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Therapeutic Advances in Infectious... 2021Malaria, a parasitic disease caused by protozoa belonging to the genus , continues to represent a formidable public health challenge. Despite being a preventable... (Review)
Review
Malaria, a parasitic disease caused by protozoa belonging to the genus , continues to represent a formidable public health challenge. Despite being a preventable disease, cases reported among travelers have continued to increase in recent decades. Protection of travelers against malaria, a potentially life-threatening disease, is of paramount importance, and it is therefore necessary for healthcare professionals to be up to date with the most recent recommendations. The present review provides an update of the existent measures for malaria prevention among travelers.
PubMed: 34484736
DOI: 10.1177/20499361211040690 -
International Journal of Molecular... May 2021A major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through...
A major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through ribosomal protein S19 (RPS19), which facilitates myeloid-derived suppressor cells (MDSCs) recruitment in tumors, which generate cytokines TGF-β and IL-10 and induce regulatory T cells (Tregs), all of which are immunosuppressive and enhance tumor progression. Hence, enhancing the immune system in breast tumors could be a strategy for anticancer therapeutics. The present study evaluated the immune response of atovaquone, an antiprotozoal drug, in three independent breast-tumor models. Our results demonstrated that oral administration of atovaquone reduced HCC1806, CI66 and 4T1 paclitaxel-resistant (4T1-PR) breast-tumor growth by 45%, 70% and 42%, respectively. MDSCs, TGF-β, IL-10 and Tregs of blood and tumors were analyzed from all of these in vivo models. Our results demonstrated that atovaquone treatment in mice bearing HCC1806 tumors reduced MDSCs from tumor and blood by 70% and 30%, respectively. We also observed a 25% reduction in tumor MDSCs in atovaquone-treated mice bearing CI66 and 4T1-PR tumors. In addition, a decrease in TGF-β and IL-10 in tumor lysates was observed in atovaquone-treated mice with a reduction in tumor Tregs. Moreover, a significant reduction in the expression of RPS19 was found in tumors treated with atovaquone.
Topics: Animals; Anti-Infective Agents; Antigen Presentation; Apoptosis; Atovaquone; Cell Proliferation; Cytokines; Female; Humans; Immunosuppression Therapy; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Myeloid-Derived Suppressor Cells; T-Lymphocytes, Regulatory; Triple Negative Breast Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 34068008
DOI: 10.3390/ijms22105150 -
Expert Opinion on Drug Discovery Sep 2022is a prolific apicomplexan parasite that infects human and nonhuman animals worldwide and can cause severe brain and eye disease. Safer, more effective therapies for...
INTRODUCTION
is a prolific apicomplexan parasite that infects human and nonhuman animals worldwide and can cause severe brain and eye disease. Safer, more effective therapies for toxoplasmosis are needed. Cytochrome inhibitors are remarkably effective against toxoplasmosis and other apicomplexan-caused diseases.
AREAS COVERED
This work reviews cytochrome inhibitors. Emphasis is placed on the structure-activity relationships of these inhibitors with regard to efficacy, pharmacokinetics, selectivity of cytochrome over host, safety, and potential therapeutic strategies.
EXPERT OPINION
Cytochrome inhibitors are highly promising compounds for toxoplasmosis that have been effective in clinical and preclinical studies. Clinical experience with atovaquone previously validated cytochrome as a tractable drug target and, over the past decade, optimization of cytochrome inhibitors has resulted in improved bioavailability, metabolic stability, potency, blood-brain barrier penetration, and selectivity for the cytochrome over the mammalian . Recent studies have demonstrated preclinical safety, identified novel therapeutic strategies for toxoplasmosis using synergistic combinations or long-acting administration and provided insight into their role in chronic infection. This research has identified drug candidates that are more effective than clinically used drugs in preclinical measures of efficacy.
Topics: Animals; Antiprotozoal Agents; Atovaquone; Cytochromes; Humans; Structure-Activity Relationship; Toxoplasma; Toxoplasmosis
PubMed: 35772172
DOI: 10.1080/17460441.2022.2096588 -
Clinical Pharmacokinetics Apr 2023CYP2C19-mediated drug interactions of acid-reducing agents are clinically important given the high possibility of concomitant administration with CYP2C19 substrates.... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
CYP2C19-mediated drug interactions of acid-reducing agents are clinically important given the high possibility of concomitant administration with CYP2C19 substrates. This study aimed to evaluate the effect of tegoprazan on the pharmacokinetics (PK) of a CYP2C19 substrate, proguanil, compared with vonoprazan or esomeprazole.
