Comparison of the Pharmacokinetics and Ex Vivo Antimalarial Activities of Artesunate–Amodiaquine and Artemisinin–Piperaquine in Healthy Volunteers for Preselection Malaria Therapy

Quang, Nguyen Ngọc; Chavchich, Marina; Anh, Chu Xuan; Birrell, Geoff W.; Breda, Karin van; Travers, Thomas; Rowcliffe, Kerryn; Edstein, Michael D.

doi:10.4269/ajtmh.17-0434

Cited by 7 publications

(7 citation statements)

References 40 publications

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“…In order to gain an insight into the ex vivo antimalarial activity of ACTs, it is necessary to acquire information on the intrinsic activity of the drugs and their active metabolites using in vitro assays and culture-adapted field isolates. In the present study, the prodrugs AS and AQ were rapidly metabolized and eliminated (31), with most of the antimalarial activity coming from their respective metabolites, DHA and DAQ. Using conditions approximating the characteristics of blood (i.e., 50% plasma) in the in vitro drug susceptibility assay, the mean (Ϯ SD) IC 50 s against the artemisinin-sensitive MRA1239 line were 1.2 Ϯ 0.7 nM for DHA, 16.2 Ϯ 4.3 nM for DAQ, and 7.8 Ϯ 2.5 nM for MB.…”

Section: Resultsmentioning

confidence: 59%

“…Ex vivo antimalarial activity of ASAQ versus ASAQ؉MB. Information concerning the ex vivo activity and PK of antimalarials, including their active metabolites in blood collected from healthy volunteers or malaria patients following drug treatment, has aided the selection and development of drugs, including ACTs (31)(32)(33)(34). Distinct advantages of the ex vivo assay are that it measures the overall activity of drugs and their metabolites at physiological concentrations achieved in the participant's blood after treatment and that it is independent of the immune status of individuals.…”

Section: Resultsmentioning

confidence: 99%

“…Both MRA lines were obtained from BEI Resources (Manassas, VA). Parasites were cultured as previously described (31).…”

Section: Methodsmentioning

confidence: 99%

“…In vitro antimalarial activity of reference drugs. Evaluation of the in vitro antimalarial activity of DAQ, DHA, and MB was carried out using the [ 3 H]hypoxanthine incorporation assay in parasites, which were cultured in RPMI 1640 media with 50% human plasma as previously described (31). Drug IC 50 s (i.e., concentrations that cause 50% inhibition of parasite growth or [ 3 H]hypoxanthine uptake compared with drug-free samples) were determined using nonlinear regression analysis (GraphPad Prism V5.0; GraphPad Software, Inc., CA).…”

Section: Methodsmentioning

confidence: 99%

“…The 50% inhibitory dilution (ID 50 ) of the volunteer plasma sample was defined as the severalfold value of the volunteer's plasma samples that resulted in a 50% inhibition of uptake of [ 3 H]hypoxanthine (surrogate for parasite growth) compared to drug-free plasma samples (controls) as previously described (30)(31)(32)34). The ID 50 values were determined by nonlinear regression analysis of the [ 3 H]hypoxanthine incorporation versus plasma sample dilution (log-transformed value) curves using GraphPad software (Prism V5.0; GraphPad Software, Inc., CA).…”

Section: Methodsmentioning

confidence: 99%

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Pharmacokinetics and Ex Vivo Antimalarial Activity of Artesunate-Amodiaquine plus Methylene Blue in Healthy Volunteers

Anh

Chavchich²,

Birrell³

et al. 2020

Antimicrob Agents Chemother

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High rates of artemisinin-based combination therapy (ACT) failures in the treatment of Plasmodium falciparum malaria in Southeast Asia have led to triple-drug strategies to extend the useful life of ACTs. In this study, we determined whether methylene blue [MB; 3,7-bis(dimethylamino)phenothiazin-5-ium chloride hydrate] alters the pharmacokinetics of artesunate-amodiaquine (ASAQ) and enhances the ex vivo antimalarial activity of ASAQ. In an open-label, randomized crossover design, a single oral dose of ASAQ (200 mg AS/540 mg AQ) alone or with MB (325 mg) was administered to 15 healthy Vietnamese volunteers. Serial blood samples were collected up to 28 days after dosing. Pharmacokinetic properties of the drugs were determined by noncompartmental analysis. After drug administration, plasma samples from seven participants were assessed for ex vivo antimalarial activity against the artemisinin-sensitive MRA1239 and the artemisinin-resistant MRA1240 P. falciparum lines, in vitro. MB significantly increased the mean area under the curve of the active metabolite of AS, dihydroartemisinin (1,246 ± 473 versus 917 ± 405 ng·h/ml, P = 0.009) but did not alter the pharmacokinetics of AQ, AS, or desethylamodiaquine. Comparing the antimalarial activities of the plasma samples from the participants collected up to 48 h after ASAQ plus MB (ASAQ+MB) and ASAQ dosing against the MRA1239 and MRA1240 lines, MB significantly enhanced the blood schizontocidal activity of ASAQ by 2.0-fold and 1.9-fold, respectively. The ring-stage survival assay also confirmed that MB enhanced the ex vivo antimalarial activity of ASAQ against MRA1240 by 2.9-fold to 3.8-fold, suggesting that the triple-drug combination has the potential to treat artemisinin-resistant malaria and for malaria elimination. (This study has been registered in the Australian New Zealand Clinical Trials Registry [https://anzctr.org.au/] under registration number ACTRN12612001298808.)

