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Annales de Biologie Clinique Oct 2021Babesiosis is a tick-borne infectious disease, caused by an intraerythrocytic parasite of the genus Babesia. It has clinical, biological and microbiological similarities...
Babesiosis is a tick-borne infectious disease, caused by an intraerythrocytic parasite of the genus Babesia. It has clinical, biological and microbiological similarities with Plasmodium related infections. In rare cases, babesiosis may be complicated by hemophagocytic lymphohistiocytosis, which occurs preferentially in the immunodeficient patient. We report here the case of a non-immunocompromised patient living in Manhattan, New York hospitalized for a complicated babesiosis of a hemophagocytic lymphohistiocytosis. After 7 days of hospitalization and treatment by azithromycin 500 mg/day and atovaquone 750 mg twice a day, the patient was discharged with an improvement in clinical symptoms and biological parameters.
Topics: Atovaquone; Azithromycin; Babesia; Babesiosis; Humans
PubMed: 34782311
DOI: 10.1684/abc.2021.1675 -
Journal of Travel Medicine Feb 2020Increasingly older adults are traveling to international destinations with malaria as a present risk. Surveillance systems indicate that older adults are more likely to... (Review)
Review
Increasingly older adults are traveling to international destinations with malaria as a present risk. Surveillance systems indicate that older adults are more likely to suffer severe complications from malaria. The role of health care providers in selecting an appropriate medication for chemoprophylaxis or treatment of malaria in adults becomes more difficult as older adults undergo physiologic changes that alter the pharmacokinetic and pharmacodynamic nature of medications potentially causing increased drug interactions, adverse events and altered drug action. A comprehensive literature search from 1970 to present, with a focus on the past 10 years, was conducted on drug interactions, pharmacokinetic and pharmacodynamic effects on antimalarials in adults. It was determined that due to pharmacodynamic and pharmacokinetic changes in older adults, especially renal and cardiovascular, special attention should be given to this population of travelers in order to minimize the likelihood of adverse events or altered drug efficacy. Antimalarial drug-disease interactions in older adults can occur more often due to QT prolongation, exacerbation of hypoglycemia, decreased renal elimination and decreased hepatic metabolism. Older antimalarials have well-documented drug-drug interactions. Tafenoquine, a new antimalarial, requires glucose-6-phosphate dehydrogenase screening like primaquine and monitoring of new potential drug interaction with MATE1 and OCT2 substrates. While drug-drug interactions in older travelers may occur more often as a result of polypharmacy, data did not indicate adverse reactions or decreased drug efficacy is greater compared with younger adults. Overall, with the exception of recently approved tafenoquine, much is known about antimalarial drug and disease interactions, but new drugs are always being approved, requiring travel health providers to understand the pharmacokinetics and pharmacodynamics of antimalarial drugs to predict the impact on safety and efficacy in travelers. This guide provides travel health providers with valuable insights on potential outcomes associated with drug interactions in adults and recommended monitoring or drug regimen modification.
Topics: Age Factors; Aging; Antimalarials; Drug Interactions; Humans; Malaria, Falciparum; Risk Factors; Travel
PubMed: 31776555
DOI: 10.1093/jtm/taz089 -
PloS One 2023Antimalarial drugs that can block the transmission of Plasmodium gametocytes to mosquito vectors would be highly beneficial for malaria elimination efforts. Identifying...
Assessment of the transmission blocking activity of antimalarial compounds by membrane feeding assays using natural Plasmodium falciparum gametocyte isolates from West-Africa.
Antimalarial drugs that can block the transmission of Plasmodium gametocytes to mosquito vectors would be highly beneficial for malaria elimination efforts. Identifying transmission-blocking drugs currently relies on evaluation of their activity against gametocyte-producing laboratory parasite strains and would benefit from a testing pipeline with genetically diverse field isolates. The aims of this study were to develop a pipeline to test drugs against P. falciparum gametocyte field isolates and to evaluate the transmission-blocking activity of a set of novel compounds. Two assays were designed so they could identify both the overall transmission-blocking activity of a number of marketed and experimental drugs by direct membrane feeding assays (DMFA), and then also discriminate between those that are active against the gametocytes (gametocyte killing or sterilizing) or those that block development in the mosquito (sporontocidal). These DMFA assays used venous blood samples from naturally infected Plasmodium falciparum gametocyte carriers and locally reared Anopheles gambiae s.s. mosquitoes. Overall transmission-blocking activity was assessed following a 24 hour incubation of compound with gametocyte infected blood (TB-DMFA). Sporontocidal activity was evaluated following addition of compound directly prior to feeding, without incubation (SPORO-DMFA); Gametocyte viability was retained during 24-hour incubation at 37°C when gametocyte infected red blood cells were reconstituted in RPMI/serum. Methylene-blue, MMV693183, DDD107498, atovaquone and P218 showed potent transmission-blocking activity in the TB-DMFA, and both atovaquone and the novel antifolate P218 were potent inhibitors of sporogonic development in the SPORO-DMA. This work establishes a pipeline for the integral use of field isolates to assess the transmission-blocking capacity of antimalarial drugs to block transmission that should be validated in future studies.
