Nano-Econazole Enhanced PD-L1 Checkpoint Blockade for Synergistic Antitumor Immunotherapy against Pancreatic Ductal Adenocarcinoma.

Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo-phototherapy nanoplatform is designed by which econazole and biliverdin can be co-assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD-L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin-induced PTT/PDT and boost the immunotherapeutic response of PD-L1 blockade. In addition, econazole simultaneously enhances PD-L1 expression to sensitize anti-PD-L1 therapy, leading to suppression of distant tumors, long-term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8+ T lymphocytes. The combined FBE NPs and α-PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo-phototherapy with PD-L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy.

Skin permeation of econazole nitrate formulated in an enhanced hydrophilic multiple emulsion.

Local delivery of imidazolic antifungals is limited by its extreme lipophilicity. Multiple emulsions (ME) are a potential vehicle to enhance the delivery of econazole nitrate (ECN), an antifungal targeted to deep-seated epidermal yeast infections. An 1% ECN hydrophilic ME was compared with a commercial formulation in terms of rheology, droplet size and in vitro antifungal activity against Candida species. Comparative in vitro drug release, human skin permeation and drug retention were investigated using vertical diffusion cells. Rheology demonstrated a pseudoplastic shear thinning with thixotropy facilitating skin residence. No significant aggregation or droplet size variations were observed during a 6-month stability storage. Both formulations exhibited similar release levels achieving asymptotic values in 5 h. ECN skin permeation levels from the multiple emulsion resulted to be significantly higher than those of the commercial formulation, attributable to differences in formulation polarity and excipients composition. Conversely, similar drug accumulation levels in skin were obtained (40-130 ppm). These concentrations resulted to be comparable with obtained MIC values (2-78 ppm), confirming the in vitro antimicrobial efficacy of both formulations. A similar skin retention and a higher permeation rate over the existing formulations is considered an improved approach to target the drug to deep epidermis.

Cutaneous alternariosis in an immunocompetent patient.

Alternaria species are a type of dematiaceous fungi that cause a wide spectrum of disease with cutaneous infections being the most common. These infections are most common in immunocompromised individuals. However, only a few cases of primary cutaneous alternariosis have been reported in immunocompetent patients. We present a case of an otherwise healthy 13-year-old male who presented with primary cutaneous alternariosis on his left ankle that responded to the use of topical econazole and oral itraconazole. We also provide a review of previously described cases of primary cutaneous alternariosis in the literature.

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.

TRPM2 contributes to antigen-stimulated Ca²âº influx in mucosal mast cells.

Food allergy (FA) is a common allergic disease without any currently available effective drug therapies. Mucosal mast cells (MMCs) play a particularly important role in FA, and the increase in their cytosolic Ca(2+) concentration ([Ca(2+)]cyt) is considered to be a principal component of the degranulation process. However, the mechanisms governing Ca(2+) influx remain poorly understood in MMCs. Recent reports have highlighted the functions of the transient receptor potential melastatin 2 (TRPM2) channel in immunocytes, including its role in monocyte chemokine production and macrophage phagocytic activity. Although TRPM2 gene expression has been demonstrated in mast cells, the significance of such expression remains virtually unknown. In this study, we found that antigen-stimulated degranulation was significantly reduced in mucosal-type bone marrow-derived mast cells (mBMMCs) prepared from TRPM2-knockout (TRPM2-KO) mice (TRPM2-KO mBMMCs) and was suppressed following the administration of three TRPM2 inhibitors with different chemical structures, including econazole, flufenamic acid (FFA), and 2-aminoethoxydiphenyl borate. Furthermore, the antigen-stimulated increase in [Ca(2+)]cyt was significantly decreased in TRPM2-KO mBMMCs and was also suppressed by the TRPM2 inhibitors econazole and FFA. In addition, thapsigargin-induced increase in [Ca(2+)]cyt was significantly decreased in TRPM2-KO mBMMCs. These results suggest that TRPM2 may participate in antigen-induced extracellular Ca(2+) influx and subsequent degranulation. In addition, TRPM2 inhibitors were shown to improve food allergic reactions in a mouse model. Together, these results suggest that TRPM2 inhibitors suppress MMC degranulation via regulation of the increase in [Ca(2+)]cyt. Thus, TRPM2 may play a key role in degranulation by modulating intracellular Ca(2+) in MMCs.

