Single ascending dose safety, tolerability, and pharmacokinetic study of econazole in healthy volunteers.

INTRODUCTION: Econazole has been found efficacious as antitubercular in in vitro and in vivo animal studies. However, limited information is available for its safety and pharmacokinetics in humans. In our present study we have conducted single ascending dose, safety, and pharmacokinetic evaluation in healthy human volunteers with the purpose of enabling translation for tuberculosis. METHODS: This study was conducted as a single-center, ascending-dose, placebo-controlled, double blind design. Three ascending dose were chosen (250 , 500 , and 1000 mg) to be administered as a single oral dose. The volunteers were screened for potential eligibility. Participants were randomized to receive either Econazole or Placebo in a 6:2 design. Safety assessments and pharmacokinetic evaluations were carried out for each cohort. RESULTS: Econazole was found to be safe at all dose levels. No serious or severe adverse events occurred during the study. The AUC (0-∞) showed a response relationship with a value of 49 ± 3.47 h* µg/ml, 17. 86 ± 8.40 hr* µg/ml, 35.54 ± 13.94 hr* µg/ml for 250 mg, 500 mg, and 1000 mg, respectively. CONCLUSION: Based on the findings of our study, a dose of 500 mg Econazole, once a day orally was considered as appropriate for further evaluation.

A Comparison of Triamcinolone Acetonide Econazole Cream and Nystatin Suspension in Treatment of Otomycosis.

OBJECTIVES/HYPOTHESIS: To compare the efficacy and adverse effects of triamcinolone acetonide econazole cream and nystatin suspension in the treatment of otomycosis, and to determine the clinical features, predisposing factors, and etiology of otomycosis. STUDY DESIGN: A prospective study. METHODS: A prospective clinical trial was conducted on 786 patients diagnosed with otomycosis. The study population was randomly divided into two treatment groups of triamcinolone acetonide econazole cream (TAEC) and nystatin suspension in a 1:1 ratio. After clearing all fungal deposits in the external auditory canal, the antimycotic drugs were locally applied for at least 2 weeks. The efficacy and adverse effects were compared between the two antifungal reagents by statistical analysis. Meanwhile, patient clinical data were collected to find out the clinical features, predisposing factors, and etiology. RESULTS: Pruritis was the most common symptom and Aspergillus niger was the leading fungal pathogen. There was high association (44.5%) of otomycosis with a history of unclean ear picking. The cure rate was 97.6% in the TAEC group and 73.5% in the nystatin group (P < .01). Treatment with TAEC resulted in 2.4% of patients complaining of discomforts (irritant dermatitis, otalgia, or headache) versus 59.8% of patients complaining discomforts treated with nystatin (P < .01). The residue rate of antifungals was 1.9% in the TAEC group and 89.9% in the nystatin group (P < .01) at the end of treatment. CONCLUSIONS: Thoroughly cleaning of the external auditory canal followed by local use of TAEC under endotoscope is an effective, convenient, and well-tolerated treatment for otomycosis. LEVEL OF EVIDENCE: 1 Laryngoscope, 131:E1640-E1646, 2021.

Efficacy of Topical Therapy with Newly Developed Terbinafine and Econazole Formulations in the Treatment of Dermatophytosis in Cats.

In the field of veterinary dermatology dermatophytosis is one of the most frequently occurring infectious diseases, therefore its treatment should be effective, convenient, safe and inexpensive. The aim of this study was to evaluate the efficacy of newly developed topical formulations in the treatment of cats with dermatophytosis. Evaluation of clinical efficacy and safety of terbinafine and econazole formulations administered topically twice a day was performed in 40 cats. Cats, suffering from the most widely spread Microsporum canis-induced dermatophytosis and treated with terbinafine hydrochloride 1% cream, recovered within 20.3±0.88 days; whereas when treated with econazole nitrate 1% cream, they recovered within 28.4±1.14 days. A positive therapeutic effect was yielded by combined treatment with local application of creams and whole coat spray with enilconazole 0.2% emulsion "Imaverol". Most cats treated with econazole cream revealed redness and irritation of the skin at the site of application. This study demonstrates that terbinafine tended to have superior clinical efficacy (p<0.001) in the treatment of dermatophytosis in cats compared to the azole tested.

Econazole nitrate foam 1% for the treatment of tinea pedis: results from two double-blind, vehicle-controlled, phase 3 clinical trials.

