In vitro activity of new artemisinin derivatives against Plasmodium falciparum clinical isolates from Gabon

Held, Jana; Soomro, Shahid A.; Kremsner, Peter G.; Jansen, F. H.; Mordmüller, Benjamin

doi:10.1016/j.ijantimicag.2010.12.022

Cited by 8 publications

(11 citation statements)

References 14 publications

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“…Thus, it was used in the Hz detection assay to obtain time-curves when investigating the drug effects in P. falciparum in vitro cultures. Still, an initial 1% parasitemia is higher than the ones used in other assays, such as the HRP2 or the WHO schizont maturation test, which can use parasitemias as low as 0.02% [8], [37], [38]. However, when investigating the lower detection limit of the Hz assay, parasite maturation and drug effects of chloroquine, artesunate and pyrimethamine could still be clearly detected at parasitemias as low as 0.3%.…”

Section: Discussionmentioning

confidence: 92%

“…However, slightly higher values were observed for some of the drugs, especially for artesunate, where most publications report values below 2.5 nM [15], [37], [47]. One explanation could be the inoculum effect, i.e., an increase in the inhibitory drug concentration when greater numbers of parasites are inoculated.…”

Section: Discussionmentioning

confidence: 97%

“…For instance other assays, such as the [3H]-hypoxanthine assay, cultures have to be incubated for additional 24 hours with the isotope before measurements are possible [6], [15], [46]–[48]. Another advantage is the early detection of inhibitory drug effects after only 18 hours (Table 1 and Figures 3, 4 and 5), in contrast to several other assays, such as the [3H]-hypoxanthine assay [6], [48], which measures drug effects at 48 hours, the SYBR green I [15], [40], [49], [50] and the HRP2 [8], [15], [37] assays, which require at least 72 hours.…”

Section: Discussionmentioning

confidence: 99%

“…This is thought to be the consequence of some drug accumulating inside the parasitized RBC [55] and has been described for drugs like artemisinin and artesunate, as well as for chloroquine and mefloquine [56]. In fact, in the Hz assay parasitemias of around 1% were used as compared to other assays, which used parasitemias ranging from 0.05 to 0.5% [6]–[9], [37]–[40]. This might explain the increased IC50 values observed in the Hz detection assay and interestingly, a decrease in the parasitemia from 1.4% to 0.7% led to a decrease in the artemisinin IC50 value from 32 to 13.2 nM.…”

Section: Discussionmentioning

confidence: 99%

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A Novel Flow Cytometric Hemozoin Detection Assay for Real-Time Sensitivity Testing of Plasmodium falciparum

Rebelo¹,

Sousa²,

Shapiro³

et al. 2013

PLoS ONE

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Resistance of Plasmodium falciparum to almost all antimalarial drugs, including the first-line treatment with artemisinins, has been described, representing an obvious threat to malaria control. In vitro antimalarial sensitivity testing is crucial to detect and monitor drug resistance. Current assays have been successfully used to detect drug effects on parasites. However, they have some limitations, such as the use of radioactive or expensive reagents or long incubation times. Here we describe a novel assay to detect antimalarial drug effects, based on flow cytometric detection of hemozoin (Hz), which is rapid and does not require any additional reagents. Hz is an optimal parasite maturation indicator since its amount increases as the parasite matures. Due to its physical property of birefringence, Hz depolarizes light, hence it can be detected using optical methods such as flow cytometry. A common flow cytometer was adapted to detect light depolarization caused by Hz. Synchronized in vitro cultures of P. falciparum were incubated for 48 hours with several antimalarial drugs. Analysis of depolarizing events, corresponding to parasitized red blood cells containing Hz, allowed the detection of parasite maturation. Moreover, chloroquine resistance and the inhibitory effect of all antimalarial drugs tested, except for pyrimethamine, could be determined as early as 18 to 24 hours of incubation. At 24 hours incubation, 50% inhibitory concentrations (IC50) were comparable to previously reported values. These results indicate that the reagent-free, real-time Hz detection assay could become a novel assay for the detection of drug effects on Plasmodium falciparum.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A Novel Flow Cytometric Hemozoin Detection Assay for Real-Time Sensitivity Testing of Plasmodium falciparum

Rebelo¹,

Sousa²,

Shapiro³

et al. 2013

PLoS ONE

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“…Details of the study are described elsewhere (13). The experiments were approved by the ethics committee of the International Foundation of the Albert Schweitzer Hospital in Lambaréné.…”

mentioning

confidence: 99%

In Vitro Activity of Fluorescent Dyes against Asexual Blood Stages of Plasmodium falciparum

