Ravuconazole self-emulsifying delivery system: in vitro activity against amastigotes and in vivo toxicity.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 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
Antimicrobial Agents and Chemotherapy Jul 2020Mining existing agents that enhance the therapeutic potential of ergosterol biosynthesis inhibitors (EBI) is a promising approach to improve Chagas disease chemotherapy....
Mining existing agents that enhance the therapeutic potential of ergosterol biosynthesis inhibitors (EBI) is a promising approach to improve Chagas disease chemotherapy. In this study, we evaluated the effect of ravuconazole, an EBI, combined with amlodipine, a calcium channel blocker, upon experimental infection. assays confirmed the trypanocidal activity of both compounds in monotherapy and demonstrated an additive effect (sum of the fractional inhibitory concentration [ΣFIC] > 0.5) of the combined treatment without additional toxicity to host cells. experiments, using a murine model of the Y strain in a short-term protocol, demonstrated that amlodipine, although lacking trypanocidal activity, dramatically increased the antiparasitic activity of underdosing ravuconazole regimens. Additional analysis using long-term treatment (20 days) showed that parasitemia relapse until 60 days after treatment was significatively lower in mice treated with the combination (4 out of 14 mice) than ravuconazole monotherapy (10 out of 14 mice), even in the presence of immunosuppressant pressure. Furthermore, the combined therapy was well tolerated and protected the mice from mortality. The treatments also impacted on the cellular and humoral immune response of infected animals, inducing a reduction of serum cytokine levels in all ravuconazole-treated mice. Our findings demonstrate that amlodipine is efficacious in enhancing the antiparasitic activity of ravuconazole in an experimental model of infection and indicates a potential strategy to be explored in Chagas disease treatment.
Topics: Amlodipine; Animals; Chagas Disease; Mice; Nitroimidazoles; Parasitemia; Thiazoles; Triazoles; Trypanocidal Agents; Trypanosoma cruzi
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
Antifungal Susceptibility of Clinical Isolates and Artificially Produced Multi-azole-resistant Strains of Cryptococcus neoformans (formerly: Cryptococcus grubii) to...Medical Mycology Journal 2020Ravuconazole (RVCZ) is a newly available human azole drug in Japan since 2018 and is a broad-spectrum antifungal agent that exhibits excellent activity against Candida...
Antifungal Susceptibility of Clinical Isolates and Artificially Produced Multi-azole-resistant Strains of Cryptococcus neoformans (formerly: Cryptococcus grubii) to Ravuconazole.
Ravuconazole (RVCZ) is a newly available human azole drug in Japan since 2018 and is a broad-spectrum antifungal agent that exhibits excellent activity against Candida albicans and Cryptococcus neoformans (formerly: Cryptococcus grubii). The drug is also highly active against isolates that are resistant to fluconazole (FLCZ). In the present study, the in vitro susceptibility to ravuconazole (RVCZ) of Japanese clinical isolates and multi-azole-resistant strains of C. neoformans was investigated using the Clinical & Laboratory Standards Institute (CLSI) M27-A3 test. The minimum inhibitory concentrations for the 14 clinical isolates and the multi-azole-resistant strains were 0.003125-0.125 mg/L and 0.25-0.5 mg/L for RVCZ, respectively. RVCZ is as effective as ITCZ and VRCZ for treating clinical isolates from cats and humans. Moreover, RVCZ is highly effective against multi-azole-resistant strains that encode a protein with a G344S substitution in ERG11. Consequently, RVCZ has considerable potential for use as a therapeutic agent for multi-azole resistant cryptococcosis.
Topics: Antifungal Agents; Cryptococcus neoformans; Drug Resistance, Fungal; Thiazoles; Triazoles
In Vitro Ravuconazole Susceptibility of Anthropophilic Dermatophyte Strains Isolated from Japanese Patients.Japanese Journal of Infectious Diseases May 2020Ravuconazole (RVCZ) is a new human anti-fungal azole drug available in Japan since 2018 and is a broad-spectrum agent that exhibits excellent activity against...
Ravuconazole (RVCZ) is a new human anti-fungal azole drug available in Japan since 2018 and is a broad-spectrum agent that exhibits excellent activity against dermatophytes. In the present study, the in vitro RVCZ susceptibility of clinical isolates of anthropophilic dermatophytes, including Trichophyton interdigitale strains with either low susceptibility to itraconazole (ITCZ) or resistance to terbinafine (TEBR), was investigated using the Clinical & Laboratory Standards Institute M38-A2 test. The MICs of RCVZ for 20 clinical isolates of T. interdigitale were < 0.03125-0.125 mg/L; for 4 clinical isolates of T. rubrum, < 0.03125-0.0625 mg/L; and for 20 clinical isolates of T. tonsurans, < 0.03125 mg/L. Similarly, the MICs of RCVZ for the T. interdigitale strains with either low susceptibility to ITCZ or resistance to TEBR were also < 0.03125 mg/L. To our knowledge, this is first study to investigate the in vitro RVCZ susceptibility of T. interdigitale strains with either low susceptibility to ITCZ or resistance to TEBR. Our results indicated that RVCZ was the most effective drug against these strains.
Topics: Antifungal Agents; Arthrodermataceae; Dermatomycoses; Drug Resistance, Fungal; Humans; Itraconazole; Microbial Sensitivity Tests; Terbinafine; Thiazoles; Triazoles
Screening the pandemic response box identified benzimidazole carbamates, Olorofim and ravuconazole as promising drug candidates for the treatment of eumycetoma.PLoS Neglected Tropical Diseases Feb 2022Eumycetoma is a chronic subcutaneous neglected tropical disease that can be caused by more than 40 different fungal causative agents. The most common causative agents...