Topics: Animals; Humans; Plasmodium falciparum; Antimalarials; Atovaquone; Folic Acid Antagonists; Malaria, Falciparum; Africa, Western
PubMed: 37494413
DOI: 10.1371/journal.pone.0284751 -
CPT: Pharmacometrics & Systems... Jan 2023Chemoprophylactics are a vital tool in the fight against malaria. They can be used to protect populations at risk, such as children younger than the age of 5 in areas of...
Chemoprophylactics are a vital tool in the fight against malaria. They can be used to protect populations at risk, such as children younger than the age of 5 in areas of seasonal malaria transmission or pregnant women. Currently approved chemoprophylactics all present challenges. There are either concerns about unacceptable adverse effects such as neuropsychiatric sequalae (mefloquine), risks of hemolysis in patients with G6PD deficiency (8-aminoquinolines such as tafenoquine), or cost and daily dosing (atovaquone-proguanil). Therefore, there is a need to develop new chemoprophylactic agents to provide more affordable therapies with better compliance through improving properties such as pharmacokinetics to allow weekly, preferably monthly, dosing. Here we present a pharmacokinetic-pharmacodynamic (PKPD) model constructed using DSM265 (a dihydroorotate dehydrogenase inhibitor with activity against the liver schizonts of malaria, therefore, a prophylaxis candidate). The PKPD model mimics the parasite lifecycle by describing parasite dynamics and drug activity during the liver and blood stages. A major challenge is the estimation of model parameters, as only blood-stage parasites can be observed once they have reached a threshold. By combining qualitative and quantitative knowledge about the parasite from various sources, it has been shown that it is possible to infer information about liver-stage growth and its initial infection level. Furthermore, by integrating clinical data, the killing effect of the drug on liver- and blood-stage parasites can be included in the PKPD model, and a clinical outcome can be predicted. Despite multiple challenges, the presented model has the potential to help translation from preclinical to late development for new chemoprophylactic candidates.
Topics: Child; Humans; Female; Pregnancy; Antimalarials; Malaria; Glucosephosphate Dehydrogenase Deficiency; Enzyme Inhibitors; Liver
PubMed: 36412499
DOI: 10.1002/psp4.12875 -
Biochimica Et Biophysica Acta.... Apr 2023Staphylococcus aureus is an opportunistic pathogen and one of the most frequent causes for community acquired and nosocomial bacterial infections. Even so, its energy...
Staphylococcus aureus is an opportunistic pathogen and one of the most frequent causes for community acquired and nosocomial bacterial infections. Even so, its energy metabolism is still under explored and its respiratory enzymes have been vastly overlooked. In this work, we unveil the dihydroorotate:quinone oxidoreductase (DHOQO) from S. aureus, the first example of a DHOQO from a Gram-positive organism. This protein was shown to be a FMN containing menaquinone reducing enzyme, presenting a Michaelis-Menten behaviour towards the two substrates, which was inhibited by Brequinar, Leflunomide, Lapachol, HQNO, Atovaquone and TFFA with different degrees of effectiveness. Deletion of the DHOQO coding gene (Δdhoqo) led to lower bacterial growth rates, and effected in cell morphology and metabolism, most importantly in the pyrimidine biosynthesis, here systematized for S. aureus MW2 for the first time. This work unveils the existence of a functional DHOQO in the respiratory chain of the pathogenic bacterium S. aureus, enlarging the understanding of its energy metabolism.
Topics: Atovaquone; Electron Transport; Quinones; Staphylococcus aureus; Quinone Reductases
PubMed: 36481274
DOI: 10.1016/j.bbabio.2022.148948 -
RMD Open Mar 2021To investigate short-term prognosis and prognostic factors for connective tissue disease-associated pneumocystis pneumonia (CTD-PCP) using the Japanese nationwide...
OBJECTIVES
To investigate short-term prognosis and prognostic factors for connective tissue disease-associated pneumocystis pneumonia (CTD-PCP) using the Japanese nationwide diagnosis procedure combination (DPC) inpatient database.
METHODS
The present retrospective cohort study from April 2014 to March 2016 included data of patients with CTD-PCP extracted from the DPC database using the 10 revision of International Classification of Diseases and Injuries codes.
RESULTS
In 15 901 766 cases registered from 1329 hospitals, 333 of 67 890 patients who were admitted with PCP were diagnosed with CTD-PCP and included in the study. The median age was 71.0 years, and 214 (64.3%), 80 (24.0%), and 29 (8.7%) patients received sulfamethoxazole/trimethoprim (ST) monotherapy and pentamidine-containing and atovaquone-containing therapy, respectively. There were 114 (34.2%) in-hospital deaths, and the 30-day and 60-day in-hospital survival rates after PCP treatment initiation were 66.0% and 53.7%, respectively. Older age (HR 1.06, 95% CI 1.03 to 1.08) and concomitant interstitial lung disease (ILD) (HR 1.65, 95% CI 1.12 to 2.42) were poor prognostic factors. Patients who completed PCP treatment with ST monotherapy had a significantly higher survival rate than those treated with those not treated with ST monotherapy (p=0.015; log-rank test). Pentamidine versus atovaquone as second-line therapy was significantly higher with atovaquone (p=0.012; log-rank test).