Joanny

Held

Mordmüller

2012

Antimicrob Agents Chemother

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bMany successful antimicrobial drugs originate from synthetic dyes. This paper reports the in vitro activity of 14 fluorescent dyes against Plasmodium falciparum. Five of these dyes (Hoechst 33342, MitoRed, DiOC 6 , SYTO 9, and rhodamine B) show activity at a low nanomolar concentration against two P. falciparum strains in the histidine-rich protein 2 drug sensitivity assay, while toxicity in HeLa cells is low. These dyes may be a starting point for developing new drugs against P. falciparum. The increasing resistance of Plasmodium falciparum to most drugs in clinical use and first reports of reduced sensitivity to artemisinin derivatives, the latest first-line drugs, made the development of new antimalarial compounds a research priority of utmost importance (20). Since existing drugs belong to only a few chemical classes, there is a high probability of the development of cross-resistance, which may shorten the product life of new drugs. In the history of drug discovery, many drugs were derived from synthetic dyes. Indeed, the pharmaceutical industry developed from the dye industry before World War II (22), and the antiplasmodial effect of dyes was shown more than a century ago by Guttman and Ehrlich (10), who cured two malaria patients with methylene blue. They were inspired to use methylene blue as an antimalarial drug after observing that it stains P. falciparum particularly well. Later, the antimalarial activity of other dyes such as rhodamine 123 (19), rhodamine B, Janus green (7), and eosin B (17) was discovered.With this work, we attempt to revive the use of staining properties as a preselection criterion for new antimalarial drugs. The use of dyes has several advantages: they accumulate in the target organism, they are easily screened for, and they belong to a large family of chemical entities not restricted to known pharmacophores. For this proof-of-concept study, we selected 14 different commercially available dyes staining mitochondria (MitoRed, MitoGreen, Daspei, DiOC 6 , rhodamine 123, rhodamine B, JC1, SYTO 18), nucleic acids (Hoechst 33342, acridine orange, SYBR green I, SYTO 9), or proteins (carboxyfluorescein diacetate [CFDA], CFDA-succinimidyl ester [CFDA-SE]). Dyes were obtained from the following sources. A yeast mitochondrial stain sampler kit containing DiOC 6 (CAS no. 53213-82-4), rhodamine B (hexyl ester perchlorate; CAS number not available), MitoGreen (MitoTracker Green FM; CAS no. 201860-17-5), and SYTO 18 (the structure is proprietary) was obtained from Invitrogen. The mitochondrial stains MitoRed (MitoTracker Red CMXRos; CAS no. 167095-09-2) and JC1 (CAS no. 47729-63-5) as well as the nucleic acid stains SYTO 9 (SYTO 9 green fluorescent nucleic acid stain; the structure is proprietary), Hoechst 33342 (CAS no. 23491-52-3), and acridine orange (CAS no. 65-61-2) were also from Invitrogen. Daspei (CAS no. 3785-01-1) was obtained from Biotium, CFDA (CAS no. 79955-27-4), CFDA-SE (CAS no. 150347-59-4), SYBR green I (CAS no. 163795-75-3), and chloroquine diphosphate (CAS no. 50-63-5) (molecu...

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Therapeutic efficacy of mebendazole and artemisinin in different phases of trichinellosis: a comparative experimental study

et al. 2021

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The present work aimed at studying the efficacy of mebendazole (MBZ) compared to artemisinin (ART) for the treatment of trichinellosis at various phases of infection. Seventy Swiss albino mice were orally infected by 300 Trichinella spiralis (T. spiralis) larvae. Mice were divided into infected untreated control group and infected groups treated with 50 mg kg−1 MBZ and 300 mg kg−1 ART for three and five consecutive days, respectively, at the enteral phase [2–4 days post infection (PI)], invasive phase (10–12 days PI) and encapsulated phase (28–30 days PI). All mice were sacrificed 35–42 days PI. MBZ and ART revealed a significant decrease in mean larval counts and increase of larval per cent reduction (LR %) when treatment was initiated during the enteral phase compared to the other phases. MBZ showed significantly higher LR % (99.7, 83.95 and 89.65%) than ART (80.58, 67.0 and 79.2%) when administered at the three infection phases. Histopathological study showed a decrease in the number of encysted larvae, their surrounding cellular infiltrates and increased regenerative muscles in all treated mice. In conclusion, ART possesses a substantial anthelmintic activity against T. spiralis infection in mice both at the enteral and encapsulated phases, yet, significantly lower than MBZ.

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In vitro activity of new artemisinin derivatives against Plasmodium falciparum clinical isolates from Gabon

Cited by 8 publications

References 14 publications

A Novel Flow Cytometric Hemozoin Detection Assay for Real-Time Sensitivity Testing of Plasmodium falciparum

A Novel Flow Cytometric Hemozoin Detection Assay for Real-Time Sensitivity Testing of Plasmodium falciparum

In Vitro Activity of Fluorescent Dyes against Asexual Blood Stages of Plasmodium falciparum

Therapeutic efficacy of mebendazole and artemisinin in different phases of trichinellosis: a comparative experimental study

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