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Clinical Infectious Diseases : An... May 2024Relapsing babesiosis often occurs in highly immunocompromised patients and has been attributed to the acquisition of resistance against drugs commonly used for treatment...
BACKGROUND
Relapsing babesiosis often occurs in highly immunocompromised patients and has been attributed to the acquisition of resistance against drugs commonly used for treatment such as atovaquone, azithromycin, and clindamycin. Tafenoquine, which is approved for malaria prophylaxis and presumptive antirelapse treatment of Plasmodium vivax malaria, has shown activity against Babesia microti in several animal models of acute infection and in a single human case of relapsing babesiosis. Here, we report 5 cases of relapsing babesiosis treated with tafenoquine, including the previous case, and begin to define the conditions for optimal use of tafenoquine in relapsing babesiosis.
METHODS
A definitive diagnosis of babesiosis was made by microscopic examination of Giemsa-stained thin blood smears or a real-time polymerase chain reaction (PCR) that targets the parasite 18S rRNA gene. Clearance of B. microti infection was ascertained by use of blood smear and real-time PCR.
RESULTS
Tafenoquine was initiated with a loading dose of 600 mg. A weekly maintenance dose consisted of 200 mg or 300 mg; the lower dose was associated with a delayed clearance of B. microti. In 2 cases, all antimicrobial agents but tafenoquine were discontinued prior to clearance of infection. In 2 other cases, clearance was achieved while tafenoquine was administered along with other antimicrobial agents. In 3 of these 4 cases, tafenoquine was used in combination with atovaquone-proguanil. Other agents included atovaquone, azithromycin, and/or clindamycin. In 1 case, tafenoquine was administered alone and failed to prevent relapse.
CONCLUSIONS
Tafenoquine can be a useful adjunct for the treatment of highly immunocompromised patients experiencing relapsing babesiosis caused by B. microti.
PubMed: 38814096
DOI: 10.1093/cid/ciae238 -
Scientific Reports Dec 2022Positron emission tomography (PET)/computed tomography (CT) using the radiotracer 18F-Fluoromisonidazole (FMISO) has been widely employed to image tumour hypoxia and is...
Positron emission tomography (PET)/computed tomography (CT) using the radiotracer 18F-Fluoromisonidazole (FMISO) has been widely employed to image tumour hypoxia and is of interest to help develop novel hypoxia modifiers and guide radiation treatment planning. Yet, the optimal post-injection (p.i.) timing of hypoxic imaging remains questionable. Therefore, we investigated the correlation between hypoxia-related quantitative values in FMISO-PET acquired at 2 and 4 h p.i. in patients with non-small cell lung cancer (NSCLC). Patients with resectable NSCLC participated in the ATOM clinical trial (NCT02628080) which investigated the hypoxia modifying effects of atovaquone. Two-hour and four-hour FMISO PET/CT images acquired at baseline and pre-surgery visits (n = 58) were compared. Cohort 1 (n = 14) received atovaquone treatment, while cohort 2 (n = 15) did not. Spearman's rank correlation coefficients (ρ) assessed the relationship between hypoxia-related metrics, including standardised uptake value (SUV), tumour-to-blood ratio (TBR), and tumour hypoxic volume (HV) defined by voxels with TBR ≥ 1.4. As the primary imaging-related trial endpoint used to evaluate the action of atovaquone on tumour hypoxia in patients with NSCLC was change in tumour HV from baseline, this was also assessed in patients (n = 20) with sufficient baseline 2- and 4-h scan HV to reliably measure change (predefined as ≥ 1.5 mL). Tumours were divided into four subregions or distance categories: edge, outer, inner, and centre, using MATLAB. In tumours overall, strong correlation (P < 0.001) was observed for SUV ρ = 0.87, SUV ρ = 0.91, TBR ρ = 0.83 and TBR ρ = 0.81 between 2- and 4-h scans. Tumour HV was moderately correlated (P < 0.001) with ρ = 0.69 between 2- and 4-h scans. Yet, in tumour subregions, the correlation of HV decreased from the centre ρ = 0.71 to the edge ρ = 0.45 (P < 0.001). SUV, TBR, and HV values were consistently higher on 4-h scans than on 2-h scans, indicating better tracer-to-background contrast. For instance, for TBR, the mean, median, and interquartile range were 1.9, 1.7, and 1.6-2.0 2-h p.i., and 2.6, 2.4, and 2.0-3.0 4-h p.i., respectively. Our results support that FMISO-PET scans should be performed at 4 h p.i. to evaluate tumour hypoxia in NSCLC.Trial registration: ClinicalTrials.gov, NCT02628080. Registered 11/12/2015, https://clinicaltrials.gov/ct2/show/NCT02628080 .
