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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 Antimicrobial... May 2013Atovaquone is used as a fixed-dose combination with proguanil (Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for... (Review)
Review
Atovaquone is used as a fixed-dose combination with proguanil (Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travellers. Indeed, in the USA, between 2009 and 2011, Malarone prescriptions accounted for 70% of all antimalarial pre-travel prescriptions. In 2013 the patent for Malarone will expire, potentially resulting in a wave of low-cost generics. Furthermore, the malaria scientific community has a number of antimalarial quinolones with a related pharmacophore to atovaquone at various stages of pre-clinical development. With this in mind, it is timely here to review the current knowledge of atovaquone, with the purpose of aiding the decision making of clinicians and drug developers involved in the future use of atovaquone generics or atovaquone derivatives.
Topics: Antimalarials; Atovaquone; Chemoprevention; Drug Combinations; Humans; Malaria; Proguanil; United States
PubMed: 23292347
DOI: 10.1093/jac/dks504 -
Molecules (Basel, Switzerland) May 2021Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete.... (Review)
Review
Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.
Topics: Acyclovir; Atenolol; Atovaquone; Catalysis; Chemistry, Pharmaceutical; Decitabine; Dopamine; Enzymes; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Molecular Conformation; Nucleosides; Phenylephrine; Prodrugs; Protons; Quantum Theory; Software; Technology, Pharmaceutical; Temperature; Tranexamic Acid
PubMed: 34071328
DOI: 10.3390/molecules26113248 -
BMC Medicine Nov 2022Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical studies suggest that the anti-malaria drug proguanil and...
BACKGROUND
Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical studies suggest that the anti-malaria drug proguanil and atovaquone might play a role in preventing CRC, but population-based evidence is still lacking.
METHODS
By accessing a couple of nationwide Swedish registers, we performed a cohort study to explore whether using proguanil and atovaquone might associate with a lower risk of CRC by adopting a new-user study design. Adults who have 1 or more first-degree relatives (parents or siblings) diagnosed with CRC were identified and linked with the Prescribed Drug Register to evaluate their administration history of proguanil and atovaquone. Survival analysis of the time to CRC diagnosis with Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS
A total of 16,817 incident proguanil/atovaquone users were identified and matched with 168,170 comparisons, who did not use proguanil/atovaquone, on the ratio of 1:10. We found a significant negative association between proguanil/atovaquone use and risk of CRC (adjusted HR, 0.76; 95% CI, 0.62-0.93). Test for trend showed significant dose- and duration-response correlations (P < 0.001). The association was more pronounced in CRC diagnosed at an advanced stage than at an early stage (adjusted HR, 0.69 vs.0.81).
CONCLUSIONS
This national-wide population-based cohort study showed that the use of proguanil and atovaquone was associated with a reduced risk of CRC among individuals with a family history of CRC.
Topics: Adult; Humans; Proguanil; Atovaquone; Cohort Studies; Drug Combinations; Antimalarials; Colorectal Neoplasms; Malaria, Falciparum
PubMed: 36357883
DOI: 10.1186/s12916-022-02643-3 -
Journal of Travel Medicine May 1999
Topics: Atovaquone; Chemoprevention; Dose-Response Relationship, Drug; Drug Combinations; Humans; Malaria, Falciparum; Plasmodium falciparum; Proguanil; Travel
PubMed: 23573544
DOI: No ID Found -
Briefings in Functional Genomics Sep 2019Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all... (Review)
Review
Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all known antimalarials. The ability of malaria parasites to develop resistance is primarily due to the high numbers of parasites in the infected person's bloodstream during the asexual blood stage of infection in conjunction with the mutability of their genomes. Identifying the genetic mutations that mediate antimalarial resistance has deepened our understanding of how the parasites evade our treatments and reveals molecular markers that can be used to track the emergence of resistance in clinical samples. In this review, we examine known genetic mutations that lead to resistance to the major classes of antimalarial medications: the 4-aminoquinolines (chloroquine, amodiaquine and piperaquine), antifolate drugs, aryl amino-alcohols (quinine, lumefantrine and mefloquine), artemisinin compounds, antibiotics (clindamycin and doxycycline) and a napthoquinone (atovaquone). We discuss how the evolution of antimalarial resistance informs strategies to design the next generation of antimalarial therapies.
