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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 -
The Journal of Antimicrobial... May 2013Atovaquone is used as a fixed-dose combination with proguanil (Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for... (Review)
Review
Atovaquone is used as a fixed-dose combination with proguanil (Malarone) for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travellers. Indeed, in the USA, between 2009 and 2011, Malarone prescriptions accounted for 70% of all antimalarial pre-travel prescriptions. In 2013 the patent for Malarone will expire, potentially resulting in a wave of low-cost generics. Furthermore, the malaria scientific community has a number of antimalarial quinolones with a related pharmacophore to atovaquone at various stages of pre-clinical development. With this in mind, it is timely here to review the current knowledge of atovaquone, with the purpose of aiding the decision making of clinicians and drug developers involved in the future use of atovaquone generics or atovaquone derivatives.
Topics: Antimalarials; Atovaquone; Chemoprevention; Drug Combinations; Humans; Malaria; Proguanil; United States
PubMed: 23292347
DOI: 10.1093/jac/dks504 -
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 -
Journal of Travel Medicine Jun 2019
Topics: Aminoquinolines; Antimalarials; Atovaquone; Chemoprevention; Drug Combinations; Drug Therapy, Combination; Humans; Malaria; Proguanil; Travel
PubMed: 30535377
DOI: 10.1093/jtm/tay133 -
Journal of Travel Medicine Jun 2019Malaria during pregnancy increases the risk of maternal and foetal complications. There are very limited options for prophylaxis in pregnant travellers....
BACKGROUND
Malaria during pregnancy increases the risk of maternal and foetal complications. There are very limited options for prophylaxis in pregnant travellers. Atovaquone-Proguanil (AP or Malarone®) is an effective and well-tolerated antimalarial medication, but is not recommended for use in pregnancy due to limited data on safety. Passively reported adverse event data may provide additional information on the safety of AP during pregnancy.
METHODS
We analysed adverse event data on pregnancy and birth outcomes following accidental exposures to AP during pregnancy, which were passively reported to GlaxoSmithKline LLC (GSK) between 13 May 1997 and 15 August 2017. Birth outcomes of interest included live birth, miscarriage, and stillbirth. Adverse outcomes of interest were defined as any of the following: small for gestational age (SGA), low birth weight (LBW, <2500 gm), congenital anomalies, and a composite 'poor live birth outcome,' including preterm birth (PTB), LBW or SGA.
RESULTS
Among 198 women who received AP during pregnancy or breastfeeding, 96.5% occurred in women taking malaria prophylaxis, and 79.8% of exposures occurred in the first trimester. Among 195 with available birth outcome data, 18.5% resulted in miscarriage and 11.8% were elective terminations. Available adverse outcomes included SGA in 3.5% (3/85), LBW in 7.0% of infants (6/86), and the composite 'poor live birth outcome' in 13.7% (14/102). Congenital anomalies were reported in 30/124 (24.2%), with no specific pattern to suggest an effect related to AP.
CONCLUSIONS
These data provide a description of outcomes in the pregnancies reported to this dataset, and it should be noted that there is likely a bias towards reporting cases resulting in poor outcomes. While there was no specific signal to suggest a teratogenic effect of AP, AP data during pregnancy were too limited to determine AP's safety with confidence. As inadvertent exposures are not infrequent, better data are needed.
Topics: Abortion, Spontaneous; Adolescent; Adult; Antimalarials; Atovaquone; Drug Combinations; Female; Humans; Infant, Newborn; Malaria; Middle Aged; Pregnancy; Pregnancy Complications, Parasitic; Pregnancy Outcome; Premature Birth; Proguanil; Travel; Young Adult
PubMed: 30544231
DOI: 10.1093/jtm/tay138 -
Pharmaceutical Patent Analyst Jul 2023Repurposing of approved drugs in a new strategy to combat cancer that leads to savings in time and investment. Atovaquone is a US FDA-approved drug for treatment of...
Repurposing of approved drugs in a new strategy to combat cancer that leads to savings in time and investment. Atovaquone is a US FDA-approved drug for treatment of pneumonia and malaria. Patent US2023017373 describe the use of mito-atovaquone for the treatment of several types of cancer. Mito-atovaquone demonstrated antiproliferative activity in cell lines of pancreatic cancer, lung cancer and brain cancer and inhibited tumor growth in syngeneic mouse models and in animals genetically prone to breast cancer. Mito-atovaquone has the potential to be used successfully in the treatment of various types of tumors.
