The chemistry, pharmacology, and clinical applications of qinghaosu (Artemisinin) and its derivatives

Luo, Xuan-De; Shen, Chia-Chiang

doi:10.1002/med.2610070103

Cited by 317 publications

(170 citation statements)

References 14 publications

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“…3). The lack of reactivity with Hb may also help to explain the absence of toxicity toward healthy erythrocytes compared to the potent activity against intraerythrocytic parasites (9,17,36). Hb is present at approximately 5 mM within the human erythrocyte (8), which, if capable of reaction with peroxide antimalarials, could potentially mediate peroxide inactivation and clearance or activation to generate toxic reactive intermediates.…”

Section: Figmentioning

confidence: 99%

Stability of Peroxide Antimalarials in the Presence of Human Hemoglobin

Creek

Ryan

Charman

et al. 2009

Antimicrob Agents Chemother

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Peroxide antimalarials, including artemisinin, are important for the treatment of multidrug-resistant malaria. These peroxides are known to react with iron or heme to produce reactive intermediates that are thought to be responsible for their antimalarial activities. This study investigated the potential interaction of selected peroxide antimalarials with oxyhemoglobin, the most abundant form of iron in the human body. The observed stability of artemisinin derivatives and 1,2,4-trioxolanes in the presence of oxyhemoglobin was in contrast to previous reports in the literature. Spectroscopic analysis of hemoglobin found it to be unstable under the conditions used for previous studies, and it appears likely that the artemisinin reactivity reported in these studies may be attributed to free heme released by protein denaturation. The stability of peroxide antimalarials with intact oxyhemoglobin, and reactivity with free heme, may explain the selective toxicity of these antimalarials toward infected, but not healthy, erythrocytes.

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Section: Figmentioning

confidence: 99%

Stability of Peroxide Antimalarials in the Presence of Human Hemoglobin

Creek

Ryan

Charman

et al. 2009

Antimicrob Agents Chemother

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“…The leaves of Artemisia annua (L.) are a rich source of artemisinin, a sesquiterpene lactone used as the raw material for the production of semi-synthetic derivatives that are more stable, bioavailable, and effective against chloroquine-resistant strains of Plasmodium falciparum (Klayman, 1985;Luo and Shen, 1987;Balint, 2001;Enserink, 2005;WHO 2005. Besides its antimalarial activity, artemisinin has proved effective against cancer (Posner et al, 1999;Singh and Lai, 2004;Efferth, 2005), Eimeria spp., Babesia spp., Leishmania spp., Neospora caninum, Trypanosoma brucei rhodesiense (Mishina et al, 2007), and Schistosoma spp.…”

Section: Introductionmentioning

confidence: 99%

Water deficit effect on the accumulation of biomass and artemisinin in annual wormwood(Artemisia annua L., Asteraceae)

Marchese

Ferreira²,

Rehder

et al. 2010

Braz. J. Plant Physiol.

