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Chemical Science Oct 2023Photodynamic therapy (PDT) has emerged as an invasive and promising antitumour treatment, however, the hypoxia in deep tumour tissues and the poor water-solubility of...
Photodynamic therapy (PDT) has emerged as an invasive and promising antitumour treatment, however, the hypoxia in deep tumour tissues and the poor water-solubility of photosensitizers as bottlenecks greatly hinder PDT efficiency. Herein, a tumour microenvironment (TME) activated supramolecular nanoplatform consisting of the pillar[5]arene-based amphiphilic polymer POPD, the phototherapeutic agent Cy7-CN, respiratory medication atovaquone (ATO) and chemotherapeutic drug pyridinyl camptothecin (CPT-Py) was constructed for imaging-guided hypoxia-ameliorated phototherapies. Owing to host-guest interaction, the photochemical and photophysical properties of cyanine were improved exceedingly due to the suppression of π-π stacking. Triggered by the acidic microenvironment in tumour sites, the supramolecular nanoplatform would dissociate and release CPT-Py and ATO which inhibits mitochondria-associated oxidative phosphorylation (OXPHOS) and encourages more oxygen to be used in enhanced PDT. and studies verified that the rational combination of ATO-enhanced PDT and PTT overcame the disadvantages of single phototherapy and formed mutual promotion, and simultaneously sensitized chemotherapeutic drugs, which resulted in high tumour inhibition. It is hoped that the supramolecular nanoplatform could shed light on the development of phototherapeutic agents.
PubMed: 37886080
DOI: 10.1039/d3sc03797e -
Scientific Reports Nov 2020Oxidative stress inhibits Na/K-ATPase (NKA), the ion channel that maintains membrane potential. Here, we investigate the role of oxidative stress-mediated by plumbagin...
Oxidative stress inhibits Na/K-ATPase (NKA), the ion channel that maintains membrane potential. Here, we investigate the role of oxidative stress-mediated by plumbagin and atovaquone in the inhibition of NKA activity. We confirm that plumbagin and atovaquone inhibit the proliferation of three human (OVCAR-3, SKOV-3, and TYKNu) and one mouse (ID8) ovarian cancer cell lines. The oxygen radical scavenger, N-acetylcysteine (NAC), attenuates the chemotoxicity of plumbagin and atovaquone. Whole-cell patch clamping demonstrates that plumbagin and atovaquone inhibit outward and the inward current flowing through NKA in SKOV-3 and OVCAR-3. Although both drugs decrease cellular ATP; providing exogenous ATP (5 mM) in the pipet solution used during patch clamping did not recover NKA activity in the plumbagin or atovaquone treated SKOV-3 and OVCAR-3 cells. However, pretreatment of the cells with NAC completely abrogated the NKA inhibitory activity of plumbagin and atovaquone. Exposure of the SKOV-3 cells to either drug significantly decreases the expression of NKA. We conclude that oxidative stress caused by plumbagin and atovaquone degrades NKA, resulting in the inability to maintain ion transport. Therefore, when evaluating compounds that induce oxidative stress, it is important to consider the contribution of NKA inhibition to their cytotoxic effects on tumor cells.
Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents, Phytogenic; Atovaquone; Cell Line, Tumor; Cell Proliferation; Enzyme Inhibitors; Female; Humans; Ion Transport; Mice; Naphthoquinones; Ovarian Neoplasms; Oxidative Stress; Patch-Clamp Techniques; Sodium-Potassium-Exchanging ATPase
PubMed: 33177587
DOI: 10.1038/s41598-020-76342-5 -
Molecular Cancer Therapeutics Oct 2019Breast cancer is the second leading cause of cancer-related mortality in women. In the current study, we evaluated the anticancer effects of an antiprotozoal drug,...
Breast cancer is the second leading cause of cancer-related mortality in women. In the current study, we evaluated the anticancer effects of an antiprotozoal drug, atovaquone, against several breast cancer cell lines. Our results showed that atovaquone treatment induced apoptosis and inhibited the growth of all the breast cancer cell lines tested, including several patient-derived cells. In addition, atovaquone treatment significantly reduced the expression of HER2, β-catenin, and its downstream molecules such as pGSK-3β, TCF-4, cyclin D1, and c-Myc Efficacy of atovaquone was further evaluated in an tumor model by orthotropic implantation of two highly aggressive 4T1 and CI66 breast cancer cells in the mammary fat pad of female mice. Our results demonstrated that oral administration of atovaquone suppressed the growth of CI66 and 4T1 tumors by 70% and 60%, respectively. Paclitaxel is the first-line chemotherapeutic agent for metastatic breast cancer. We demonstrate that atovaquone administration suppressed the growth of 4T1 paclitaxel-resistant tumors by 40%. Tumors from atovaquone-treated mice exhibited reduced HER2, β-catenin, and c-Myc levels alongside an increase in apoptosis in all the three tumor models when analyzed by Western blotting, IHC, and TUNEL assay. Taken together, our results indicate that atovaquone effectively reduces the growth of primary and paclitaxel-resistant breast tumors. Atovaquone is already in the clinics with high safety and tolerability profile. Therefore, the findings from our studies will potentially prompt further clinical investigation into repurposing atovaquone for the treatment of patients with advanced breast cancer.
