In vitro effects of artemisinin ether, cycloguanil hydrochloride (alone and in combination with sulfadiazine), quinine sulfate, mefloquine, primaquine phosphate, trifluoperazine hydrochloride, and verapamil on Toxoplasma gondii

Holfels, Ellen; McAuley, James B.; Mack, Douglas G.; Milhous, Wilbur K.; McLeod, Rima

doi:10.1128/aac.38.6.1392

Cited by 52 publications

(46 citation statements)

References 22 publications

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“…At this time supernatants were removed from parallel cultures and stored at Ϫ70°C for measurement of IFN-␥. [ 3 H]Thymidine-pulsed wells were cultured for an additional 12 h, after which they were harvested onto glass-fiber filter strips (Cambridge Technology, Watertown, MA) using an automated PHD cell harvester (Cambridge Technology) and processed as previously described (25). Results are expressed as the mean stimulation index Ϯ SE for each group of animals.…”

Section: T Cell Proliferation Assaymentioning

confidence: 99%

In Vitro Correlates ofLd-Restricted Resistance to Toxoplasmic Encephalitis and Their Critical Dependence on Parasite Strain

Johnson

Roberts

Pope

et al. 2002

The Journal of Immunology

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Resistance to murine toxoplasmic encephalitis has been precisely and definitively mapped to the Ld class I gene. Consistent with this, CD8+ T cells can adoptively transfer resistance to toxoplasmic encephalitis. However, cytotoxic CD8+ T cells, capable of killing class I-matched, infected target cells, are generated during the course of Toxoplasma gondii infection even in mice lacking the Ld gene. Ld-restricted killing could not be demonstrated, and the functional correlate of the Ld gene has therefore remained elusive. Herein, Ld-restricted killing of T. gondii-infected target cells is demonstrated for the first time. Ld-restricted killing is critically dependent on the strain of T. gondii and is observed with all the derivatives of type II strains tested, but not with a type I strain. These results have important implications for vaccine development.

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Section: T Cell Proliferation Assaymentioning

confidence: 99%

In Vitro Correlates ofLd-Restricted Resistance to Toxoplasmic Encephalitis and Their Critical Dependence on Parasite Strain

Johnson

Roberts

Pope

et al. 2002

The Journal of Immunology

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“…Published studies have indicated that the naturally occurring 1,2,4-trioxane artemisinin and artemisinin derivatives such as artemether, originally developed for the treatment of malaria, have the ability to inhibit toxoplasma replication in vitro (2,4,6,10). While these trioxanes have a number of advantages in terms of rapid action and low levels of toxicity, they are limited in terms of absorption, bioavailability, and short half-life (i.e., easy hydrolysis into toxic dihydroartemisinin) (9).…”

mentioning

confidence: 99%

In Vitro Inhibition of Toxoplasma gondii by Four New Derivatives of Artemisinin

Jones‐Brando

D’Angelo

Posner

et al. 2006

Antimicrob Agents Chemother

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Toxoplasmosis, caused by the protozoan Toxoplasma gondii, is medically important and distributed worldwide. Currently available medications are limited in terms of efficacy and side effects. We synthesized novel, nonacetal, hydrolytically stable derivatives of artemisinin and showed that they inhibit the replication of Toxoplasma gondii in cell culture.Toxoplasma gondii is an apicomplexan protozoan of worldwide medical importance. Humans are infected by T. gondii through contact with feces from infected cats, by the consumption of undercooked meat from infected animals, or by transmission from infected mother to fetus. This parasite can cause systemic infection and widespread organ damage in immunocompromised individuals and neonates. Infection of immunocompetent adults can result in fever and adenopathy (11). Serological studies indicate that T. gondii could be associated with chronic neuropsychiatric diseases or behavioral abnormalities in some populations (1,12).Available medications for the prevention and treatment of toxoplasma infection show limited efficacy and have substantial side effects (5). Published studies have indicated that the naturally occurring 1,2,4-trioxane artemisinin and artemisinin derivatives such as artemether, originally developed for the treatment of malaria, have the ability to inhibit toxoplasma replication in vitro (2, 4, 6, 10). While these trioxanes have a number of advantages in terms of rapid action and low levels of toxicity, they are limited in terms of absorption, bioavailability, and short half-life (i.e., easy hydrolysis into toxic dihydroartemisinin) (9). Thus, we have designed and synthesized five C-10 nonacetal, hydrolytically stable derivatives of artemisinin (8) and measured their ability to inhibit the replication of T. gondii in vitro.Artemisinin was obtained from Holley Pharmaceuticals Co., Inc., Fullerton, CA. Artemether was generously donated by Huiling Wang, University of Wuhan, China. Trimethoprim was purchased from Sigma Chemical Co. (St. Louis, MO). Chlorophenol red-␤-D-galactopyranoside (Roche, Indianapolis, IN), 100 mM in 100 mM HEPES (pH 7.2), was stored frozen at Ϫ80°C. CellTiter 96 AQ ueous One Solution Reagent for determining cytotoxicity was purchased from Promega Corp., Madison, WI.Structures of artemisinin and the derivatives are shown in Fig. 1. Trioxane C-10 primary alcohol 2a was prepared in 74% yield by hydroboration-oxidation of the corresponding known C-10 allyl trioxane. Esterification of primary alcohol 2a with benzoyl chloride led to benzoate ester 2b in 92% yield, and esterification with 2-bromobenzoyl chloride produced 2-bromobenzoate ester 2c in 86% yield. Deprotonation of the primary alcohol 2a using sodium hydride and then displacement of the bromide anion from citronelyl bromide gave citronelyl ether 2d in 55% yield. First, zinc-promoted deoxygenation of the known C-10 allyl trioxane and then hydroboration-oxidation produced dioxolane deoxy-2a in 72% yield. Each of these new lipid-soluble chromatographically purified artemisinin deriva...

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“…We obtained a better inhibition of parasite growth results in vivo with our cyst-forming strain than with the RH strain, but in vitro it was lower than that previously observed by other investigators. 8,15 We believe that the differences observed are due mainly to the strains of T. gondii used, which show differences in sensitivity to various drugs. A recent study showed the selection of mutants of the RH strain of T. gondii resistant to artemisin.…”

Section: Discussionmentioning

confidence: 99%

“…Arteether concentrations Ͼ0.5 g/ml were inhibitory 1 hr after the addition of the drug to the RH strain in in vitro assays with macrophage and enterocyte cultures. 15 In vitro studies performed on fibroblasts infected with the RH strain showed a 100% reduction in parasite growth after treatment with arteether (1 g/ml), a 100% reduction in parasite growth after treatment with artemether (0.1-1 g/ml), and a 98% reduction in parasite growth after treatment with a lower concentration of artemether (0.01 g/ ml). 8 We obtained similar results in this study with our cystic strain.…”

Section: Discussionmentioning

confidence: 99%

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

Sarciron

Saccharin²,

Pétavy³

et al. 2000

Am J Trop Med Hyg

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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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In vitro effects of artemisinin ether, cycloguanil hydrochloride (alone and in combination with sulfadiazine), quinine sulfate, mefloquine, primaquine phosphate, trifluoperazine hydrochloride, and verapamil on Toxoplasma gondii

Cited by 52 publications

References 22 publications

In Vitro Correlates ofLd-Restricted Resistance to Toxoplasmic Encephalitis and Their Critical Dependence on Parasite Strain

In Vitro Correlates ofLd-Restricted Resistance to Toxoplasmic Encephalitis and Their Critical Dependence on Parasite Strain

In Vitro Inhibition of Toxoplasma gondii by Four New Derivatives of Artemisinin

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

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