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Medical Mycology Journal 2016Onychomycosis is a fungal infection of the nail apparatus caused by dermatophytes, Candida and non-dermatophytic molds. It is highly prevalent in the general population... (Review)
Review
Onychomycosis is a fungal infection of the nail apparatus caused by dermatophytes, Candida and non-dermatophytic molds. It is highly prevalent in the general population worldwide and also responsible for significant morbidity and complications and does not usually cure itself. Thus, the condition needs to be treated in view of physical and psychological problems produced. Currently, oral medications using terbinafine are the most effective therapy, but it has relatively limited therapeutic success, particularly for long-term management. Such existing oral therapies are associated with high recurrence rates and treatment failure, as well as with potential adverse events and drug-drug interactions. In the light of these issues, development of more efficacious and safer alternatives for the treatment of onychomycosis is warranted.Ravuconazole and its prodrugs are promising new drug candidates for oral therapy of onychomycosis, among which a water-soluble prodrug, mono-lysine phosphoester derivative (E1224 or BFE1224) is in the most advanced stage of clinical development; a Phase II dose-finding study has been successfully completed and Phase III comparative studies are in progress in Japan.This review aims to summarize our current status of knowledge and information on ravuconazole and its prodrugs, particularly BFE1224, as the potential oral treatment option for onychomycosis. It also summarize the clinical features of onychomycosis with particular stress on its etiology, epidemiology, and current therapeutic options and their limitations. Given its clinical usefulness, BFE1224 may become a valuable addition to the current armamentarium for the treatment of onychomycosis.
Topics: Administration, Oral; Antifungal Agents; Arthrodermataceae; Candida; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Discovery; Humans; Onychomycosis; Prodrugs; Thiazoles; Triazoles
PubMed: 27904057
DOI: 10.3314/mmj.16-00006 -
Journal of Fungi (Basel, Switzerland) Jul 2022Dermatophytomas are characterized as a hyperkeratotic fungal mass in the subungual space, showing as dense white or yellow, typically in longitudinal streaks or patches.... (Review)
Review
Dermatophytomas are characterized as a hyperkeratotic fungal mass in the subungual space, showing as dense white or yellow, typically in longitudinal streaks or patches. Masses can be visualized by traditional microscopy or histology. Newer technologies such as dermoscopy and optical coherence tomography also provide visual features for dermatophytoma diagnosis. The density of fungal mass, and lack of adherence to the nail structures, as well as possible biofilm development, may play a role in the reduction in drug penetration and subsequent lack of efficacy with traditional oral therapies such as terbinafine and itraconazole. A combination of drug treatment with mechanical or chemical debridement/avulsion has been recommended to increase efficacy. The topical antifungal solutions such as tavaborole, efinaconazole, and luliconazole may reach the dermatophytoma by both the transungual and subungual routes, due to low affinity for keratin and low surface tension. Current data indicates these topicals may provide efficacy for dermatophytoma treatment without debridement/avulsion. Similarly, fosravuconazole (F-RVCZ) has an improved pharmacological profile versus ravuconazole and may be an improved treatment option versus traditional oral therapies. The availability of improved treatments for dermatophytomas is crucial, as resistance to traditional therapies is on the increase.
PubMed: 35887497
DOI: 10.3390/jof8070742 -
Antimicrobial Agents and Chemotherapy Aug 2020The activities of 11 antifungals against 84 dematiaceous fungi were tested. For most tested fungal species, the MIC values of ravuconazole and isavuconazole were lower...
The activities of 11 antifungals against 84 dematiaceous fungi were tested. For most tested fungal species, the MIC values of ravuconazole and isavuconazole were lower than those obtained with itraconazole, voriconazole, and posaconazole. Ravuconazole and isavuconazole appear to be more efficient against most dematiaceous fungal infections than the other triazoles. However, some pigmented fungi, such as and , remain more susceptible to other triazoles or to echinocandins.