Eumycetoma is a chronic subcutaneous neglected tropical disease that can be caused by more than 40 different fungal causative agents. The most common causative agents produce black grains and belong to the fungal orders Sordariales and Pleosporales. The current antifungal agents used to treat eumycetoma are itraconazole or terbinafine, however, their cure rates are low. To find novel drugs for eumycetoma, we screened 400 diverse drug-like molecules from the Pandemic Response Box against common eumycetoma causative agents as part of the Open Source Mycetoma initiative (MycetOS). 26 compounds were able to inhibit the growth of Madurella mycetomatis, Madurella pseudomycetomatis and Madurella tropicana, 26 compounds inhibited Falciformispora senegalensis and seven inhibited growth of Medicopsis romeroi in vitro. Four compounds were able to inhibit the growth of all five species of fungi tested. They are the benzimidazole carbamates fenbendazole and carbendazim, the 8-aminoquinolone derivative tafenoquine and MMV1578570. Minimal inhibitory concentrations were then determined for the compounds active against M. mycetomatis. Compounds showing potent activity in vitro were further tested in vivo. Fenbendazole, MMV1782387, ravuconazole and olorofim were able to significantly prolong Galleria mellonella larvae survival and are promising candidates to explore in mycetoma treatment and to also serve as scaffolds for medicinal chemistry optimisation in the search for novel antifungals to treat eumycetoma.
Topics: Acetamides; Animals; Antifungal Agents; Ascomycota; Drug Discovery; Drug Evaluation, Preclinical; Fenbendazole; Madurella; Moths; Mycetoma; Neglected Diseases; Piperazines; Pyrimidines; Pyrroles; Thiazoles; Triazoles
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)
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
Clinical Drug-Drug Interaction Potential of BFE1224, Prodrug of Antifungal Ravuconazole, Using Two Types of Cocktails in Healthy Subjects.Clinical and Translational Science Sep 2018BFE1224, prodrug of ravuconazole, is a novel, once-daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical... (Clinical Trial)
BFE1224, prodrug of ravuconazole, is a novel, once-daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical drug-drug interaction (DDI) potential of BFE1224 with cytochrome P450 (CYP) and transporter was assessed by using two types of cocktails in healthy subjects in separate clinical studies. The CYP and transporter cocktails consisted of caffeine/tolbutamide/omeprazole/dextromethorphan/midazolam used in study 1 and digoxin/rosuvastatin used in study 2. In addition, repaglinide was separately administered to the same subjects in study 2. There were no major effects on the pharmacokinetics of CYP and transporter substrates, except for an approximate threefold increase in midazolam exposure after oral administration of BFE1224. The clinical DDIs of BFE1224 were mild for CYP3A and minor for other major CYPs (CYP1A2/2C8/2C9/2C19/2D6) as well as those of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3.
Topics: Administration, Oral; Adult; Antifungal Agents; Biological Assay; Cytochrome P-450 Enzyme System; Drug Interactions; Female; Healthy Volunteers; Humans; Male; Metabolome; Onychomycosis; Prodrugs; Thiazoles; Triazoles; Young Adult
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)
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
Effects of ravuconazole treatment on parasite load and immune response in dogs experimentally infected with Trypanosoma cruzi.Antimicrobial Agents and Chemotherapy Jul 2010In this work, we investigated the in vivo activity of ravuconazole against the Y and Berenice-78 Trypanosoma cruzi strains using acutely infected dogs as hosts....
In this work, we investigated the in vivo activity of ravuconazole against the Y and Berenice-78 Trypanosoma cruzi strains using acutely infected dogs as hosts. Ravuconazole was well tolerated, as no significant side effects were observed during the treatment using 6.0 mg/kg twice a day (12 mg/kg/day) for up to 90 days. In all treated animals, parasitemia was permanently suppressed by the first day of treatment, independently of the parasite strain. Cultures of blood obtained posttreatment were negative for 90% of the animals, confirming that the drug induced a marked reduction in the parasite load. The results of PCR tests for T. cruzi in blood performed 1 month posttreatment were consistently negative for three of five and two of five animals infected with the Y and Berenice-78 strains, respectively. All ravuconazole-treated dogs consistently had negative serological test results during and until 30 days after treatment, regardless of the therapeutic scheme used. However, after the end of treatment, an increase in specific antibody levels was observed in all treated animals, although the antibody levels were always significantly lower than those of the nontreated control dogs. Despite being unable to induce a parasitological cure, ravuconazole treatment led to significant reductions in the levels of gamma interferon expression and lesions in cardiac tissues in animals infected with the Y strain, while the level of interleukin-10 mRNA expression increased. We conclude that ravuconazole has potent suppressive but not curative activity in the canine model of acute Chagas' disease, probably due to its unfavorable pharmacokinetic properties (half-life, 8.8 h). The longer half-life of ravuconazole in humans (4 to 8 days) makes it a promising drug for assessment for use as chemotherapy in human Chagas' disease.
Topics: Animals; Chagas Disease; Dogs; Enzyme-Linked Immunosorbent Assay; Immunoglobulin G; Interferon-gamma; Interleukin-10; Myocardium; Polymerase Chain Reaction; Thiazoles; Triazoles; Trypanocidal Agents; Trypanosoma cruzi