ravuconazole and benzonidazole
ravuconazole has been researched along with benzonidazole* in 6 studies
*benzonidazole: used in treatment of Chagas' disease [MeSH]
*benzonidazole: used in treatment of Chagas' disease [MeSH]
Trials
2 trial(s) available for ravuconazole and benzonidazole
Article | Year |
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Usefulness of Serial Blood Sampling and PCR Replicates for Treatment Monitoring of Patients with Chronic Chagas Disease.
This work evaluated a serial blood sampling procedure to enhance the sensitivity of duplex real-time quantitative PCR (qPCR) for baseline detection and quantification of parasitic loads and posttreatment identification of failure in the context of clinical trials for treatment of chronic Chagas disease, namely, DNDi-CH-E1224-001 (ClinicalTrials.gov registration no. NCT01489228) and the MSF-DNDi PCR Sampling Optimization Study (NCT01678599). Patients from Cochabamba ( Topics: Adolescent; Adult; Chagas Disease; DNA, Protozoan; Humans; Middle Aged; Monitoring, Physiologic; Nitroimidazoles; Parasite Load; Placebos; Real-Time Polymerase Chain Reaction; Thiazoles; Treatment Outcome; Triazoles; Trypanocidal Agents; Trypanosoma cruzi; Young Adult | 2019 |
Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial.
Chagas disease is a major neglected vector-borne disease. In this study, we investigated the safety and efficacy of three oral E1224 (a water-soluble ravuconazole prodrug) regimens and benznidazole versus placebo in adult chronic indeterminate Chagas disease.. In this proof-of-concept, double-blind, randomised phase 2 clinical trial, we recruited adults (18-50 years) with confirmed diagnosis of Trypanosoma cruzi infection from two outpatient units in Bolivia. Patients were randomised with a computer-generated randomisation list, which was stratified by centre and used a block size of ten. Patients were randomly assigned (1:1:1:1:1) to five oral treatment groups: high-dose E1224 (duration 8 weeks, total dose 4000 mg), low-dose E1224 (8 weeks, 2000 mg), short-dose E1224 (4 weeks + 4 weeks placebo, 2400 mg), benznidazole (60 days, 5 mg/kg per day), or placebo (8 weeks, E1224-matched tablets). Double-blinding was limited to the E1224 and placebo arms, and assessors were masked to all treatment allocations. The primary efficacy endpoint was parasitological response to E1224 at the end of treatment, assessed by PCR. The secondary efficacy endpoints were parasitological response to benznidazole at end of treatment, assessed by PCR; sustainability of parasitological response until 12 months; parasite clearance and changes in parasite load; incidence of conversion to negative response in conventional and non-conventional (antigen trypomastigote chemiluminescent ELISA [AT CL-ELISA]) serological response; changes in levels of biomarkers; and complete response. The primary analysis population consisted of all randomised patients by their assigned treatment arms. This trial is registered with ClinicalTrials.gov, number NCT01489228.. Between July 19, 2011, and July 26, 2012, we screened 560 participants with confirmed Chagas disease, of whom 231 were enrolled and assigned to high-dose E1224 (n=45), low-dose E1224 (n=48), short-dose E1224 (n=46), benznidazole (n=45), or placebo (n=47). Parasite clearance was observed with E1224 during the treatment phase, but no sustained response was seen with low-dose and short-dose regimens, whereas 13 patients (29%, 95% CI 16·4-44·3) had sustained response with the high-dose regimen compared with four (9%, 2·4-20·4) in the placebo group (p<0·0001). Benznidazole had a rapid and sustained effect on parasite clearance, with 37 patients (82%, 67·9-92·0) with sustained response at 12-month follow-up. After 1 week of treatment, mean quantitative PCR repeated measurements showed a significant reduction in parasite load in all treatment arms versus placebo. Parasite levels in the low-dose and short-dose E1224 groups gradually returned to placebo levels. Both treatments were well tolerated. Reversible, dose-dependent liver enzyme increases were seen with E1224 and benznidazole. 187 (81%) participants developed treatment-emergent adverse events and six (3%) developed treatment-emergent serious adverse events. Treatment-emergent adverse events were headaches, nausea, pruritus, peripheral neuropathy, and hypersensitivity.. E1224 is the first new chemical entity developed for Chagas disease in decades. E1224 displayed a transient, suppressive effect on parasite clearance, whereas benznidazole showed early and sustained efficacy until 12 months of follow-up. Despite PCR limitations, our results support increased diagnosis and access to benznidazole standard regimen, and provide a development roadmap for novel benznidazole regimens in monotherapy and in combinations with E1224.. Drugs for Neglected Diseases initiative. Topics: Administration, Oral; Adolescent; Adult; Bolivia; Chagas Disease; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Male; Middle Aged; Nitroimidazoles; Parasite Load; Placebos; Polymerase Chain Reaction; Prospective Studies; Thiazoles; Treatment Outcome; Triazoles; Trypanocidal Agents; Trypanosoma cruzi; Young Adult | 2018 |
Other Studies
4 other study(ies) available for ravuconazole and benzonidazole
Article | Year |
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A functional assay using human whole blood and flow cytometry analysis to evaluate cytotoxicity and immunomodulatory effect of anti-Trypanosoma cruzi drugs.