Topics: Animals; Antiprotozoal Agents; Apoptosis; Atovaquone; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Resistance, Neoplasm; Female; Gene Silencing; Humans; Mice, Inbred BALB C; Paclitaxel; Proteasome Endopeptidase Complex; Receptor, ErbB-2; Signal Transduction; beta Catenin
PubMed: 31270151
DOI: 10.1158/1535-7163.MCT-18-1286 -
Clinical Microbiology and Infection :... Jul 2024Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several... (Meta-Analysis)
Meta-Analysis Comparative Study Review
Comparative efficacy and safety of Pneumocystis jirovecii pneumonia prophylaxis regimens for people living with HIV: a systematic review and network meta-analysis of randomized controlled trials.
BACKGROUND
Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several regimens are available for the prophylaxis of PCP, including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone-based regimens (DBRs), aerosolized pentamidine (AP), and atovaquone.
OBJECTIVES
To compare the efficacy and safety of PCP prophylaxis regimens in PWH by network meta-analysis.
METHODS
DATA SOURCES: Embase, MEDLINE, and CENTRAL from inception to June 21, 2023.
STUDY ELIGIBILITY CRITERIA
Comparative randomized controlled trials (RCTs).
PARTICIPANTS
PWH.
INTERVENTIONS
Regimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo.
ASSESSMENT OF RISK OF BIAS
Cochrane risk-of-bias tool for RCTs 2.
METHODS OF DATA SYNTHESIS
Title or abstract and full-text screening and data extraction were performed in duplicate by two independent reviewers. Data on PCP incidence, all-cause mortality, and discontinuation due to toxicity were pooled and ranked by network meta-analysis. Subgroup analyses of primary versus secondary prophylaxis, by year, and by dosage were performed.
RESULTS
A total of 26 RCTs, comprising 55 treatment arms involving 7516 PWH were included. For the prevention of PCP, TMP-SMX was ranked the most favourable agent and was superior to DBRs (risk ratio [RR] = 0.54; 95% CI, 0.36-0.83) and AP (RR = 0.53; 95% CI, 0.36-0.77). TMP-SMX was also the only agent with a mortality benefit compared with no treatment/placebo (RR = 0.79; 95% CI, 0.64-0.98). However, TMP-SMX was also ranked as the most toxic agent with a greater risk of discontinuation than DBRs (RR = 1.25; 95% CI, 1.01-1.54) and AP (7.20; 95% CI, 5.37-9.66). No significant differences in PCP prevention or mortality were detected among the other regimens. The findings remained consistent within subgroups.
CONCLUSIONS
TMP-SMX is the most effective agent for PCP prophylaxis in PWH and the only agent to confer a mortality benefit; consequently, it should continue to be recommended as the first-line agent. Further studies are necessary to determine the optimal dosing of TMP-SMX to maximize efficacy and minimize toxicity.
Topics: Humans; Pneumonia, Pneumocystis; Randomized Controlled Trials as Topic; Network Meta-Analysis; Trimethoprim, Sulfamethoxazole Drug Combination; Pneumocystis carinii; HIV Infections; AIDS-Related Opportunistic Infections; Dapsone; Pentamidine; Atovaquone; Antifungal Agents; Treatment Outcome
PubMed: 38583518
DOI: 10.1016/j.cmi.2024.03.037 -
Malaria Journal May 2018Malaria chemoprophylaxis options in pregnancy are limited, and atovaquone-proguanil (AP) is not recommended because of insufficient safety evidence. An anonymous,... (Comparative Study)
Comparative Study
BACKGROUND
Malaria chemoprophylaxis options in pregnancy are limited, and atovaquone-proguanil (AP) is not recommended because of insufficient safety evidence. An anonymous, internet-based survey was disseminated to describe outcomes of pregnancies accidentally exposed to AP. Outcomes of interest included miscarriage (defined as pregnancy loss before 20 weeks), stillbirth (defined as pregnancy loss at or after 20 weeks), preterm birth or live birth prior to 37 weeks, and the presence of congenital anomalies.
