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The American Journal of Tropical... Feb 2007The fixed dose combination of atovaquone and proguanil hydrochloride, marketed under the trade name Malarone, is the most recently approved agent in North America for...
The fixed dose combination of atovaquone and proguanil hydrochloride, marketed under the trade name Malarone, is the most recently approved agent in North America for the prevention and treatment of chloroquine- and multi-drug resistant Plasmodium falciparum malaria. In both adult and pediatric populations, atovaquone-proguanil demonstrates consistently high protective efficacy against P. falciparum, and in treatment trials, cure rates exceed 93%. Only a handful of genetically confirmed treatment failures have been reported to date. Atovaquone-proguanil has an excellent safety profile during both prophylaxis and treatment courses, with severe adverse events rarely reported. This topical review will examine the evidence behind the current indications for use of atovaquone-proguanil, and will summarize the current body of literature surrounding safety and tolerability.
Topics: Adult; Animals; Antimalarials; Atovaquone; Child; Drug Combinations; Female; Humans; Malaria, Falciparum; Male; Plasmodium falciparum; Pregnancy; Proguanil; Randomized Controlled Trials as Topic; Travel
PubMed: 17297027
DOI: No ID Found -
Journal of Biochemical and Molecular... Sep 2018Targeting mitochondria respiration is an effective therapeutic strategy in renal cell carcinoma (RCC). Atovaquone is a FDA-approved antibiotic but is also known as a... (Comparative Study)
Comparative Study
Targeting mitochondria respiration is an effective therapeutic strategy in renal cell carcinoma (RCC). Atovaquone is a FDA-approved antibiotic but is also known as a mitochondrial inhibitor. We found that atovaquone inhibited proliferation and induced apoptosis of RCC cells. Mechanistically, atovaquone inhibits mitochondrial respiration in a concentration-dependent and time-dependent manner, via targeting mitochondrial respiratory complex III. Although increased glycolysis was observed in atovaquone-treated cells, atovaquone decreased ATP levels. As a consequence of mitochondrial respiration inhibition, reactive oxygen species levels were increased by atovaquone. The complete rescue of atovaquone's effects by an antioxidant suggests the important role of oxidative stress in the action of atovaquone in RCC. Importantly, atovaquone enhanced the in vitro and in vivo efficacy of 5-fluorouracil (5-FU) and interferon-α (IFN-α). Our preclinical findings suggest that atovaquone is a useful addition for RCC treatment. Our work also further demonstrates that RCC is more dependent on mitochondrial respiration than glycolysis.
Topics: Animals; Anthelmintics; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Apoptosis; Atovaquone; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Electron Transport Complex III; Enzyme Inhibitors; Humans; Interferon-alpha; Kidney Neoplasms; Male; Mice, SCID; Mitochondria; Oxidative Stress; Random Allocation; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 30004155
DOI: 10.1002/jbt.22195 -
European Journal of Drug Metabolism and... Oct 2016Atovaquone is a hydroxynaphthoquinone with selective action in the mitochondrial respiratory chain of malaria parasite. It is employed for both the treatment and...
BACKGROUND AND OBJECTIVES
Atovaquone is a hydroxynaphthoquinone with selective action in the mitochondrial respiratory chain of malaria parasite. It is employed for both the treatment and prevention of malaria, in a combination with proguanil. The aim of this study was to elucidate the in vitro metabolites from atovaquone and to evaluate their cytotoxic activities.
METHODS
The biotransformation of atovaquone was performed using Mucor rouxii NRRL 1894, Cunninghamella echinulata var. elegans ATCC 8688a and C. elegans ATCC 10028b, which have been reported as microbial models of mammalian drug metabolism. Experiments were also carried out with two probiotic strains from the human intestinal tract: Bifidobacterium sp. and Lactobacillus acidophilus. The phase I metabolite was isolated, its chemical structure was elucidated and its toxicity was evaluated using the neoplastic cell line SKBR-3 derived from human breast cancer and normal human fibroblast cell line GM07492-A. Cell cytotoxicity assays were also carried out with atovaquone.