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Despite the importance of Artemisia annua L. as the only source of the anti-parasitic drug artemisinin, little is known on the effects of biotic and abiotic stress on artemisinin accumulation. Water deficit is the most limiting factor on plant growth, however it can trigger secondary metabolite accumulation, depending on the plant growth stage and intensity. A. annua cultivated in growth chambers was submitted to five water deficit treatments (watered, 14, 38, 62 e 86 hours without irrigation). Water deficits of 38 and 62 hours (Ψw = -1.39 and -2.51 MPa, respectively) increased leaf artemisinin content, but only 38 hours led to a significant increase in both leaf and plant artemisinin (29%), with no detriment to plant biomass production. The other treatments had no effect on, or decreased artemisinin accumulation. A. annua plants tolerated well water deficit treatments, including the most severe water deficit applied (Ψw -3.97 MPa or 86 hs without irrigation) and recovered their turgor pressure after rehydration. These results suggest that moderate water deficit prior to harvesting the crop may not only reduce time and costs in drying the crop, but can also induce artemisinin accumulation, both of which increase crop profit margins. Results also suggest that artemisinin could be part of A. annua chemical system of defense against water deficit.Key words: Malaria; secondary metabolism; terpene; drought; water stress. resuMoA despeito da importância da Artemisia annua L. como a única fonte da droga anti-parasitária artemisinina, muito pouco é sabido sobre o papel dessa molécula em plantas sob estresses biótico e abiótico. A deficiência hídrica é o principal fator limitante no crescimento vegetal, mas pode induzir a acumulação de metabólitos secundários, dependendo da intensidade e fase de desenvolvimento da planta. Plantas de A. annua cultivadas em câmaras de crescimento foram submetidas a cinco tratamentos (plantas irrigadas e com 14, 38, 62 e 86 horas sem irrigação). Deficiências hídricas de 38 e 62 horas (Ψw = -1.39 e -2.51 MPa, respectivamente) aumentaram o conteúdo foliar de artemisinina, mas somente a deficiência hídrica de 38 horas induziu um Braz. J. Plant Physiol., 22(1): 1-9, 2010 2 J. A. MARCHESE et al. aumento significativo da molécula em folhas (29%) e planta inteira, sem afetar o acúmulo de biomassa. Os outros tratamentos não afetaram significativamente o conteúdo de artemisinina. As plantas de A. annua apresentaram uma boa tolerância a deficiência hídrica, incluindo o tratamento mais severo (Ψw -3.97 MPa ou 86 h sem irrigação) e recuperaram a pressão de turgor após a reidratação. Estes resultados sugerem que uma deficiência hídrica moderada imediatamente antes da colheita de A. annua pode não somente reduzir o tempo e os custos de secagem da cultura, mas também induzir ao acúmulo de artemisinina, condições que, conjuntamente, são benéficas para o cultivo commercial da espécie. Finalmente, estes resultados sugerem que a artemisinina pode ser parte do sistema químico de defesa da A. annua c...

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“…Molar units of ARS and DHA concentration measurements were transformed into their natural logarithms and characterized simultaneously, assuming complete and irreversible in vivo conversion of ARS into DHA (25,26). The fraction of data below the LLOQ was high (~40%).…”

Section: Population Pharmacokineticsmentioning

confidence: 99%

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

Das

Dondorp

Nosten

et al. 2017

AAPS J

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Abstract.Orally administered artemisinin-based combination therapy is the first-line treatment against uncomplicated P. falciparum malaria worldwide. However, the increasing prevalence of artemisinin resistance is threatening efforts to treat and eliminate malaria in Southeast Asia. This study aimed to characterize the exposure-response relationship of artesunate in patients with artemisinin sensitive and resistant malaria infections. Patients were recruited in Pailin, Cambodia (n = 39), and Wang Pha, Thailand (n = 40), and received either 2 mg/kg/day of artesunate mono-therapy for 7 consecutive days or 4 mg/kg/day of artesunate monotherapy for 3 consecutive days followed by mefloquine 15 and 10 mg/kg for 2 consecutive days. Plasma concentrations of artesunate and its active metabolite, dihydroartemisinin, and microscopy-based parasite densities were measured and evaluated using nonlinear mixed-effects modeling. All treatments were well tolerated with minor and transient adverse reactions. Patients in Cambodia had substantially slower parasite clearance compared to patients in Thailand. The pharmacokinetic properties of artesunate and dihydroartemisinin were well described by transit-compartment absorption followed by one-compartment disposition models. Parasite density was a significant covariate, and higher parasite densities were associated with increased absorption. Dihydroartemisinin-dependent parasite killing was described by a delayed sigmoidal Emax model, and a mixture function was implemented to differentiate between sensitive and resistant infections. This predicted that 84% and 16% of infections in Cambodia and Thailand, respectively, were artemisinin resistant. The final model was used to develop a simple diagnostic nomogram to identify patients with artemisinin-resistant infections. The nomogram showed > 80% specificity and sensitivity, and outperformed the current practice of day 3 positivity testing.

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The chemistry, pharmacology, and clinical applications of qinghaosu (Artemisinin) and its derivatives

Cited by 317 publications

References 14 publications

Stability of Peroxide Antimalarials in the Presence of Human Hemoglobin

Stability of Peroxide Antimalarials in the Presence of Human Hemoglobin

Water deficit effect on the accumulation of biomass and artemisinin in annual wormwood(Artemisia annua L., Asteraceae)

Population Pharmacokinetic and Pharmacodynamic Modeling of Artemisinin Resistance in Southeast Asia

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