Topics: Antifungal Agents; Ascomycota; Fungi; Microbial Sensitivity Tests; Nitriles; Pyridines; Thiazoles; Triazoles; Voriconazole
PubMed: 32571811
DOI: 10.1128/AAC.00643-20 -
Medical Principles and Practice :... 2005This review addresses trends in outcome and risk factors for invasive fungal infections, current antifungal agents and new therapeutic strategies. Current prospects for... (Review)
Review
This review addresses trends in outcome and risk factors for invasive fungal infections, current antifungal agents and new therapeutic strategies. Current prospects for new therapies rest upon caspofungin, the first of a new class of antifungal molecules, the echinocandins, and new extended-spectrum azoles, voriconazole, posaconazole and ravuconazole. Approval by the Food and Drug Administration of the USA and the European Medicine Agency was given in 2001-2002 to voriconazole and caspofungin. Voriconazole clearly demonstrated a decrease in mortality in invasive aspergillosis and fusariosis fungal infections.
Topics: Amphotericin B; Antifungal Agents; Drug Resistance, Microbial; Humans; Mycoses; Pyrimidines; Triazoles; Voriconazole
PubMed: 15863983
DOI: 10.1159/000084627 -
Current Drug Metabolism Feb 2013Invasive fungal infections in infants admitted to the neonatal intensive care unit are common and often fatal. The mainstay of therapy against invasive fungal infections... (Review)
Review
Invasive fungal infections in infants admitted to the neonatal intensive care unit are common and often fatal. The mainstay of therapy against invasive fungal infections is antifungal agents. Over the last two decades, the development and approval of these drugs evolved tremendously, and the azole class emerged as important agents in the treatment and prevention of invasive fungal infections. Among the azoles, fluconazole has been used extensively due to its favorable pharmacokinetics, excellent activity against Candida spp, and safety profile. This drug has been well studied in children, but data for its use in infants are largely limited to Candida prophylaxis studies. Voriconazole, a second generation triazole, has excellent activity against Candida and Aspergillus spp. However, data on its use in neonates are extremely limited. Posaconazole and ravuconazole are the newest agents of the triazole family. The antimicrobial spectrum of posaconazole is similar to voriconazole, but with additional activity against zygomycetes. Experience with posaconazole in children is very limited, and there are no reports of its use in infants. Ravuconazole is not approved for use by the FDA, but studies in animals and humans show that it is often fungicidal and has favorable pharmacokinetics. In conclusion, the management of invasive fungal infections has progressed greatly over the last two decades with the azole antifungals playing a significant role. Related to this class, future research is needed in order to better assess dosing, safety, schedules and areas of use of these agents in infants admitted to the neonatal intensive care unit.
Topics: Antifungal Agents; Extracorporeal Membrane Oxygenation; Humans; Infant, Newborn; Mycoses; Triazoles
PubMed: 22935068
DOI: No ID Found -
Mycoses Dec 2022Eumycetoma is a neglected tropical disease. It is a chronic inflammatory subcutaneous infection characterised by painless swellings which produce grains. It is currently...
BACKGROUND
Eumycetoma is a neglected tropical disease. It is a chronic inflammatory subcutaneous infection characterised by painless swellings which produce grains. It is currently treated with a combination of itraconazole and surgery. In an ongoing clinical study, the efficacy of fosravuconazole, the prodrug of ravuconazole, is being investigated. For both itraconazole and ravuconazole, no clinical breakpoints or epidemiological cut-off values (ECV) to guide treatment are currently available.
OBJECTIVE
To determine tentative ECVs for itraconazole and ravuconazole in Madurella mycetomatis, the main causative agent of eumycetoma.
MATERIALS AND METHODS
Minimal inhibitory concentrations (MICs) for itraconazole and ravuconazole were determined in 131 genetically diverse clinical M. mycetomatis isolates with the modified CLSI M38 broth microdilution method. The MIC distributions were established and used to determine ECVs with the ECOFFinder software. CYP51A sequences were sequenced to determine whether mutations occurred in this azole target gene, and comparisons were made between the different CYP51A variants and the MIC distributions.