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Positron Emission Tomography Computed Tomography; Atovaquone; Radiopharmaceuticals; Lung Neoplasms; Misonidazole; Positron-Emission Tomography; Hypoxia; Cell Hypoxia
PubMed: 36526815
DOI: 10.1038/s41598-022-26199-7 -
Ticks and Tick-borne Diseases Jul 2023In the present study, the effect of a combination therapy consisting of diminazene aceturate (DA) and imidocarb dipropionate (ID) on the in vitro growth of several...
In the present study, the effect of a combination therapy consisting of diminazene aceturate (DA) and imidocarb dipropionate (ID) on the in vitro growth of several parasitic piroplasmids, and on Babesia microti in BALB/c mice was evaluated using a fluorescence-based SYBR Green I test. We evaluated the structural similarities between the regularly used antibabesial medications, DA and ID, and the recently found antibabesial drugs, pyronaridine tetraphosphate, atovaquone, and clofazimine, using atom pair fingerprints (APfp). The Chou-Talalay approach was used to determine the interactions between the two drugs. A Celltac MEK-6450 computerized hematology analyzer was used to detect hemolytic anemia every 96 hours in mice infected with B. microti and in those treated with either mono- or combination therapy. According to the APfp results, DA and ID have the most structural similarities (MSS). DA and ID had synergistic and additive interactions against the in vitro growth of Babesia bigemina and Babesia bovis, respectively. Low dosages of DA (6.25 mg kg) and ID (8.5 mg kg) in conjunction with each other inhibited B. microti growth by 16.5 %, 32 %, and 4.5 % more than 25 mg kg DA, 6.25 mg kg DA, and 8.5 mg kg ID monotherapies, respectively. In the blood, kidney, heart, and lung tissues of mice treated with DA/ID, the B. microti small subunit rRNA gene was not detected. The obtained findings suggest that DA/ID could be a promising combination therapy for treating bovine babesiosis. Also, such combination may overcome the potential problems of Babesia resistance and host toxicity induced by utilizing full doses of DA and ID.
Topics: Animals; Mice; Babesiosis; Theileria; Babesia; Imidocarb
PubMed: 37011497
DOI: 10.1016/j.ttbdis.2023.102145 -
European Journal of Pharmacology Sep 2021Chemoresistance has been associated with increased reliance on mitochondrial functions in many cancers, including lung cancer. Atovaquone is an anti-malaria drug and...
Chemoresistance has been associated with increased reliance on mitochondrial functions in many cancers, including lung cancer. Atovaquone is an anti-malaria drug and mitochondrial inhibitor. In this work, we attempted to explore whether atovaquone can be repurposed for lung cancer treatment to overcome chemoresistance. We showed that atovaquone inhibited proliferation, colony formation and survival in non-small cell lung cancer cell (NSCLC) cells. Of note, the effective dose of atovaquone was clinically achievable. Combination index value indicated that atovaquone and carboplatin were synergistic in inhibiting NSCLC. The potent efficacy of atovaquone and its synergism with chemotherapeutic drug were also demonstrated in NSCLC xenograft mice model. Mechanism studies showed that the synergism between atovaquone and carboplatin was due to atovaquone's ability in disrupting mitochondrial functions via specifically inhibiting complex III induced oxygen consumption. Subsequently, atovaquone activated AMP-activated protein kinase (AMPK) and inhibited mammalian target of rapamycin (mTOR) signaling. AMPK inhibition reversed the anti-NSCLC activity of atovaquone, suggesting that the action of atovaquone is also dependent on AMPK. Our work suggests that atovaquone is an attractive candidate for NSCLC treatment. Our findings emphasize that inhibition of mitochondrial function is a promising therapeutic strategy to enhance NSCLC chemosensitivity.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Mice; Mitochondria; TOR Serine-Threonine Kinases
PubMed: 34129882
DOI: 10.1016/j.ejphar.2021.174256 -
ACS Applied Materials & Interfaces May 2022The development of robust phototherapeutic strategies for eradicating tumors remains a significant challenge in the transfer of cancer phototherapy to clinical practice....
