Imidazole Antifungal Drug Research Articles

Ketoconazole ionic liquids with citric and tartaric acid: Synthesis, characterization and solubility study

Solid forms of drugs have some potential problems such as low solubility, slow dissolution rate, variable bioavailability and polymorphism. One of the strategies to overcome these problems is the preparation of ionic liquid forms of drugs. Recently, active pharmaceutical ingredient (API) was employed to produce an ionic liquid, using a counter-ion. Ketoconazole (KTZ) (synthetic imidazole antifungal drug), which is a practically insoluble drug, citric acid (CA), and tartaric acid (TA) were chosen as counter-ions for preparing the ionic liquid. Different molar ratios (1:1, 1:2.5, 1:5) of KTZ–CA and KTZ–TA were prepared applying solvent evaporation method with methanol as the solvent. The viscosity and the solubility in phosphate buffer (0.1 M) (pH = 6.8 at 37 °C of KTZ–CA and KTZ–CA) were measured. More than three unit differences between pKa of KTZ and the studied carboxylic acids, characterization by different instrumental analysis methods, and previous studies on imidazole ring and carboxylic acid confirm the formation of ionic hydrogen bond between the imidazole functional group of KTZ and the carboxyl group of CA and TA. The findings of this study indicated that as molar ratio of CA and TA increases, the apparent solubility of the IL improves, while the solubility of the physical mixtures has a minor difference with non-processed KTZ. These results could be utilized in overcoming the disadvantages of KTZ solid form and increasing its solubility.

Comparison of efficacy, safety and cost-effectiveness of clotrimazole 1% cream and sertaconazole 2% cream in patients suffering from of mild to moderate tinea corporis, attending tertiary care hospital out-patient department: a randomized, open-labeled, comparative, parallel group trial

Background: Tinea corporis is a common dermatophytic infection of the body involving keratin layer of skin. This lesion presents as an annular plaque with an advancing border along with central clearing. Clotrimazole is topical, conventional imidazole antifungal drug and has given good efficacy in tinea corporis. Sertaconazole is new topical imidazole antifungal claimed to be superior to old topical imidazoles in tinea corporis. The aim of this study was to compare efficacy, safety and cost effectiveness of topical antifungals, clotrimazole 1% cream and sertaconazole 2% cream in patients suffering from mild to moderate tinea corporis attending out-patient department of tertiary care hospital in Vidarbha region of Maharashtra. Methods: This was a prospective, comparative, randomized trial with 2 parallel treatment arms of 4 weeks duration. Patients were diagnosed on the basis of clinical evaluation and microscopic findings of KOH mount. Hundred patients were randomly assigned into two groups of clotrimazole 1% cream, and sertaconazole 2% cream with 50 patients in each group. Evaluation was carried out at baseline, 1 st week, 2 nd week and 4 th week for efficacy parameters viz. itching, erythema and scaling, physician’s global assessment (PGA), safety and cost effectiveness. Results: Topical sertaconazole 2% cream was highly efficacious and superior to clotrimazole 1% cream in improvement of clinical parameters, PGA and mycological cure at the end of the treatment phase. At end of the follow-up phase both the trial drugs were effective with no recurrence or relapse of tinea corporis. However, clotrimazole 1% cream was safe and cheaper. Conclusions: Topical clotrimazole 1% cream and sertaconazole 2% were effective and well tolerated in patients of tinea corporis. Effectiveness of sertaconazole was early and superior with tolerable side-effects. However, clotrimazole was cost-effective.

Sucrose ester stabilized solid lipid nanoparticles and nanostructured lipid carriers: II. Evaluation of the imidazole antifungal drug-loaded nanoparticle dispersions and their gel formulations

This study focused on: (i) feasibility of the previously developed sucrose ester stabilized SLNs and NLCs to encapsulate different imidazole antifungal drugs and (ii) preparation and evaluation of topical gel formulations of those SLNs and NLCs. Three imidazole antifungal drugs; clotrimazole, ketoconazole and climbazole were selected for this study. The results suggested that size, size distribution and drug encapsulation efficiency depend on the drug molecule and type of nanoparticles (SLN/NLC). The drug release experiment always showed faster drug release from NLCs than SLNs when the same drug molecule was loaded in both nanoparticles. However, drug release rate from both SLNs and NLCs followed the order of climbazole > ketoconazole > clotrimazole. NLCs demonstrated better physicochemical stability than SLNs in the case of all drugs. The drug release rate from ketoconazole- and clotrimazole-loaded SLNs became faster after three months than a fresh formulation. There was no significant change in drug release rate from climbazole-loaded SLNs and all drug-loaded NLCs. Gel formulations of SLNs and NLCs were prepared using polycarbophil polymer. Continuous flow measurements demonstrated non-Newtonian flow with shear-thinning behavior and thixotropy. Oscillation measurements depicted viscoelasticity of the gel formulations. Similar to nanoparticle dispersion, drug release rate from SLN- and NLC-gel was in the order of climbazole > ketoconazole > clotrimazole. However, significantly slower drug release was noticed from all gel formulations than their nanoparticle counterparts. Unlike nanoparticle dispersions, no significant difference in drug release from gel formulations containing SLNs and NLCs was observed for each drug. This study concludes that gel formulation of imidazole drug-loaded SLNs and NLCs can be used for sustained/prolonged topical delivery of the drugs.

