Stability of Peroxide Antimalarials in the Presence of Human Hemoglobin

Creek, Darren J.; Ryan, Eileen; Charman, William N.; Chiu, Francis Chi Keung; Prankerd, Richard J.; Vennerstrom, Jonathan L.; Charman, Susan A.

doi:10.1128/aac.00363-09

Cited by 22 publications

(15 citation statements)

References 39 publications

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“…Hemolysis, another condition related to severe manifestations of malaria, was reproduced in the present work by incubating the drug in erythrocyte lysate. Previous studies show that Fe(II), but not Fe(III), can decompose artemisinin (19,20) and that peroxidic antimalarials are stable in the presence of hemoglobin but react with free heme (21). In this work, further evidence of the role of Fe(II)-heme is that flushing RBC lysate with CO, which tightly binds Fe(II)-heme inhibiting its reactivity, moderated the effects on DHA activity.…”

Section: Discussionsupporting

confidence: 54%

Stability of the Antimalarial Drug Dihydroartemisinin under Physiologically Relevant Conditions: Implications for Clinical Treatment and Pharmacokinetic and In Vitro Assays

Parapini

Olliaro

Navaratnam

et al. 2015

Antimicrob Agents Chemother

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f Artemisinins are peroxidic antimalarial drugs known to be very potent but highly chemically unstable; they degrade in the presence of ferrous iron, Fe(II)-heme, or biological reductants. Less documented is how this translates into chemical stability and antimalarial activity across a range of conditions applying to in vitro testing and clinical situations. Dihydroartemisinin (DHA) is studied here because it is an antimalarial drug on its own and the main metabolite of other artemisinins. The behaviors of DHA in phosphate-buffered saline, plasma, or erythrocyte lysate at different temperatures and pH ranges were examined. The antimalarial activity of the residual drug was evaluated using the chemosensitivity assay on Plasmodium falciparum, and the extent of decomposition of DHA was established through use of high-performance liquid chromatography with electrochemical detection analysis. The role of the Fe(II)-heme was investigated by blocking its reactivity using carbon monoxide (CO). A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocyte lysate. Activity was reduced by half after 3 h and almost completely abolished after 24 h. Serum-enriched media also affected DHA activity. Effects were temperature and pH dependent and paralleled the increased rate of decomposition of DHA from pH 7 upwards and in plasma. These results suggest that particular care should be taken in conducting and interpreting in vitro studies, prone as their results are to experimental and drug storage conditions. Disorders such as fever, hemolysis, or acidosis associated with malaria severity may contribute to artemisinin instability and reduce their clinical efficacy.A rtemisinin derivatives have been the most potent antimalarials available to date; they are highly active against all Plasmodium species and parasite stages, including young gametocytes, and constitute the backbone of malaria case management for severe and uncomplicated malaria (as a component of artemisinin combination therapy [ACT]) (1). The emergence and spread of artemisinin resistance in Southeast Asia is, therefore, a serious threat to malaria control (2, 3).All artemisinin derivatives share a distinctive 1,2,4-trioxane pharmacophore, which confers their antimalarial activity (the corresponding acyclic analogues lacking the endoperoxide bridge are inactive) (4, 5) but also makes these molecules particularly highly reactive and thus difficult to quantify in plasma or blood. Of the various artemisinin-type compounds in use, dihydroartemisinin (DHA), the reduced lactol derivative of artemisinin, is an antimalarial compound on its own (currently coformulated with piperaquine) and the main bioactive metabolite of artesunate and artemether. DHA itself is chemically fragile and displays a marked propensity to undergo ring opening of the lactol and rearrangement under neutral conditions, leading to a new, biologically active peroxide, which in turn rapidly decays to the inert end product deoxyartemisi...

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Section: Discussionsupporting

confidence: 54%

Stability of the Antimalarial Drug Dihydroartemisinin under Physiologically Relevant Conditions: Implications for Clinical Treatment and Pharmacokinetic and In Vitro Assays

Parapini

Olliaro

Navaratnam

et al. 2015

Antimicrob Agents Chemother

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“…This reaction is relatively slow and is likely to reflect Hb that is destabilized by limited proteolysis [25,26]. It is possible that such an 'unstable' Hb is produced in acidic digestive compartments and is capable of activating ART.…”

Section: The Art Activator: What Is It and Where Does It Come From?mentioning

confidence: 98%

Iron and heme metabolism in Plasmodium falciparum and the mechanism of action of artemisinins

Klonis

Creek

Tilley

2013

Current Opinion in Microbiology

104

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“…It is believed that unbound ferrous heme or ferrous ion produced in the parasitic food vacuole during hemoglobin digestion would be responsible for artemisinin activity. In contrast, the hemoglobin in the cytosol of erythrocytes is unlikely to react with artemisinin because of the stability of the drug in hemoglobin solution, 8) suggesting the selective toxicity of the drug against the parasitized erythrocytes. Therefore, it remains unknown whether the plasma or extracellular heme could have effect on the drug activity.…”

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confidence: 99%

Extracellular Heme Enhances the Antimalarial Activity of Artemisinin

Tangnitipong

Thaptimthong

Srihirun

et al. 2012

Biological & Pharmaceutical Bulletin

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Artemisinin exerts the antimalarial activity through activation by heme. The hemolysis in malaria results in the elevated levels of plasma heme which may affect the activity of artemisinin. We hypothesized that the extracellular heme would potentiate the antimalarial activity of artemisinin. Hemin (ferric heme) at the pathologic concentrations enhanced the activity of artemisinin against Plasmodium falciparum in vitro and increased the levels of the lipid peroxidation products in the presence of artemisinin. The antimalarial activity of artemisinin and potentiation by hemin was decreased by vitamin E. Hemin had no effect on the activity of quinoline drugs (chloroquine, quinine and mefloquine). Furthermore, the oxidative effect of hemin in the presence of artemisinin or quinoline drugs was studied using low-density lipoprotein (LDL) oxidation as a model. Artemisinin enhanced the effects of hemin on lipid peroxidation and a decrease of tryptophan fluorescence in LDL whereas the quinoline drugs inhibited the oxidation by hemin. In conclusion, the extracellular hemin enhances the antimalarial activity of artemisinin as a result of the increasing oxidative effect of hemin.

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Stability of Peroxide Antimalarials in the Presence of Human Hemoglobin

Cited by 22 publications

References 39 publications

Stability of the Antimalarial Drug Dihydroartemisinin under Physiologically Relevant Conditions: Implications for Clinical Treatment and Pharmacokinetic and In Vitro Assays

Stability of the Antimalarial Drug Dihydroartemisinin under Physiologically Relevant Conditions: Implications for Clinical Treatment and Pharmacokinetic and In Vitro Assays

Iron and heme metabolism in Plasmodium falciparum and the mechanism of action of artemisinins

Extracellular Heme Enhances the Antimalarial Activity of Artemisinin

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