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Blood Oct 2016The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological...
The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron), an antimicrobial approved by the US Food and Drug Administration, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells. These effects were also observed with atovaquone treatment of primary blasts isolated from patients with acute myelogenous leukemia or acute lymphocytic leukemia. Atovaquone is not a kinase inhibitor but instead rapidly and specifically downregulates cell-surface expression of glycoprotein 130, which is required for STAT3 activation in multiple contexts. The administration of oral atovaquone to mice inhibited tumor growth and prolonged survival in a murine model of multiple myeloma. Finally, in patients with acute myelogenous leukemia treated with hematopoietic stem cell transplantation, extended use of atovaquone for prophylaxis was associated with improved relapse-free survival. These findings establish atovaquone as a novel, clinically accessible STAT3 inhibitor with evidence of anticancer efficacy in both animal models and humans.
Topics: Animals; Antineoplastic Agents; Apoptosis; Atovaquone; Cell Line, Tumor; Cell Membrane; Cell Survival; Cytokine Receptor gp130; Disease Models, Animal; Down-Regulation; Drug Discovery; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myeloid, Acute; Mice; Phosphorylation; Phosphotyrosine; STAT3 Transcription Factor; Treatment Outcome
PubMed: 27531676
DOI: 10.1182/blood-2015-07-660506 -
Journal of Travel Medicine Jun 2016Alternative approaches to malaria chemoprophylaxis are discussed in light of the difficulties of executing clinical trials within limits of infection rates and ethics.
Alternative approaches to malaria chemoprophylaxis are discussed in light of the difficulties of executing clinical trials within limits of infection rates and ethics.
Topics: Antimalarials; Atovaquone; Chemoprevention; Drug Therapy, Combination; Humans; Malaria; Proguanil; Travel
PubMed: 27694470
DOI: 10.1093/jtm/taw065 -
Journal of Clinical Psychopharmacology
Topics: Atovaquone; Drug Combinations; Humans; Malaria; Mania; Proguanil
PubMed: 35489033
DOI: 10.1097/JCP.0000000000001541 -
The Journal of Veterinary Medical... Dec 2020A single-nucleotide polymorphism causing the replacement of methionine with isoleucine (M121I) in cytochrome b of Babesia gibsoni has been reported to reduce the...
A single-nucleotide polymorphism causing the replacement of methionine with isoleucine (M121I) in cytochrome b of Babesia gibsoni has been reported to reduce the susceptibility to atovaquone (ATV) in B. gibsoni infection. In our previous study, B. gibsoni with M121I was suggested to exist in nature. Thus, further examinations were performed. In total, 105 genomic DNA samples from B. gibsoni-infected dogs were collected from western (98 samples from 15 prefectures) and eastern areas (7 samples from 4 prefectures) in Japan. The M121I variant population was identified using allele-specific real-time PCR: it was then detected in nine samples (8.57%), which was higher than that in the previous study (4.11%). Although there are unclear points, such as the history of ATV usage, careful attention should be given to emerging ATV resistance.
Topics: Animals; Atovaquone; Babesia; Babesiosis; Dog Diseases; Dogs; Japan
PubMed: 32908117
DOI: 10.1292/jvms.20-0382 -
Communications Biology 2019Atovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment. While the cytochrome bc1-inhibitor atovaquone has potent activity, proguanil's action is...
Atovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment. While the cytochrome bc1-inhibitor atovaquone has potent activity, proguanil's action is attributed to its cyclization-metabolite, cycloguanil. Evidence suggests that proguanil has limited intrinsic activity, associated with mitochondrial-function. Here we demonstrate that proguanil, and cyclization-blocked analogue tBuPG, have potent, but slow-acting, in vitro anti-plasmodial activity. Activity is folate-metabolism and isoprenoid biosynthesis-independent. In yeast dihydroorotate dehydrogenase-expressing parasites, proguanil and tBuPG slow-action remains, while bc1-inhibitor activity switches from comparatively fast to slow-acting. Like proguanil, tBuPG has activity against liver-stage parasites. Both analogues act synergistically with bc1-inhibitors against blood-stages in vitro, however cycloguanil antagonizes activity. Together, these data suggest that proguanil is a potent slow-acting anti-plasmodial agent, that bc1 is essential to parasite survival independent of dihydroorotate dehydrogenase-activity, that Malarone® is a triple-drug combination that includes antagonistic partners and that a cyclization-blocked proguanil may be a superior combination partner for bc1-inhibitors in vivo.