RESULTS
The MICs ranged from 0.008 to 1 mg/L for itraconazole and from 0.002 to 0.125 mg/L for ravuconazole. The M. mycetomatis ECV for itraconazole was 1 mg/L and for ravuconazole 0.064 mg/L. In the wild-type population, two CYP51A variants were found for M. mycetomatis, which differed in one amino acid at position 499 (S499G). The MIC distributions for itraconazole and ravuconazole were similar between the two variants. No mutations linked to decreased susceptibility were found.
CONCLUSION
The proposed M. mycetomatis ECV for itraconazole is 1 mg/L and for ravuconazole 0.064 mg/L.
Topics: Humans; Madurella; Itraconazole; Mycetoma; Triazoles; Antifungal Agents
PubMed: 36005544
DOI: 10.1111/myc.13509 -
Mycoses Jun 2022Eumycetoma is a subcutaneous mutilating disease that can be caused by many different fungi. Current treatment consists of prolonged itraconazole administration in...
INTRODUCTION
Eumycetoma is a subcutaneous mutilating disease that can be caused by many different fungi. Current treatment consists of prolonged itraconazole administration in combination with surgery. In many centres, due to their slow growth rate, the treatment for eumycetoma is often started before the causative agent is identified. This harbours the risk that the causative fungus is not susceptible to the given empirical therapy. In the open-source drug program MycetOS, ravuconazole and luliconazole were promising antifungal agents that were able to inhibit the growth of Madurella mycetomatis, the most common causative agent of mycetoma. However, it is currently not known whether these drugs inhibit the growth of other eumycetoma causative agents.
MATERIALS AND METHODS
Here, we determined the in vitro activity of luliconazole, lanoconazole and ravuconazole against commonly encountered eumycetoma causative agents. MICs were determined for lanoconazole, luliconazole and ravuconazole against 37 fungal isolates which included Madurella species, Falciformispora senegalensis, Medicopsis romeroi and Trematosphaeria grisea and compared to those of itraconazole.
RESULTS
Ravuconazole, luliconazole and lanoconazole showed high activity against all eumycetoma causative agents tested with median minimal inhibitory concentrations (MICs) ranging from 0.008-2 µg/ml, 0.001-0.064 µg/ml and 0.001-0.064 µg/ml, respectively. Even Ma. fahalii and Me. romeroi, which are not inhibited in growth by itraconazole at a concentration of 4 µg/ml, were inhibited by these azoles.
CONCLUSION
The commonly encountered eumycetoma causative agents are inhibited by lanoconazole, luliconazole and ravuconazole. These drugs are promising candidates for further evaluation as potential treatment for eumycetoma.
Topics: Antifungal Agents; Humans; Imidazoles; Itraconazole; Madurella; Mycetoma; Thiazoles; Triazoles
PubMed: 35398930
DOI: 10.1111/myc.13442 -
Journal of Experimental Pharmacology 2021Chagas disease is a neglected tropical disease caused by the protozoan . Currently, only nitroheterocyclic nifurtimox (NFX) and benznidazole (BNZ) are available for the... (Review)
Review
Chagas disease is a neglected tropical disease caused by the protozoan . Currently, only nitroheterocyclic nifurtimox (NFX) and benznidazole (BNZ) are available for the treatment of Chagas disease, with limitations such as variable efficacy, long treatment regimens and toxicity. Different strategies have been used to discover new active molecules for the treatment of Chagas disease. Target-based and phenotypic screening led to thousands of compounds with anti- activity, notably the nitroheterocyclic compounds, fexinidazole and its metabolites. In addition, drug repurposing, drug combinations, re-dosing regimens and the development of new formulations have been evaluated. The CYP51 antifungal azoles, as posaconazole, ravuconazole and its prodrug fosravuconazole presented promising results in experimental Chagas disease. Drug combinations of nitroheterocyclic and azoles were able to induce cure in murine infection. New treatment schemes using BNZ showed efficacy in the experimental chronic stage, including against dormant forms of . And finally, sesquiterpene lactone formulated in nanocarriers displayed outstanding efficacy against different strains of , susceptible or resistant to BNZ, the reference drug. These pre-clinical results are encouraging and provide interesting evidence to improve the treatment of patients with Chagas disease.
