Light Microscopic Changes in Plasmodium falciparum from Gabonese Children Treated with Artemether

Kombila, Maryvonne; Duong, T. H.; Dufillot, D; Koko, J.; Guiyedi, Vincent; Guiguen, Claude; Ferrer, Alain; Richard-Lenoble, D

doi:10.4269/ajtmh.1997.57.643

Cited by 9 publications

(5 citation statements)

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“…After treatment with mefloquine, we observed a loss of structural integrity, resulting in multiple vacuoles, which is in keeping with the in vitro findings reported by Jacobs et al (17). Similarly, we found that dihydroartemisinin was highly effective against all stages of the parasites (34), and Kombila et al (19) observed that 24 h after the treatment of infected children with artemether, all of their parasites were abnormal. Thus, the similarity of effects on parasite morphology and parasitic stages in our model or in treated humans and in vitro studies suggests that the modes of action of these antimalarial drugs are also similar.…”

Section: Discussionsupporting

confidence: 90%

Human Malaria in Immunocompromised Mice: New In Vivo Model for Chemotherapy Studies

Moreno

Badell

Rooijen

et al. 2001

Antimicrob Agents Chemother

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We have recently designed a new Plasmodium falciparum mouse model and documented its potential for the study of immune effector mechanisms. In order to determine its value for drug studies, we evaluated its response to existing antimalarial drugs compared to that observed in humans. Immunocompromised BXN (bg/bg xid/xid nu/nu) mice were infected with either the sensitive NF54 strain or the multiresistant T24 strain and then treated with chloroquine, quinine, mefloquine, or dihydroartemisinin. A parallelism was observed between previously reported human responses and P. falciparum-parasitized human red blood cell (huRBC)-BXN mouse responses to classical antimalarial drugs, measured in terms of speed of decrease in parasitemia and of morphological alterations of the parasites. Mice infected with the sensitive strain were successfully cured after treatment with either chloroquine or mefloquine. In contrast, mice infected with the multiresistant strain failed to be cured by chloroquine or quinine but thereafter responded to dihydroartemisinin treatment. The speed of parasite clearance and the morphological alterations induced differed for each drug and matched previously reported observations, hence stressing the relevance of the model. These data thus suggest that P. falciparum-huRBC-BXN mice can provide a valuable in vivo system and should be included in the short list of animals that can be used for the evaluation of P. falciparum responses to drugs.In the absence of a long-awaited effective vaccine, antimalarial drugs remain the main means by which to control morbidity and mortality due to Plasmodium falciparum malaria. Although several antimalarials are available, P. falciparum has gradually developed resistance to nearly all of them. Furthermore, the prevalence and degree of resistance are increasing and the pipeline of new antimalarial compounds is drying out (26). Thus, there is an urgent need to find either new combined therapies using available compounds or to develop new antimalarial drugs to replace failing ones. However, among the various reasons for the shortage of new drugs are the small number of animal species receptive to P. falciparum and their price.Immunodeficient mice have been widely used as xenogeneic transplantation models allowing in vivo investigations of human cells and organs. Recently, Badell et al. developed a model (1) in which P. falciparum-parasitized human red blood cells (P. falciparum-huRBC) can be grafted into immunodeficient (bg/bg xid/xid nu/nu) BXN laboratory mice (P. falciparumhuRBC-BXN). In this mouse strain, which lacks T-cell, LAKC, and T-independent B-cell functions, a main factor in the survival of P. falciparum is the concomitant decrease in innate, nonadaptive immunity. Through chemical reduction of tissue macrophages and blood leukocytes, in vivo development of medium-grade P. falciparum parasitemia can be obtained in these mice in several weeks. This new model may eventually provide a valuable tool with which to investigate the biology of this malaria parasite under ...

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Section: Discussionsupporting

confidence: 90%

Human Malaria in Immunocompromised Mice: New In Vivo Model for Chemotherapy Studies

Moreno

Badell

Rooijen

et al. 2001

Antimicrob Agents Chemother

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“…15,16 While parasite clearance tended to be faster in the present study in the artemotil group as has been reported in other studies of artemisinin derivatives, 17 the data from this study did not reach statistical significance. In addition, the higher mean baseline parasite counts in the quinine group make interpretation of the data difficult.…”

Section: Discussionsupporting

confidence: 56%

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

Thuma¹,

Bhat²,

Mabeza³

et al. 2000

The American Journal of Tropical Medicine and Hygiene

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Abstract. The efficacy and safety of intramuscular artemotil (ARTECEF ) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days.