The development of robust phototherapeutic strategies for eradicating tumors remains a significant challenge in the transfer of cancer phototherapy to clinical practice. Here, a phototherapeutic nanococktail atovaquone/17-dimethylaminoethylamino-17-demethoxygeldanamycin/glyco-BODIPY (ADB) was developed to enhance photodynamic therapy (PDT) and photothermal therapy (PTT) via alleviation of hypoxia and thermal resistance that was constructed using supramolecular self-assembly of glyco-BODIPY (BODIPY-SS-LAC, BSL-1), hypoxia reliever atovaquone (ATO), and heat shock protein inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). Benefiting from a glyco-targeting and glutathione (GSH) responsive units BSL-1, ADB can be rapidly taken up by hepatoma cells, furthermore the loaded ATO and 17-DMAG can be released in original form into the cytoplasm. Using and results, it was confirmed that ADB enhanced the synergetic PDT and PTT upon irradiation using 685 nm near-infrared light (NIR) under a hypoxic tumor microenvironment where ATO can reduce O consumption and 17-DMAG can down-regulate HSP90. Moreover, ADB exhibited good biosafety, and tumor eradication . Hence, this as-developed phototherapeutic nanococktail overcomes the substantial obstacles encountered by phototherapy in tumor treatment and offers a promising approach for the eradication of tumors.
Topics: Atovaquone; Cell Line, Tumor; Humans; Hypoxia; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Phototherapy
PubMed: 35481368
DOI: 10.1021/acsami.2c03463 -
Frontiers in Pharmacology 2022Ulcerative colitis (UC) is a chronic relapsing disease featuring aberrant accumulation of neutrophils in colonic mucosa and the luminal space. Although significant...
Ulcerative colitis (UC) is a chronic relapsing disease featuring aberrant accumulation of neutrophils in colonic mucosa and the luminal space. Although significant advances in UC therapy have been made with the development of novel biologics and small molecules targeting immune responses, success of most current therapies is still limited, with significant safety concerns. Thus, there is a need to develop additional safe and effective therapies for the treatment of UC. Antimalarial drugs have been safely used for many years to resolve tissue inflammation and the associated pathologies. Atovaquone is a recent FDA-approved antimalarial drug that has shown anti-viral and tumor-suppressive properties however, its role in mucosal inflammation has not been evaluated. Using pre-clinical murine DSS-induced colitis model combined with complementary peritonitis and human neutrophil activation and chemotaxis assays we investigated functional and mechanistic impacts of atovaquone on disease resolution and neutrophil trafficking. We demonstrate that atovaquone promotes resolution of DSS-induced murine colitis by reducing neutrophil accumulation in the inflamed colonic mucosa. Mechanistically, we show that atovaquone suppressed induction of CD11b expression in neutrophils, reducing their polarization and migratory ability. Thus, our findings identify a new role of atovaquone in promoting resolution of mucosal inflammation, supporting the idea of potential repurposing of this FDA-approved drug as UC therapeutic.
PubMed: 36313299
DOI: 10.3389/fphar.2022.1011115 -
Cureus Feb 2022Human babesiosis is commonly caused by , an infectious protozoan with a preference for erythrocytes. We describe a case of babesiosis presenting with acute acalculous...
Human babesiosis is commonly caused by , an infectious protozoan with a preference for erythrocytes. We describe a case of babesiosis presenting with acute acalculous cholecystitis. A 74-year-old man with a history of diabetes mellitus presented with four days of fever, chills, dyspnea on exertion, and dark brown urine. A physical exam was notable for scleral icterus. Laboratory findings were significant for lactate dehydrogenase (LDH) of 518, total bilirubin of 7.4, and direct bilirubin of 6.2. Imaging, including abdominal ultrasound, CT abdomen and pelvis, magnetic resonance cholangiopancreatography (MRCP), and hepatobiliary iminodiacetic acid (HIDA) scans, demonstrated acute acalculous cholecystitis. On further history, the patient confirmed a recent hiking trip in Virginia. Further evaluation, including peripheral smear and polymerase chain reaction (PCR), was consistent with infection. Babesiosis is common in the Northeastern and Midwestern United States, and symptoms can range from asymptomatic infection to nonspecific malaise and fever to severe end-organ dysfunction. Diagnosis is via peripheral smear or PCR, which can be confirmed via serology. The combination of clindamycin and quinine or atovaquone and azithromycin are the cornerstones of pharmacotherapy. Acute acalculous cholecystitis is a very uncommon presentation of babesiosis. Babesia infection must be considered in the differential in a patient with nonspecific symptoms living in an endemic area.
PubMed: 35308700
DOI: 10.7759/cureus.22165 -
Journal of Nanobiotechnology Oct 2021Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can...
BACKGROUND
Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can alleviate tumor hypoxia by inhibiting mitochondrial complex III activity. The present study exploits atovaquone/albumin nanoparticles to improve bioavailability and tumor targeting of atovaquone, enhancing the efficacy of anti-PD-1 therapy by normalizing tumor hypoxia.
