What question did this study set out to answer?

To determine whether zebrafish heart rate responses can serve as a high-throughput in vivo model for identifying drug-induced repolarization abnormalities and QT prolongation.

March 18, 2003CirculationOpen Access

Drugs That Induce Repolarization Abnormalities Cause Bradycardia in Zebrafish

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Why the study?

Does screening small molecules in zebrafish predict drug-induced repolarization abnormalities?

Population

Zebrafish (Danio rerio) model

Design

Preclinical

Authors

DMDavid J. MilanElectrophysiology TPTravis A. PetersonHarvard University JRJeremy N. RuskinElectrophysiology

Discussion

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Implication

Zebrafish assay concordance supports further preclinical validation; leaves open translation to human cardiotoxicity screening.

Key Points

To determine whether zebrafish heart rate responses can serve as a high-throughput in vivo model for identifying drug-induced repolarization abnormalities and QT prolongation.
Screened the effects of 100 small molecules on Danio rerio heart rate, including 23 drugs documented to cause QT prolongation in humans, using immersion and microinjection.
Used antisense knockdown of the zebrafish KCNH2 ortholog to examine heart rate alterations following reduction of repolarizing potassium current.
Assessed classic drug-drug interactions by co-administering erythromycin with cisapride and cimetidine with terfenadine.
Of 23 human QT-prolonging drugs tested, 18 initially induced bradycardia and AV block, and microinjection resolved 4 false negatives, identifying 22 of 23 total compounds.
Antisense knockdown of the KCNH2 ortholog produced dose-dependent bradycardia, verifying that repolarizing potassium current reduction mimics the drug phenotype.
Established clinical drug-drug interactions between erythromycin-cisapride and cimetidine-terfenadine were successfully recapitulated in the zebrafish assay.

Structured PICO

Does screening small molecules in zebrafish predict drug-induced repolarization abnormalities?

Population

Zebrafish (Danio rerio) model

Intervention

100 small molecules, including 23 drugs known to cause QT prolongation in humans; antisense knockdown of zebrafish KCNH2 ortholog

Outcome

Heart rate (bradycardia) and AV blocksurrogate

Zebrafish heart rate screening is a promising high-throughput preclinical assay for predicting drug-induced repolarization abnormalities.

Cite This Study

Milan et al. (2003) studied this question.

synapsesocial.com/papers/6a7dffa08b7e38892f151550 https://doi.org/10.1161/01.cir.0000061912.88753.87

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Drugs That Induce Repolarization Abnormalities Cause Bradycardia in Zebrafish

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Drugs That Induce Repolarization Abnormalities Cause Bradycardia in Zebrafish

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

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