Population pharmacokinetic properties of artemisinin in healthy male Vietnamese volunteers

Birgersson, Sofia; Toi, Pham Van; Truong, Nguyen Thanh; Dung, Nguyen Thi; Ashton, Michael; Hien, Tran Tinh; Äbelö, Angela; Tärning, Joel

doi:10.1186/s12936-016-1134-8

Cited by 22 publications

(13 citation statements)

References 49 publications

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“…The LPV/r model by Dickinson et al (2011) was built from data of healthy volunteers receiving 400/100 mg, the dose that was under investigation in WHO Solidarity. For ART we directly implemented the model developed by Birgersson et al in healthy male volunteers with a dosing regimen of 500 mg daily for 5 days (similar to historical dosing recommendations in malaria) ( Birgersson et al, 2016 ). No published pharmacometric model is available for NTZ.…”

Section: Methodsmentioning

confidence: 99%

Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing

et al. 2021

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Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro, an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3–0.6 log units and exposure by 8.8–22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts.

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Section: Methodsmentioning

confidence: 99%

Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing

et al. 2021

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“…Weak or slow activity could have been occluded by ART's powerful, rapid antimalarial action in both the IC50 and RSA experiments. Because of ART's brief elimination half-time of about 2 hours [47][48][49], residual antimalarial activity from persisting A. annua phytochemicals such as quercetin [50,51] could become medicinally significant after biological elimination of ART. There are, to our knowledge, no human pharmacokinetic data for ART delivery via DLA.…”

Section: Plos Onementioning

confidence: 99%

In vitro analyses of Artemisia extracts on Plasmodium falciparum suggest a complex antimalarial effect

Gruessner

Weathers

2021

PLoS ONE

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Dried-leaf Artemisia annua L. (DLA) antimalarial therapy was shown effective in prior animal and human studies, but little is known about its mechanism of action. Here IC50s and ring-stage assays (RSAs) were used to compare extracts of A. annua (DLAe) to artemisinin (ART) and its derivatives in their ability to inhibit and kill Plasmodium falciparum strains 3D7, MRA1252, MRA1240, Cam3.11 and Cam3.11rev in vitro. Strains were sorbitol and Percoll synchronized to enrich for ring-stage parasites that were treated with hot water, methanol and dichloromethane extracts of DLA, artemisinin, CoArtem™, and dihydroartemisinin. Extracts of A. afra SEN were also tested. There was a correlation between ART concentration and inhibition of parasite growth. Although at 6 hr drug incubation, the RSAs for Cam3.11rev showed DLA and ART were less effective than high dose CoArtem™, 8 and 24 hr incubations yielded equivalent antiparasitic results. For Cam3.11, drug incubation time had no effect. DLAe was more effective on resistant MRA-1240 than on the sensitive MRA-1252 strain. Because results were not as robust as observed in animal and human studies, a host interaction was suspected, so sera collected from adult and pediatric Kenyan malaria patients was used in RSA inhibition experiments and compared to sera from adults naïve to the disease. The sera from both age groups of malaria patients inhibited parasite growth ≥ 70% after treatment with DLAe and compared to malaria naïve subjects suggesting some host interaction with DLA. The discrepancy between these data and in-vivo reports suggested that DLA’s effects require an interaction with the host to unlock their potential as an antimalarial therapy. Although we showed there are serum-based host effects that can kill up to 95% of parasites in vitro, it remains unclear how or if they play a role in vivo. These results further our understanding of how DLAe works against the malaria parasite in vitro.

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“…In the AP treatment, artemisinin has fast and complete oral absorption, wide distribution, fast metabolism and excretion, and a short half-life (1.93 hours) [25] . And piperaquine disappears slowly in the body, with a long half-life (11.7 days) [26] .…”

Section: Discussionmentioning

confidence: 99%