BACKGROUND: Econazole nitrate is a broad-spectrum topical antifungal with activity against a variety of dermatophytes and yeasts. A new topical dosage form, econazole nitrate topical foam 1%, utilizing patented Proderm Technology® has been developed for treatment of interdigital tinea pedis. OBJECTIVE: To evaluate econazole nitrate foam 1% versus foam vehicle for treatment of interdigital tinea pedis. METHODS: Two randomized, double-blind, parallel-group, vehicle-controlled, multicenter studies enrolled males and females ≥12 years old with a clinical diagnosis of interdigital tinea pedis and baseline fungal culture positive for a dermatophyte. Subjects applied econazole nitrate foam 1% (n=246) or foam vehicle (n=249) once daily for 4 weeks. The primary endpoint was proportion of subjects achieving a complete cure (negative KOH, negative fungal culture, complete resolution of all signs and symptoms) at 2 weeks post-treatment (Day 43). Secondary endpoints included mycologic cure (negative KOH and negative culture) and effective treatment (mycologic cure + no or mild erythema and/or scaling and all other signs and symptoms absent). RESULTS: The complete cure rate at Day 43 was 24.3% for econazole nitrate foam 1% vs 3.6% for foam vehicle. In addition, higher rates of mycologic cure (67.6% vs 16.9%) and effective treatment (48.6% vs 10.8%) were observed with econazole nitrate foam 1% versus the foam vehicle. There were few adverse events and only nasopharyngitis and headache were experienced by >1% of subjects. No serious adverse events were reported for econazole nitrate foam 1%. CONCLUSIONS: Econazole nitrate foam 1% exhibited superiority over foam vehicle for the primary and secondary endpoints with a high mycologic cure rate for all pathogens evaluated. Econazole nitrate foam 1% was safe and well tolerated with a safety profile comparable with the foam vehicle. Econazole nitrate foam 1% presents a novel alternative for the management of tinea pedis.

Laryngeal dyspnea in relation to an interaction between acenocoumarol and topical econazole lotion.

BACKGROUND: Bleeding is the most serious complication of oral anticoagulant therapy used for the prevention of thromboembolic complications. Drug-drug interactions are an important concern, as they may increase drug toxicity and, in the case of anticoagulant therapies, increase the risk of hemorrhage. CASE SUMMARY: An 84-year-old woman presented to the emergency department with a bilateral cervical hematoma and symptoms of upper-airway obstruction that had been increasing for 72 hours, with dyspnea and difficulty speaking developing in the previous 24 hours. Transnasal fiberoptic laryngoscopy revealed a significant laryngeal hematoma, as well as a hematoma on the floor of the mouth and in the tonsil area. Laboratory abnormalities included a prothrombin time < 10%, an international normalized ratio exceeding the laboratory limits, and an activated partial thromboplastin time >120 seconds. The patient had been receiving acenocoumarol 4 mg/d for 10 years for episodes of atrial fibrillation and recurrent deep venous thrombosis. Seventeen days earlier, she had received a prescription for topical econazole lotion 1% to be applied 3 times daily for 1 month to treat a dermatitis affecting 12% of the body surface. The patient was admitted to the intensive care unit for treatment of respiratory failure, where oxygen was delivered by face mask. The coagulation disorders were treated with prothrombin complex concentrate 30 IU/kg IV and vitamin K1 10 mg IV, and values normalized within 36 hours. Surgical evacuation of the laryngeal hematoma was not necessary. After 48 hours, improvement in the patient's respiratory symptoms allowed transfer to the ear, nose, and throat unit, where daily endoscopic examination was performed. Aspirin was substituted for acenocoumarol, and the patient returned home after 10 days without sequelae. Based on a Naranjo score of 7, this episode was probably related to an interaction between acenocoumarol and econazole. CONCLUSION: This report describes a case of a probable interaction between topical econazole lotion 1% and acenocoumarol that resulted in overanticoagulation and a life-threatening laryngeal hematoma in this elderly patient.

A population-based case-control teratological study of vaginal econazole treatment during pregnancy.

OBJECTIVE: To study human risk and benefit of vaginal econazole treatment during pregnancy. MATERIALS AND METHODS: Pair analysis of cases with congenital abnormalities and matched controls in the population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980-1996. RESULTS: Of 38151 pregnant women who had newborn infants without any congenital abnormalities (control group), 122 (0.3%), of 22843 case pregnant women who had newborns or fetuses with congenital abnormalities, 68 (0.3%) used vaginal suppository of econazole (crude prevalence odds ratio (POR): 0.9, with 95% confidence interval (CI): 0.7-1.3). The matched case-control pair analysis did not indicate any teratogenic potential of econazole use during the second and third months of gestation, i.e. in the critical period for most major congenital abnormalities. CONCLUSION: Treatment with econazole during pregnancy does not indicate any teratogenic risk to the fetus.

