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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 -
Journal of Travel Medicine May 1999Safe and effective new drugs are needed for treatment of malaria. Atovaquone and proguanil hydrochloride is a new antimalarial combination that has recently become... (Review)
Review
BACKGROUND
Safe and effective new drugs are needed for treatment of malaria. Atovaquone and proguanil hydrochloride is a new antimalarial combination that has recently become available in many countries.
METHODS
Data from clinical trials evaluating atovaquone/proguanil for treatment of malaria were reviewed.
RESULTS
In 10 open-label clinical trials, treatment of uncomplicated falciparum malaria with 1000 mg atovaquone and 400 mg proguanil hydrochloride (or the equivalent based on body weight in patients < or = 40 kg) once daily for 3 days achieved cure in 514 of 521 (99%) evaluable patients. Treatment-limiting adverse events occurred in < 1% of patients (vomiting in four, anaphylaxis in one). Atovaquone/proguanil has been used to provide radical cure of asymptomatic Plasmodium falciparum infections prior to initiation of placebo-controlled trials of malaria prophylaxis. Recurrent parasitemia occurred within 28 days in 0 of 99 subjects who subsequently received prophylaxis with atovaquone/proguanil and 1 of 81 subjects who subsequently received placebo. Atovaquone/proguanil is also effective for treatment of malaria caused by the other three Plasmodium species that cause malaria in humans. For treatment of vivax malaria, therapy with primaquine in addition to atovaquone/proguanil is needed to prevent relapse from latent hepatic hypnozoites.
CONCLUSION
Atovaquone and proguanil hydrochloride is a safe and effective combination for treatment of malaria.
Topics: Antimalarials; Atovaquone; Chemoprevention; Drug Combinations; Humans; Malaria, Falciparum; Plasmodium falciparum; Proguanil; Travel
PubMed: 23573548
DOI: No ID Found -
Viruses Aug 2023The emergence of SARS-CoV-1 in 2003 followed by MERS-CoV and now SARS-CoV-2 has proven the latent threat these viruses pose to humanity. While the SARS-CoV-2 pandemic...
The emergence of SARS-CoV-1 in 2003 followed by MERS-CoV and now SARS-CoV-2 has proven the latent threat these viruses pose to humanity. While the SARS-CoV-2 pandemic has shifted to a stage of endemicity, the threat of new coronaviruses emerging from animal reservoirs remains. To address this issue, the global community must develop small molecule drugs targeting highly conserved structures in the coronavirus proteome. Here, we characterized existing drugs for their ability to inhibit the endoribonuclease activity of the SARS-CoV-2 non-structural protein 15 (nsp15) via in silico, in vitro, and in vivo techniques. We have identified nsp15 inhibition by the drugs pibrentasvir and atovaquone which effectively inhibit SARS-CoV-2 and HCoV-OC43 at low micromolar concentrations in cell cultures. Furthermore, atovaquone, but not pibrentasvir, is observed to modulate HCoV-OC43 dsRNA and infection in a manner consistent with nsp15 inhibition. Although neither pibrentasvir nor atovaquone translate to clinical efficacy in a murine prophylaxis model of SARS-CoV-2 infection, atovaquone may serve as a basis for the design of future nsp15 inhibitors.
Topics: Animals; Mice; SARS-CoV-2; COVID-19; Atovaquone; Endoribonucleases; Coronavirus OC43, Human
PubMed: 37766247
DOI: 10.3390/v15091841 -
Investigative Ophthalmology & Visual... Mar 2018Aspergillus and Fusarium molds cause blinding corneal infections as a consequence of ocular trauma and in association with contact lens wear. As these fungi require zinc...
PURPOSE
Aspergillus and Fusarium molds cause blinding corneal infections as a consequence of ocular trauma and in association with contact lens wear. As these fungi require zinc for fungal growth, we examined the effect of atovaquone, a ubiquinone analog that disrupts zinc homeostasis, on fungal growth in vitro and in vivo.
METHODS
In vitro: Aspergillus and Fusarium germinating conidia were incubated overnight with atovaquone, and hyphal growth was measured by fluorimetry. In vivo: C57BL/6 mouse corneas were infected with Aspergillus or Fusarium conidia. Atovaquone was added topically and corneal opacification and fungal growth were quantified.
RESULTS
Atovaquone has antifungal activity against Aspergillus and Fusarium clinical isolates, with Fusarium species being more sensitive to atovaquone than Aspergillus species. Atovaquone also reduced labile intracellular zinc levels and increased the sensitivity of Aspergillus to metal shock. Atovaquone reduced vacuolar acidification, which regulates storage of intracellular free zinc, and also acted synergistically with voriconazole and itraconazole to kill hyphae. Furthermore, mitochondrial potential and ATP production were reduced in both Aspergillus and Fusarium following atovaquone treatment. Finally, topical application of atovaquone to the ocular surface significantly inhibited fungal growth and corneal opacification in murine models of fungal keratitis.
CONCLUSIONS
These studies demonstrate that atovaquone has pronounced in vitro and in vivo antifungal activity against filamentous fungi by disrupting both metal homeostasis and mitochondrial function, and therefore has potential as a novel antifungal agent.
