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Cancer Communications (London, England) Mar 2024
Topics: Humans; Atovaquone; Tumor Microenvironment; Energy Metabolism; Mitochondria; Lung Neoplasms
PubMed: 37930151
DOI: 10.1002/cac2.12500 -
Investigative Ophthalmology & Visual... Mar 2018Aspergillus and Fusarium molds cause blinding corneal infections as a consequence of ocular trauma and in association with contact lens wear. As these fungi require zinc...
PURPOSE
Aspergillus and Fusarium molds cause blinding corneal infections as a consequence of ocular trauma and in association with contact lens wear. As these fungi require zinc for fungal growth, we examined the effect of atovaquone, a ubiquinone analog that disrupts zinc homeostasis, on fungal growth in vitro and in vivo.
METHODS
In vitro: Aspergillus and Fusarium germinating conidia were incubated overnight with atovaquone, and hyphal growth was measured by fluorimetry. In vivo: C57BL/6 mouse corneas were infected with Aspergillus or Fusarium conidia. Atovaquone was added topically and corneal opacification and fungal growth were quantified.
RESULTS
Atovaquone has antifungal activity against Aspergillus and Fusarium clinical isolates, with Fusarium species being more sensitive to atovaquone than Aspergillus species. Atovaquone also reduced labile intracellular zinc levels and increased the sensitivity of Aspergillus to metal shock. Atovaquone reduced vacuolar acidification, which regulates storage of intracellular free zinc, and also acted synergistically with voriconazole and itraconazole to kill hyphae. Furthermore, mitochondrial potential and ATP production were reduced in both Aspergillus and Fusarium following atovaquone treatment. Finally, topical application of atovaquone to the ocular surface significantly inhibited fungal growth and corneal opacification in murine models of fungal keratitis.
CONCLUSIONS
These studies demonstrate that atovaquone has pronounced in vitro and in vivo antifungal activity against filamentous fungi by disrupting both metal homeostasis and mitochondrial function, and therefore has potential as a novel antifungal agent.
Topics: Animals; Antifungal Agents; Aspergillus; Atovaquone; Disease Models, Animal; Epithelial Cells; Eye Infections, Fungal; Fusarium; Homeostasis; Hyphae; Keratitis; Mice; Mice, Inbred C57BL; Mitochondria; Zinc
PubMed: 29625485
DOI: 10.1167/iovs.17-22585 -
The Journal of Antimicrobial... Nov 2007A systematic review and meta-analysis of the effectiveness of atovaquone-proguanil (Malarone) as a chemoprophylactic agent against malaria. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
A systematic review and meta-analysis of the effectiveness of atovaquone-proguanil (Malarone) as a chemoprophylactic agent against malaria.
METHODS
The data sources searched for this study included Cochrane systematic reviews (on infectious diseases), MEDLINE and EMBASE, Web of Knowledge and Annals of Tropical Medicine. All unconfounded randomized controlled trials assessing the chemoprophylaxis against malaria with atovaquone-proguanil were included in the review. Data on study design, study sample, inclusion and exclusion criteria, allocation, blinding, primary and secondary study end points were all extracted by one reviewer and independently rechecked by the second reviewer.
RESULTS
In general, all 10 studies identified had excellent quality with total scores of >or=4 using the Jadad criteria. Ten controlled trials comprising 4,539 participants were included for this review. A meta-analysis of six of the ten studies found chemoprophylaxis with atovaquone-proguanil, with a prophylaxis efficacy of 95.8% (95% CI = 91.5-97.9), to be superior to placebo. It was also considered safe and better tolerated with fewer treatment-related adverse events that could lead to premature discontinuation of prophylaxis than in controls. Comparison with alternative chemoprophylaxis also showed atovaquone-proguanil to be better tolerated with fewer treatment-related self-reported adverse events (RR = 0.8234; 95% CI = 0.673164-1.01) or severe adverse events (RR = 0.6140; 95% CI = 0.420055-0.8975). Atovaquone-proguanil is well tolerated with no difference in non-compliance with placebo (RR = 0.8804; 95% CI = 0.6964-1.113; I(2) = 31.4%).