Light and electron microscopic findings in a model of human cutaneous candidosis based on reconstructed human epidermis following the topical application of different econazole formulations.

The effects of two commercially available econazole formulations (econazole nitrate cream, econazole liposome gel) on uninfected reconstructed human epidermis and on a model of human cutaneous candidosis were investigated. The morphological alterations of the reconstructed epidermis after infection and treatment were analysed with light and electron microscopy. The most important Candida albicans-specific alterations of the recently established in vitro model of human cutaneous candidosis were scaling, hyperkeratosis, parakeratosis, dyskeratosis and spongiosis. A single application of the cream to the uninfected reconstructed epidermis caused more epidermal barrier damage and irritative toxic effects than the liposome gel. Treatment of the modelled human cutaneous candidosis with the cream also resulted in increased toxic effects, e.g., enhancement of scaling with invasion of Candida albicans blastospores into the stratum corneum and intracellular vacuoles. After application of the liposomal preparation invasion of Candida albicans in the stratum corneum could not be detected and toxic effects were reduced. Some of the Candida albicans-specific alterations such as hyperkeratosis, focal thickening of the stratum corneum, dyskeratosis and parakeratosis were completely eliminated. The liposomal formulation increased slightly the morphological alterations of the blastospores. Remnants of the cream formulation could be detected only very rarely in the stratum corneum or the blastospores. The liposomal preparation showed a strong affinity for the Candida albicans cells and the stratum corneum. Intact liposomes could even be observed in the intercellular spaces of the upper stratum corneum. As successful treatment depends on the ability to target the liposomal agent to the wanted site of action, this might be useful for more effective treatment of cutaneous candidosis.

Toxicity of antibiotics and antifungals on cultured human corneal cells: effect of mixing, exposure and concentration.

Toxic effects of topical drugs may be masked by manifestations of the disease they cure. The toxicity of drug mixtures has not been thoroughly studied. We therefore investigated cytopathic effects on primary cultures of human corneal cells of six topical antimicrobials singly and in combinations of any two, to determine the combined toxicity ranking and the interaction between duration of exposure and concentration. Preconfluent cultures were exposed to fixed dilutions of single drugs, or to equal-dilution mixtures of two drugs, for 7 and 14 days. Diminishing concentrations of single drugs were applied sequentially to cultures for 14 days. The number of metabolically competent cells was assessed by measuring hexosaminidase and total protein. Toxic effects depended on substance, concentration and exposure. The scale of toxicity determined for single drugs after 7 days of exposure was: gentamicin > econazole > or = methicillin > or = clotrimazole > or = miconazole > or = chloramphenicol. After 14 days this order changed: in particular chloramphenicol showed a highly increased toxicity. The order of diminishing effects was: gentamicin > chloramphenicol > or = methicillin > miconazole > econazole > clotrimazole. A clear reduction in cytopathic effects was observed when drug concentration was decreased progressively only in cultures treated with gentamicin or methicillin. All drug combinations were more toxic than their components at equal dilution. Combinations containing chloramphenicol ranked most toxic overall, those containing econazole least. A tapering off combination regime did not improve cell survival. These in vitro toxicity data complement clinical studies and suggest ways in which topical drugs can be chosen to minimise toxic effects to corneal surface.

Econazole and clotrimazole in the treatment of vaginal candidiasis: a double blind comparative study.

OBJECTIVES: To compare the efficacy of treatment with econazole and clotrimazole in patients with vaginal candidiasis. DESIGN: A double blind study. Patients with vaginal candidiasis were randomly treated with vaginal depot preparations of econazole and clotrimazole. Efficacy after treatment by reduction of symptoms, a gynaecological examination and microbiological analysis of vaginal fluid. Adverse reactions were noted. SETTING: University gynaecological clinic at the de Soysa Hospital for Women, Colombo. PATIENTS: 102 patients microbiologically confirmed as having vaginal candidiasis. RESULTS: Two weeks after econazole treatment 19% still complained of a discharge and 7.5% had pruritus. The respective values for clotrimazole were 18% and 12%. The finding on gynaecological examination generally supported the reduction of symptoms. Microbiological assessment showed that 90.5% in the econazole group and 96% in the clotrimazole group became culture negative at two weeks after treatment. Adverse effects were similar in incidence and number for both treatment groups. Econazole was less acceptable to patients than clotrimazole. CONCLUSIONS: Econazole and clotrimazole are of equal efficacy for treatment of vaginal candidiasis. Econazole was less acceptable to patients.