RESULTS
A total of 487 women responded and reported on 822 pregnancies. Of the 807 pregnancies with information available on exposure and outcomes, 10 (1.2%) had atovaquone-proguanil exposure, all in the first trimester, and all resulted in term births with no birth defects.
CONCLUSIONS
Use of an anti-malarial not recommended in pregnancy is likely to occur before the woman knows of her pregnancy. This study adds to the limited evidence of the safety of AP in pregnancy. Further study on use of AP in pregnancy should be a high priority, as an alternative option for the prevention of malaria in pregnancy in non-immune travellers is urgently needed.
Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Adult; Antimalarials; Atovaquone; Chemoprevention; Chloroquine; Drug Combinations; Female; Humans; Live Birth; Mefloquine; Middle Aged; Pregnancy; Pregnancy Outcome; Premature Birth; Proguanil; Stillbirth; United States; Young Adult
PubMed: 29764439
DOI: 10.1186/s12936-018-2352-z -
Veterinary World Jun 2023New anticancer drugs are being developed to avoid the toxicity and chemoresistance of the currently available drugs. The Food and Drug Administration-approved...
BACKGROUND AND AIM
New anticancer drugs are being developed to avoid the toxicity and chemoresistance of the currently available drugs. The Food and Drug Administration-approved anti-malarial drug atovaquone is known to act as a selective oxidative phosphorylation inhibitor in the mitochondria by competing with CO Q10 (mitochondrial complex II and III). This study aimed to investigate the effect of atovaquone by examining the Na/K-ATPase (NKA) activity in various canine cell lines.
MATERIALS AND METHODS
Canine cell lines were treated with various concentrations (2.5, 5, 10, 15, and 20 μM) of atovaquone for 24, 48, and 72 h. Human cell lines were used as a control to validate the canine cancer cell lines. The activities of the drugs against the cancer cell lines were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromideassay. The cell metabolic activity was determined by measuring the activities of the nicotinamide adenine dinucleotide phosphate-dependent cellular oxidoreductase enzymes. The NKA activity was measured using the single-cell patch clamping assay.
RESULTS
Atovaquone-induced apoptosis by elevating the concentration of reactive oxygen species (ROS) in the tumor cells, leading to cell death. Treatment of canine cancer cells with N-acetylcysteine (ROS inhibitor) reduced the activity of the drug. Furthermore, atovaquone inhibited more than 45% of the NKA ion current.
CONCLUSION
This study demonstrated effects of atovaquone against canine cancer cell lines. The data may prove beneficial in repurposing the drug as a new anticancer agent in canine clinical trials, which might aid in fighting human cancer.
PubMed: 37577204
DOI: 10.14202/vetworld.2023.1185-1192 -
Frontiers in Pharmacology 2022Obtaining triphenylphosphonium salts derived from anticancer compounds to inhibit mitochondrial metabolism is of major interest due to their pivotal role in reactive...
Obtaining triphenylphosphonium salts derived from anticancer compounds to inhibit mitochondrial metabolism is of major interest due to their pivotal role in reactive oxygen species (ROS) production, calcium homeostasis, apoptosis, and cell proliferation. However, the use of this type of antitumor compound presents a risk of bleeding since the platelet activation is especially dependent on the mitochondrial function. In this study, we evaluated the effect of three triphenylphosphonium-based compounds, honokiol (HNK), lonidamine (LDN), and atovaquone (ATO), on the platelet function linked to the triphenylphosphonium cation by a lineal 10-carbon alkyl chain and also the decyltriphenylphosphonium salt (decylphos). Platelets obtained by phlebotomy from healthy donors were exposed to different concentrations (0.1-10 μM) of the three compounds; cellular viability, exposure of phosphatidylserine, the mitochondrial membrane potential (∆Ψm), intracellular calcium release, and intracellular ROS generation were measured. Platelet activation and aggregation were induced by agonists (adenosine diphosphate, thrombin receptor-activating peptide-6, convulxin, or phorbol-12-myristate-13-acetate) and were evaluated by flow cytometry and light transmission, respectively. The three compounds showed a slight cytotoxic effect from 1 μM, and this was concomitant with a decrease in ∆Ψm and intracellular calcium increase. Only ATO produced a modest but significant increase in intra-platelet ROS. Also, the three compounds increased the exposure to phosphatidylserine in platelets expressed in platelets positive for annexin V. None of the compounds had an inhibitory effect on the aggregation or activation markers of platelets stimulated with three different agonists. Similar results were obtained with decylphos. Triphenylphosphonium derivatives showed slight platelet toxicity below 1 μM, probably associated with their effect on ∆Ψm and exposure to phosphatidylserine, but no significant effect on platelet activation and aggregation, making them an antitumoral alternative with a low risk of bleeding. However, future assays on animal models and human trials are required to evaluate if their effects with a low risk for hemostasis are replicated .
