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Nature Communications Jan 2018Chemoprophylaxis is currently the best available prevention from malaria, but its efficacy is compromised by non-adherence to medication. Here we develop a long-acting...
Chemoprophylaxis is currently the best available prevention from malaria, but its efficacy is compromised by non-adherence to medication. Here we develop a long-acting injectable formulation of atovaquone solid drug nanoparticles that confers long-lived prophylaxis against Plasmodium berghei ANKA malaria in C57BL/6 mice. Protection is obtained at plasma concentrations above 200 ng ml and is causal, attributable to drug activity against liver stage parasites. Parasites that appear after subtherapeutic doses remain atovaquone-sensitive. Pharmacokinetic-pharmacodynamic analysis indicates protection can translate to humans at clinically achievable and safe drug concentrations, potentially offering protection for at least 1 month after a single administration. These findings support the use of long-acting injectable formulations as a new approach for malaria prophylaxis in travellers and for malaria control in the field.
Topics: Animals; Anopheles; Antimalarials; Atovaquone; Chemoprevention; Disease Models, Animal; Drug Carriers; Drug Resistance; Female; Humans; Malaria; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Plasmodium berghei; Theranostic Nanomedicine
PubMed: 29358624
DOI: 10.1038/s41467-017-02603-z -
Journal of Travel Medicine Nov 2020
Topics: Antimalarials; Atovaquone; Drug Combinations; Humans; Malaria, Falciparum; Proguanil; Ulcer
PubMed: 33043369
DOI: 10.1093/jtm/taaa198 -
Travel Medicine and Infectious Disease 2020
Atovaquone/proguanil for malaria chemoprophylaxis - Could a difference in susceptibility during hepatic development explain the need to continue drug intake for 7 days post-exposure?
Topics: Atovaquone; Chemoprevention; Drug Combinations; Humans; Malaria; Proguanil
PubMed: 31759143
DOI: 10.1016/j.tmaid.2019.101527 -
ChemMedChem Mar 2008
Topics: Amino Acids; Animals; Antimalarials; Atovaquone; Drug Resistance; Hydrogen-Ion Concentration; Plasmodium falciparum; Structure-Activity Relationship
PubMed: 18064618
DOI: 10.1002/cmdc.200700166 -
European Journal of Pharmaceutical... Apr 2016Emerging parasite resistance and poor oral bioavailability of anti-malarials are the two cardinal issues which hinder the clinical success of malaria chemotherapy....
Emerging parasite resistance and poor oral bioavailability of anti-malarials are the two cardinal issues which hinder the clinical success of malaria chemotherapy. Atovaquone-Proguanil is a WHO approved fixed dose combination used to tackle the problem of emerging resistance. However, Atovaquone is a highly lipophilic drug having poor aqueous solubility (less than 0.2 μg/ml) thus reducing its oral bioavailability. The aim of the present investigation was to explore hot melt extrusion (HME) as a solvent-free technique to enhance solubility and oral bioavailability of Atovaquone and to develop an oral dosage form for Atovaquone-Proguanil combination. Solid dispersion of Atovaquone was successfully developed using HME. The solid dispersion was characterized for DSC, FTIR, XRD, SEM, and flow properties. It was filled in size 2 hard gelatin capsules. The formulation showed better release as compared to Malarone® tablets, and 3.2-fold and 4.6-fold higher bioavailability as compared to Malarone® tablets and Atovaquone respectively. The enhanced bioavailability also resulted in 100% anti-malarial activity in murine infection model at 1/8(th) therapeutic dose. Thus the developed methodology shows promising potential to solve the problems associated with Atovaquone therapy, namely its high cost and poor oral bioavailability, resulting in increased therapeutic efficacy of Atovaquone.
Topics: Administration, Oral; Animals; Antimalarials; Atovaquone; Biological Availability; Drug Combinations; Drug Liberation; Hot Temperature; Malaria; Male; Mice; Plasmodium berghei; Proguanil; Rats, Sprague-Dawley; Solubility; Technology, Pharmaceutical
PubMed: 26969110
DOI: 10.1016/j.ejps.2016.03.005 -
Antimicrobial Agents and Chemotherapy Jun 1997Atovaquone is an antiprotozoal compound with good in vitro stability against metabolic inactivation. Previous human studies which did not involve radiolabelling had not...
Atovaquone is an antiprotozoal compound with good in vitro stability against metabolic inactivation. Previous human studies which did not involve radiolabelling had not accounted for a substantial proportion of the dose. The possible metabolism of atovaquone in men was examined in a radiolabelling study involving four healthy male volunteers. Radioactivity was eliminated almost exclusively via the feces. All radioactivity in plasma, urine, and feces was accounted for by atovaquone, with no evidence of metabolites. Radiolabelled atovaquone was administered to a patient with an indwelling biliary tube after surgery. Biliary radioactivity was approximately 10- to 40-fold higher than that in plasma and was accounted for by atovaquone. Atovaquone is not significantly metabolized in humans but is excreted into bile against a high concentration gradient.
Topics: Adult; Antiprotozoal Agents; Atovaquone; Bile; Biliary Tract; Biliary Tract Surgical Procedures; Carbon Radioisotopes; Feces; Humans; Male; Middle Aged; Naphthoquinones
PubMed: 9174191
DOI: 10.1128/AAC.41.6.1319 -
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 -
Transplant Infectious Disease : An... Feb 2020
Topics: Atovaquone; Hematopoietic Stem Cell Transplantation; Humans; Toxoplasmosis; Transplant Recipients; Treatment Failure
PubMed: 31614058
DOI: 10.1111/tid.13198 -
Journal of Clinical Apheresis Aug 2019
Topics: Anti-Infective Agents; Atovaquone; Color; Humans; Plasma; Plasma Exchange
PubMed: 30597613
DOI: 10.1002/jca.21682 -
Travel Medicine and Infectious Disease 2019Malaria infection poses a significant risk in pregnancy, yet chemoprophylaxis for pregnant women is limited. A systematic review was conducted to evaluate the incidence...
BACKGROUND
Malaria infection poses a significant risk in pregnancy, yet chemoprophylaxis for pregnant women is limited. A systematic review was conducted to evaluate the incidence of adverse outcomes after atovaquone-proguanil (AP) exposure during pregnancy.
METHODS
Following PRISMA guidelines, the authors searched PubMed, MEDLINE, and the Malaria in Pregnancy Consortium Library to identify relevant literature including infant outcomes after exposure to atovaquone, proguanil, or AP in pregnancy. Two authors independently screened the titles, abstracts, and full texts, and extracted data into an EpiInfo database. Overall proportions and 95% confidence intervals of adverse outcomes were determined by pooling data across studies.
RESULTS
Of 455 records identified, 16 studies were included: ten AP studies and six proguanil studies. The overall proportions and 95% confidence intervals (CI) of adverse outcomes reported for the 446 women exposed to AP include miscarriage (8.08% CI: 5.07, 12.08%), stillbirth (1.05% CI: 0.03, 5.73%), early neonatal death (0% CI: 0, 7.4%), and congenital anomalies (2.56% CI: 1.28, 4.53%).
CONCLUSIONS
The limited available data suggest that outcomes following AP exposure during pregnancy are similar to expected rates in similar populations. AP may be a promising option for pregnant women, but further data are needed on its safety in pregnancy.
Topics: Abortion, Spontaneous; Antimalarials; Atovaquone; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Infant, Newborn; Malaria; Malaria, Falciparum; Pregnancy; Pregnancy Complications, Parasitic; Proguanil; Stillbirth; Travel
PubMed: 30654041
DOI: 10.1016/j.tmaid.2019.01.008