title: Zebrafish based assays for the assessment of cardiac, visual and gut function--potential safety screens for early drug discovery.
abstract: BACKGROUND
  Safety pharmacology is integral to the non-clinical safety assessment of new chemical entities prior to first administration to humans. The zebrafish is a well established model organism that has been shown to be relevant to the study of human diseases. The potential role of zebrafish in safety pharmacology was evaluated using reference compounds in three models assessing cardiac, visual and intestinal function.
  
  
  METHODS
  Compound toxicity was first established in zebrafish to determine the non toxic concentration of a blinded set of 16 compounds. In the cardiac assay, zebrafish larvae at 3 days post fertilisation (d.p.f.) were exposed to compounds for 3 h before measurement of the atrial and ventricular rates. To investigate visual function, the optomotor response was assessed in 8 d.p.f. larvae following a 5 day compound exposure. In the intestinal function assay, the number of gut contractions was measured in 7 d.p.f. larvae after a 1 h compound exposure. Finally, compound uptake was determined for 9 of the 16 compounds to measure the concentration of compound absorbed by the zebrafish larvae.
  
  
  RESULTS
  Seven compounds out of nine produced an expected effect that was statistically significant in the cardiac and visual functions assays. In the gut contraction assay, six out of ten compounds showed a statistically significant effect that was also the expected result whilst two displayed anticipated but non-significant effects. The compound uptake method was used to determine larval tissue concentrations and allowed the identification of false negatives when compound was poorly absorbed into the zebrafish.
  
  
  CONCLUSIONS
  Overall, results generated in three zebrafish larvae assays demonstrated a good correlation between the effects of compounds in zebrafish and the data available from other in vivo models or known clinical adverse effects. These results suggest that for the cardiac, intestinal and visual function, zebrafish assays have the potential to predict adverse drug effects and supports their possible role in early safety assessment of novel compounds.
authors.affiliation: Summit (Cambridge) Ltd., Cambridge, United Kingdom.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Berghmans
authors.forename: Paul
authors.initials: P
authors.lastname: Butler
authors.forename: Paul
authors.initials: P
authors.lastname: Goldsmith
authors.forename: Gareth
authors.initials: G
authors.lastname: Waldron
authors.forename: Iain
authors.initials: I
authors.lastname: Gardner
authors.forename: Zoe
authors.initials: Z
authors.lastname: Golder
authors.forename: Frances M
authors.initials: FM
authors.lastname: Richards
authors.forename: Gillian
authors.initials: G
authors.lastname: Kimber
authors.forename: Alan
authors.initials: A
authors.lastname: Roach
authors.forename: Wendy
authors.initials: W
authors.lastname: Alderton
authors.forename: Angeleen
authors.initials: A
authors.lastname: Fleming
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007814:Larva / Q000187:drug effects / Q000378:metabolism; D023421:Models, Animal; D004364:Pharmaceutical Preparations / Q000378:metabolism; D013045:Species Specificity; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*; D014785:Vision, Ocular / Q000187:drug effects / Q000502:physiology; D015027:Zebrafish / Q000502:physiology
chemical_list: D004364:Pharmaceutical Preparations