PubMed: 35645840
DOI: 10.3389/fphar.2022.893873 -
Journal of Fungi (Basel, Switzerland) Dec 2020pneumonia (PJP) is an opportunistic infection that mostly affects children with suppressed cellular immunity. PJP was the most common cause of infectious death in... (Review)
Review
pneumonia (PJP) is an opportunistic infection that mostly affects children with suppressed cellular immunity. PJP was the most common cause of infectious death in children with acute lymphoblastic leukemia prior to the inclusion of cotrimoxazole prophylaxis as part of the standard medical care in the late 1980s. Children with acute leukemia, lymphomas, and those undergoing hematopoietic stem cell transplantation, especially allogeneic transplantation, are also at high risk of PJP. Persistent lymphopenia, graft versus host disease, poor immune reconstitution, and lengthy use of corticosteroids are significant risk factors for PJP. Active infection may be due to reactivation of latent infection or recent acquisition from environmental exposure. Intense hypoxemia and impaired diffusing capacity of the lungs are hallmarks of PJP, while computerized tomography of the lungs is the diagnostic technique of choice. Immunofluorescence testing with monoclonal antibodies followed by fluorescent microscopy and polymerase chain reaction testing of respiratory specimens have emerged as the best diagnostic methods. Measurement of (1-3)-β-D-glucan in the serum has a high negative predictive value in ruling out PJP. Oral cotrimoxazole is effective for prophylaxis, but in intolerant patients, intravenous and aerosolized pentamidine, dapsone, and atovaquone are effective alternatives. Ιntravenous cotrimoxazole is the treatment of choice, but PJP has a high mortality even with appropriate therapy.
PubMed: 33276699
DOI: 10.3390/jof6040331 -
Frontiers in Microbiology 2014Toxoplasmosis is a major cause of foodborne disease, congenital complication, and morbidity. There is an urgent need for safe and effective therapies to encounter...
UNLABELLED
Toxoplasmosis is a major cause of foodborne disease, congenital complication, and morbidity. There is an urgent need for safe and effective therapies to encounter congenital and persisting toxoplasmosis. The hypothesis was: combination diclazuril plus atovaquone to exert a novel therapeutic synergy to prevent toxoplasmosis syndromes.
METHODS
Pregnant dams were treated with diclazuril and atovaquone monotherapy or combination therapy and infected i.p with Toxoplasma tachyzoites.
RESULTS
Infected dams developed severe toxoplasmosis associated syndrome with increases in the abdominal adiposity surrounding uteri, gansterointestinal and other internal organs and excessive weight gain. Numerous organisms along with infiltration of inflammatory cells were detected scattered into adipose tissues. Combination therapy (p < 0.01) and to a lesser extent diclazuril (p < 0.05) protected dams from inflammatory fat and excess weight gains. This was consistent with pancreatitis development in infected dams (versus normal p < 0.05) with infiltration of inflammatory cells, degeneration and necrosis of pancreatic cells followed by the degeneration and loss of islets. Combination and monotherapy protected dams from these inflammatory and pathological aspects of pancreatitis. Infected dams exhibited severe colitis, and colonic tissues significantly shortened in length. Brush border epithelial cells were replaced with infiltration of lymphocytes, granulocytes, and microabscess formations into cryptic microstructures. Combination therapy synergistically preserved colonic structure and normalized pathological damages (p < 0.001) and to a lesser degree diclazuril monotherapy protected dams from colitis (p < 0.05) and gastrointestinal toxoplasmosis. Other complications included severe splenitis (p < 0.001) and hepatitis (p < 0.001) which were normalized with combination therapy.
CONCLUSION
Combination diclazuril plus atovaquone was safe and with a novel therapeutic synergism protected dams and fetuses from toxoplasmosis.
PubMed: 25309522
DOI: 10.3389/fmicb.2014.00484 -
Morbidity and Mortality Weekly Report.... Dec 2014Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles mosquito....
PROBLEM/CONDITION
Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is also occasionally acquired by persons who have not traveled out of the country, through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission. Malaria surveillance in the United States is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers.