RESULT
Only the fungi were able to convert atovaquone to metabolite trans-3-[4'-(4″-chlorophenyl)cyclohexyl)-1,2-dioxo-dihydro-1H-indene-3-carboxylic acid. The metabolite displayed 50 % inhibitory concentration (IC50) values of 110.20 ± 2.2 and 108.80 ± 1.5 µmol/L against breast cancer cell line SKBR-3 and fibroblasts cell line GM07492-A, respectively. The IC50 values of atovaquone were 282.30 ± 1.8 and 340.50 ± 1.4 µmol/L against breast cancer and normal fibroblasts cell lines, respectively.
CONCLUSIONS
The produced metabolite was more toxic than atovaquone and was not selective to normal or cancer cell lines. The present study is the first to report the production of atovaquone metabolite.
Topics: Animals; Antimalarials; Atovaquone; Breast Neoplasms; Caenorhabditis elegans; Cell Line; Cell Line, Tumor; Female; Fibroblasts; Fungi; Humans; Inhibitory Concentration 50; Malaria, Falciparum; Metabolic Detoxication, Phase I; Proguanil
PubMed: 26253156
DOI: 10.1007/s13318-015-0294-1 -
Cell Death & Disease Jan 2024Immune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells....
Immune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells. However, a substantial number of patients treated with ICB develop relapse or do not respond, which has been partly attributed to the immune-suppressive effect of tumour hypoxia. We have previously demonstrated that the mitochondrial complex III inhibitor atovaquone alleviates tumour hypoxia both in human xenografts and in cancer patients by decreasing oxygen consumption and consequently increasing oxygen availability in the tumour. Here, we show that atovaquone alleviates hypoxia and synergises with the ICB antibody anti-PD-L1, significantly improving the rates of tumour eradication in the syngeneic CT26 model of colorectal cancer. The synergistic effect between atovaquone and anti-PD-L1 relied on CD8+ T cells, resulted in the establishment of a tumour-specific memory immune response, and was not associated with any toxicity. We also tested atovaquone in combination with anti-PD-L1 in the LLC (lung) and MC38 (colorectal) cancer syngeneic models but, despite causing a considerable reduction in tumour hypoxia, atovaquone did not add any therapeutic benefit to ICB in these models. These results suggest that atovaquone has the potential to improve the outcomes of patients treated with ICB, but predictive biomarkers are required to identify individuals likely to benefit from this intervention.
Topics: Humans; Animals; Mice; Atovaquone; Electron Transport Complex III; Neoplasms; CD8-Positive T-Lymphocytes; Immunotherapy; B7-H1 Antigen; Tumor Microenvironment
PubMed: 38212297
DOI: 10.1038/s41419-023-06405-8 -
Parasitology International Jun 2015Atovaquone, a coenzyme Q analogue has been indicated to specifically target the cytochrome bc1 complex of the mitochondrial respiratory chain in the malarial parasite...
Atovaquone, a coenzyme Q analogue has been indicated to specifically target the cytochrome bc1 complex of the mitochondrial respiratory chain in the malarial parasite and other protozoan. Various mutations in the quinone binding site of the cytochrome b gene of Plasmodium spp. such as M133I, L144S, L271V, K272R, Y268C, Y268S, Y268N, and V284F are suggesting to associate with resistance to atovaquone. There is no direct evidence of relation between the mutations and resistance to atovaquone in Plasmodium parasite that has been available. Technical difficulties in isolating active assayable mitochondria in the malarial parasite hinder us to obtain direct biochemical evidence to support the relation between the mutations and drug resistance. The establishment of a mitochondrial isolation method for the malaria parasite has allowed us to test the degree of resistance of Plasmodium berghei isolates to atovaquone directly. We have tested the activity of dihydroorotate (DHO)-cytochrome c reductase in various P. berghei atovaquone resistant clones in the presence of a wide concentration range of atovaquone. Our results show the IC(50) of P. berghei atovaquone resistant clones is much higher (1.5 up to 40 nM) in comparison to the atovaquone sensitive clones (0.132-0.465 nM). The highest IC(50) was revealed in clones carrying Y268C and Y268N mutations (which play an important role in atovaquone resistance in Plasmodium falciparum), with an approximately 100-fold increase. The findings indicate the importance of the mutation in the quinone binding site of the cytochrome b gene and that provide a direct evidence for the atovaquone inhibitory mechanism in the cytochrome bc1 complex of the parasite.