METHODS
A two-part, randomized, open-label, two-sequence, three-period crossover study was conducted in 16 healthy CYP2C19 extensive metabolizers (eight subjects per part). In each period, a single oral dose of atovaquone/proguanil 250/100 mg was administered alone or co-administered with tegoprazan 50 mg, esomeprazole 40 mg (Part 1 only) or vonoprazan 20 mg (Part 2 only). The plasma and urine concentrations of proguanil and its metabolite, cycloguanil, were measured up to 48 h post-dose. PK parameters were calculated using a non-compartmental method and compared between administered alone and co-administered with tegoprazan, vonoprazan or esomeprazole.
RESULTS
Co-administration of tegoprazan did not significantly affect the systemic exposure of proguanil and cycloguanil. In contrast, co-administration of vonoprazan or esomeprazole increased proguanil systemic exposure and decreased cycloguanil systemic exposure, and the magnitude of the corresponding change was greater with esomeprazole co-administration than vonoprazan co-administration.
CONCLUSION
Tegoprazan, unlike vonoprazan and esomeprazole, exhibited negligible CYP2C19-mediated PK interaction. It suggests that as an alternative to other acid-reducing agents, tegoprazan can be used concomitantly with CYP2C19 substrates in clinical settings.
TRIAL REGISTRATION
Clinicaltrials.gov identifier: NCT04568772 (Registered on September 29, 2020).
Topics: Humans; Atovaquone; Cross-Over Studies; Cytochrome P-450 CYP2C19; Drug Interactions; Esomeprazole; Proguanil; Reducing Agents
PubMed: 36897544
DOI: 10.1007/s40262-023-01228-4 -
Travel Medicine and Infectious Disease 2019Malaria in pregnancy can cause severe maternal and fetal complications. Chloroquine (CQ) and mefloquine (MQ) are recommended for chemoprophylaxis in pregnancy, but are...
BACKGROUND
Malaria in pregnancy can cause severe maternal and fetal complications. Chloroquine (CQ) and mefloquine (MQ) are recommended for chemoprophylaxis in pregnancy, but are not always suitable. Atovaquone-proguanil (AP) might be a viable option for malaria prevention in pregnancy, but more safety data are needed.
METHODS
Data for pregnancies and live births among active duty military women, 2003-2014, from the Department of Defense Birth and Infant Health Research program were linked with pharmacy data to determine antimalarial exposure. Multivariable Cox and logistic regression models were used to assess the relationship of antimalarial exposure with fetal and infant outcomes, respectively.
RESULTS
Among 198,164 pregnancies, 50 were exposed to AP, 156 to MQ, and 131 to CQ. Overall, 17.6% of unexposed pregnancies and 28.0%, 16.0%, and 6.1% of pregnancies exposed to AP, MQ, and CQ, respectively, ended in fetal loss (spontaneous abortion or stillbirth) (adjusted hazard ratios [aHR] = 1.46, 95% confidence interval [CI] 0.87-2.46; aHR = 1.06, 95% CI 0.72-1.57; and aHR = 0.47, 95% CI 0.24-0.94, respectively).
CONCLUSIONS
The small number of AP exposed pregnancies highlights the difficulty in assessing safety. While definitive conclusions are not possible, these data suggest further research of AP exposure in pregnancy and fetal loss is warranted.
TWITTER LINE
More research on fetal loss following atovaquone-proguanil exposure in pregnancy is warranted.
PubMed: 31747537
DOI: 10.1016/j.tmaid.2019.101519 -
Journal of Mass Spectrometry and... Nov 2022Atovaquone has traditionally been used as an antiparasitic and antifungal agent, but recent studies have shown its potential as an anticancer agent. The high variability...
BACKGROUND
Atovaquone has traditionally been used as an antiparasitic and antifungal agent, but recent studies have shown its potential as an anticancer agent. The high variability in atovaquone bioavailability highlights the need for therapeutic drug monitoring, especially in pediatric patients. The goal of our study was to develop and validate the performance of an assay to quantify atovaquone plasma concentrations collected from pediatric cancer patients using LC-MS/MS.
METHODS
Atovaquone was extracted from a 10 µL volume of K-EDTA human plasma using a solution consisting of ACN: EtOH: DMF (8:1:1 v:v:v), separated using reverse-phase chromatography, and detected using a SCIEX 5500 QTrap MS system. LC-MS/MS assay performance was evaluated for precision, accuracy, carryover, sensitivity, specificity, linearity, and interferences.