Synergistic Antimicrobial Effect of Colistin in Combination with Econazole against Multidrug-Resistant Acinetobacter baumannii and Its Persisters.

Colistin is a last-line antibiotic which acts by causing membrane permeabilization in Gram-negative bacteria. However, its clinical value has been limited by its toxicity and the emergence of resistant organisms. In this study, we showed that econazole and colistin can act synergistically to produce a strong antimicrobial effect sufficient for eradication of starvation-induced tolerant and multidrug-resistant populations of Acinetobacter baumannii, a notorious pathogen causing recalcitrant infections, both in vitro and in mouse infection models. Investigation of the underlying mechanism showed that, while colistin disrupts the membrane structure, econazole causes the dissipation of proton motive force, eliciting a vicious cycle of membrane structural damages and disruption of membrane protein functions, and eventually cell death. This drug combination therefore achieves our goal of using a much smaller dosage of colistin to produce a much stronger antimicrobial effect to tackle the problems of toxicity and resistance associated with colistin usage. IMPORTANCE Findings described in this study constitute concrete evidence that it is possible to significantly enhance the antimicrobial activity of colistin by using an antifungal drug, econazole, as a colistin adjuvant. We showed that this drug combination can kill not only multidrug-resistant A. baumannii but also the tolerant subpopulation of such strains known as persisters, which may cause chronic and recurrent infections in clinical settings. The synergistic killing effect of the econazole and colistin combination was also observable in mouse infection models at a very low concentration, suggesting that such a drug combination has high potential to be used clinically. Findings in this study therefore have important implications for enhancing its clinical application potential as well as developing new approaches to enhance treatment effectiveness and reduce suffering in patients.

Efficacy of Clotrimazole 1% Solution Compared to Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% Cream in Patient with Otomycosis.

Fungal infection of the ear canal is called Otomycosis. It is more common in hot and humid condition. There are many modalities of treatment or therapeutic agent for treatment of otomycosis. Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream is a topical antifungal agent described to be effective in the treatment of otomycosis. This study was performed to compare the efficacy of topical application clotrimazole 1% solution and Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream in the treatment of otomycosis. A controlled, randomized and open clinical trial was carried out in ENT department of Mymensingh Medical College Hospital, Mymensingh, Bangladesh from January 2020 to July 2020. Patients diagnosed with fungal otitis externa who were treated with topical antifungals were included in this study. They were randomized into two treatment groups: i) Clotrimazole 1% solution, 2) Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream. Patients were microscopically evaluated at two weeks of treatment to determine resolution of disease. Recurrence and complications were recorded. Demographic and clinical variables were collected and analyzed, follow up and final outcomes (absence of infection) were compared between two groups. One hundred & two (102) patients were included, 51 in the clotrimazole 1% solution group and 51 in the Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream group. Predominant symptoms are pain, pruritus, aural fullness and hearing loss. Aspergillus organism was isolated most frequently (63.73%). Treatment with clotrimazole 1% solution groups resulted in 88.23% resolution vs. 80.39% resolution with Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream at 2 weeks of treatment. Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream group demonstrated higher treatment failure 11.76 and 19.60 respectively. Clotrimazole 1% solution is more effective than Econazole Nitrate 1% + Triamcinolone Acetonide 0.1% cream for uncomplicated otomycosis. More study is needed to corroborate our results.

First case of Trichophyton soudanense isolated in Tunisia.

This is a first case of Trichophyton soudanense isolated from Ivoiran student in Tunisia. A 24-year-old man was addressed for extensive erythematous, scaling lesions. Examination disclosed tinea capitis, tinea corporis, tinea pedis, and onychomycosis of toenails and fingernails. Isolates were identified as Trichophyton soudanense on the basis of macroscopy and microscopy colony characteristics. The patient was treated with fluconazole, topical econazole, and ciclopiroxolamine varnish. Although T. soudanense was identified since the late 1950s outside the African continent especially in the North America, Brazil, Australia, and many European countries, this is the first case reported in Tunisia. Accessibility to our universities for African students makes possible the emergence of this dermatophyte.

Novel chemotherapy for tuberculosis: chemotherapeutic potential of econazole- and moxifloxacin-loaded PLG nanoparticles.

