Abstract
BackgroundNew antimalarial drugs need to be developed because over time resistance against the existing drugs develops. Furthermore, some of the drugs have severe side effects. Here we describe a behavioral small-fish model for early detection of neurotoxic effects of new drugs. As case example we compare the effects of two mefloquine diastereomers on the behavior of goldfish using an automated 3D tracking system.FindingsIn a preliminary experiment, the overall toxic effects in terms of motor and respiratory impairments were determined during a 3-hour exposure to the drugs at relatively high doses (21.5 and 43 mgL). In the second experiment, behavioral testing was performed 24 h after a 3.5-h drug exposure to a low dose (14.25 mgL) of either drug. For the two high doses, erythro-mefloquine resulted in severe motor problems and respiratory problems occurred. In goldfish treated with threo-mefloquine, at 43 mgL the motor/respiratory impairments were less severe and at 21.5 mgL no such problems were observed. For the lower dose (14.25 mgL), erythro-mefloquine reduced locomotion. There was also a tendency for increased freezing, and the preference for quadrant two of the observation container was increased. No behavioral effects of threo-mefloquine were found.ConclusionsThe results demonstrate that in goldfish exposed to the drugs dissolved in the water, threo-mefloquine has less severe toxic effects as compared to erythro-mefloquine. These findings are consistent with other studies and support the usefulness of the small-fish model for predicting adverse effects of new antimalarial drugs during the initial phases of drug development.
Highlights
New antimalarial drugs need to be developed because over time resistance against the existing drugs develops
The results demonstrate that in goldfish exposed to the drugs dissolved in the water, threo-mefloquine has less severe toxic effects as compared to erythro-mefloquine
These findings are consistent with other studies and support the usefulness of the small-fish model for predicting adverse effects of new antimalarial drugs during the initial phases of drug development
Summary
New antimalarial drugs need to be developed because over time resistance against the existing drugs develops. As case example we compare the effects of two mefloquine diastereomers on the behavior of goldfish using an automated 3D tracking system. Mefloquine, doxycycline, a combination of atovaquone and proguanile (Malarone), and chloroquine (for areas where resistance is not yet prevalent) are the drugs used for prophylaxis of malaria caused by P. falciparum. Mefloquine (or more precisely, erythro-mefloquine) was traditionally preferred for use by the US military because it has to be administered on a weekly basis. It is still perceived as a standard, with tafenoquine as one of the few alternatives [2]. Mefloquine has more severe and longer-lasting side effects than the other antimalarial drugs. The US military decided to replace it with doxycycline (when not contraindicated) [3]
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