Safety and Efficacy of Tafenoquine for Plasmodium vivax Malaria Prophylaxis and Radical Cure: Overview and Perspectives

Markus, Miles B.

doi:10.2147/tcrm.s269336

Cited by 8 publications

(7 citation statements)

References 105 publications

(125 reference statements)

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“…Nevertheless, future work could directly quantify the magnitude of these site-specific biases by fitting transmission models directly to clinical trial data collected from trial sites that vary with respect to transmission intensity, heterogeneity in biting, and relapse rate. Second, there remains much about P. vivax biology that is not well understood [ 50 , 51 ], so the simplified representation of hypnozoite activation and death in the transmission model may not fully capture reality. Third, it did not account for the effect of cytochrome P-450 polymorphisms on drug efficacy directly.…”

Section: Discussionmentioning

confidence: 99%

How radical is radical cure? Site-specific biases in clinical trials underestimate the effect of radical cure on Plasmodium vivax hypnozoites

Huber

Koepfli

España

et al. 2021

Malar J

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Background Plasmodium vivax blood-stage relapses originating from re-activating hypnozoites are a major barrier for control and elimination of this disease. Radical cure is a form of therapy capable of addressing this problem. Recent clinical trials of radical cure have yielded efficacy estimates ranging from 65 to 94%, with substantial variation across trial sites. Methods An analysis of simulated trial data using a transmission model was performed to demonstrate that variation in efficacy estimates across trial sites can arise from differences in the conditions under which trials are conducted. Results The analysis revealed that differences in transmission intensity, heterogeneous exposure and relapse rate can yield efficacy estimates ranging as widely as 12–78%, despite simulating trial data under the uniform assumption that treatment had a 75% chance of clearing hypnozoites. A longer duration of prophylaxis leads to a greater measured efficacy, particularly at higher transmission intensities, making the comparison between the protection of different radical cure treatment regimens against relapse more challenging. Simulations show that vector control and parasite genotyping offer two potential means to yield more standardized efficacy estimates that better reflect prevention of relapse. Conclusions Site-specific biases are likely to contribute to variation in efficacy estimates both within and across clinical trials. Future clinical trials can reduce site-specific biases by conducting trials in low-transmission settings where re-infections from mosquito bite are less common, by preventing re-infections using vector control measures, or by identifying and excluding likely re-infections that occur during follow-up, by using parasite genotyping methods.

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Section: Discussionmentioning

confidence: 99%

How radical is radical cure? Site-specific biases in clinical trials underestimate the effect of radical cure on Plasmodium vivax hypnozoites

Huber

Koepfli

España

et al. 2021

Malar J

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“…1 ), is largely unknown. Hypnozoites comprise a large hidden subpopulation of the total P. vivax parasite biomass [ 196 ], and treatment options to kill them are currently limited to primaquine and tafenoquine, both with contraindications for pregnant individuals and anyone with glucose-6-phosphate-dehydrogenase deficiency; thus neither are ideal drugs [ 10 , 166 , 197 ]. Hypnozoites have low metabolic activity and are few in number in the liver, and therefore they have been a challenge to study and in turn discover essential biologically pathways to help advance non-haemolytic radical curative treatments.…”

Section: Twenty-first Century—turning Point In Malaria Researchmentioning

confidence: 99%

Systems biology of malaria explored with nonhuman primates

Galinski

2022

Malar J

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Abstract“The Primate Malarias” book has been a uniquely important resource for multiple generations of scientists, since its debut in 1971, and remains pertinent to the present day. Indeed, nonhuman primates (NHPs) have been instrumental for major breakthroughs in basic and pre-clinical research on malaria for over 50 years. Research involving NHPs have provided critical insights and data that have been essential for malaria research on many parasite species, drugs, vaccines, pathogenesis, and transmission, leading to improved clinical care and advancing research goals for malaria control, elimination, and eradication. Whilst most malaria scientists over the decades have been studying Plasmodium falciparum, with NHP infections, in clinical studies with humans, or using in vitro culture or rodent model systems, others have been dedicated to advancing research on Plasmodium vivax, as well as on phylogenetically related simian species, including Plasmodium cynomolgi, Plasmodium coatneyi, and Plasmodium knowlesi. In-depth study of these four phylogenetically related species over the years has spawned the design of NHP longitudinal infection strategies for gathering information about ongoing infections, which can be related to human infections. These Plasmodium-NHP infection model systems are reviewed here, with emphasis on modern systems biological approaches to studying longitudinal infections, pathogenesis, immunity, and vaccines. Recent discoveries capitalizing on NHP longitudinal infections include an advanced understanding of chronic infections, relapses, anaemia, and immune memory. With quickly emerging new technological advances, more in-depth research and mechanistic discoveries can be anticipated on these and additional critical topics, including hypnozoite biology, antigenic variation, gametocyte transmission, bone marrow dysfunction, and loss of uninfected RBCs. New strategies and insights published by the Malaria Host–Pathogen Interaction Center (MaHPIC) are recapped here along with a vision that stresses the importance of educating future experts well trained in utilizing NHP infection model systems for the pursuit of innovative, effective interventions against malaria.

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“…Another 8-aminoquinoline in clinical development for the treatment of malaria is tafenoquine [ 35 ]. This drug also exhibits antileishmanial activity in vitro against several Leishmania species, and in vivo in the L. donovani /BALB/c mice model, with 50% effective dose (ED 50 ) values of 1.2 to 3.5 mg/kg for 5 days [ 36 ].…”

Section: The Place Of Quinolines As Drug Candidates In the Treatment ...mentioning

confidence: 99%

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

et al. 2022

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There is a need for new, cost-effective drugs to treat leishmaniasis. A strategy based on traditional medicine practiced in Bolivia led to the discovery of the 2-substituted quinoline series as a source of molecules with antileishmanial activity and low toxicity. This review documents the development of the series from the first isolated natural compounds through several hundred synthetized molecules to an optimized compound exhibiting an in vitro IC50 value of 0.2 µM against Leishmania donovani, and a selectivity index value of 187, together with in vivo activity on the L. donovani/hamster model. Attempts to establish structure–activity relationships are described, as well as studies that have attempted to determine the mechanism of action. For the latter, it appears that molecules of this series act on multiple targets, possibly including the immune system, which could explain the observed lack of drug resistance after in vitro drug pressure. We also show how nanotechnology strategies could valorize these drugs through adapted formulations and how a mechanistic targeting approach could generate new compounds with increased activity.

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Safety and Efficacy of Tafenoquine for Plasmodium vivax Malaria Prophylaxis and Radical Cure: Overview and Perspectives

Cited by 8 publications

References 105 publications

How radical is radical cure? Site-specific biases in clinical trials underestimate the effect of radical cure on Plasmodium vivax hypnozoites

How radical is radical cure? Site-specific biases in clinical trials underestimate the effect of radical cure on Plasmodium vivax hypnozoites

Systems biology of malaria explored with nonhuman primates

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

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