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Section: Resultsmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 99%

“…Both MRA lines were obtained from BEI Resources (Manassas, VA). Parasites were cultured as previously described (31).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacokinetics and Ex Vivo Antimalarial Activity of Artesunate-Amodiaquine plus Methylene Blue in Healthy Volunteers

Anh

Chavchich²,

Birrell³

et al. 2020

Antimicrob Agents Chemother

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Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19

Bocci

Bradfute

et al. 2020

ACS Pharmacol. Transl. Sci.

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The urgent need for a cure for early phase COVID-19 infected patients critically underlines drug repositioning strategies able to efficiently identify new and reliable treatments by merging computational, experimental, and pharmacokinetic expertise. Here we report new potential therapeutics for COVID-19 identified with a combined virtual and experimental screening strategy and selected among already approved drugs. We used hydroxychloroquine (HCQ), one of the most studied drugs in current clinical trials, as a reference template to screen for structural similarity against a library of almost 4000 approved drugs. The top-ranked drugs, based on structural similarity to HCQ, were selected for in vitro antiviral assessment. Among the selected drugs, both zuclopenthixol and nebivolol efficiently block SARS-CoV-2 infection with EC 50 values in the low micromolar range, as confirmed by independent experiments. The anti-SARS-CoV-2 potential of ambroxol, amodiaquine, and its active metabolite ( N -monodesethyl amodiaquine) is also discussed. In trying to understand the “hydroxychloroquine” mechanism of action, both p K a and the HCQ aromatic core may play a role. Further, we show that the amodiaquine metabolite and, to a lesser extent, zuclopenthixol and nebivolol are active in a SARS-CoV-2 titer reduction assay. Given the need for improved efficacy and safety, we propose zuclopenthixol, nebivolol, and amodiaquine as potential candidates for clinical trials against the early phase of the SARS-CoV-2 infection and discuss their potential use as adjuvant to the current (i.e., remdesivir and favipiravir) COVID-19 therapeutics.

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Therapeutic efficacy of pyronaridine-artesunate (Pyramax) in treating Plasmodium vivax malaria in the central highlands of Vietnam

Manh,

Thanh,

Quang

et al. 2024

Antimicrob Agents Chemother

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The emergence and spread of chloroquine-resistant Plasmodium vivax have necessitated the assessment of alternative blood schizonticidal drugs. In Vietnam, chloroquine-resistant P. vivax malaria has been reported. In an open-label, single-arm trial, the safety, tolerability, and efficacy of pyronaridine-artesunate (Pyramax, PA) was evaluated in Dak Nong province, Vietnam. A 3-day course of PA was administered to adults and children (≥20 kg) infected with P. vivax . Patients also received primaquine (0.25 mg/kg daily for 14 days). PA was well tolerated with transient asymptomatic increases in liver transaminases. The per-protocol proportion of patients with day 42 PCR-unadjusted adequate clinical and parasitological response was 96.0% (95% CI, 84.9%–99.0%, n = 48/50). The median parasite clearance time was 12 h (range, 12–36 h), with a median fever clearance time of 24 h (range, 12–60 h). Single nucleotide polymorphisms (SNPs) as potential genetic markers of reduced drug susceptibility were analyzed in three putative drug resistance markers, Pvcrt-o , Pvmdr1 , and PvK12 . Insertion at position K10 of the Pvcrt-o gene was found in 74.6% (44/59) of isolates. Pvmdr1 SNPs at Y976F and F1076L were present in 61% (36/59) and 78% (46/59), respectively. Amplification of Pvmdr1 gene (two copies) was found in 5.1% (3/59) of parasite samples. Only 5.1% (3/59) of isolates had mutation 552I of the PvK12 gene. Overall, PA rapidly cleared P. vivax blood asexual stages and was highly efficacious in treating vivax malaria, with no evidence of artemisinin resistance found. PA provides an alternative to chloroquine treatment for vivax malaria in Vietnam. CLINICAL TRIALS This study is registered with the Australian New Zealand Clinical Trials Registry as ACTRN12618001429246 .

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Comparison of the Pharmacokinetics and Ex Vivo Antimalarial Activities of Artesunate–Amodiaquine and Artemisinin–Piperaquine in Healthy Volunteers for Preselection Malaria Therapy

Cited by 7 publications

References 40 publications

Pharmacokinetics and Ex Vivo Antimalarial Activity of Artesunate-Amodiaquine plus Methylene Blue in Healthy Volunteers

Pharmacokinetics and Ex Vivo Antimalarial Activity of Artesunate-Amodiaquine plus Methylene Blue in Healthy Volunteers

Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19

Therapeutic efficacy of pyronaridine-artesunate (Pyramax) in treating Plasmodium vivax malaria in the central highlands of Vietnam

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