Morphologic Effects of Artemisinin in Plasmodium Falciparum

Maeno, Yoshimasa; Toyoshima, Tetsuhiko; Fujioka, Hisashi; Ito, Yoshihiro; Meshnick, Steven R.; Benakis, A.; Milhous, Wilbur K.; Aikawa, Masamichi

doi:10.4269/ajtmh.1993.49.485

Cited by 79 publications

(56 citation statements)

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“…Maeno and others 17 demonstrated that the earliest pathologic effect of artemisinin is on the parasitic membrane in P. falciparum, which seems to be the case in our study. We used a short treatment duration because we wanted to know if the artesunate-dihydroartemisinin combination could act as rapidly against T. gondii as observed against P. falciparum.…”

Section: Discussionsupporting

confidence: 67%

Effects of artesunate, dihydroartemisinin, and an artesunate-dihydroartemisinin combination against Toxoplasma gondii.

Sarciron

Saccharin²,

Pétavy³

et al. 2000

The American Journal of Tropical Medicine and Hygiene

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Abstract. The effect of artesunate and its metabolite dihydroartemisinin against the cerebral cysts of Toxoplasma gondii was studied. In vitro experiments were performed with the THP-1 cell line and showed an inhibition of parasite growth of approximately 70% with 0.1-0.5 g/ml of dihydroartemisinin for 96 hr. However, with artesunate, dihydroartemisinin, or a combination (50:50) of them, the number of tachyzoites decreased approximately 40-50% and they appeared motionless. Fifty-eight to 72 hr after washing of the tachyzoites and THP-1 cells in culture, parasitized cells reappeared. In vivo, the 50:50 artesunate-dihydroartemisinin combination produced a decrease in cerebral cysts of approximately 40% after only 5 days of treatment. However, transplantations into naïve mice using brains of treated mice gave positive results.Artemisinin, a peroxide-containing sesquiterpene lactone isolated from the herb Artemisia annua, has been found to possess potent antimalarial activity and low toxicity both in animals and humans. 1,2 Artesunate (a water soluble half-ester succinate derivative) and artemether (a methyl ether derivative) are the only 2 derivatives of artemisinin that have been licensed in Thailand for treatment of Plasmodium falciparum malaria since 1990.Because of their low solubility in either water or oil 1 and the short plasma half-life of artemisinin, artesunate and artemether have been studied, in particular, sodium artesunate. 3 All artemisinin derivatives are metabolized to an active metabolite, dihydroartemisinin, whose half-life is 2 hr compared with the 45 min half-life of artesunate. 4 Artesunate and dihydroartemisinin are active against severe or complicated P. falciparum malaria. 5 Artesunate contains an endo-peroxide bridge. The peroxide moiety has been demonstrated to be responsible for the antimalarial activity of these compounds 6,7 and presumably for antitoxoplasmal activity. 8 Since these drugs cross the blood-brain barrier, they have been tested as a treatment for toxoplasmosis. To our knowledge, these qinghaosu derivatives have been only tested on the RH strain, a highly virulent strain of Toxoplasma gondii. [8][9][10] The purpose of the present study was to evaluate the in vitro and in vivo effects of artesunate, dihydroartemisinin, and their combination on the cyst-forming strain of T. gondii. MATERIALS AND METHODSParasite. Toxoplasma gondii strain DUR was isolated from the amniotic fluid of a pregnant woman. This isolate is considered to be of low virulence because it causes a chronic infection in mice and grows slowly in culture. This avirulent strain was maintained in our laboratory by oral passage of cysts from the brain of an infected mouse.Cell culture. The human myelomonocytic cell line THP-1 (European Collection of Animal Cell Cultures number 88081201; Sophia-Antipolis, France) was used for T. gondii culture. These non-adherent cells were suspended in RPMI 1640 medium (DAP, Vogelgrun, France) supplemented with 100 U/ml of penicillin, 100 g/ml of streptomycin (SigmaAldrich, L'Isle...

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Section: Discussionsupporting

confidence: 67%

Effects of artesunate, dihydroartemisinin, and an artesunate-dihydroartemisinin combination against Toxoplasma gondii.