Topics: Antimalarials; Atovaquone; Binding Sites; Computer Simulation; Cytochromes b; Drug Resistance; Electron Transport Complex III; Genes, Mitochondrial; Models, Molecular; Mutation; Oxidoreductases; Parasitic Sensitivity Tests; Plasmodium falciparum; Sequence Alignment
PubMed: 25264100
DOI: 10.1016/j.parint.2014.09.011 -
The Journal of Antimicrobial... Mar 2018Atovaquone/proguanil, registered as Malarone®, is a fixed-dose combination recommended for first-line treatment of uncomplicated Plasmodium falciparum malaria in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atovaquone/proguanil, registered as Malarone®, is a fixed-dose combination recommended for first-line treatment of uncomplicated Plasmodium falciparum malaria in non-endemic countries and its prevention in travellers. Mutations in the cytochrome bc1 complex are causally associated with atovaquone resistance.
METHODS
This systematic review assesses the clinical efficacy of atovaquone/proguanil treatment of uncomplicated malaria and examines the extent to which codon 268 mutation in cytochrome b influences treatment failure and recrudescence based on published information.
RESULTS
Data suggest that atovaquone/proguanil treatment efficacy is 89%-98% for P. falciparum malaria (from 27 studies including between 18 and 253 patients in each case) and 20%-26% for Plasmodium vivax malaria (from 1 study including 25 patients). The in vitro P. falciparum phenotype of atovaquone resistance is an IC50 value >28 nM. Case report analyses predict that recrudescence in a patient presenting with parasites carrying cytochrome b codon 268 mutation will occur on average at day 29 (95% CI: 22, 35), 19 (95% CI: 7, 30) days longer than if the mutation is absent.
CONCLUSIONS
Evidence suggests atovaquone/proguanil treatment for P. falciparum malaria is effective. Late treatment failure is likely to be associated with a codon 268 mutation in cytochrome b, though recent evidence from animal models suggests these mutations may not spread within the population. However, early treatment failure is likely to arise through alternative mechanisms, requiring further investigation.
Topics: Atovaquone; Drug Combinations; Drug Resistance, Multiple; Drug Therapy, Combination; Electron Transport Complex III; Humans; Malaria, Falciparum; Malaria, Vivax; Mutation; Plasmodium falciparum; Proguanil; Travel; Treatment Failure
PubMed: 29237012
DOI: 10.1093/jac/dkx431 -
Journal of Pharmaceutical and... Jan 2021Atovaquone (ATQ) is a poorly soluble drug. Therefore, formulating ATQ into its supersaturated state through solid dispersion for bioavailability enhancement can be of...
Atovaquone (ATQ) is a poorly soluble drug. Therefore, formulating ATQ into its supersaturated state through solid dispersion for bioavailability enhancement can be of great value. However, due to fast crystallising properties of ATQ, the quantification of ATQ in a supersaturated solid dispersion system can be complicated. Therefore, in pursuit of accurate quantification of such sample, a simple HPLC analytical method utilising a C column (250 × 4.6 mm ID, 5 μm) for the quantitation of ATQ has been developed and validated. Atovaquone elution using the proposed method demonstrated a retention time around 7.6 min with good linearity (R > 0.999). The system suitability is also detailed with the tailing factor at 1.365 ± 0.002. The addition of solubilising agent as sample treatment step aided in ensuring the accurate quantitation of the fast crystallising ATQ. The developed HPLC quantitation method has been successfully employed in the analysis of ATQ from solid dispersion samples in in vitro dissolution as well as ex vivo permeation studies for formulation development.