Development and Oral Bioavailability of Self-Emulsifying Formulation of Ketoconazole

Ketoconazole is an imidazole antifungal drug belonging to the class II of Biopharmaceutic Classification System. Maintenance of gastric acidity is essential for adequate dissolution and absorption of ketoconazole. Concurrent administration of antacid and antiulcer preparations decreases the oral absorption of ketoconazole often causing therapeutic failure. The aim of this study was to evaluate whether a self-emulsifying formulation of ketoconazole would be able to overcome the pH dependent dissolution and oral bioavailability. Self-emulsifying drug delivery system (SEDDS) was prepared after selecting the oil, surfactant and co-surfactant by solubility analysis. Optimum ratio of the components was finalized on the basis of drug content, self-emulsification and mean droplet diameter. The effect of pH on dissolution was studied in comparison to the pure drug. Oral bioavailability was determined in comparison to aqueous suspension in rats and the effect of co-administration of ranitidine hydrochloride solution and a commercially available liquid antacid preparation was studied. The optimized formulation containing 20% Capryol 90 and 40% each of Carbitol and Tween 80, exhibited 100% drug release regardless of the pH whereas the pure drug exhibited a highly pH dependent dissolution. The AUC0-24 resulted with oral administration of the SEDDS formulation was about 34%, 43% and 60% higher compared to the aqueous suspension when administered alone, administered with ranitidine and administered with antacid respectively. The results of the present study demonstrate that self-emulsifying formulations can be utilized for oral delivery of weakly basic drugs like ketoconazole which exhibit pH dependent dissolution.

ChemInform Abstract: Structure-Activity Relationships of a New Antifungal Imidazole, AFK-108, and Related Compounds.

Fungicidal activity of widely used imidazole antifungal drugs in topical applications is not so strong in spite of their potent fungistatic activities against dermatophytes and pathogenic yeasts. In order to improve fungicidal activity of imidazole antifungal agents, a series of novel imidazole derivatives having a hydrophobic substituent derived from isoprenoid were synthesized. The efficacy of these compounds was evaluated with respect to direct cell-membrane damaging activity, ergosterol biosynthesis inhibition, minimum growth-inhibitory concentration (MIC) and therapeutic effect for experimental dermatophytosis of guinea pigs. Among the newly synthesized compounds, the geranyl derivative named AFK-108 (2a) showed the highest in vivo fungicidal activity with both cell membrane damaging activity and ergosterol biosynthesis inhibition in vitro.

Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth

In a screen of drugs previously tested in humans we identified itraconazole, a systemic antifungal, as a potent antagonist of the Hedgehog (Hh) signaling pathway that acts by a mechanism distinct from its inhibitory effect on fungal sterol biosynthesis. Systemically administered itraconazole, like other Hh pathway antagonists, can suppress Hh pathway activity and the growth of medulloblastoma in a mouse allograft model and does so at serum levels comparable to those in patients undergoing antifungal therapy. Mechanistically, itraconazole appears to act on the essential Hh pathway component Smoothened (SMO) by a mechanism distinct from that of cyclopamine and other known SMO antagonists, and prevents the ciliary accumulation of SMO normally caused by Hh stimulation.

Chiral Separations of Imidazole Antifungal Drugs on AmyCoat RP Column in HPLC

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

Allergic Contact Dermatitis from Luliconazole: Implication of the Dithioacetal Structure

This article does not have an abstract.

69: Therapeutic monitoring of sirolimus is essential in pediatric BMT recipients

Limited data on sirolimus (SRL) in adult BMT patients is consistent with a long elimination half-life (t1/2; 57-63 h) and little effect of an occasional missed dose on overall drug exposure. Pharmacokinetic (PK) studies in pediatric organ transplant recipients suggest that SRL may be metabolized more rapidly in children. BMT patients may have variable SRL exposure due to gastrointestinal toxicity, and interactions with calcineurin inhibitors and imidazole antifungaldrugs.

