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Frontiers in Pharmacology 2022An screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (M), followed by viral replication assays, and pharmacokinetic studies...
An screen was performed to identify FDA approved drugs that inhibit SARS-CoV-2 main protease (M), followed by viral replication assays, and pharmacokinetic studies in mice. These studies identified atovaquone as a promising candidate for inhibiting viral replication. A 2-center, randomized, double-blind, placebo-controlled trial was performed among patients hospitalized with COVID-19 infection. Enrolled patients were randomized 2:1 to atovaquone 1500 mg BID matched placebo. Patients received standard of care treatment including remdesivir, dexamethasone, or convalescent plasma as deemed necessary by the treating team. Saliva was collected at baseline and twice per day for up to 10 days for RNA extraction for SARS-CoV-2 viral load measurement by quantitative reverse-transcriptase PCR. The primary outcome was the between group difference in log-transformed viral load (copies/mL) using a generalized linear mixed-effect models of repeated measures from all samples. Of the 61 patients enrolled; 41 received atovaquone and 19 received placebo. Overall, the population was predominately male (63%) and Hispanic (70%), with a mean age of 51 years, enrolled a mean of 5 days from symptom onset. The log viral load was 5.25 copies/mL . 4.79 copies/mL at baseline in the atovaquone . placebo group. Change in viral load did not differ over time between the atovaquone plus standard of care arm the placebo plus standard of care arm. Pharmacokinetic (PK) studies of atovaquone plasma concentration demonstrated a wide variation in atovaquone levels, with an inverse correlation between BMI and atovaquone levels, (Rho -0.45, = 0.02). In post hoc analysis, an inverse correlation was observed between atovaquone levels and viral load (Rho -0.54, = 0.005). In this prospective, randomized, placebo-controlled trial, atovaquone did not demonstrate evidence of enhanced SARS-CoV-2 viral clearance compared with placebo. However, based on the observed inverse correlation between atovaquone levels and viral load, additional PK-guided studies may be warranted to examine the antiviral effect of atovaquone in COVID-19 patients.
PubMed: 36249792
DOI: 10.3389/fphar.2022.1020123 -
The Journal of Infectious Diseases Aug 2023Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects...
BACKGROUND
Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling.
METHODS
We screened 132 approved drugs using an MPXV infection cell system. We quantified antiviral activities of potential drug candidates by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment.
RESULTS
Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted postentry processes. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by 7 days at clinically relevant drug concentrations.
CONCLUSIONS
These data suggest that atovaquone would be a potential candidate for treating mpox.
Topics: Humans; Atovaquone; Mefloquine; Monkeypox virus
PubMed: 36892247
DOI: 10.1093/infdis/jiad058 -
MMWR. Morbidity and Mortality Weekly... Jul 2017Babesiosis is an emerging zoonotic disease caused primarily by Babesia microti, an intraerythocytic protozoan. Babesia microti, like the causal agents for Lyme disease...
Babesiosis is an emerging zoonotic disease caused primarily by Babesia microti, an intraerythocytic protozoan. Babesia microti, like the causal agents for Lyme disease and anaplasmosis, is endemic to the northeastern and upper midwestern United States where it is usually transmitted by the blacklegged tick, Ixodes scapularis. Although babesiosis is usually a mild to moderate illness, older or immunocompromised persons can develop a serious malaria-like illness that can be fatal without prompt treatment. The most common initial clinical signs and symptoms of babesiosis (fever, fatigue, chills, and diaphoresis) are nonspecific and present diagnostic challenges that can contribute to delays in diagnosis and effective treatment with atovaquone and azithromycin (1). Results of one study revealed a mean delay of 12-14 days from symptom onset to treatment (2). Knowledge of the incidence and geographic distribution of babesiosis can raise the index of clinical suspicion and facilitate more prompt diagnosis and lifesaving treatment (1). The first known case of babesiosis in Wisconsin was detected in 1985 (3), and babesiosis became officially reportable in the state in 2001. Wisconsin babesiosis surveillance data for 2001-2015 were analyzed in 3-year intervals to compare demographic, epidemiologic, and laboratory features among patients with cases of reported babesiosis. To determine possible reasons for an increase in reported Babesia infection, trends in electronic laboratory reporting and diagnosis by polymerase chain reaction testing (PCR) were examined. Between the first and last 3-year analysis intervals, there was a 26-fold increase in the incidence of confirmed babesiosis, in addition to geographic expansion. These trends might be generalizable to other states with endemic disease, similar suburbanization and forest fragmentation patterns, and warming average temperatures (4). Accurate surveillance in states where babesiosis is endemic is necessary to estimate the increasing burden of babesiosis and other tickborne diseases and to develop appropriate public health interventions for prevention and practice.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Babesia microti; Babesiosis; Child; Clinical Laboratory Information Systems; Electronic Health Records; Female; Humans; Incidence; Male; Middle Aged; Polymerase Chain Reaction; Population Surveillance; Wisconsin; Young Adult
PubMed: 28683059
DOI: 10.15585/mmwr.mm6626a2 -
BMC Medicine Nov 2022Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical studies suggest that the anti-malaria drug proguanil and...