Topics: Atovaquone; Biological Availability; Chromatography, High Pressure Liquid; Solubility
PubMed: 33011581
DOI: 10.1016/j.jpba.2020.113631 -
BioDrugs : Clinical Immunotherapeutics,... 2003Each year at least 30 000 Western travellers acquire malaria and approximately 1-4% of those who acquire Plasmodium falciparum malaria will die as a result of infection.... (Review)
Review
Each year at least 30 000 Western travellers acquire malaria and approximately 1-4% of those who acquire Plasmodium falciparum malaria will die as a result of infection. Almost all cases and fatalities are preventable with the use of measures to reduce mosquito bites and appropriate chemoprophylaxis for those at high risk of infection. There are currently a limited number of licensed drugs available to prevent malaria in travellers. New effective and well tolerated agents are urgently needed because of increasing resistance to antimalarials such as chloroquine and proguanil, and real and perceived intolerance to standard drugs such as mefloquine. A newly licensed antimalarial (atovaquone plus proguanil; Malarone) compares favourably with other drug options, although some prescribers may be unfamiliar with the specific advantages and disadvantages of this antimalarial. This article reviews recent clinical experience and randomised controlled trial data in order to address frequently asked questions about this new combination drug.
Topics: Antimalarials; Atovaquone; Drug Administration Schedule; Drug Combinations; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil; Randomized Controlled Trials as Topic; Travel
PubMed: 12785875
DOI: 10.2165/00063030-200317001-00006 -
Nanoemulsion of atovaquone as a promising approach for treatment of acute and chronic toxoplasmosis.European Journal of Pharmaceutical... May 2018Treatment of toxoplasmosis is necessary in congenital form and immunocompromised patients. Atovaquone is a powerful suppressor of protozoan parasites with a...
Treatment of toxoplasmosis is necessary in congenital form and immunocompromised patients. Atovaquone is a powerful suppressor of protozoan parasites with a broad-spectrum activity, but an extremely low water solubility and bioavailability. In this study, nanoemulsion of this drug was prepared with grape seed oil using spontaneous emulsification method to increase bioavailability and efficacy of atovaquone for treatment of toxoplasmosis. In vitro activity of atovaquone nanoemulsion against T. gondii, RH and Tehran strains, was assessed in HeLa cell culture. For in vivo assessment, BALB/c mice were infected with RH and Tehran strains and then treated with nanoemulsion of atovaquone, compared to that treated with free atovaquone. Concentration of atovaquone nanoemulsion showed in vitro anti-parasitic effects in both strains of T. gondii. Furthermore, oral administration of atovaquone nanoemulsion increased oral bioavailability, tissue distribution and mice survival time and reduced parasitemia and number and size of the brain cysts. Decrease of cyst numbers was verified by down regulation of BAG1 using real-time polymerase chain reaction (real-time PCR) assay. Effective therapeutic activity of atovaquone at a reduced dose is the major achievement of this study.
Topics: Acute Disease; Animals; Anti-Infective Agents; Atovaquone; Chronic Disease; Emulsions; Female; Grape Seed Extract; HeLa Cells; Humans; Mice, Inbred BALB C; Nanostructures; Toxoplasma; Toxoplasmosis
PubMed: 29452213
DOI: 10.1016/j.ejps.2018.02.018 -
Travel Medicine and Infectious Disease 2017
Topics: Antimalarials; Atovaquone; Drug Combinations; Drug Therapy, Combination; Humans; Malaria, Falciparum; Pharmacies; Plasmodium falciparum; Proguanil
PubMed: 29169852
DOI: 10.1016/j.tmaid.2017.11.011