Nail Penetration of Sertaconazole with a Sertaconazole-Containing Nail Patch Formulation

Sertaconazole, an imidazole antifungal drug, has been proven to have broad and potent antifungal activity. In the present study, the pharmacokinetics of sertaconazole nail patches, developed for treatment of onychodystrophy and onychomycosis, were investigated in healthy volunteers. The objective of the study was to investigate the penetration of sertaconazole into the nail and plasma and the residual sertaconazole concentration in patches after 1 week of application onto the nails. In a double-blind study, 16 healthy adults were treated with a 2.2 cm2 nail patch containing sertaconazole 3.63 mg and another patch containing no antifungal agent, which were placed on the left and right thumbnail of each subject, respectively (or vice versa), in a randomized order. The treatment period was 6 weeks and the patches were replaced weekly. Nail clippings, used nail patches, and blood samples were investigated to determine sertaconazole concentrations. Sertaconazole was detected in all sertaconazole-treated nail samples with mean concentrations of >100 microg/g, which exceeds the minimum inhibitory concentrations (MICs) for all relevant fungi in this context. Measurements of the residual dose in the patches suggested that 16-71% of the active ingredient had penetrated into the nail. No plasma sertaconazole concentrations could be detected. By virtue of their positive influence (occlusion) on water and lipid metabolism in dystrophic nails, nail patches should have beneficial therapeutic effects in onychodystrophic conditions. Addition of the antifungal agent sertaconazole adds broad-spectrum antimicrobial activity. In this study, the concentrations of sertaconazole in the nails were shown to be well above the MIC values for pathogenic fungi relevant to onychomycosis. No systemic absorption of the active ingredient was detectable, which should exclude unwanted systemic effects of the drug.

Econazole and miconazole inhibit steroidogenesis and disrupt steroidogenic acute regulatory (StAR) protein expression post-transcriptionally

The imidazole antifungal drugs econazole and miconazole have previously been shown to disrupt steroidogenesis in Leydig and adrenal cells by inhibiting 17α-hydroxylase/17,20-lyase (P450c17) enzyme activity, thus reducing the conversion of progesterone to androstenedione. However, a recent study in Y-1 adrenal cells indicated that these compounds may also reduce the availability of cholesterol to the cytochrome P450 side chain cleavage (P450 scc) enzyme, the first enzyme in the steroidogenic pathway. Since the steroidogenic acute regulatory protein (StAR) mediates the transfer of cholesterol from the outer to the inner mitochondrial membrane where the P450 scc enzyme resides, an action which constitutes the rate-limiting and acutely-regulated step in steroidogenesis, we hypothesized that these drugs may also reduce StAR expression and/or activity. Our studies demonstrate that these drugs reversibly inhibited (Bu) 2cAMP-stimulated progesterone production in a dose- and time-dependent manner in MA-10 cells without affecting total protein synthesis or P450 scc and 3β-hydroxysteroid dehydrogenase (3β-HSD) enzyme expression or activity. In contrast, they dramatically decreased (Bu) 2cAMP-stimulated StAR protein expression post-transcriptionally. This study indicates that StAR protein is susceptible to inhibition by at least some imidazole compounds that inhibit steroidogenesis.

Analysis of some antifungal drugs by spectrophotometric and spectrofluorimetric methods in different pharmaceutical dosage forms

Simple spectrophotometric and spectrofluorimetric methods are suggested for the determination of antifungal drugs; clotrimazole, econazole nitrate, ketoconazole, miconazole and tolnaftate. Spectrophotometric one depends on the interaction between imidazole antifungal drugs as n-electron donor with the π acceptor 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in methanol or with p-chloranilic acid ( p-CA) in acetonitrile. The produced chromogens obey Beer’s law at λ max 460, and 520 nm in the concentration range 22.5–200 and 7.9–280 μg ml −1 for DDQ, and p-CA, respectively. Spectrofluorimetric method is based on the measurement of the native fluorescence of ketoconazole at 375 nm with excitation at 288 nm and or the induced fluorescence after alkaline hydrolysis of tolnaftate with 5 M NaOH solution at 420 nm with excitation at 344 nm. Fluorescence intensity versus concentration is linear for ketoconazole at 49.7–800 ng ml −1 while for tolnaftate, it is in the range of 20.4–400 ng ml −1. The proposed methods were applied successfully for the determination of all the studied drugs in their pharmaceutical formulations.

