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Mefloquine--an aminoalcohol with promising antischistosomal properties in mice.

Keiser J, Chollet J, Xiao SH, Mei JY, Jiao PY, Utzinger J, Tanner M - PLoS Negl Trop Dis (2009)

Bottom Line: Both mefloquine erythro-enantiomers resulted in high and comparable total and female worm burden reductions when given to mice with either a sub-patent or patent S. mansoni infection.Our findings hold promise for the development of a novel antischistosomal drug based on an aminoalcohol functionality.Further in vitro and in vivo studies have been launched to elucidate the possible mechanism of action and to study the effect of mefloquine on S. haematobium and other trematodes.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Basel, Switzerland. jennifer.keiser@unibas.ch

ABSTRACT

Background: The treatment and control of schistosomiasis, an often neglected tropical disease that exacerbates poverty, depends on a single drug, praziquantel. The large-scale use of praziquantel might select for drug-resistant parasites, hence there is a need to develop new antischistosomal compounds. Here, we report that the antimalarial drug mefloquine possesses promising antischistosomal properties in mice.

Methodology/principal findings: A single dose of mefloquine (200 or 400 mg/kg) administered orally to mice infected with adult Schistosoma mansoni or adult S. japonicum resulted in high or complete total and female worm burden reductions (72.3%-100%). Importantly, high worm burden reductions were also observed for young developing stages of S. mansoni and S. japonicum harbored in the mouse. Both mefloquine erythro-enantiomers resulted in high and comparable total and female worm burden reductions when given to mice with either a sub-patent or patent S. mansoni infection.

Conclusions/significance: Our findings hold promise for the development of a novel antischistosomal drug based on an aminoalcohol functionality. Further in vitro and in vivo studies have been launched to elucidate the possible mechanism of action and to study the effect of mefloquine on S. haematobium and other trematodes. It will be interesting to investigate whether mefloquine, which is widely and effectively used for the treatment of malaria, has an impact on schistosomiasis in areas where both malaria and schistosomiasis co-exist.

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Stage-specific susceptibility of mefloquine compared to praziquantel in the S. mansoni- and S. japonicum-mouse models.Red squares: mefloquine 400 mg/kg, blue circles: praziquantel 400 mg/kg. The stage-specific susceptibilities of praziquantel and mefloquine on S. mansoni have been established in the laboratories of the Swiss Tropical Institute (Basel, Switzerland). The efficacy of praziquantel against S. japonicum has been reported by Yue et al. [51] and that of mefloquine has been established at the laboratories of the National Institute of Parasitic Diseases (Shanghai, China).
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pntd-0000350-g002: Stage-specific susceptibility of mefloquine compared to praziquantel in the S. mansoni- and S. japonicum-mouse models.Red squares: mefloquine 400 mg/kg, blue circles: praziquantel 400 mg/kg. The stage-specific susceptibilities of praziquantel and mefloquine on S. mansoni have been established in the laboratories of the Swiss Tropical Institute (Basel, Switzerland). The efficacy of praziquantel against S. japonicum has been reported by Yue et al. [51] and that of mefloquine has been established at the laboratories of the National Institute of Parasitic Diseases (Shanghai, China).

Mentions: In contrast to other recently portrayed schistosomicides such as the oxadiazoles [10] or the cysteine protease inhibitor K11777 [14], which thus far have only been tested intraperitoneally and in multiple doses, mefloquine at a single oral dose resulted in high worm burden reductions. Moreover, the consistently high worm burden reductions observed against all development stages of the schistosome worms in the rodent model seems to be an advantage of mefloquine over praziquantel; the latter only displaying high activity against very young stages (skin penetration) and adult schistosomes [30],[31]. Actually, the minor activity of praziquantel against juvenile (2- to 3-week-old) schistosomes is believed to be a key factor explaining observed treatment ‘failures’ in areas highly endemic for schistosomiasis and that require frequent retreatments [11],[32],[33]. For comparison, the stage-specific susceptibility of praziquantel and mefloquine are juxtaposed in Figure 2. It is evident that mefloquine exceeds benchmark criteria set forth by the World Health Organization (WHO) for highly active lead compounds (defined as worm burden reduction of >80% in the adult S. mansoni-mouse model following five consecutive doses given intraperitoneally or subcutaneously) [34]. We approached or exceeded this benchmark level with a single dose of 400 mg/kg given orally to mice infected with either adult or juvenile stages of S. mansoni and S. japonicum.