METHODS
We prepared atovaquone-loaded human serum albumin (HSA) nanoparticles stabilized by intramolecular disulfide bonds, termed HSA-ATO NPs. The average size and zeta potential of HSA-ATO NPs were measured by particle size analyzer. The morphology of HSA-ATO NPs was characterized by transmission electron microscope (TEM). The bioavailability and safety of HSA-ATO NPs were assessed by animal experiments. Flow cytometry and ELISA assays were used to evaluate tumor immune microenvironment.
RESULTS
Our data first verified that atovaquone effectively alleviated tumor hypoxia by inhibiting mitochondrial activity both in vitro and in vivo, and successfully encapsulated atovaquone in vesicle with albumin, forming HSA-ATO NPs of approximately 164 nm in diameter. We then demonstrated that the HSA-ATO NPs possessed excellent bioavailability, tumor targeting and a highly favorable biosafety profile. When combined with anti-PD-1 antibody, we observed that HSA-ATO NPs strongly enhanced the response of mice bearing tumor xenografts to immunotherapy. Mechanistically, HSA-ATO NPs promoted intratumoral CD8 T cell recruitment by alleviating tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy.
CONCLUSIONS
Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by alleviating hypoxic tumor microenvironment.
Topics: Animals; Atovaquone; Cell Line, Tumor; Cells, Cultured; Drug Carriers; Immunotherapy; Mice; Mice, Inbred C57BL; Mice, SCID; Nanoparticles; Programmed Cell Death 1 Receptor; Smegmamorpha; Tumor Hypoxia; Tumor Microenvironment
PubMed: 34600560
DOI: 10.1186/s12951-021-01034-9 -
ChemistryOpen May 2022The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin-based combination therapies makes an urgent need for new efficient drugs....
The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin-based combination therapies makes an urgent need for new efficient drugs. Aiming to kill artemisinin-resistant Plasmodium, a series of novel hybrid drugs named Atokels were synthesized and characterized. Atokels are based on an 8-amino- or 8-hydroxyquinoline entity covalently bound to a 1,4-naphthoquinone through a polyamine linker. These drugs have been designed to target the parasite mitochondrion by their naphthoquinone moiety reminiscent of the antimalarial drug atovaquone, and to trigger a damaging oxidative stress due to their ability to chelate metal ions in order to generate redox active complexes in situ. The most effective Atokel drug shown a promising antimalarial activity (IC =622 nm on an artemisinin-resistant P. falciparum strain) and no cytotoxicity at 50 μm indicating a specific antiplasmodial mode of action.
Topics: Antimalarials; Artemisinins; Atovaquone; Folic Acid Antagonists; Plasmodium; Plasmodium falciparum
PubMed: 35543215
DOI: 10.1002/open.202200064 -
ACS Infectious Diseases Apr 2021In malaria, chemical genetics is a powerful method for assigning function to uncharacterized genes. MMV085203 and GNF-Pf-3600 are two structurally related napthoquinone...
In malaria, chemical genetics is a powerful method for assigning function to uncharacterized genes. MMV085203 and GNF-Pf-3600 are two structurally related napthoquinone phenotypic screening hits that kill both blood- and sexual-stage parasites in the low nanomolar to low micromolar range. In order to understand their mechanism of action, parasites from two different genetic backgrounds were exposed to sublethal concentrations of MMV085203 and GNF-Pf-3600 until resistance emerged. Whole genome sequencing revealed all 17 resistant clones acquired nonsynonymous mutations in the gene encoding the orphan apicomplexan transporter PF3D7_0312500 () predicted to encode a member of the major facilitator superfamily (MFS). Disruption of and testing against a panel of antimalarial compounds showed decreased sensitivity to MMV085203 and GNF-Pf-3600 as well as other compounds that have a mitochondrial mechanism of action. In contrast, mutations in provided no protection against compounds that act in the food vacuole or the cytosol. A dihydroorotate dehydrogenase rescue assay using transgenic parasite lines, however, indicated a different mechanism of action for both MMV085203 and GNF-Pf-3600 than the direct inhibition of cytochrome bc1. Green fluorescent protein (GFP) tagging of PfMFR3 revealed that it localizes to the parasite mitochondrion. Our data are consistent with PfMFR3 playing roles in mitochondrial transport as well as drug resistance for clinically relevant antimalarials that target the mitochondria. Furthermore, given that is naturally polymorphic, naturally occurring mutations may lead to differential sensitivity to clinically relevant compounds such as atovaquone.
Topics: Antimalarials; Drug Resistance; Humans; Malaria; Mutation; Plasmodium falciparum
PubMed: 33715347
DOI: 10.1021/acsinfecdis.0c00676