ArticleJCI insight2018
Assessing drug efficacy against Plasmodium falciparum liver stages in vivo.
Article in JCI insight, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 28 citations in OpenAlex.
- Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study.The Lancet. Infectious diseases · 2018Trial
- A humanized mouse model of APOB deficiency recapitulates hypobetalipoproteinemia.Journal of lipid research · 2026Article
- Poly(I:C) and R848 adjuvants elicit sizeable humoral immunity to liver stage malaria antigens.Frontiers in immunology · 2026Article
- The Importance of Murine Models in Determining In Vivo Pharmacokinetics, Safety, and Efficacy in Antimalarial Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.Journal of medicinal chemistry · 2025Article
- Novel hydrazone compounds with broad-spectrum antiplasmodial activity and synergistic interactions with antimalarial drugs.Antimicrobial agents and chemotherapy · 2024Article
- Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening.Communications biology · 2023Article
- A pharmacokinetic-pharmacodynamic model for chemoprotective agents against malaria.CPT: pharmacometrics & systems pharmacology · 2023Article
- Article
- Model-informed target product profiles of long-acting-injectables for use as seasonal malaria prevention.PLOS global public health · 2022Article
- Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.Journal of medicinal chemistry · 2021Article
- Identification ofMicroorganisms · 2021Article
- Humanized Mice and the Rebirth of Malaria Genetic Crosses.Trends in parasitology · 2020Review
- Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.Journal of medicinal chemistry · 2020Article
- Generation of NovelFrontiers in cellular and infection microbiology · 2020Article
- Reassessing therapeutic antibodies for neglected and tropical diseases.PLoS neglected tropical diseases · 2020Review
- DSM265 at 400 Milligrams Clears Asexual Stage Parasites but Not Mature Gametocytes from the Blood of Healthy Subjects Experimentally Infected withAntimicrobial agents and chemotherapy · 2019Article
- AFrontiers in cellular and infection microbiology · 2019Article
- Injectable anti-malarials revisited: discovery and development of new agents to protect against malaria.Malaria journal · 2018Review
- Recent updates in the discovery and development of novel antimalarial drug candidates.MedChemComm · 2018Review
Corrections and comments
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Authors and funding
22 authors at 6 institutions in 3 countries.
Funding
Abstract
Malaria eradication necessitates new tools to fight the evolving and complex Plasmodium pathogens. These tools include prophylactic drugs that eliminate Plasmodium liver stages and consequently prevent clinical disease, decrease transmission, and reduce the propensity for resistance development. Currently, the identification of these drugs relies on in vitro P. falciparum liver stage assays or in vivo causal prophylaxis assays using rodent malaria parasites; there is no method to directly test in vivo liver stage activity of candidate antimalarials against the human malaria-causing parasite P. falciparum. Here, we use a liver-chimeric humanized mouse (FRG huHep) to demonstrate in vivo P. falciparum liver stage development and describe the efficacy of clinically used and candidate antimalarials with prophylactic activity. We show that daily administration of atovaquone-proguanil (ATQ-PG; ATQ, 30 mg/kg, and PG, 10 mg/kg) protects 5 of 5 mice from liver stage infection, consistent with the use in humans as a causal prophylactic drug. Single-dose primaquine (60 mg/kg) has similar activity to that observed in humans, demonstrating the activity of this drug (and its active metabolites) in FRG huHep mice. We also show that DSM265, a selective Plasmodial dihydroorotate dehydrogenase inhibitor with causal prophylactic activity in humans, reduces liver stage burden in FRG huHep mice. Finally, we measured liver stage-to-blood stage transition of the parasite, the ultimate readout of prophylactic activity and measurement of infective capacity of parasites in the liver, to show that ATQ-PG reduces blood stage patency to below the limit of quantitation by quantitative PCR (qPCR). The FRG huHep model, thus, provides a platform for preclinical evaluation of drug candidates for liver stage causal prophylactic activity, pharmacokinetic/pharmacodynamics studies, and biological studies to investigate the mechanism of action of liver stage active antimalarials.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.