Topics: Aminoquinolines; Anti-Bacterial Agents; Antimalarials; Artemisinins; Atovaquone; Drug Resistance; Drug Resistance, Multiple; Folic Acid Antagonists; Humans; Malaria; Plasmodium falciparum; Plasmodium vivax; Quinine
PubMed: 31119263
DOI: 10.1093/bfgp/elz008 -
Cancers May 2022Oxidative phosphorylation is an active metabolic pathway in cancer. Atovaquone is an oral medication that inhibits oxidative phosphorylation and is FDA-approved for the...
Oxidative phosphorylation is an active metabolic pathway in cancer. Atovaquone is an oral medication that inhibits oxidative phosphorylation and is FDA-approved for the treatment of malaria. We investigated its potential anti-cancer properties by measuring cell proliferation in 2D culture. The clinical formulation of atovaquone, Mepron, was given to mice with ovarian cancers to monitor its effects on tumor and ascites. Patient-derived cancer stem-like cells and spheroids implanted in NSG mice were treated with atovaquone. Atovaquone inhibited the proliferation of cancer cells and ovarian cancer growth in vitro and in vivo. The effect of atovaquone on oxygen radicals was determined using flow and imaging cytometry. The oxygen consumption rate (OCR) in adherent cells was measured using a Seahorse XFe96 Extracellular Flux Analyzer. Oxygen consumption and ATP production were inhibited by atovaquone. Imaging cytometry indicated that the majority of the oxygen radical flux triggered by atovaquone occurred in the mitochondria. Atovaquone decreased the viability of patient-derived cancer stem-like cells and spheroids implanted in NSG mice. NMR metabolomics showed shifts in glycolysis, citric acid cycle, electron transport chain, phosphotransfer, and metabolism following atovaquone treatment. Our studies provide the mechanistic understanding and preclinical data to support the further investigation of atovaquone's potential as a gynecologic cancer therapeutic.
PubMed: 35565426
DOI: 10.3390/cancers14092297 -
BMC Cancer Nov 2023Colorectal cancer is a common malignant tumour. Invasive growth and distant metastasis are the main characteristics of its malignant biological behaviour, and they are...
BACKGROUND
Colorectal cancer is a common malignant tumour. Invasive growth and distant metastasis are the main characteristics of its malignant biological behaviour, and they are also the primary factors leading to death in colon cancer patients. Atovaquone is an antimalarial drug, and its anticancer effect has recently been demonstrated in several cancer models in vitro and in vivo, but it has not been examined in the treatment of colorectal cancer.
METHODS
To elucidate the effect of atovaquone on colorectal cancer. We used RNA transcriptome sequencing, RT‒PCR and Western blot experiments to examine the expression of NF-κB (p-P65), EMT-related proteins and related inflammatory factors (IL1B, IL6, CCL20, CCL2, CXCL8, CXCL6, IL6ST, FAS, IL10 and IL1A). The effect of atovaquone on colorectal cancer metastasis was validated using an animal model of lung metastases. We further used transcriptome sequencing, the GCBI bioinformatics database and the STRING database to predict relevant target proteins. Furthermore, pathological sections were collected from relevant cases for immunohistochemical verification.
RESULTS
This study showed that atovaquone could inhibit colorectal cancer metastasis and invasion in vivo and in vitro, inhibit the expression of E-cadherin protein, and promote the protein expression of N-cadherin, vimentin, ZEB1, Snail and Slug. Atovaquone could inhibit EMT by inhibiting NF-κB (p-P65) and related inflammatory factors. Further bioinformatics analysis and verification showed that PDGFRβ was one of the targets of atovaquone.
CONCLUSION
In summary, atovaquone can inhibit the expression of NF-κB (p-P65) and related inflammatory factors by inhibiting the protein expression of p-PDGFRβ, thereby inhibiting colorectal cancer metastasis. Atovaquone may be a promising drug for the treatment of colorectal cancer metastasis.
Topics: Animals; Humans; NF-kappa B; Atovaquone; Cell Line, Tumor; Signal Transduction; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Cell Movement
PubMed: 37932661
DOI: 10.1186/s12885-023-11585-9 -
Reproduction (Cambridge, England) Jun 2023Developing novel therapies to cure and manage endometriosis is a major unmet need that will benefit over 180 million women worldwide. Results from the current study...
IN BRIEF
Developing novel therapies to cure and manage endometriosis is a major unmet need that will benefit over 180 million women worldwide. Results from the current study suggest that inhibitors of oxidative phosphorylation may serve as novel agents for the treatment of endometriosis.