CONCLUSION
Older age and concomitant ILD were poor prognostic factors for CTD-PCP. ST was a reasonable first-line therapy in patients with CTD-PCP, and patients with inadequate response to ST treated with atovaquone tended to have a better prognosis than those treated with pentamidine.
Topics: Aged; Connective Tissue Diseases; Humans; Pneumonia, Pneumocystis; Prognosis; Retrospective Studies; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 33688083
DOI: 10.1136/rmdopen-2020-001508 -
PloS One 2022Despite ongoing efforts to control malaria infection, progress in lowering the number of deaths and infections appears to have stalled. The continued high incidence of...
Despite ongoing efforts to control malaria infection, progress in lowering the number of deaths and infections appears to have stalled. The continued high incidence of malaria infection and mortality is in part due to emergence of parasites resistant to frontline antimalarials. This highlights the need for continued identification of novel protein drug targets. Mitochondrial functions in Plasmodium falciparum, the deadliest species of human malaria parasite, are targets of validated antimalarials including atovaquone and proguanil (Malarone). Thus, there has been great interest in identifying other essential mitochondrial proteins as candidates for novel drug targets. Garnering an increased understanding of the proteomic landscape inside the P. falciparum mitochondrion will also allow us to learn about the basic biology housed within this unique organelle. We employed a proximity biotinylation technique and mass spectrometry to identify novel P. falciparum proteins putatively targeted to the mitochondrion. We fused the leader sequence of a mitochondrially targeted chaperone, Hsp60, to the promiscuous biotin ligase TurboID. Through these experiments, we generated a list of 122 "putative mitochondrial" proteins. To verify whether these proteins were indeed mitochondrial, we chose five candidate proteins of interest for localization studies using ectopic expression and tagging of each full-length protein. This allowed us to localize four candidate proteins of unknown function to the mitochondrion, three of which have previously been assessed to be essential. We suggest that phenotypic characterization of these and other proteins from this list of 122 could be fruitful in understanding the basic mitochondrial biology of these parasites and aid antimalarial drug discovery efforts.
Topics: Antimalarials; Atovaquone; Biotinylation; Drug Combinations; Humans; Malaria; Malaria, Falciparum; Plasmodium falciparum; Proguanil; Proteomics
PubMed: 35984838
DOI: 10.1371/journal.pone.0273357 -
Biomaterials Advances Dec 2022Nanozymes can regulate metabolism to achieve precise anti-tumor therapy. However, the application of nanozymes with single catalytic properties is limited by complex...
Nanozymes can regulate metabolism to achieve precise anti-tumor therapy. However, the application of nanozymes with single catalytic properties is limited by complex tumor microenvironment (TME). Herein, we report a rarely discovered nanozyme ruthenium (Ru), which has double catalytic activity of glucose-oxidase-like (GOx-like) activity and peroxidase-like (POD-like) activity. Importantly, the GOx-like activity of Ru was proposed for the first time, which can catalyze glucose and O to product HO. And then, Ru nanozyme can connect the tandem catalysis to enhance various tumor therapy. Firstly, the atovaquone (ATO) and Ru NPs were covered with a hybrid membrane of tumor cells and liposomes to obtain Ru@ATO-Lip/M with homologous targeting. Due to the enhanced permeability and retention (EPR) effect and the tumor targeting, the Ru@ATO-Lip/M NPs could be efficiently delivered to tumor and taken up by tumor cells. Subsequently, the acidic environment of tumor activated Ru to catalyze HO producing OH (Fenton-like reaction). Meanwhile, newly discovered ability of Ru catalyzed glucose and O to produce gluconic acid and HO, which provided sufficient substrates (HO) for continuously generating more OH. Therefore, Ru nanozyme aggravated the starvation and chemodynamic therapy (CDT). Further, ATO improved the hypoxia of the tumor microenvironment, achieving steadily synergistic anti-tumor effect. This study verified the glucose oxidase-like properties of Ru NPs for the first time, and the strategy enhanced the synergistic anti-tumor effects by CDT and starvation therapy, which provided a basis for further exploration of Ru nanozyme activity and application on antitumor.
Topics: Humans; Hydrogen Peroxide; Tumor Microenvironment; Glucose Oxidase; Catalysis; Neoplasms; Receptors, Chimeric Antigen; Ruthenium; Glucose; Adenosine Triphosphate
PubMed: 36347175
DOI: 10.1016/j.bioadv.2022.213181 -
British Journal of Haematology Apr 2020
Topics: Allografts; Atovaquone; Azithromycin; Babesia microti; Babesiosis; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged
PubMed: 32128759
DOI: 10.1111/bjh.16403 -
Ticks and Tick-borne Diseases Feb 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 h 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.
PubMed: 36812788
DOI: 10.1016/j.ttbdis.2023.102141