Sarciron

Saccharin²,

Pétavy³

et al. 2000

The American Journal of Tropical Medicine and Hygiene

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“…Reports that artemisinin derivatives antagonize the actions of some antimalarials have been widely published (3,9,28), including a study of P. berghei and P. yoelii with a mouse model (4). Accumulation studies show that artemisinin derivatives accumulate in many parasite organelles, including the mitochondria (20), and the ultrastructural changes induced in P. falciparum by artemisinins include the early swelling of parasite mitochondria (15,16,20). The antimitochondrial effects of both ATV and DHA may bear some relationship to the antagonism that they exert, and it is interesting that in the present study an indifferent effect was seen against an ATV-resistant isolate with high ATV concentrations.…”

Section: Discussionmentioning

confidence: 99%

Modified Fixed-Ratio Isobologram Method for Studying In Vitro Interactions between Atovaquone and Proguanil or Dihydroartemisinin against Drug-Resistant Strains of Plasmodium falciparum

Fivelman

Adagu

Warhurst

2004

Antimicrob Agents Chemother

264

286

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A modified fixed-ratio isobologram method for studying the in vitro interactions between antiplasmodial drugs is described. This method was used to examine the interactions between atovaquone, proguanil, and dihydroartemisinin. The interaction between atovaquone and proguanil was synergistic against atovaquonesensitive strains K1 and T996; however, there was a loss of synergy against atovaquone-resistant strain NGATV01 isolated after Malarone (the combination of atovaquone and proguanil) treatment failure. While the interaction between atovaquone and dihydroartemisinin was indifferent against isolate NGATV01, the interaction displayed indifference tending toward antagonism against the atovaquone-sensitive strains tested. The relevance of in vitro interactions to in vivo treatment is discussed.Combination drug regimens for the treatment of cancer, AIDS, and tuberculosis often achieve a therapeutic efficacy greater than that achieved with monotherapy. Other benefits may include decreased toxicity, the delay or prevention of drug resistance development, and the favorable effects of synergistic drug interactions. Antimalarial drug resistance is becoming a major public health disaster in many areas of the tropical world (31). In the search for effective combination regimens, Malarone (the combination of atovaquone and proguanil), LapDap (the combination of chlorproguanil and dapsone), and Coartem (the combination of artemether and lumefantrine) have recently become available or are in development. Other combination therapies involving artemisinin derivatives such as artesunate-mefloquine have many benefits and are thought to be very effective against drug resistance (31). It is hoped that combination chemotherapy will delay the onset of resistance to new agents and reduce the effects of resistance to existing agents (24,30).In vitro interactions between antiplasmodials, as represented in isobolograms, provide an essential background for clinical studies. However, they do not necessarily determine the efficacy of a combination in the host, since this also depends on pharmacokinetic characteristics. Synergism, indifference (addition), and antagonism are the expected outcomes of drug-drug interactions. The antimalarial Malarone (GlaxoSmithKline) is a recently introduced combination regimen for the treatment (18, 19) and prophylaxis (14, 23) of falciparum malaria. It has been previously reported that the synergistic interaction between the components of Malarone, atovaquone (ATV) and proguanil (PG), is reduced to an indifferent interaction in ATV-resistant Plasmodium yoelii parasites (25). However, this interaction has been demonstrated to remain synergistic in ATV-resistant isolate C2B of P. falciparum derived from a clinical trial of ATV alone, although the parasites showed a 95-fold decrease in sensitivity to ATV compared to that of the pretreatment isolate (2). Despite recent reports of Malarone treatment failures (7,8), no studies have investigated the in vitro interaction between these two drugs against isolates fr...

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“…These results suggest that in drug-sensitive cell lines, in comparison with drug-resistant cell lines which need more ATP concentration to assure their ATPase activity, the decrease in intracellular ATP does not produce a deleterious effect, as it does in drug-resistant cell lines. It was clearly shown by electron microscope that in NB2a neuroblastoma cells, 31) as well as in plasmodium infected erythrocytes, 32) dihydroartemisinin (2 mM) caused damage to mitochondrial cristae and the endoplasmic reticulum, but affected neither the cellular cytoskeleton nor the plasma membrane. The same authors proposed that artemisinin and its deriva- Ϫ4 M stock THP solution was added to the cells, yielding a C T ϭ1 mM THP solution.…”

Section: Co-treatment Using Pirarubicin and Qinghaosu Or Doxorubicin mentioning

confidence: 99%

Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines.