ABSTRACT
Current therapeutic strategies for endometriosis focus on symptom management and are not curative. Here, we provide evidence supporting the inhibition of oxidative phosphorylation (OXPHOS) as a novel treatment strategy for endometriosis. Additionally, we report an organotypic organ-on-a-chip luminal model for endometriosis. The OXPHOS inhibitors, curcumin, plumbagin, and the FDA-approved anti-malarial agent, atovaquone, were tested against the endometriosis cell line, 12Z, in conventional as well as the new organotypic model. The results suggest that all three compounds inhibit proliferation and cause cell death of the endometriotic cells by inhibiting OXPHOS and causing an increase in intracellular oxygen radicals. The oxidative stress mediated by curcumin, plumbagin, and atovaquone causes DNA double-strand breaks as indicated by the elevation of phospho-γH2Ax. Mitochondrial energetics shows a significant decrease in oxygen consumption in 12Z cells. These experiments also highlight differences in the mechanism of action as curcumin and plumbagin inhibit complex I whereas atovaquone blocks complexes I, II, and III. Real-time assessment of cells in the lumen model showed inhibition of migration in response to the test compounds. Additionally, using two-photon lifetime imaging, we demonstrate that the 12Z cells in the lumen show decreased redox ratio (NAD(P)H/FAD) and lower fluorescence lifetime of NAD(P)H in the treated cells confirming major metabolic changes in response to inhibition of mitochondrial electron transport. The robust chemotoxic responses observed with atovaquone suggest that this anti-malarial agent may be repurposed for the effective treatment of endometriosis.
Topics: Female; Humans; Curcumin; Atovaquone; Antimalarials; Oxidative Phosphorylation; Endometriosis; NAD; Antineoplastic Agents; Cell Proliferation
PubMed: 37068140
DOI: 10.1530/REP-22-0265 -
Journal of Travel Medicine May 1999Safe and effective antimalarial drugs are needed for treatment and prophylaxis of malaria. The combination of atovaquone and proguanil hydrochloride is a new... (Review)
Review
BACKGROUND
Safe and effective antimalarial drugs are needed for treatment and prophylaxis of malaria. The combination of atovaquone and proguanil hydrochloride is a new antimalarial drug combination that has recently become available in many countries.
METHODS
Data were reviewed from nonclinical studies evaluating the microbiology, secondary pharmacology, pharmacokinetics, and toxicology of atovaquone and proguanil hydrochloride.
RESULTS
Atovaquone is highly active against asexual erythrocytic stages of Plasmodium falciparum in vitro (IC50 0.7-6 nM) and in animal models. Proguanil per se has only weak antimalarial activity in vitro (IC50 2.4-19 microM), and its effectiveness depends on the active metabolite cycloguanil (IC50 0.5-2.5 nM). The combination of atovaquone and proguanil is synergistic in vitro. Both drugs also have activity against gametocytes and pre-erythrocytic (hepatic) stages of malaria parasites. Atovaquone is a ubiquinone antagonist that inhibits mitochondrial electron transport and collapses mitochondrial membrane potential. The proguanil metabolite cycloguanil is a dihydrofolate reductase inhibitor, but the mode of action of proguanil is unknown. In screening evaluations of secondary pharmacology, neither atovaquone nor proguanil had activity that adversely affected gastrointestinal, cardiovascular, or central or autonomic nervous system functions at clinically relevant concentrations. After oral administration, atovaquone exposure is extensive in rats but limited in dogs, while proguanil and cycloguanil exposure is extensive in dogs but limited in rats. In both species, toxicity was related to proguanil exposure, the principal manifestations being salivation, emesis, and loss of body weight. Neither atovaquone nor proguanil was teratogenic or mutagenic. An increased incidence of hepatic adenomas and adenocarcinomas was seen in mice, but not rats, after lifetime exposure to atovaquone, and appears to be related to species-specific differences in hepatic enzymatic activity. No additional toxicity was evident in animals treated with the combination of atovaquone and proguanil hydrochloride compared to those treated with either drug alone.
CONCLUSION
Nonclinical studies of atovaquone and proguanil hydrochloride supported the clinical development of this combination for treatment and prophylaxis of malaria.
Topics: Animals; Antimalarials; Atovaquone; Chemoprevention; Disease Outbreaks; Dogs; Drug Combinations; Humans; Malaria; Mice; Models, Animal; Plasmodium falciparum; Plasmodium malariae; Proguanil; Rats; Travel
PubMed: 23573546
DOI: No ID Found