Topics: Mice; Animals; Atovaquone; Drug Repositioning; Antifungal Agents; Naphthoquinones; Pneumonia, Pneumocystis; Neoplasms; Mitomycin
PubMed: 37801038
DOI: 10.4155/ppa-2023-0015 -
Journal of Travel Medicine May 1999The spread of drug-resistant malaria and appreciation of side effects associated with existing antimalarial drugs emphasize the need for new drugs to prevent malaria.... (Review)
Review
BACKGROUND
The spread of drug-resistant malaria and appreciation of side effects associated with existing antimalarial drugs emphasize the need for new drugs to prevent malaria. The combination of atovaquone and proguanil hydrochloride was previously shown to be safe and highly effective for treatment of malaria, including multi-drug-resistant Plasmodium falciparum.
METHODS
We reviewed results of clinical trials that evaluated either a fixed-dose combination of atovaquone and proguanil hydrochloride for malaria prophylaxis or atovaquone alone for causal prophylactic activity against P. falciparum.
RESULTS
In three placebo-controlled trials, 331 subjects received 250 mg atovaquone and 100 mg proguanil hydrochloride (or an equivalent dose based on body weight in children) once daily for 10 to 12 weeks. The overall efficacy for preventing parasitemia was 98%. Among 175 nonimmune volunteers taking the same dose of atovaquone/proguanil once daily for 10 weeks while temporarily residing in a malaria-endemic area, malaria developed in one patient who was noncompliant with therapy. Results of volunteer challenge studies indicate that both atovaquone and proguanil have causal prophylactic activity directed against the liver stages of P. falciparum. Adverse events occurred with similar or lower frequencies in subjects treated with atovaquone/proguanil compared to placebo. Less than 1% of patients discontinued from these studies due to a treatment-related adverse event.
CONCLUSION
A fixed-dose combination of atovaquone and proguanil hydrocloride is a promising new alternative for malaria prophylaxis.
Topics: Animals; Antimalarials; Atovaquone; Chemoprevention; Drug Combinations; Humans; Malaria, Falciparum; Plasmodium falciparum; Proguanil; Randomized Controlled Trials as Topic; Travel; Treatment Outcome
PubMed: 23573549
DOI: No ID Found -
Viruses Dec 2021Epidemic RNA viruses seem to arise year after year leading to countless infections and devastating disease. SARS-CoV-2 is the most recent of these viruses, but there...
Epidemic RNA viruses seem to arise year after year leading to countless infections and devastating disease. SARS-CoV-2 is the most recent of these viruses, but there will undoubtedly be more to come. While effective SARS-CoV-2 vaccines are being deployed, one approach that is still missing is effective antivirals that can be used at the onset of infections and therefore prevent pandemics. Here, we screened FDA-approved compounds against SARS-CoV-2. We found that atovaquone, a pyrimidine biosynthesis inhibitor, is able to reduce SARS-CoV-2 infection in human lung cells. In addition, we found that berberine chloride, a plant-based compound used in holistic medicine, was able to inhibit SARS-CoV-2 infection in cells through direct interaction with the virion. Taken together, these studies highlight potential avenues of antiviral development to block emerging viruses. Such proactive approaches, conducted well before the next pandemic, will be essential to have drugs ready for when the next emerging virus hits.
Topics: Alveolar Epithelial Cells; Animals; Antiviral Agents; Atovaquone; Berberine; Cell Proliferation; Chlorides; Chlorocebus aethiops; Drug Synergism; Humans; Proguanil; SARS-CoV-2; Vero Cells; Virion; Virus Replication
PubMed: 34960706
DOI: 10.3390/v13122437 -
The Cochrane Database of Systematic... Oct 2005Many conventional treatments for uncomplicated malaria are failing because malaria parasites develop resistance to them. One way to combat this resistance is to treat... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Many conventional treatments for uncomplicated malaria are failing because malaria parasites develop resistance to them. One way to combat this resistance is to treat people with a combination of drugs, such as atovaquone-proguanil.
OBJECTIVES
To compare atovaquone-proguanil with other antimalarial drugs (alone or in combination) for treating children and adults with uncomplicated Plasmodium falciparum malaria.
SEARCH STRATEGY
We searched the Cochrane Infectious Diseases Group Specialized Register (June 2005), CENTRAL (The Cochrane Library Issue 2, 2005), MEDLINE (1966 to June 2005), EMBASE (1980 to June 2005), LILACS (1982 to June 2005), reference lists, and conference abstracts. We also contacted relevant pharmaceutical manufacturers and researchers.
SELECTION CRITERIA
Randomized controlled trials comparing atovaquone-proguanil with other antimalarial drugs for treating children and adults confirmed to have uncomplicated P. falciparum malaria.
