of extracellular Ca 2+ partly reduced the miconazole response. Mn 2+ quench of fura-2 fluorescence confirmed that miconazole induced Ca 2+ influx. The miconazole-sensitive intracellular Ca 2+ store overlaped with that sensntive to thapsigargin, an inhibitor of the endoplasmic reticulum Ca 2+ pump, because 20 μM miconazole depleted the thapsigargin (1 μM)-sensitive store and conversely, thapsigargin abolished miconazole-induced internal Ca 2+ release. Miconazole (20–50 μM) partly inhibited the capacitative Ca 2+ entry induced by 1 μM thapsigargin, measured by depleting intracellular Ca 2+ store in Ca 2+-free medium followed by addition of 10 mM CaCl 2. Miconazole induced capacitative Ca 2+ entry on its own. Pretreatment with 0.1 mM La 3+ partly inhibited 20 μM miconazole-induced Mn 2+ quench of fura-2 fluorescence and [Ca 2+] i rise, suggesting that miconazole induced Ca 2+ influx via two pathways separable by 0.1 mM La 3+. Miconazole-induced internal Ca 2+ release was not altered when the cytosolic level of inositol 1,4,5-trisphosphate (IP 3) was substantially inhibited by the phospholipase C inhibitor U73122.

Cytochrome P-450-dependent arachidonate metabolites and renal functions in the Lyon hypertensive rat.

1. The present work aimed to assess the role of cytochrome P-450 (CP-450) metabolites of arachidonic acid such as epoxy-eicosatrienoic (EET) and hydroxyeicosatetraenoic acids (HETE) in the renal vasoconstriction and decreased natriuresis exhibited by genetically hypertensive (LH) rats of the Lyon strain. 2. The experiment was performed on single-pass isolated perfused kidney preparations from 8-week-old male LH rats and their low blood pressure (LL) controls. The effects of miconazole (an inhibitor of the formation of EET) and of 17-octadecynoic acid (17-ODYA, an inhibitor of both EET and HETE synthesis) were studied before and after stimulation of the kidneys with two noradrenaline (NA) infusions (65 and 110 nmol/L). 3. Unstimulated LH kidneys (n = 12) differed from LL (n = 12) by increased vascular resistance (RVR) and decreased glomerular filtration rate and urinary sodium excretion (UNaV). 4. Miconazole (1 mumol/L) did not change the functions of LH and LL unstimulated kidneys, but blunted the vasoconstrictor response to NA (110 nmol/L), the difference being significant in LH kidneys only (1.7 +/- 0.2 vs 3.6 +/- 1.2 mmHg/mL per min per g; P < 0.05). 5. Addition of 17-ODYA (3 mumol/L) to miconazole did not modify RVR in LH and LL kidneys or the response to NA infusion. On the contrary, it increased UNaV, the differences being significant in LH kidneys only (22.9 +/- 1.4 vs 17.5 +/- 1.4 mumol/min per g; P < 0.05 after NA 110 nmol/L). 6. It is suggested that EET may contribute to the elevated RVR and HETE to the reduced ability to excrete sodium, of LH kidneys.

Inhibition of brain P-450 arachidonic acid epoxygenase decreases baseline cerebral blood flow.

Arachidonic acid (AA) is metabolized by the cytochrome P-450 (P-450) epoxygenase pathway to epoxyeicosatrienoic acids (EETs) in the brain parenchymal tissue and perivascular astrocytes. EETs dilate cerebral microvessels and enhance K+ current in cerebrovascular smooth muscle cells. In the current study, the effect of a subdural administration of miconazole, an inhibitor of P-450 epoxygenase, on microvascular perfusion of rat cerebral cortex was evaluated using laser-Doppler flowmetry (LDF) Baseline cerebral blood flow (CBF) decreased by 29.7 +/- 7.3% (n = 5) after administration of 20 microM miconazole into the subdural space for 30 min. Responses of CBF to sodium nitroprusside and 5-hydroxytryptamine were unaltered by miconazole treatment. Administration of vehicle alone in time-control experiments had no effect on CBF. In other experiments, the effects of miconazole on the metabolism of [14C]AA by cultured rat astrocytes and on nitric oxide synthase activity in homogenates of rat brain were examined. Miconazole inhibited conversion of AA to EETs by cultured astrocytes but had no effect on the conversion of L-arginine to L-citrulline by homogenates of rat brain. These results implicate endogenous P-450 epoxides of AA in the regulation of basal blood flow in cerebral microcirculation.