CONCLUSIONS
Evidence from this review shows that atovaquone-proguanil is highly efficacious as a prophylactic agent against malaria infection and is very well tolerated compared with other antimalarial agents.
Topics: Antimalarials; Atovaquone; Drug Combinations; Humans; Malaria; Proguanil
PubMed: 17848375
DOI: 10.1093/jac/dkm337 -
Acta Haematologica 2015Toxoplasmosis and infections by other opportunistic agents such as Pneumocystis jirovecii constitute life-threatening risks for patients after allogeneic hematopoietic...
Toxoplasmosis and infections by other opportunistic agents such as Pneumocystis jirovecii constitute life-threatening risks for patients after allogeneic hematopoietic stem cell transplantation. Trimethoprim/sulfamethoxazole (TMP-SMX) has been well established for post-transplant toxoplasmosis and pneumocystis prophylaxis, but treatment may be limited due to toxicity. We explored atovaquone as an alternative and compared it with TMP-SMX regarding toxicity and efficacy during the first 100 days after transplantation in 155 consecutive adult stem cell recipients. Eight patients with a prior history of TMP-SMX intolerance received atovaquone as first-line prophylaxis. TMP-SMX was used for 141 patients as first-line strategy, but 13 patients (9.2%) were later switched to atovaquone due to TMP-SMX toxicity or gastrointestinal symptoms. No active toxoplasmosis or active P. jirovecii infection developed under continued prophylaxis with either TMP-SMX or atovaquone. However, for reasons of TMP-SMX and/or atovaquone toxicity, 7 patients were unable to tolerate any efficacious toxoplasmosis prophylaxis and therefore obtained inhalative pentamidine as P. jirovecii prophylaxis but no toxoplasmosis prophylaxis. Importantly, 2 of these patients developed severe toxoplasmosis. In summary, atovaquone appears as a valid alternative for at least some post-transplant patients who cannot tolerate TMP-SMX. This should be further confirmed by multicenter trials.
Topics: Adolescent; Adult; Aged; Anti-Infective Agents; Atovaquone; Brain Diseases; Female; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Retrospective Studies; Toxoplasmosis; Transplantation, Homologous; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult
PubMed: 25968483
DOI: 10.1159/000380757 -
Antiviral Research Sep 2023The antimalarial drug atovaquone was recently reported to inhibit the in vitro replication of different arboviruses, including chikungunya virus (CHIKV) and Zika virus...
The antimalarial drug atovaquone was recently reported to inhibit the in vitro replication of different arboviruses, including chikungunya virus (CHIKV) and Zika virus (ZIKV). Furthermore, atovaquone was shown to block Plasmodium parasite transmission by Anopheles mosquitoes when the mosquitoes were exposed to low concentrations on treated surfaces (i.e. tarsal exposure). Therefore, we evaluated the anti-CHIKV and -ZIKV effects of atovaquone via tarsal exposure in Aedes aegypti mosquitoes. We first confirmed that atovaquone exerted a dose-dependent antiviral effect on CHIKV and ZIKV replication in mosquito-derived cells. The modest antiviral effect could be rescued by adding exogenous uridine. Next, we assessed the effect of tarsal exposure to atovaquone on the fitness of Ae. aegypti. Concentrations up to 100 μmol/m did not affect the fecundity and egg-hatching rate. No significant effect on mosquito survival was observed when mosquitoes were exposed to concentrations up to 25 μmol/m. To evaluate the antiviral effect of atovaquone against CHIKV, we exposed female mosquitoes to 100 μmol/m atovaquone for 1h, after which the mosquitoes were immediately infected with CHIKV or ZIKV via bloodmeal. Atovaquone did not significantly reduce ZIKV or CHIKV infection in Ae. aegypti, but successfully blocked the transmission of CHIKV in saliva. Tarsal exposure to antiviral drugs could therefore be a potential new strategy to reduce virus transmission by mosquitoes.