DATA COLLECTION AND ANALYSIS
Three authors independently assessed trial eligibility and methodological quality, and extracted data for an intention-to-treat analysis (where possible). We used relative risk (RR) and 95% confidence intervals (CI) for dichotomous data. We contacted trial authors for additional information where needed.
MAIN RESULTS
Ten trials, with a total of 2345 participants, met the inclusion criteria. The trials were conducted in four geographical regions and were often small, but they included comparisons across eight drugs. Nine trials were funded by a pharmaceutical company, only three carried out an intention-to-treat analysis, and allocation concealment was unclear in seven. Atovaquone-proguanil had fewer treatment failures by day 28 than chloroquine (RR 0.04, 95% CI 0.00 to 0.57; 27 participants, 1 trial), amodiaquine (RR 0.22, 95% CI 0.13 to 0.36; 342 participants, 2 trials), and mefloquine (RR 0.04, 95% CI 0.00 to 0.73; 158 participants, 1 trial). There were insufficient data to draw a conclusion for this outcome from comparisons with sulfadoxine-pyrimethamine (172 participants, 2 trials), halofantrine (205 participants, 1 trial), artesunate plus mefloquine (1063 participants, 1 trial), quinine plus tetracycline (154 participants, 1 trial), and dihydroartemisinin-piperaquine-trimethoprim-primaquine (161 participants, 1 trial). Adverse events were mainly common symptoms of malaria and did not differ in frequency between groups.
AUTHORS' CONCLUSIONS
Data are limited but appear to suggest that atovaquone-proguanil is more effective than chloroquine, amodiaquine, and mefloquine. There are insufficient data for comparisons against sulfadoxine-pyrimethamine, halofantrine, artesunate plus mefloquine, quinine plus tetracycline, and dihydroartemisinin-piperaquine-trimethoprim-primaquine in treating malaria. There are not enough data to assess safety, but a number of adverse events were identified with all drugs. Large trials comparing atovaquone-proguanil with other new combination therapies are needed.
Topics: Antimalarials; Atovaquone; Drug Combinations; Humans; Malaria, Falciparum; Naphthoquinones; Proguanil; Randomized Controlled Trials as Topic
PubMed: 16235366
DOI: 10.1002/14651858.CD004529.pub2 -
Journal of Travel Medicine May 1999Atovaquone and proguanil hydrochloride is a new antimalarial combination that is used for treatment and prophylaxis of malaria. (Review)
Review
BACKGROUND
Atovaquone and proguanil hydrochloride is a new antimalarial combination that is used for treatment and prophylaxis of malaria.
METHODS
The clinical pharmacology of atovaquone and proguanil was reviewed.
RESULTS
Atovaquone is a highly lipophilic compound with low aqueous solubility, the absorption of which is limited by the rate and extent of dissolution. Dietary fat increases the rate and extent of atovaquone absorption, increasing AUC two- to threefold and C(max) fivefold over fasting. Proguanil is rapidly and extensively absorbed regardless of food intake. Atovaquone is highly protein bound (> 99%) but does not displace other highly protein bound drugs in vitro, indicating significant drug interactions arising from displacement are unlikely. Atovaquone is predominantly eliminated unchanged in feces, with negligible excretion in urine. Proguanil is partially metabolized and partially excreted unchanged in urine. Its principal metabolite, cycloguanil, is also excreted in urine. Metabolism of proguanil is mediated in the liver by the cytochrome P450 3A and 2C subfamilies. The elimination half-life of atovaquone is 2 to 3 days in adults and 1 to 2 days in children. The elimination half-lives of proguanil and cycloguanil are 12 to 15 hours in adults and children. Dosage adjustments based on body weight categories in children (1/4 dose for 11-20 kg, 1/2 dose for > 20-30 kg, 3/4 dose for > 30-40 kg, and full dose for > 40 kg) achieve plasma concentrations that are safe and effective during prophylaxis and treatment of malaria. No dose adjustments for race, proguanil metabolizer status, gender, or elderly patients are needed, or for patients with mild to moderately impaired renal or hepatic function.
CONCLUSION
The clinical pharmacology of atovaquone and proguanil provides a rationale for the dosing regimens recommended for treatment and prophylaxis of malaria.
Topics: Animals; Antimalarials; Atovaquone; Dose-Response Relationship, Drug; Drug Combinations; Enzyme Activation; Humans; Intestinal Absorption; Intestinal Mucosa; Lymphocytes; Malaria; Malaria, Falciparum; Malaria, Vivax; Proguanil
PubMed: 23573547
DOI: No ID Found