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“…Ichimori et al [27] with P. yoelii nigeriensis and Gautret et al [9] with P. chabaudi showed an increase in mosquito infectivity after treatment with chloroquine. As mentioned above, our study revealed the presence of damaged gametocytes (morphological changes and pigment clumping) after treatment (data not shown), and Kombila et al [28] H1h30 and H5. In our experiments with P. y. yoelii, a general reduction in infectivity of about 60-80% at H1h30 and 75% (73%)-100% (98%) at H5 posttreatment was observed (table 4), as reported by others [7,22].…”

Section: Discussionsupporting

confidence: 75%

Effects of the antimalarial drugs ferroquine and artesunate on Plasmodium yoelii yoelii gametocytegenesis and vectorial transmission

Mustfa¹,

Landau²,

Chabaud³

et al. 2011

Cahiers Santé

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Chemistry still has a role in the management of malaria, alongside the mosquito netting soaked in insecticide that is used increasingly, as we continue to await the long anticipated vaccine. During its cycle, the hematozoon parasite develops through three major periods. The first, malarial infection, corresponds to the intrahepatic development of infective forms from the mosquito vector; this period is not sensitive to treatment and is often asymptomatic. The period of erythrocytic schizogony is the most urgent, and treatment activity is primordial. Finally, the phase of sexual reproduction, when gametocytes develop within the erythrocytes ensures the perpetuation of the species when these reach the blood-feeding female anopheles mosquitoes. The aim of our work was to study the effect on gametocytes of drugs known to be effective on the asexual blood forms of the protozoan and thus the potential repercussions on malaria transmission. This experimental study was conducted with an animal model whose parasite cycle and modes of transmission are close to those of human malaria: Plasmodium yoelii, maintained on Swiss mice, with the Anopheles stephensi vector (maintained in an animal facility at the National Museum of Natural History in Paris). Two drugs were tested: ferroquine (a chloroquine derivative with a ferrocene molecule at the lateral carbon chain that restores its efficacy against chloroquine-resistant strains) and artesunate (a derivative of artemisinin, from ginghao, a Chinese plant also known as artemisia annua, or sweet wormwood), a treatment of choice in the combined therapies recommended by WHO. The efficacy of these drugs, prescribed at doses subcurative for the asexual forms, were tested against gametocyte production, quantitatively by counting them in the blood and qualitatively by counting the quantity of oocysts developed on the mosquito's midgut, which are indicators of gametocyte activity. The mice that were parasite-infected and then treated served as their own controls: lots of 30 mosquitoes fed on each mouse before treatment and then 90 minutes and 5 hours after treatment. Quantitatively, the comparison of the blood parasite level and the gametocyte index shows that treated mice had a higher level of circulating gametocytes than untreated parasite infested mice, regardless of drug or dose (5 or 10 mg/kg). For artesunate at 5 mg/kg, we noted that the blood gametocyte level was almost double that of the controls. On the other hand, qualitatively, the first results obtained with optical and electronic microscopy showed morphologic alterations of the circulating gametocytes (pigment clumping and lateralisation within red blood cells) and reduced infectivity of the gametocytes for the mosquitoes that fed at 1 and 5 hours after treatment. We were able to demonstrate statistically that the infectivity of gametocytes, measured by the quantity of oocysts counted in the mosquito midgut, was reduced by 70% for those treated with ferroquine and by 85% for those from mice treated by artesunate. Complementa...

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Light Microscopic Changes in Plasmodium falciparum from Gabonese Children Treated with Artemether

Cited by 9 publications

References 0 publications

Human Malaria in Immunocompromised Mice: New In Vivo Model for Chemotherapy Studies

Human Malaria in Immunocompromised Mice: New In Vivo Model for Chemotherapy Studies

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

Effects of the antimalarial drugs ferroquine and artesunate on Plasmodium yoelii yoelii gametocytegenesis and vectorial transmission

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