PubMed: 33833592
DOI: 10.2147/JEP.S267378 -
International Journal of Nanomedicine 2017Self-emulsifying drug delivery systems (SEDDSs) are lipid-based anhydrous formulations composed of an isotropic mixture of oil, surfactant, and cosurfactants usually...
Self-emulsifying drug delivery systems (SEDDSs) are lipid-based anhydrous formulations composed of an isotropic mixture of oil, surfactant, and cosurfactants usually presented in gelatin capsules. Ravuconazole (Biopharmaceutics Classification System [BCS] Class II) is a poorly water-soluble drug, and a SEDDS type IIIA was designed to deliver it in a predissolved state, improving dissolution in gastrointestinal fluids. After emulsification, the droplets had mean hydrodynamic diameters <250 nm, zeta potential values in the range of -45 mV to -57 mV, and showed no signs of ravuconazole precipitation. Asymmetric flow field-flow fractionation with dynamic and multiangle laser light scattering was used to characterize these formulations in terms of size distribution and homogeneity. The fractograms obtained at 37°C showed a polydisperse profile for all blank and ravuconazole-SEDDS formulations but no large aggregates. SEDDS increased ravuconazole in vitro dissolution extent and rate (20%) compared to free drug (3%) in 6 h. The in vivo toxicity of blank SEDDS comprising Labrasol surfactant in different concentrations and preliminary safety tests in repeated-dose oral administration (20 days) showed a dose-dependent Labrasol toxicity in healthy mice. Ravuconazole-SEDDS at low surfactant content (10%, v/v) in -infected mice was safe during the 20-day treatment. The anti- activity of free ravuconazole, ravuconazole-SEDDS and each excipient were evaluated in vitro at equivalent ravuconazole concentrations needed to inhibit 50% or 90% (IC and IC), respectively of the intracellular amastigote form of the parasite in a cardiomyocyte cell line. The results showed a clear improvement of the ravuconazole anti- activity when associated with SEDDS. Based on our results, the repurposing of ravuconazole in SEDDS dosage form is a strategy that deserves further in vivo investigation in preclinical studies for the treatment of human infections.
Topics: Administration, Oral; Animals; Chagas Disease; Drug Delivery Systems; Emulsions; Excipients; Female; Glycerides; Lipids; Male; Mice; Solubility; Surface-Active Agents; Thiazoles; Triazoles; Trypanosoma cruzi
PubMed: 28553114
DOI: 10.2147/IJN.S133708 -
PLoS Neglected Tropical Diseases Jun 2014The current treatment of eumycetoma utilizing ketoconazole is unsatisfactory because of high recurrence rates, which often leads to complications and unnecessary... (Comparative Study)
Comparative Study
The current treatment of eumycetoma utilizing ketoconazole is unsatisfactory because of high recurrence rates, which often leads to complications and unnecessary amputations, and its comparatively high cost in endemic areas. Hence, an effective and affordable drug is required to improve therapeutic outcome. E1224 is a potent orally available, broad-spectrum triazole currently being developed for the treatment of Chagas disease. E1224 is a prodrug that is rapidly converted to ravuconazole. Plasma levels of E1224 are low and transient, and its therapeutically active moiety, ravuconazole is therapeutically active. In the present study, the in vitro activity of ravuconazole against Madurella mycetomatis, the most common etiologic agent of eumycetoma, was evaluated and compared to that of ketoconazole and itraconazole. Ravuconazole showed excellent activity with MICs ranging between ≤ 0.002 and 0.031 µg/ml, which were significantly lower than the MICs reported for ketoconazole and itraconazole. On the basis of our findings, E1224 with its resultant active moiety, ravuconazole, could be an effective and affordable therapeutic option for the treatment of eumycetoma.
Topics: Antifungal Agents; Itraconazole; Ketoconazole; Madurella; Microbial Sensitivity Tests; Thiazoles; Triazoles
PubMed: 24945848
DOI: 10.1371/journal.pntd.0002942