Artemether administered together with haemin damages schistosomes in vitro

Abstract

We conducted experiments in vitro to assess the effect of artemether in combination with haemin on adult Schisrosoma japonicum, S. mansoni and S. haematobium. When schistosomes were maintained in a medium containing artemether at concentrations of 20 p,g/mL or less for 72 h, no apparent effect on the schistosomes was seen, When the medium contained 50 or 100 pg/mL haemin as well as artemether, the schistosomes showed decreased motor activity 2-24 h after exposure, which was followed by the staining of the whole worm body a reddish-yellow colour, dilatation of the intestine, and extensive vesiculation of the tegument. Some of the schistosomes died 24 h after exposure? and almost all died within 48-72 h. When scbistosomes were exposed to the same concentrations of haemm alone, they were stained a light yelfow colout but there was no apparent effect on their survival. Our findings suggest that artemether interacts with haemin to exert a toxic effect on the worms, which might be of importance in the further elucidation of the mechanism of action of aaemether on schistosomes.

Antischistosomal Activity of Trioxaquines: In Vivo Efficacy and Mechanism of Action on Schistosoma mansoni

“…ARTM is inactive on cercariae and schistosomules, and only poorly active on adult worms. In fact, this latter drug was reported to be active only when hemin was added in the culture medium [32].…”

Artemether and Praziquantel: Origin, Mode of Action, Impact, and Suggested Application for Effective Control of Human Schistosomiasis

“…The current working hypothesis is that this drug acts through haeme-dependent reduction to sequentially generate free radicals: the haeme iron first attacks and breaks the endoperoxide linkage to artemisinin, producing an oxygen-free radical, which is then rearranged to produce a carbon-free radical that causes lethal damage through the alkylation of parasite proteins [36]. Work by Xiao et al [31,37,38,39] and Chaturvedi et al [36], further developed and summarized by Xiao and Sun [26], indicates that the same pathway is followed with respect to Schistosoma . Antioxidant enzymes systems available in adult worms, but not common in immature ones, can prevent this effect.…”

Natural Products as Leads in Schistosome Drug Discovery

“…Curiously, schistosomules appear to be more sensitive than adult worms, a fact that may be associated with the effects and mechanisms of the action of artemisinins on different developmental stages of schistosomes. Artemisinins react with the iron ions of heme, derived from hemoglobin digestion, to yield reactive oxygen species and chelates [ 50 , 51 ]. In addition, adult worms have the highest level of specific antioxidant enzymes that neutralize reactive oxygen species as compared to schistosomules [ 52 ], which may explain why artemisinins are more effective in killing schistosomules than adults under the same treatment protocols.…”