The discovery and development of new drugs for the treatment of Chagas disease is urgent due to the high toxicity and low cure efficacy, mainly during the chronic phase of this disease. Other chemotherapeutic approaches for Chagas disease treatment are being researched and require screening assays suitable for evaluating the effectivity of new biologically active compounds. This study aims to evaluate a functional assay using the internalization of epimastigotes forms of Trypanosoma cruzi by human peripheral blood leukocytes from healthy volunteers and analyses by flow cytometry of cytotoxicity, anti-T. cruzi activity, and immunomodulatory effect of benznidazole, ravuconazole, and posaconazole. The culture supernatant was used to measure cytokines (IL-1-β, IL-6, INF-γ, TNF and IL-10) and chemokines (MCP-1/CCL2, CCL5/RANTES and CXCL8/IL-8). The data showed a reduction in the internalization of T. cruzi epimastigote forms treated with ravuconazole, demonstrating its potential anti-T. cruzi activity. In addition, an increased amount of IL-10 and TNF cytokines was observed in the supernatant of cultures upon the addition of the drug, mainly IL-10 in the presence of benznidazole, ravuconazole and posaconazole, and TNF in the presence of ravuconazole and posaconazole. Moreover, the results revealed a decrease in the MCP-1/CCL2 index in cultures in the presence of benznidazole, ravuconazole, and posaconazole. A decrease in the CCL5/RANTES and CXCL8/IL-8 index in cultures with BZ, when compared to the culture without drugs, was also observed. In conclusion, the innovative functional test proposed in this study may be a valuable tool as a confirmatory test for selecting promising compounds identified in prospecting programs for new drugs for Chagas disease treatment. Topics: Chagas Disease; Cytokines; Flow Cytometry; Humans; Interleukin-10; Interleukin-8; Nitroimidazoles; Trypanocidal Agents; Trypanosoma cruzi | 2023 |
Novel structural CYP51 mutation in Trypanosoma cruzi associated with multidrug resistance to CYP51 inhibitors and reduced infectivity.
Ergosterol biosynthesis inhibitors, such as posaconazole and ravuconazole, have been proposed as drug candidates for Chagas disease, a neglected infectious tropical disease caused by the protozoan parasite Trypanosoma cruzi. To understand better the mechanism of action and resistance to these inhibitors, a clone of the T. cruzi Y strain was cultured under intermittent and increasing concentrations of ravuconazole until phenotypic stability was achieved. The ravuconazole-selected clone exhibited loss in fitness in vitro when compared to the wild-type parental clone, as observed in reduced invasion capacity and slowed population growth in both mammalian and insect stages of the parasite. In drug activity assays, the resistant clone was above 300-fold more tolerant to ravuconazole than the sensitive parental clone, when the half-maximum effective concentration (EC Topics: 14-alpha Demethylase Inhibitors; Animals; Cell Line; Chagas Disease; Drug Resistance, Multiple; Genes, Protozoan; Mutation; Nitroimidazoles; Sterol 14-Demethylase; Thiazoles; Triazoles; Trypanocidal Agents; Trypanosoma cruzi | 2020 |
Outcome of E1224-Benznidazole Combination Treatment for Infection with a Multidrug-Resistant Trypanosoma cruzi Strain in Mice.
Combination therapy has been proposed as an alternative therapeutic approach for the treatment of Chagas disease. In this study, we evaluated the effect of treatment with benznidazole combined with E1224 (ravuconazole prodrug) in an experimental murine model of acute infection. The first set of experiments assessed the range of E1224 doses required to induce parasitological cure using Topics: Animals; Combined Modality Therapy; Disease Models, Animal; Drug Interactions; Female; Mice; Microbial Sensitivity Tests; Nitroimidazoles; Thiazoles; Triazoles; Trypanocidal Agents; Trypanosoma cruzi | 2018 |
In vitro and in vivo studies of the antiparasitic activity of sterol 14α-demethylase (CYP51) inhibitor VNI against drug-resistant strains of Trypanosoma cruzi.
Chagas disease affects more than 10 million people worldwide, and yet, as it has historically been known as a disease of the poor, it remains highly neglected. Two currently available drugs exhibit severe toxicity and low effectiveness, especially in the chronic phase, while new drug discovery has been halted for years as a result of a lack of interest from pharmaceutical companies. Although attempts to repurpose the antifungal drugs posaconazole and ravuconazole (inhibitors of fungal sterol 14α-demethylase [CYP51]) are finally in progress, development of cheaper and more efficient, preferably Trypanosoma cruzi-specific, chemotherapies would be highly advantageous. We have recently reported that the experimental T. cruzi CYP51 inhibitor VNI cures with 100% survival and 100% parasitological clearance both acute and chronic murine infections with the Tulahuen strain of T. cruzi. In this work, we further explored the potential of VNI by assaying nitro-derivative-resistant T. cruzi strains, Y and Colombiana, in highly stringent protocols of acute infection. The data show high antiparasitic efficacy of VNI and its derivative (VNI/VNF) against both forms of T. cruzi that are relevant for mammalian host infection (bloodstream and amastigotes), with the in vivo potency, at 25 mg/kg twice a day (b.i.d.), similar to that of benznidazole (100 mg/kg/day). Transmission electron microscopy and reverse mutation tests were performed to explore cellular ultrastructural and mutagenic aspects of VNI, respectively. No mutagenic potential could be seen by the Ames test at up to 3.5 μM, and the main ultrastructural damage induced by VNI in T. cruzi was related to Golgi apparatus and endoplasmic reticulum organization, with membrane blebs presenting an autophagic phenotype. Thus, these preliminary studies confirm VNI as a very promising trypanocidal drug candidate for Chagas disease therapy. Topics: 14-alpha Demethylase Inhibitors; Animals; Chagas Disease; Drug Resistance; Endoplasmic Reticulum; Golgi Apparatus; Imidazoles; Male; Mice; Microscopy, Electron, Transmission; Nitroimidazoles; Oxadiazoles; Protozoan Proteins; Sterol 14-Demethylase; Thiazoles; Triazoles; Trypanocidal Agents; Trypanosoma cruzi | 2013 |