Topics: Animals; Antifungal Agents; Aspergillus; Atovaquone; Disease Models, Animal; Epithelial Cells; Eye Infections, Fungal; Fusarium; Homeostasis; Hyphae; Keratitis; Mice; Mice, Inbred C57BL; Mitochondria; Zinc
PubMed: 29625485
DOI: 10.1167/iovs.17-22585 -
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 -
Interdisciplinary Perspectives on... 2009Human babesiosis is an emerging tick-borne infectious disease caused by intraerythrocytic protozoan species of the genus Babesia with many clinical features similar to...
Human babesiosis is an emerging tick-borne infectious disease caused by intraerythrocytic protozoan species of the genus Babesia with many clinical features similar to those of malaria. Over the last 50 years, the epidemiology of human babesiosis has changed from a few isolated cases to the establishment of endemic areas in the northeastern and midwestern United States. Episodic cases are reported in Europe, Asia, Africa, and South America. The severity of infection ranges from asymptomatic infection to fulminant disease resulting in death, although the majority of healthy adults experience a mild-to-moderate illness. People over the age of 50 years and immunocompromised individuals are at the highest risk of severe disease, including those with malignancy, HIV, lacking a spleen, or receiving immunosuppressive drugs. Asymptomatic carriers present a blood safety risk when they donate blood. Definitive diagnosis of babesial infection generally is made by microscopic identification of the organism on thin blood smear, amplification of Babesia DNA using PCR, and detection of Babesia antibody in acute and convalescent sera. Specific antimicrobial therapy consists of atovaquone and azithromycin or clindamycin and quinine. Exchange transfusion is used in severe cases. The use of multiple prevention strategies is recommended and consists of personal, residential, and community approaches.
PubMed: 19727410
DOI: 10.1155/2009/984568 -
Biomedicine & Pharmacotherapy =... Jun 2023The continuing heavy toll of the COVID-19 pandemic necessitates development of therapeutic options. We adopted structure-based drug repurposing to screen FDA-approved...
The continuing heavy toll of the COVID-19 pandemic necessitates development of therapeutic options. We adopted structure-based drug repurposing to screen FDA-approved drugs for inhibitory effects against main protease enzyme (Mpro) substrate-binding pocket of SARS-CoV-2 for non-covalent and covalent binding. Top candidates were screened against infectious SARS-CoV-2 in a cell-based viral replication assay. Promising candidates included atovaquone, mebendazole, ouabain, dronedarone, and entacapone, although atovaquone and mebendazole were the only two candidates with IC50s that fall within their therapeutic plasma concentration. Additionally, we performed Mpro assays on the top hits, which demonstrated inhibition of Mpro by dronedarone (IC50 18 µM), mebendazole (IC50 19 µM) and entacapone (IC50 9 µM). Atovaquone showed only modest Mpro inhibition, and thus we explored other potential mechanisms. Although atovaquone is Dihydroorotate dehydrogenase (DHODH) inhibitor, we did not observe inhibition of DHODH at the respective SARS-CoV-2 IC50. Metabolomic profiling of atovaquone treated cells showed dysregulation of purine metabolism pathway metabolite, where ecto-5'-nucleotidase (NT5E) was downregulated by atovaquone at concentrations equivalent to its antiviral IC50. Atovaquone and mebendazole are promising candidates with SARS-CoV-2 antiviral activity. While mebendazole does appear to target Mpro, atovaquone may inhibit SARS-CoV-2 viral replication by targeting host purine metabolism.
Topics: Humans; Antiviral Agents; SARS-CoV-2; COVID-19; Dihydroorotate Dehydrogenase; Drug Repositioning; Dronedarone; Pandemics; Atovaquone; Mebendazole; Purines; Molecular Docking Simulation; Protease Inhibitors; Molecular Dynamics Simulation
PubMed: 37068330
DOI: 10.1016/j.biopha.2023.114614 -
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 -
Antimicrobial Agents and Chemotherapy Dec 2015Toxoplasma gondii is an apicomplexan parasite of humans and other mammals, including livestock and companion animals. While chemotherapeutic regimens, including... (Review)
Review
Toxoplasma gondii is an apicomplexan parasite of humans and other mammals, including livestock and companion animals. While chemotherapeutic regimens, including pyrimethamine and sulfadiazine regimens, ameliorate acute or recrudescent disease such as toxoplasmic encephalitis or ocular toxoplasmosis, these drugs are often toxic to the host. Moreover, no approved options are available to treat infected women who are pregnant. Lastly, no drug regimen has shown the ability to eradicate the chronic stage of infection, which is characterized by chemoresistant intracellular cysts that persist for the life of the host. In an effort to promote additional chemotherapeutic options, we now evaluate clinically available drugs that have shown efficacy in disease models but which lack clinical case reports. Ideally, less-toxic treatments for the acute disease can be identified and developed, with an additional goal of cyst clearance from human and animal hosts.
Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Antiprotozoal Agents; Antipsychotic Agents; Atovaquone; Clindamycin; Drug Repositioning; Humans; Macrolides; Parasitic Sensitivity Tests; Pyrimethamine; Sulfadiazine; Toxoplasma; Toxoplasmosis
PubMed: 26392504
DOI: 10.1128/AAC.02009-15 -
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