Topics: Animals; Female; Zika Virus; Chikungunya virus; Aedes; Zika Virus Infection; Atovaquone; Mosquito Vectors; Chikungunya Fever; Antiviral Agents
PubMed: 37532005
DOI: 10.1016/j.antiviral.2023.105694 -
Travel Medicine and Infectious Disease 2020
Topics: Antimalarials; Atovaquone; Child; Drug Combinations; Drug Resistance; Drug Therapy, Combination; Humans; Malaria, Falciparum; Plasmodium falciparum; Proguanil; Treatment Failure
PubMed: 32763494
DOI: 10.1016/j.tmaid.2020.101829 -
Clinical Cancer Research : An Official... May 2021Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial...
PURPOSE
Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC).
PATIENTS AND METHODS
Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed.
RESULTS
Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% [95% confidence interval (CI), -58.2 to -4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 ( = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported.
CONCLUSIONS
This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.
Topics: Atovaquone; Carcinoma, Non-Small-Cell Lung; Energy Metabolism; Epithelial-Mesenchymal Transition; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Lung Neoplasms; Male; Mitochondria; Molecular Imaging; Oxidative Phosphorylation; Positron Emission Tomography Computed Tomography; STAT3 Transcription Factor; Tumor Hypoxia
PubMed: 33597271
DOI: 10.1158/1078-0432.CCR-20-4128 -
The Journal of Infectious Diseases Jul 2021Although atovaquone is effective in treating and preventing Pneumocystis pneumonia (PCP), its use is limited by nonlinear absorption and adverse events. The current...
Although atovaquone is effective in treating and preventing Pneumocystis pneumonia (PCP), its use is limited by nonlinear absorption and adverse events. The current study was undertaken to examine the activity of encochleated atovaquone (eATQ), a novel lipid-crystal nanoparticle formulation, in a mouse model of PCP. eATQ 100-200 mg was superior to commercially available atovaquone at 14 days in decreasing total Pneumocystis nuclei and asci. eATQ plus anidulafungin reduced nuclei significantly better than commercial atovaquone plus anidulafungin. eATQ is a novel formulation of atovaquone that warrants further evaluation for treatment and prevention of PCP.
Topics: Anidulafungin; Animals; Antifungal Agents; Atovaquone; Disease Models, Animal; Mice; Pneumonia, Pneumocystis
PubMed: 33245345
DOI: 10.1093/infdis/jiaa731 -
Biology of Blood and Marrow... Sep 2018
Topics: Atovaquone; Hematopoietic Stem Cell Transplantation; Incidence
PubMed: 29909155
DOI: 10.1016/j.bbmt.2018.06.012 -
The Journal of Infectious Diseases Jan 2022Human babesiosis caused by Babesia microti can be fatal in immunocompromised patients, and the currently used drugs are often ineffective. A recent study found that...
Human babesiosis caused by Babesia microti can be fatal in immunocompromised patients, and the currently used drugs are often ineffective. A recent study found that clofazimine clears B. microti Munich strain in immunocompromised mice. In the present study, we investigated the efficacies of clofazimine and 2-drug combinations involving clofazimine, atovaquone, and azithromycin against B. microti Peabody mjr strain in immunocompromised mice. Treatment with clofazimine alone, clofazimine plus azithromycin, and atovaquone plus azithromycin was ineffective and failed to eliminate the parasites completely, while a 44-day treatment with clofazimine plus atovaquone was highly effective and resulted in a radical cure.
Topics: Animals; Anti-Bacterial Agents; Antiprotozoal Agents; Atovaquone; Azithromycin; Babesia microti; Babesiosis; Clofazimine; Drug Therapy, Combination; Humans; Immunocompromised Host; Mice
PubMed: 34664651
DOI: 10.1093/infdis/jiab537