BACKGROUND
Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical studies suggest that the anti-malaria drug proguanil and atovaquone might play a role in preventing CRC, but population-based evidence is still lacking.
METHODS
By accessing a couple of nationwide Swedish registers, we performed a cohort study to explore whether using proguanil and atovaquone might associate with a lower risk of CRC by adopting a new-user study design. Adults who have 1 or more first-degree relatives (parents or siblings) diagnosed with CRC were identified and linked with the Prescribed Drug Register to evaluate their administration history of proguanil and atovaquone. Survival analysis of the time to CRC diagnosis with Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
RESULTS
A total of 16,817 incident proguanil/atovaquone users were identified and matched with 168,170 comparisons, who did not use proguanil/atovaquone, on the ratio of 1:10. We found a significant negative association between proguanil/atovaquone use and risk of CRC (adjusted HR, 0.76; 95% CI, 0.62-0.93). Test for trend showed significant dose- and duration-response correlations (P < 0.001). The association was more pronounced in CRC diagnosed at an advanced stage than at an early stage (adjusted HR, 0.69 vs.0.81).
CONCLUSIONS
This national-wide population-based cohort study showed that the use of proguanil and atovaquone was associated with a reduced risk of CRC among individuals with a family history of CRC.
Topics: Adult; Humans; Proguanil; Atovaquone; Cohort Studies; Drug Combinations; Antimalarials; Colorectal Neoplasms; Malaria, Falciparum
PubMed: 36357883
DOI: 10.1186/s12916-022-02643-3 -
Travel Medicine and Infectious Disease 2018We evaluated existing data on the prophylactic efficacy of atovaquone-proguanil (AP) in order to determine whether prophylaxis in travellers can be discontinued on the... (Review)
Review
BACKGROUND
We evaluated existing data on the prophylactic efficacy of atovaquone-proguanil (AP) in order to determine whether prophylaxis in travellers can be discontinued on the day of return from a malaria-endemic area instead of seven days after return as per currently recommended post-travel schedule.
METHODS
PubMed and Embase databases were searched to identify relevant studies. This PROSPERO-registered systematic review followed PRISMA guidelines. The search strategy included terms or synonyms relevant to AP combined with terms to identify articles relating to prophylactic use of AP and inhibitory and half-life properties of AP. Studies considered for inclusion were: randomized controlled trials, cohort studies, quasi-experimental studies, open-label trials, patient-control studies, cross-sectional studies; as well as case-series and non-clinical studies. Data on study design, characteristics of participants, interventions, and outcomes were extracted. Primary outcomes considered relevant were prophylactic efficacy and prolonged inhibitory activity and half-life properties of AP.
RESULTS
The initial search identified 1,482 publications, of which 40 were selected based on screening. Following full text review, 32 studies were included and categorized into two groups, namely studies in support of the current post-travel regimen (with a total of 2,866 subjects) and studies in support of an alternative regimen (with a total of 533 subjects).
CONCLUSION
There is limited direct and indirect evidence to suggest that an abbreviated post-travel regimen for AP may be effective. Proguanil, however, has a short half-life and is essential for the synergistic effect of the combination. Stopping AP early may result in mono-prophylaxis with atovaquone and possibly select for atovaquone-resistant parasites. Furthermore, the quality of the studies in support of the current post-travel regimen outweighs the quality of the studies in support of an alternative short, post-travel regimen, and the total sample size of the studies to support stopping AP early comprises a small percentage of the total sample size of the studies performed to establish the efficacy of the current AP regimen. Additional research is required - especially from studies evaluating impact on malaria parasitaemia and clinical illness and conducted among travellers in high malaria risk settings - before an abbreviated regimen can be recommended in current practice.
PROSPERO REGISTRATION NUMBER
CRD42017055244.
