Abstract:
Ivermectin is a well‐known and widely used anti‐parasitic drug. Recently, in vitro data suggest anti‐viral efficacy
of the drug, albeit at much higher concentrations than currently approved. Despite warnings by several
governing bodies, the (uncontrolled) human use of ivermectin has significantly increased during the COVID‐
19 epidemic. This study thus aimed to elucidate potential neurological risk of particularly the veterinary formulation
of ivermectin in comparison to pure ivermectin. Zebrafish eggs (1hpf) and larvae (4dpf) were exposed
to a range of concentrations of either pure ivermectin (IVM) or a veterinary formulation (V‐IVM) for a period of
24 hours. Behavioral responses to both treatments were assessed at various timepoints using the pentylenetetrazol
assay, the light–dark assay and a 5‐day teratogenesis protocol. In addition, dissolution rates were calculated
for both treatments. Acute responses of larvae at 4–<5dpf was similar for both treatments – a transient
hyperlocomotion was followed by a general hypolocomotion (ANOVA dose effect, P < 0.01). Both IVM and VIVM‐
treated larvae showed significant dose‐dependent (ANOVA dose effect, P < 0.0001) decreases in responsiveness
to repeated light–dark transitions, which again was more pronounced in IVM. These effects were
maintained after 24 hours of exposure. In contrast, when ivermectin was administered prior to establishment
of the blood brain‐barrier in the teratogenesis protocol, V‐IVM treatment was linked to more severe activity
decline on <5dpf. Differences in dissolution rates cannot account for these differences. In conclusion, current
data suggest significantly higher neurological risk of a veterinary formulation of ivermectin under conditions of
penetration across the blood brain‐barrier.