The potential of econazole (ECZ) and moxifloxacin (MOX) individually against tuberculosis (TB) caused by multidrug-resistant and latent Mycobacterium tuberculosis has been demonstrated. In this study, poly-(dl-lactide-co-glycolide) (PLG) nanoparticle-encapsulated ECZ and MOX were evaluated against murine TB (drug susceptible) in order to develop a more potent regimen for TB. PLG nanoparticles were prepared by the multiple emulsion and solvent evaporation technique and were administered orally to mice. A single oral dose of PLG nanoparticles resulted in therapeutic drug concentrations in plasma for up to 5 days (ECZ) or 4 days (MOX), whilst in the organs (lungs, liver and spleen) it was up to 6 days. In comparison, free drugs were cleared from the same organs within 12-24h. In M. tuberculosis-infected mice, eight oral doses of the formulation administered weekly were found to be equipotent to 56 doses (MOX administered daily) or 112 doses (ECZ administered twice daily) of free drugs. Furthermore, the combination of MOX+ECZ proved to be significantly efficacious compared with individual drugs. Addition of rifampicin (RIF) to this combination resulted in total bacterial clearance from the organs of mice in 8 weeks. PLG nanoparticles appear to have the potential for intermittent therapy of TB, and combination of MOX, ECZ and RIF is the most potent.

[Tinea nigra palmaris: a clinical case in Argentina]. / Tinea nigra palmaris: presentacion de un caso clínico en la República Argentina.

A clinical case of a female patient with a black spot on the palm of her left hand is presented. The infection was due to a black fungus identified as Hortaea werneckii, the aetiological agent of tinea nigra palmaris. This infection can be easily diagnosed and it is important to establish the differential diagnosis from other skin pathologies. Normally, the treatment has a successful outcome. In this case, the patient was treated with econazole locally applied during one month, with complete remission of the lesions. In conclusion, the early diagnosis of this disease is very important since the mycology procedures are fast and non-invasive and cure is obtained with local treatment.

Econazole nitrate inhibits PI3K activity and promotes apoptosis in lung cancer cells.

The phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in many cellular processes, including the proliferation, survival and differentiation of lung cancer cells. Thus, PI3K is a promising therapeutic target for lung cancer treatment. In this study, we applied free and open-source protein-ligand docking software, screened 3167 FDA-approved small molecules, and identified putative PI3Kα inhibitors. Among them, econazole nitrate, an antifungal agent, exhibited the highest activity in decreasing cell viability in pathological types of NSCLC cell lines, including H661 (large cell lung cancer) and A549 (adenocarcinoma). Econazole decreased the protein levels of p-AKT and Bcl-2, but had no effect on the phosphorylation level of ERK. It inhibited cell growth and promote apoptosis in a dose-dependent manner. Furthermore, the combination of econazole and cisplatin exhibited additive and synergistic effects in the H661 and A549 lung cancer cell lines, respectively. Finally, we demonstrated that econazole significantly suppressed A549 tumor growth in nude mice. Our findings suggest that econazole is a new PI3K inhibitor and a potential drug that can be used in lung cancer treatment alone or in combination with cisplatin.

The potential of azole antifungals against latent/persistent tuberculosis.

The aim of the present study was to evaluate the chemotherapeutic potential of econazole against latent tuberculosis. The activity of econazole and clotrimazole was tested against the latent bacilli (Mycobacterium tuberculosis H(37)Rv) developed by nutrient starvation under in vitro conditions and by drugs under in vivo conditions. The latent bacteria developed under in vitro latent conditions were acid-fast negative, nonreplicating, resistant to conventional antitubercular drugs and showed low respiration rates. Econazole as well as clotrimazole were found to have strong antimycobacterial potential against latent Mycobacterium tuberculosis under in vitro conditions as seen by reductions in colony-forming units. Further, econazole prevented the formation of drug-induced latency and significantly reduced bacterial burden from lungs and spleens of latent tuberculosis-infected mice. We conclude that azole drugs bear significant therapeutic potential against latent tuberculosis.

Azole antifungals as novel chemotherapeutic agents against murine tuberculosis.

The present study was designed to evaluate the in vivo antimycobacterial potential of econazole alone and in combination with antitubercular drugs against tuberculosis in mice. Econazole was found to reduce bacterial burden by 90% in the lungs and spleen of mice infected with 1 x 10(7) cells of Mycobacterium tuberculosis and was found to be equipotent to rifampicin. Further, our results indicate that econazole can replace rifampicin/isoniazid as well as both rifampicin and isoniazid in chemotherapy of murine tuberculosis. Econazole alone or in combination with antitubercular drugs did not produce any hepatotoxicity in normal or M. tuberculosis-infected mice.