Effect of miconazole on diO-C6-(3) accumulation in mitochondria of Candida albicans

A flow cytometric method was used to investigate the effect of miconazole (MCZ) on yeast-form cells ofCandida albicans. Relative changes in electric potential of mitochondrial and cytoplasmic membranes were assessed by 3,3′-dihexyloxacarbocyanine iodide (diO-C6-(3)) and bis-(1,3-dibutyl-barbituric acid) trimethine oxonol (diBA-C4-(3)) stainings, respectively. WhenC. albicans was exposed to MCZ at 10 μg/ml (a fungistatic concentration) for 2 h, no change appeared in cytoplasmic membrane potential, which was revealed by constant fluorescence intensity of diBA-C4-(3)-stained cells. On the other hand, the cells lost the ability to accumulate diO-C6-(3) in mitochondria by MCZ treatment. Time- and dose-responses in fluorescence intensity reflected that MCZ affected the mitochondrial activity ofC. albicans.

Effect of miconazole on the structure and function of plasma membrane of Candida albicans.

The primary mode of action of azoles is the inhibition of cytochrome P-450 dependent 14 alpha-demethylase, a key enzyme in ergosterol biosynthesis in fungi. Our results demonstrated that Candida albicans cells grown in the presence of 10 micrograms ml-1 of miconazole (miconazole-grown), do not possess ergosterol in their plasma membranes and this ergosterol depletion leads to a drastic change in membrane fluidity as shown by fluorescence polarization measurements and unsaturation index. There was an increase in membrane order in miconazole-grown cells and a reduced rate of uptake of amino acids. We also checked for membrane permeability changes in normal mid-log phase cells (normal-grown) in short incubations (10 min) with 10 micrograms ml-1 miconazole (miconazole-incubated). Interestingly, the amino acid uptake rates except that of Gly were not affected significantly in these cells. The results suggest that in the miconazole-incubated cells, the drug is not able to alter the level of ergosterol or inhibit ergosterol biosynthesis during 10 min incubation and therefore the interaction of the drug neither leads to significant disorganization of membrane components, nor affects permease activity, whereas in the miconazole-grown cells there is ergosterol depletion leading to accumulation of biosynthetic intermediates, resulting in membrane rearrangement thereby causing a major fluidity change. This fluidity change may explain the drastic reduction of amino acid transport in miconazole-grown cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of miconazole on the structure and function of plasma membrane of Candida albicans

The primary mode of action of azoles is the inhibition of cytochrome P-450 dependent 14α-demethylase, a key enzyme in ergosterol biosynthesis in fungi. Our results demonstrated that Candida albicans cells grown in the presence of 10 μg ml−1 of miconazole (miconazole-grown), do not possess ergosterol in their plasma membranes and this ergosterol depletion leads to a drastic change in membrane fluidity as shown by fluorescence polarization measurements and unsaturation index. There was an increase in membrane order in miconazole-grown cells and a reduced rate of uptake of amino acids. We also checked for membrane permeability changes in normal mid-log phase cells (normal-grown) in short incubations (10 min) with 10 μg ml−1 miconazole (miconazole-incubated). Interestingly, the amino acid uptake rates except that Gly were not affected significantly in these cells. The results suggest that in the miconazole-incubated cells, the drug is not able to alter the level of ergosterol of inhibit ergosterol biosynthesis during 10 min incubation and therefore the interaction of the drug neither leads to significant disorganization of membrane components, nor affects permease activity, whereas in the miconazole-grown cells there is ergosterol depletion leading to accumulation of biosynthetic intermediates, resulting in membrane rearrangement thereby causing a major fluidity change. This fluidity change may explain the drastic reduction of amino acid transport in miconazole-grown cells. To investigate whether the reduction in amino acid transport was only due to change in membrane fluidity, as a consequence of absence of ergosterol, the PM-ATPase activity was checked in the miconazole-grown cells and was found to be unaffected, which suggests that changes in amino acid uptake were due to change in membrane fluidity.

Miconazole Chewing Gum as a Drug Delivery System Application of Solid Dispersion Technique and Lecithin

AbstractThe release of the antifungal drug miconazole from chewing gum was evaluated both in vitro and in vivo. It was proved that the addition of lecithin and the application of a miconazole polyethyleneglycol 6000 solid dispersion increased the release of miconazole from chewing gum. The in vitro results correlated well with the in vivo results. 6 healthy volunteers obtained therapeutically active concentrations of miconazole in saliva when they chewed gum. In the microbiological experiments performed, lecithin did not antagonize the anti-Candida albicans effect of miconazole at pH 7.2.

Effect of miconazole on growth and aflatoxin production by Aspergillus parasiticus.

At 5 microM, miconazole prevented the growth of Aspergillus parasiticus Speare in a number of media. Sensitivity to miconazole was increased approximately 10-fold in a medium containing glycerol. At sub-inhibitory concentrations, miconazole stimulated aflatoxin synthesis on media which normally support toxin formation. Miconazole inhibited respiration and altered mitochondrial ultrastructure, suggesting that miconazole inhibits growth and stimulates aflatoxin production by depressing mitochondrial activity.