Structure-activity relationships of a new antifungal imidazole, AFK-108, and related compounds.

Fungicidal activity of widely used imidazole antifungal drugs in topical applications is not so strong in spite of their fungistatic activities against dermatophytes and pathogenic yeasts. In order to improve fungicidal activity of imidazole antifungal agents, a series of novel imidazole derivatives having a hydrophobic substituent derived from isoprenoid were synthesized. The efficacy of these compounds was evaluated with respect to direct cell-membrane damaging activity, ergosterol biosynthesis inhibition, minimum growth-inhibitory concentration (MIC) and therapeutic effect for experimental dermatophytosis of guinea pigs. Among the newly synthesized compounds, the geranyl derivative named AFK-108 (2a) showed the highest in vivo fungicidal activity with both cell membrane damaging activity and ergosterol biosynthesis inhibition in vitro.

Clotrimazole-induced modulation of hepatic cytochrome P450 enzymes in Syrian and Chinese hamsters

Clotrimazole, an imidazole antifungal drug, is known to induce cytochrome P450 isozymes of the P450IIIA and P450IIB subfamilies in rats. This agent modulated hepatic cytochrome P450 enzymes differently in golden Syrian and Chinese hamsters and also in hamsters and rats. Clotrimazole at a daily intraperitoneal dose of 100 mg/kg for three days increased the amount of cytochrome P450 in the livers of the two hamster strains. In Syrian hamsters, clotrimazole significantly induced the activities of 7-pentoxyresorufin O-dealkylase, coumarin 7-hydroxylase, benzphetamine N-demethylase and testosterone 15α- and 16α-hydroxylases, but reduced those of testosterone 15β-, 7α-, 6β-, 2α- and 2β-hydroxylases. In Chinese hamsters, clotrimazole markedly stimulated the activities of coumarin 7-hydroxylase and testosterone 15α-, 16α- and 2α-hydroxylases as well as the formation of androstenedione. Western blot analysis revealed that clotrimazole treatment induced mainly cytochrome P450 isozymes immunorelated to the P450IIB and P450IIA subfamilies in Syrian hamsters and isozymes immunorelated to the P450IIA subfamily in Chinese hamsters. In contrast, in both hamster strains, clotrimazole did not induce the isozymes corresponding to the P450IIIA subfamily.

New antifungal agents

For more than two decades, amphotericin B has been the single broad-spectrum agent for the treatment of systemic mycoses. Amphotericin B is not always effective, must be given parenterally, and is associated with a host of adverse reactions. Despite amphotericin B toxicity, until recently the systemic mycoses did not rate enough attention to prompt a search for new alternatives. However, three recent events have overcome this inertia: the gradually increasing use of potent immunosuppressive agents and broad-spectrum antibacterial drugs; the discovery of the relatively nontoxic azole classes of antifungal drugs in the 1980s and the rapid emergence of AIDS, with its severe accompanying opportunistic fungal infections. In just ten years we have seen the emergence of second-generation imidazole and third-generation triazole antifungal drugs and, most recently, entirely new classes of agents. It is remarkable that so many alternatives are becoming available just at the time when new antifungal drugs have become a major need. This discussion will concentrate on the new antifungal drugs of the past ten years, with the exception of developments in the polyenes and flucytosine, which are covered elsewhere.

Ketoconazole and other imidazole derivatives as inhibitors of steroidogenesis.

Background IMIDAZOLE antifungal drugs are effective therapeutic agents in the treatment of mycotic infections (1). Because ketoconazole can be administered orally and has a broad spectrum of activity against both superficial and deep mycoses, this imidazole derivative has become widely used throughout the world as an antifungal agent (1, 2). In recent years it as become apparent that ketoconazole has additional potent actions to inhibit steroidogenesis. Much of the discussion to follow will be directed at the specific drug ketoconazole and its ability to suppress the synthesis of steroid hormones. However, other structurally related imidazole antifungal agents share in these antihormonal actions. In addition, other categories of drugs contain imidazole or azole structures, and some element of the hormonal effects to be discussed for ketoconazole may also apply to these drugs as well. Prominent examples are cimetidine, thiobendazole, and metronidazole. The ability to inhibit steroidogenesis is especially r...