PERIOD COVERED
This report summarizes cases in persons with onset of symptoms in 2012 and summarizes trends during previous years.
DESCRIPTION OF SYSTEM
Malaria cases diagnosed by blood film, polymerase chain reaction, or rapid diagnostic tests are mandated to be reported to local and state health departments by health-care providers or laboratory staff. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS), National Notifiable Diseases Surveillance System (NNDSS), or direct CDC consults. For the first time, CDC conducted antimalarial drug resistance testing on blood samples submitted to CDC by health-care providers or local/state health departments. Data from these reporting systems serve as the basis for this report.
RESULTS
CDC received 1,687 reported cases of malaria with an onset of symptoms in 2012 among persons in the United States, including 1,683 cases classified as imported, one laboratory-acquired case, one nosocomial case, and two cryptic cases. The total number of cases represents a 12% decrease from the 1,925 cases reported for 2011. Plasmodium falciparum, P. vivax, P. malariae, and P. ovale were identified in 58%, 17%, 3%, and 3% of cases, respectively. Twenty (1%) patients were infected by two species. The infecting species was unreported or undetermined in 17% of cases, a decrease of 6 percentage points from 2011. Polymerase chain reaction testing determined or corrected the species for 45 (43%) of the 104 samples submitted for drug resistance testing. Of the 909 patients who reported purpose of travel, 604 (66%) were visiting friends or relatives (VFR). Among the 983 cases in U.S. civilians for whom information on chemoprophylaxis use and travel region was known, 63 (6%) patients reported that they had followed and adhered to a chemoprophylaxis drug regimen recommended by CDC for the regions to which they had traveled. Thirty-two cases were reported in pregnant women, among whom only one adhered to chemoprophylaxis. Among all reported cases, 231 (14%) were classified as severe infections in 2012. Of these, six persons with malaria died in 2012. Beginning in 2012, there were 104 blood samples submitted to CDC that were tested for molecular markers associated with antimalarial drug resistance. Of the 65 P. falciparum-positive samples, 53 (82%) had genetic polymorphisms associated with pyrimethamine drug resistance, 61 (94%) with sulfadoxine resistance, 29 (45%) with chloroquine resistance, 1 (2%) with mefloquine drug resistance, 2 (3%) with atovaquone resistance, and none with artemisinin resistance.
INTERPRETATION
Despite the 12% decline in the number of cases reported in 2012 compared with 2011, the overall trend in malaria cases has been increasing since 1973. Although progress has been made in reducing the global burden of malaria, the disease remains endemic in many regions, and the use of appropriate prevention measures by travelers is still inadequate.
PUBLIC HEALTH ACTIONS
Completion of data elements on the malaria case report form increased slightly in 2012 compared with 2011, but still remains unacceptably low. This incomplete reporting compromises efforts to examine trends in malaria cases and prevent infections. VFRs continue to be a difficult population to reach with effective malaria prevention strategies. Evidence-based prevention strategies that effectively target VFRs need to be developed and implemented to have a substantial impact on the numbers of imported malaria cases in the United States. Although more patients reported taking chemoprophylaxis to prevent malaria, the majority reported not taking it, and adherence was poor among those who did take chemoprophylaxis. Proper use of malaria chemoprophylaxis will prevent the majority of malaria illness and reduce the risk for severe disease (http://www.cdc.gov/malaria/travelers/drugs.html). Malaria infections can be fatal if not diagnosed and treated promptly with antimalarial medications appropriate for the patient's age and medical history, the likely country of malaria acquisition, and previous use of antimalarial chemoprophylaxis. Recent molecular laboratory advances have enabled CDC to identify and conduct molecular surveillance of antimalarial drug resistance (http://www.cdc.gov/malaria/features/ars.html). These advances will allow CDC to track, guide treatment, and manage drug resistant malaria parasites both domestically and globally. For this to be successful, specimens should be submitted for cases diagnosed in the United States and for ongoing specimen collection and testing globally. Clinicians should consult the CDC Guidelines for Treatment of Malaria and contact the CDC's Malaria Hotline for case management advice when needed. Malaria treatment recommendations can be obtained online (http://www.cdc.gov/malaria/diagnosis_treatment) or by calling the Malaria Hotline (770-488-7788 or toll-free at 855-856-4713).
Topics: Adolescent; Adult; Antimalarials; Child; Child, Preschool; Drug Resistance; Female; Humans; Infant; Malaria; Male; Middle Aged; Military Personnel; Plasmodium; Population Surveillance; Pregnancy; Seasons; Severity of Illness Index; Travel; United States; Young Adult
PubMed: 25474160
DOI: No ID Found