Mefloquine--an aminoalcohol with promising antischistosomal properties in mice.

Keiser J, Chollet J, Xiao SH, Mei JY, Jiao PY, Utzinger J, Tanner M - PLoS Negl Trop Dis (2009)

Stage-specific susceptibility of mefloquine compared to praziquantel in the S. mansoni- and S. japonicum-mouse models.Red squares: mefloquine 400 mg/kg, blue circles: praziquantel 400 mg/kg. The stage-specific susceptibilities of praziquantel and mefloquine on S. mansoni have been established in the laboratories of the Swiss Tropical Institute (Basel, Switzerland). The efficacy of praziquantel against S. japonicum has been reported by Yue et al. [51] and that of mefloquine has been established at the laboratories of the National Institute of Parasitic Diseases (Shanghai, China).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2600813&req=5

pntd-0000350-g002: Stage-specific susceptibility of mefloquine compared to praziquantel in the S. mansoni- and S. japonicum-mouse models.Red squares: mefloquine 400 mg/kg, blue circles: praziquantel 400 mg/kg. The stage-specific susceptibilities of praziquantel and mefloquine on S. mansoni have been established in the laboratories of the Swiss Tropical Institute (Basel, Switzerland). The efficacy of praziquantel against S. japonicum has been reported by Yue et al. [51] and that of mefloquine has been established at the laboratories of the National Institute of Parasitic Diseases (Shanghai, China).
Mentions: In contrast to other recently portrayed schistosomicides such as the oxadiazoles [10] or the cysteine protease inhibitor K11777 [14], which thus far have only been tested intraperitoneally and in multiple doses, mefloquine at a single oral dose resulted in high worm burden reductions. Moreover, the consistently high worm burden reductions observed against all development stages of the schistosome worms in the rodent model seems to be an advantage of mefloquine over praziquantel; the latter only displaying high activity against very young stages (skin penetration) and adult schistosomes [30],[31]. Actually, the minor activity of praziquantel against juvenile (2- to 3-week-old) schistosomes is believed to be a key factor explaining observed treatment ‘failures’ in areas highly endemic for schistosomiasis and that require frequent retreatments [11],[32],[33]. For comparison, the stage-specific susceptibility of praziquantel and mefloquine are juxtaposed in Figure 2. It is evident that mefloquine exceeds benchmark criteria set forth by the World Health Organization (WHO) for highly active lead compounds (defined as worm burden reduction of >80% in the adult S. mansoni-mouse model following five consecutive doses given intraperitoneally or subcutaneously) [34]. We approached or exceeded this benchmark level with a single dose of 400 mg/kg given orally to mice infected with either adult or juvenile stages of S. mansoni and S. japonicum.

Bottom Line: Both mefloquine erythro-enantiomers resulted in high and comparable total and female worm burden reductions when given to mice with either a sub-patent or patent S. mansoni infection.Our findings hold promise for the development of a novel antischistosomal drug based on an aminoalcohol functionality.Further in vitro and in vivo studies have been launched to elucidate the possible mechanism of action and to study the effect of mefloquine on S. haematobium and other trematodes.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Basel, Switzerland. jennifer.keiser@unibas.ch

ABSTRACT

Background: The treatment and control of schistosomiasis, an often neglected tropical disease that exacerbates poverty, depends on a single drug, praziquantel. The large-scale use of praziquantel might select for drug-resistant parasites, hence there is a need to develop new antischistosomal compounds. Here, we report that the antimalarial drug mefloquine possesses promising antischistosomal properties in mice.

Methodology/principal findings: A single dose of mefloquine (200 or 400 mg/kg) administered orally to mice infected with adult Schistosoma mansoni or adult S. japonicum resulted in high or complete total and female worm burden reductions (72.3%-100%). Importantly, high worm burden reductions were also observed for young developing stages of S. mansoni and S. japonicum harbored in the mouse. Both mefloquine erythro-enantiomers resulted in high and comparable total and female worm burden reductions when given to mice with either a sub-patent or patent S. mansoni infection.

Conclusions/significance: Our findings hold promise for the development of a novel antischistosomal drug based on an aminoalcohol functionality. Further in vitro and in vivo studies have been launched to elucidate the possible mechanism of action and to study the effect of mefloquine on S. haematobium and other trematodes. It will be interesting to investigate whether mefloquine, which is widely and effectively used for the treatment of malaria, has an impact on schistosomiasis in areas where both malaria and schistosomiasis co-exist.

Show MeSH
Related in: MedlinePlus