Ketoconazole in the Treatment of Acne in Women

To the Editor.— The great interest recently aroused by the use of antiandrogens in dermatology 1 prompts us to report the preliminary results that we obtained using a new antiandrogen, ketoconazole, in the treatment of acne and hirsutism in women. Ketoconazole, an oral imidazole antifungal drug, is a potent inhibitor of testosterone synthesis that has been recently used to induce and maintain a remission in patients with advanced prostatic cancer. 2,3 In the last few months, we have used oral ketoconazole in the treatment of three female patients affected by severe acne and hirsutism. At the start of therapy, serum total testosterone levels were raised in all three patients, ranging from 1.12 to 1.54 ng/mL (normal, 0.36 to 0.80 in women and 2.58 to 7.78 in men). Ketoconazole was administered at the dosage of 300 mg twice daily for three months. No topical therapy was added. All three patients experienced

Inhibition of steroidogenic cytochrome P-450 enzymes in rat testis by ketoconazole and related imidazole anti-fungal drugs

Ketoconazole, an imidazole antifungal drug, has previously been shown to diminish testosterone and cortisol production in patients as well as rat and mouse cells in vitro. Inhibition of adrenal mitochondrial cytochrome P-450 enzymes was demonstrated. In this study we tested several imidazole antifungal drugs and examined the individual steps in testicular steroidogenesis to determine which enzymes in the androgen pathway were blocked. In addition, we studied 25-hydroxyvitamin D 24-hydroxylase activity in cultured pig kidney cells (LLC-PK 1) to assess a mitochondrial P-450 enzyme in another organ. All imidazoles tested inhibited both total testosterone production and 24-hydroxylase activity but the relative potencies differed. We next studied the individual testicular enzymatic steps between cholesterol and testosterone. Ketoconazole inhibited cholesterol-side-chain-cleavage enzyme (mitochondrial) and C-17,20 lyase (microsomal). The three inhibited enzymes (two testicular and one renal) are all P-450 cytochromes. Testicular 17-hydroxylase, also a P-450 cytochrome, was not inhibited even at high doses of ketoconazole. This is an interesting finding because the testicular hydroxylase and lyase have been shown to be a single protein. Non-cytochrome P-450 enzymes in the androgen pathway were not inhibited. The results demonstrate that several imidazole antifungal drugs all inhibit both microsomal and mitochondrial cytochrome P-450 enzymes in multiple organs.

Reversible adrenal insufficiency induced by ketoconazole

KETOCONAZOLE, an imidazole antifungal drug, blocks testicular and adrenal steroid synthesis in a dosedependent and time-dependent manner, presumably correlating with serum levels of ketoconazole. 1-5 Although hypogonadism and gynecomastia caused by ketoconazole have been reported, symptomatic hypoadrenalism has not yet been described, 1,4,6 to the best of our knowledge. We report a patient who developed symptoms and signs of hypoadrenalism while receiving an experimentally high daily dose of ketoconazole. The results of serum and urinary steroid measurements confirmed this clinical impression. All symptoms and signs of adrenal insufficiency resolved promptly following discontinuation of ketoconazole therapy. Methods A one-hour intravenous adrenocorticotropic hormone (ACTH) (cosyntropin [Cortrosyn]) test, 7 a 48-hour intravenous ACTH (Cortrosyn) test, 8 and a metyrapone (Metopirone) test 9 were performed during ketoconazole therapy and were repeated after its discontinuation. Report of a Case A hypertensive 48-year-old black man had an average blood pressure of 140/90 mm Hg with methyldopa (Aldomet),

Reversible Adrenal Insufficiency Induced by Ketoconazole

KETOCONAZOLE, an imidazole antifungal drug, blocks testicular and adrenal steroid synthesis in a dosedependent and time-dependent manner, presumably correlating with serum levels of ketoconazole.^1-5Although hypogonadism and gynecomastia caused by ketoconazole have been reported, symptomatic hypoadrenalism has not yet been described,^1,4,6to the best of our knowledge. We report a patient who developed symptoms and signs of hypoadrenalism while receiving an experimentally high daily dose of ketoconazole. The results of serum and urinary steroid measurements confirmed this clinical impression. All symptoms and signs of adrenal insufficiency resolved promptly following discontinuation of ketoconazole therapy. <h3>Methods</h3> A one-hour intravenous adrenocorticotropic hormone (ACTH) (cosyntropin [Cortrosyn]) test,⁷a 48-hour intravenous ACTH (Cortrosyn) test,⁸and a metyrapone (Metopirone) test⁹were performed during ketoconazole therapy and were repeated after its discontinuation. <h3>Report of a Case</h3> A hypertensive 48-year-old black man had an average blood pressure of 140/90 mm Hg with methyldopa (Aldomet),