Topics: Antimalarials; Atovaquone; Drug Administration Schedule; Drug Combinations; Drug Synergism; Endemic Diseases; Humans; Malaria; Post-Exposure Prophylaxis; Proguanil; Travel; Travel-Related Illness
PubMed: 29242073
DOI: 10.1016/j.tmaid.2017.12.005 -
Biomaterials Research Sep 2022Mitochondria play an essential role in cellular redox homeostasis maintenance and meanwhile serve as an important target for organelle targeted therapy. Photodynamic...
BACKGROUND
Mitochondria play an essential role in cellular redox homeostasis maintenance and meanwhile serve as an important target for organelle targeted therapy. Photodynamic therapy (PDT) is a promising strategy for organelle targeted therapy with noninvasive nature and highly spatiotemporal selectivity. However, the efficacy of PDT is not fully achieved due to tumor hypoxia. Moreover, aerobic respiration constantly consumes oxygen and leads to a lower oxygen concentration in mitochondria, which continuously limited the therapeutic effects of PDT. The lack of organelle specific oxygen delivery method remains a main challenge.
METHODS
Herein, an Oxygen Tank is developed to achieve the organelle targeted synergistic hypoxia reversal strategy, which not only act as an oxygen storage tank to open sources and reduce expenditure, but also coated with red blood cell membrane like the tank with stealth coating. Within the oxygen tank, a mitochondrion targeted photosensitizer (IR780) and a mitochondria respiration inhibitor (atovaquone, ATO) are co-loaded in the RBC membrane (RBCm) coated perfluorocarbon (PFC) liposome core.
RESULTS
Inside these bio-mimic nanoparticles, ATO effectively inhibits mitochondrial respiration and economized endogenous oxygen consumption, while PFC supplied high-capacity exogenous oxygen. These Oxygen modulators reverse the hypoxia status in vitro and in vivo, and exhibited a superior anti-tumor activity by mitochondria targeted PDT via IR780. Ultimately, the anti-tumor effects towards gastric cancer and colon cancer are elicited in vivo.
CONCLUSIONS
This oxygen tank both increases exogeneous oxygen supply and decreases endogenous oxygen consumption, may offer a novel solution for organelle targeted therapies.
PubMed: 36138489
DOI: 10.1186/s40824-022-00296-0 -
Frontiers in Pharmacology 2023
PubMed: 37767402
DOI: 10.3389/fphar.2023.1282233 -
Heliyon Jun 2023Babesiosis is a protozoal disease affect livestock and pet animals such as cattle, buffaloes, sheep, goats, horses, donkeys, mules, dogs, and cats. It causes severe... (Review)
Review
Babesiosis is a protozoal disease affect livestock and pet animals such as cattle, buffaloes, sheep, goats, horses, donkeys, mules, dogs, and cats. It causes severe economic losses in livestock as well as in pet animals. A large number of dairy animals are imported in order to fulfill the demands of milk, milk, meat and its products. In addition, different pet animals are transported from Pakistan to various parts of the world, therefore, it is important to identify the current status and distribution of babesiosis throughout Pakistan in order to control the disease and draw attention for future research, diagnosis, treatment and control of this diseases. No work has been done on a complete review on up-to-date on blood protozoal disease burden in Pakistan. This article will provide about the complete background of babesiosis in ruminants, equines and pet animals, its current status, distribution, vectors in Pakistan and allopathic and ethnoveterinary treatments used against babesiosis. Babesiosis may be subclinical (apparently normal) and may be clinical with acute to chronic disease and sometimes fatal. Babesia is found and develops inside the erythrocytes (red blood cells). Clinically, it causes fever, fatigue, lethargy, pallor mucus membranes, malaise, cachexia, respiratory distress, jaundice, icterus, hemolytic anemia, hemoglobinuria, lymphadenopathy, chollangocytitis, hepatomegaly, and splenomegaly. Chemotherapy for babesiosis includes Imidocarb dipropionate, Diaminazine aceturate Atovaquone and Bupravaquone, Azithromycin, Quinuronium sulfate and Amicarbalidesio-thionate are most widely used. Supportive therapy includes multivitamins, fluid therapy, antipyretics intravenous fluids, and blood transfusions are used if necessary. In addition, there are certain ethnoveterinary (homeopathic) ingredients which having anti-babesial activity. As the resistance against these drugs is developing every day. New more specific long-lasting drugs should be developed for the treatment of Babesiosis. Further studies should be done on disease genome of different species of for vaccine development like malarial parasites.