Reungpatthanaphong

Mankhetkorn

2002

Biological & Pharmaceutical Bulletin

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Multidrug resistance (MDR) is a principle cause of failure in human drug treatment. MDR phenomena are intensively studied in anti-cancer, anti-bacterial, anti-paludism, and human immunodeficiency virus-1. [1][2][3][4][5] The MDR phenotype is characterized by a low free intracellular cytotoxic drug concentration in comparison with their corresponding drugsensitive cells. This is frequently associated with protein membrane transporters, such as P-glycoprotein and MRP1-protein, which ATP-dependently extrude cytotoxic agents out of cells, thus reducing their efficacy. To overcome MDR phenomena, the direct interaction between inhibitors and proteins has been researched by many groups. A variety of small molecules, such as verapamil, dihydropyridines, forskolin and cyclosporin were found to bind to P-glycoprotein and inhibit its ability to pump out antitumor drugs. 6-9) All compounds cited are difficult to use in vivo due to their toxicity. As a consequence, the clinical utility of non-toxic derivatives of these and other molecules as chemosensitizing agents has been extensively studied. 10,11) It was reported that in MDR plasmodium falciparum strains, the pfmdr-1 gene and pgh-1 were characterized, which has about 54% homology to mdr-1 gene of MDR cancer cells. [12][13][14][15] However, its function is still not clear. Recently, it was reported that qinghaosu is an effective compound against MDR plasmodium falciparum strains, 16,17) but studies regarding its effect on protein transporters have not been performed, neither in erythrocytes infected by MDR plasmodium falciparum strains nor in cancer MDR cells. Qinghaosu drugs such as artemisinin and artesunate are now in widespread use, particularly in Southast Asia, and are used as a prophylaxis in China. 18,19) In this study we have demonstrated that artemisinin, artesunate and dihydroartemisinin poorly inhibited P-glycoprotein and did not inhibit MRP1 protein function in multidrug resistant K562/adr cells, overexpression P-glycoprotein, or in GLC4/adr cells overexpression of MRP1-protein, respectively. However, they increased in cytotoxic effect induced by pirarubicin or doxorubicin only in MDR cell lines. We also demonstrated that these qinghaosu modulate mitochondrial function, leading to a decrease in intracellular ATP content in all cell lines tested. MATERIALS AND METHODS Cell Culture and Cytotoxicity AssayThe erythromyelogenous leukemic, K562, and its P-glycoprotein-overexpressing K562/adr, 20,21) and the human small cell lung cancer, GLC4 and its MRP1-overexpressing GLC4/adr, [22][23][24] were kindly provided by Professor Arlette Garnier-Suillerot, Laboratoire de Chimie Physique, Biomoleculaire et Cellulaire, UFR Sante Medecine Biologie Humaine, Universite de Paris Nord, France. These cells were routinely cultured in RPMI 1640 medium supplemented with 10% fetal calf serum (Gibco Biocult, Ltd.). The resistant K562/adr and GLC4/adr cells were cultured with 100 nM doxorubicin two weeks before the experiments. For the assays, a culture was initiated at 5ϫ10 5 cells ...

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Morphologic Effects of Artemisinin in Plasmodium Falciparum

Cited by 79 publications

References 0 publications

Effects of artesunate, dihydroartemisinin, and an artesunate-dihydroartemisinin combination against Toxoplasma gondii.

Effects of artesunate, dihydroartemisinin, and an artesunate-dihydroartemisinin combination against Toxoplasma gondii.

Modified Fixed-Ratio Isobologram Method for Studying In Vitro Interactions between Atovaquone and Proguanil or Dihydroartemisinin against Drug-Resistant Strains of Plasmodium falciparum

Modulation of Multidrug Resistance by Artemisinin, Artesunate and Dihydroartemisinin in K562/adr and GLC4/adr Resistant Cell Lines.

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