Topics: Animals; Anopheles; Antimalarials; Atovaquone; Cyclization; Dihydroorotate Dehydrogenase; Dose-Response Relationship, Drug; Drug Combinations; Electron Transport Complex III; Enzyme Inhibitors; Erythrocytes; Folic Acid; Hep G2 Cells; Humans; Inhibitory Concentration 50; Liver; Oxidoreductases Acting on CH-CH Group Donors; Plasmodium berghei; Plasmodium falciparum; Proguanil; Sporozoites; Terpenes; Triazines
PubMed: 31069275
DOI: 10.1038/s42003-019-0397-3 -
Clinical Pharmacology and Therapeutics Apr 2022Atovaquone-proguanil (ATV-PG) plus amodiaquine (AQ) has been considered as a potential replacement for sulfadoxine-pyrimethamine plus AQ for seasonal malaria... (Randomized Controlled Trial)
Randomized Controlled Trial
Atovaquone-proguanil (ATV-PG) plus amodiaquine (AQ) has been considered as a potential replacement for sulfadoxine-pyrimethamine plus AQ for seasonal malaria chemoprevention in African children. This randomized, double-blind, placebo-controlled, parallel group study assessed the safety, tolerability, and pharmacokinetics (PKs) of ATV-PG plus AQ in healthy adult males and females of Black sub-Saharan African origin. Participants were randomized to four treatment groups: ATV-PG/AQ (n = 8), ATV-PG/placebo (n = 12), AQ/placebo (n = 12), and placebo/placebo (n = 12). Treatments were administered orally once daily for 3 days (days 1-3) at daily doses of ATV-PQ 1000/400 mg and AQ 612 mg. Co-administration of ATV-PG/AQ had no clinically relevant effect on PK parameters for ATV, PG, the PG metabolite cycloguanil, AQ, or the AQ metabolite N-desethyl-amodiaquine. Adverse events occurred in 8 of 8 (100%) of participants receiving ATV-PG/AQ, 11 of 12 (91.7%) receiving ATV-PG, 11 of 12 (91.7%) receiving AQ, and 3 of 12 (25%) receiving placebo. The safety and tolerability profiles of ATV-PG and AQ were consistent with previous reports. In the ATV-PG/AQ group, 2 of 8 participants experienced extrapyramidal adverse effects (EPAEs) on day 3, both psychiatric and physical, which appeared unrelated to drug plasma PKs or cytochrome P450 2C8 phenotype. Although rare cases are reported with AQ administration, the high incidence of EPAE was unexpected in this small study. Owing to the unanticipated increased frequency of EPAE observed, the combination of ATV-PQ plus AQ is not recommended for further evaluation in prophylaxis of malaria in African children.
Topics: Amodiaquine; Antimalarials; Atovaquone; Drug Combinations; Drug Therapy, Combination; Female; Humans; Malaria; Malaria, Falciparum; Male; Proguanil; Treatment Outcome
PubMed: 34453327
DOI: 10.1002/cpt.2404 -
Antimicrobial Agents and Chemotherapy Aug 2016Antimalarial combination therapies play a crucial role in preventing the emergence of drug-resistant Plasmodium parasites. Although artemisinin-based combination...
Antimalarial combination therapies play a crucial role in preventing the emergence of drug-resistant Plasmodium parasites. Although artemisinin-based combination therapies (ACTs) comprise the majority of these formulations, inhibitors of the mitochondrial cytochrome bc1 complex (cyt bc1) are among the few compounds that are effective for both acute antimalarial treatment and prophylaxis. There are two known sites for inhibition within cyt bc1: atovaquone (ATV) blocks the quinol oxidase (Qo) site of cyt bc1, while some members of the endochin-like quinolone (ELQ) family, including preclinical candidate ELQ-300, inhibit the quinone reductase (Qi) site and retain full potency against ATV-resistant Plasmodium falciparum strains with Qo site mutations. Here, we provide the first in vivo comparison of ATV, ELQ-300, and combination therapy consisting of ATV plus ELQ-300 (ATV:ELQ-300), using P. yoelii murine models of malaria. In our monotherapy assessments, we found that ATV functioned as a single-dose curative compound in suppressive tests whereas ELQ-300 demonstrated a unique cumulative dosing effect that successfully blocked recrudescence even in a high-parasitemia acute infection model. ATV:ELQ-300 therapy was highly synergistic, and the combination was curative with a single combined dose of 1 mg/kg of body weight. Compared to the ATV:proguanil (Malarone) formulation, ATV:ELQ-300 was more efficacious in multiday, acute infection models and was equally effective at blocking the emergence of ATV-resistant parasites. Ultimately, our data suggest that dual-site inhibition of cyt bc1 is a valuable strategy for antimalarial combination therapy and that Qi site inhibitors such as ELQ-300 represent valuable partner drugs for the clinically successful Qo site inhibitor ATV.
Topics: Animals; Antimalarials; Atovaquone; Drug Combinations; Drug Therapy, Combination; Electron Transport Complex III; Female; Malaria, Falciparum; Mice; Parasitemia; Plasmodium falciparum; Proguanil; Quinolones
PubMed: 27270285
DOI: 10.1128/AAC.00791-16 -
Annals of Internal Medicine Feb 1995
Topics: AIDS-Related Opportunistic Infections; Antifungal Agents; Atovaquone; Humans; Naphthoquinones; Pneumonia, Pneumocystis; Treatment Failure
PubMed: 7825772
DOI: 10.7326/0003-4819-122-4-199502150-00015 -
Travel Medicine and Infectious Disease 2023According to current guidelines, atovaquone-proguanil (AP) malaria chemoprophylaxis should be taken once daily starting one day before travel and continued for seven...
According to current guidelines, atovaquone-proguanil (AP) malaria chemoprophylaxis should be taken once daily starting one day before travel and continued for seven days post-exposure. However, drug-sparing regimens, including discontinuing AP after leaving malaria-endemic areas are cost-saving and probably more attractive to travelers, and may thus enhance adherence. AP has causal prophylactic effects, killing malaria parasites during the hepatic stage. If early hepatic stages were already targeted by AP, AP could possibly be discontinued upon return. Pharmacokinetic data and studies on drug-sparing AP regimens suggest this to be the case. Nevertheless, the evidence is weak and considered insufficient to modify current recommendations. Field trials require large numbers of travelers and inherently suffer from the lack of a control group. Safely-designed controlled human malaria infection trials could significantly reduce study participant numbers and safely establish an effective AP abbreviated regimen which we propose as the optimal trial design to test this concept.
Topics: Humans; Antimalarials; Proguanil; Atovaquone; Malaria; Drug Combinations; Travel; Malaria, Falciparum
PubMed: 36526126
DOI: 10.1016/j.tmaid.2022.102520 -
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