PubMed: 37441378
DOI: 10.1016/j.heliyon.2023.e17172 -
Tropical Diseases, Travel Medicine and... 2016Recreational diving occurs annually in areas of the world where malaria is endemic. The safety and efficacy of antimalarials for travelers in a hyperbaric environment is... (Review)
Review
BACKGROUND
Recreational diving occurs annually in areas of the world where malaria is endemic. The safety and efficacy of antimalarials for travelers in a hyperbaric environment is unknown. Of particular concern would be medications with adverse effects that could either mimic diving related illnesses such as barotrauma, decompression sickness (DCS) and gas toxicities, or increase the risk for such illnesses.
METHODS
We conducted a review of PubMed and Cochrane databases to determine rates of neurologic adverse effects or other effects from antimalarials that may be a problem in the diving environment.
RESULTS
One case report was found on diving and mefloquine. Multiple case reports and clinical trials were found describing neurologic adverse effects of the major chemoprophylactic medications atovaquone/proguanil, chloroquine, doxycycline, mefloquine, and primaquine.
CONCLUSIONS
Of the available literature, atovaquone/proguanil and doxycycline are most likely the safest agents and should be preferred; atovaquone/proguanil is superior due to reduced rates of sunburn in the marine environment. Primaquine also appears to be safe, but has reduced efficacy against ; mefloquine possesses the highest rate of neurologic side effects and therefore these agents should be limited to extreme cases of patients intolerant to other agents. Chloroquine appears unsafe in the hyperbaric environment and should be avoided. More studies are required to include database reviews of returned divers traveling to malaria endemic areas and randomized controlled trials in the hyperbaric environments.
PubMed: 28883967
DOI: 10.1186/s40794-016-0041-x -
PloS One 2020The plenteous resistance to and undesirable consequences of the existing antipiroplasmic therapies have emphasized the urgent need for new chemotherapeutics and drug...
BACKGROUND
The plenteous resistance to and undesirable consequences of the existing antipiroplasmic therapies have emphasized the urgent need for new chemotherapeutics and drug targets for both prophylaxis and chemotherapy. Hydroxyurea (HYD) is an antineoplastic agent with antitrypanosomal activity. Eflornithine (α-difluoro-methyl ornithine, DFMO) is the best choice therapy for the treatment of late-stage Gambian human African trypanosomiasis.
METHODS
In this study, the inhibitory and combination efficacy of HYD and DFMO with existing babesicidal drugs (diminazene aceturate (DA), atovaquone (ATV), and clofazimine (CLF)) deoxyribonucleotide in vitro against the multiplication of Babesia and Theileria. As well as, their chemotherapeutic effects were assessed on B. microti strain that infects rodents. The Cell Counting Kits-8 (CCK-8) test was used to examine their cytotoxicity on human foreskin fibroblast (HFF), mouse embryonic fibroblast (NIH/3T3), and Madin-Darby bovine kidney (MDBK) cells.
FINDINGS
HYD and DFMO suppressed the multiplication of all tested species (B. bigemina, B. bovis, B. caballi, B. divergens, and T. equi) in a dose-related manner. HFF, NIH/3T3, or MDBK cell viability was not influenced by DFMO at 1000 μM, while HYD affected the MDBK cell viability at EC50 value of 887.5±14.4 μM. The in vitro combination treatments of DFMO and HYD with CLF, DA, and ATV exhibited synergistic and additive efficacy toward all tested species. The in vivo experiment revealed that HYD and DFMO oral administration at 100 and 50 mg/kg inhibited B. microti multiplication in mice by 60.1% and 78.2%, respectively. HYD-DA and DFMO-DA combined treatments showed higher chemotherapeutic efficacy than their monotherapies.
CONCLUSION
These results indicate the prospects of HYD and DFMO as drug candidates for piroplasmosis treatment, when combined mainly with DA, ATV, and CLF. Therefore, further studies are needed to combine HYD or DFMO with either ATV or CLF and examine their impact on B. microti infection in mice.
Topics: Animals; Antineoplastic Agents; Antiprotozoal Agents; Atovaquone; Babesia; Cell Survival; Clofazimine; Diminazene; Dogs; Eflornithine; Foreskin; Humans; Hydroxyurea; Male; Mice; NIH 3T3 Cells; Theileria
PubMed: 32053698
DOI: 10.1371/journal.pone.0228996