Evaluation of skin irritation and contact sensitizing potential of fenticonazole.

A double blind, randomized clinical trial was performed on twelve healthy volunteers to evaluate the irritation potential of fenticonazole 2% cream (Lomexin) and spray versus micomazole 2% cream and econazole 1% spray. The contact-sensitizing potential of the two fenticonazole preparations was also investigated. There was no evidence of irritation after the treatments with fenticonazole cream, its excipients, miconazole cream and fenticonazole spray excipients, whereas signs of irritation were observed in four cases after treatment with the spray formulations (two after fenticonazole, two after econazole). The contact-sensitizing test was performed only with fenticonazole 2% cream and spray. Neither spray nor cream formulation of fenticonazole showed evidence of sensitization in any of the twelve subjects.

Contact allergy to imidazole antimycotics.

Between 1977 and 1986, 9 patients with contact allergy to the active ingredient of imidazole antimycotics were found at the Department of Dermatology, University of Heidelberg. The number of positive reactions decreased in the following order: miconazole (6), clotrimazole (3), econazole (3), isconazole (3), and oxiconazole (1). When 5 patients were tested with a series of imidazoles in different concentrations and vehicles (petrolatum, ethyl methyl ketone, ethanol), petrolatum turned out to be the least effective one. The active ingredient at 1% in ethanol seems to be the most suitable choice for routine patch testing. Bifonazole may be the therapeutic alternative for patients sensitive to miconazole or clotrimazole, since no cross reactivity was observed.

Naftifine cream 1% versus econazole cream 1% in the treatment of tinea cruris and tinea corporis.

Data from 104 subjects with tinea cruris or tinea corporis were evaluated in this double-blind, randomized study. The subjects applied naftifine cream 1% or econazole nitrate cream 1% to affected areas twice daily for 4 weeks. After 1 week of treatment naftifine had an overall cure rate of 19% compared with 4% for econazole (p = 0.03). A difference in favor of naftifine, although not statistically significant after the first week, persisted throughout treatment. Two weeks after the end of treatment both medications had overall cure rates of approximately 80%. Three percent of the naftifine-treated subjects had side effects compared with 13% of the econazole-treated subjects. In two subjects using econazole, the side effects were severe enough to warrant discontinuation of treatment.

Double-blind comparison of the efficacy, toleration and safety of tioconazole base 1% and econazole nitrate 1% creams in the treatment of patients with fungal infections of the skin or erythrasma.

A total of 61 patients with proven fungal infection of the skin or with erythrasma took part in a double-blind comparison of the efficacy, toleration and safety of tioconazole base 1% w/w and econazole nitrate 1% creams applied twice daily. Some patients had more than one site of infection and some were infected with more than one fungal/bacterial species. The mean duration of treatment in the tioconazole group of patients was 40 days (range: 12-68) and in the econazole group 38 days (range: 17-101). Clinical and mycologic cure was achieved in 27 of 29 (93.1%) tioconazole-treated and 29 of 31 (93.5%) econazole-treated patients. All but 1 of the cured patients in each treatment group were seen some 6 weeks after the end of treatment; all remained clinically and mycologically cured. Both creams were found to be generally acceptable in terms of ease of application. Some staining was reported in both treatment groups. One side effect of mild intermittent pruritus was reported in an econazole-treated patient. The minimum inhibitory concentrations were determined.

Tioconazole in the treatment of fungal infections of the skin. An international clinical research program.

In 32 studies involving 1,304 patients tioconazole 1% dermal cream has been shown to be effective and safe in the treatment of a wide variety of superficial fungal infections of the skin and erythrasma. Tioconazole cream is more effective than miconazole nitrate 2% cream in the treatment of pityriasis versicolor and in infections with Trichophyton rubrum and Trichophyton mentagrophytes which cause 70% of dermatophyte infections in man. Data from comparisons with econazole and clotrimazole are too few to allow conclusions to be drawn on relative efficacy. All the creams were easy to apply and there were no serious adverse reactions, local or systemic.