Pruritic, lightly-scaled patches on wrists.

A rash first appeared on this patient's left wrist and then spread to his right. Was his chrome-colored watch to blame--or was there a different cause?

[Congenital cutaneous candidiasis: a case report and review]. / La candidose cutanée congenitale: a propos d'une observation et revue de la littérature.

The aim of this article is to report a case of congenital cutaneous candidiasis (CCC). We describe the clinical features and emphasize the role of laboratory testings to assess diagnosis in the newborn and to prevent this condition by screening vaginal candidiasis in pregnant women. A full-term, 3500-g male was born by spontaneous vaginal delivery to a 30-year-old healthy woman. On physical examination, he was a well-developed, vigorous newborn. Since the first hours of his life he presented erythematous maculae diffusely distributed on the skin and pustules overlying areas of confluent macular erythema on his trunk and extremities. The palms and soles were not affected. Neither oral thrush nor peri-anal lesions have been observed. The rest of the physical examination was normal. Microscopic examination of skin scrapings showed the presence of many yeasts and the culture permitted the identification of a strain of Candida albicans. Precocity and extent of the cutaneous signs attest a congenital cutaneous candidiasis and eliminate the other skin diseases of similar clinical symptoms. Topical antifungal therapy (econazole) was given and the cutaneous lesions disappeared after 20 days. CCC appears to be acquired in utero by the ascension of organisms from an infected vagina into the uterine cavity. This condition is preventable with systematic screening and treatment of vulvo-vaginitis due to Candida albicans in pregnant women, The important role played by the laboratory of mycology remains essential.

Econazole: a review of its antifungal activity and therapeutic efficacy.

Econazole1 is a recently introduced imidazole antifungal agent which is very closely related structurally to another imidazole derivative, miconazole. For local application the nitrate salt of econazole is used, while in preliminary investigations of systemic use in a few patients econazole base has been administered orally or intravenously. In uncontrolled studies in large numbers of patients, econazole nitrate has been administered topically in the treatment of dermatomycoses due to a wide variety of fungi, and vaginally in the treatment of vaginal candidosis; but it has not been compared with any other antifungal drug in controlled therapeutic trials in mycoses of the skin and has only been compared with nystatin in a few patients with vaginal candidosis. Until adequate comparative studies are done the relative place of econazole in the treatment of dermatomycoses and vaginal condidosis, compared with traditional antifungal agents and with other imidazole derivatives such as miconazole or clotrimazole, cannot be clearly stated. Nevertheless, econazole nitrate is an effective antifungal drug. In dermatological studies about 90% of a large number of patients were cured, often after a relatively short treatment period (2 to 6 weeks, as occurs with other imidazole antifungal agents). The cure rate was only slightly lower (about 85%) in patients with severe mycoses of many years' duration than in those whose infections were of more recent onset. In vaginal candidosis a 3-day treatment regimen using a 150mg suppository once daily was only slightly less effective (85% mycological cure rate) than a 15-day regimen using a 50mg dose (suppository or cream) once daily (90% cure rate). A 3 to 5 day 'higher' dose regimen was slightly more effective than a standard 15-day regimen of nystatin vaginal inserts in a small group of patients with vaginal candidosis. The convenience of the higher-dose shorter term regimen would likely be an important advantage to most patients. Whether other agents useful in vaginal candidosis would be as effective as econazole were they to be used in this way, has not been determined. Topical or intravaginal econazole nitrate has usually been well tolerated, side effects being limited to local irritation in about 1 to 4% of patients in most studies.

R34000, a dioxolane imidazole in the therapy for experimental coccidioidomycosis. Comparison with miconazole and econazole.

Comparisons were made on the therapeutic influence of three imidazole drugs in experimental lethal coccidioidomycosis of mice. When administered by the intramuscular route, miconazole and a closely related structural analogue, econazole, were effective in preventing death, restricting fungal replication in the lungs, and minimizing the extent of extrapulmonary dissemination. Neither drug was as effective when administered by the oral route as by the intramuscular route. This contrasted sharply with results obtained using R34000, a dioxolane imidazole. It was very highly effective when administered by the oral route and less so by intramuscular injection. All orally treated mice survived a challenge lethal to more than 80 percent of control animals. Plasma or serum concentrations of orally administered R34000 in mice and in man exceeded the minimum inhibitory concentration for a virulent strain of Coccidioides immitis.