RESULTS
Atovaquone and its deuterated internal standard were analyzed using a gradient chromatographic method that had an overall cycle-time of 7.4 min per injection, and retention times of 4.3 min. Atovaquone was measured over a dynamic concentration range of 0.63 - 80 µM with a deviation within ≤ ± 5.1 % of the target value. Intra- and inter-assay precision were ≤ 2.7 % and ≤ 8.4 %, respectively. Dilutional, carryover, and interference studies were also within acceptable limits.
CONCLUSIONS
Our studies have shown that our LC-MS/MS-based method is both reliable and robust for the quantification of plasma atovaquone concentrations and can be used to determine the effective dose of atovaquone for pediatric patients treated for AML.
PubMed: 36388060
DOI: 10.1016/j.jmsacl.2022.09.004 -
Advanced Science (Weinheim,... Apr 2022Atovaquone, an FDA-approved drug for malaria, is known to inhibit mitochondrial electron transport. A recently synthesized mitochondria-targeted atovaquone increased...
Atovaquone, an FDA-approved drug for malaria, is known to inhibit mitochondrial electron transport. A recently synthesized mitochondria-targeted atovaquone increased mitochondrial accumulation and antitumor activity in vitro. Using an in situ vaccination approach, local injection of mitochondria-targeted atovaquone into primary tumors triggered potent T cell immune responses locally and in distant tumor sites. Mitochondria-targeted atovaquone treatment led to significant reductions of both granulocytic myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment. Mitochondria-targeted atovaquone treatment blocks the expression of genes involved in oxidative phosphorylation and glycolysis in granulocytic-myeloid-derived suppressor cells and regulatory T cells, which may lead to death of granulocytic-myeloid-derived suppressor cells and regulatory T cells. Mitochondria-targeted atovaquone inhibits expression of genes for mitochondrial complex components, oxidative phosphorylation, and glycolysis in both granulocytic-myeloid-derived suppressor cells and regulatory T cells. The resulting decreases in intratumoral granulocytic-myeloid-derived suppressor cells and regulatory T cells could facilitate the observed increase in tumor-infiltrating CD4 T cells. Mitochondria-targeted atovaquone also improves the anti-tumor activity of PD-1 blockade immunotherapy. The results implicate granulocytic-myeloid-derived suppressor cells and regulatory T cells as novel targets of mitochondria-targeted atovaquone that facilitate its antitumor efficacy.
Topics: Atovaquone; Humans; Mitochondria; Neoplasms; Oxidative Phosphorylation; Tumor Microenvironment; Vaccination
PubMed: 35243806
DOI: 10.1002/advs.202101267 -
The American Journal of Tropical... Jun 2019Malaria chemoprophylaxis has become increasingly prominent now that it is used for vulnerable populations in endemic regions in addition to nonimmune travelers to those...
Malaria chemoprophylaxis has become increasingly prominent now that it is used for vulnerable populations in endemic regions in addition to nonimmune travelers to those regions. The objective would be a drug with > 95% efficacy and that is easily tolerated, including in children and pregnant women. For individuals who prefer weekly rather than daily drug administration, a further objective is a product that is administered weekly. The deficiencies of present agents are parasite resistance to chloroquine, neuropsychiatric liability of mefloquine, the need for daily dosing for atovaquone-proguanil, and daily dosing plus adverse reactions for doxycycline. A primaquine analogue, tafenoquine, has a 17-day half-life and was approved for weekly prophylaxis in the United States and in Australia in 2018. Weekly tafenoquine was equal to mefloquine in efficacy in nonimmunes. The tafenoquine label contains a contraindication for preexisting psychosis, but not for the broad number of other neuropsychiatric disorders which are listed as contraindications in the mefloquine label. As an 8-aminoquinoline, tafenoquine is contraindicated for glucose-6-phosphate dehydrogenase (G6PD)-deficient persons or in pregnancy if the fetus might be G6PD deficient. Other possible significant adverse reactions for tafenoquine are declines in hemoglobin levels reported in some G6PD-normal patients, asymptomatic elevations in methemoglobin, and minor psychiatric events. The lack of broad neuropsychiatric adverse reactions suggests that tafenoquine may have a role as the weekly prophylactic of choice for G6PD-normal persons.
Topics: Aminoquinolines; Antimalarials; Australia; Chemoprevention; Child; Contraindications, Drug; Drug Administration Schedule; Drug Approval; Female; Fetus; Glucosephosphate Dehydrogenase Deficiency; Hemoglobins; Humans; Malaria, Falciparum; Methemoglobin; Pregnancy; Psychotic Disorders; United States
PubMed: 30887947
DOI: 10.4269/ajtmh.19-0001 -
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 -
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