Differential Cardiac Effect With Different Cardiovascular Drugs in Zebrafish: A Predictive Tool in Cardiac Risk Assessment

Posted: 10 Feb 2020

See all articles by Dipanjali Kamthe

Dipanjali Kamthe

affiliation not provided to SSRN

Rohan Takawale

Smt. N. M. Padalia Pharmacy College

Vandana Nikam

Smt. N. M. Padalia Pharmacy College

Date Written: February 7, 2020

Abstract

During the last two decades, the development of drug discovery is slow down due to drug withdrawal from the market or reported to have post-market safety events. The organ-specific toxicity, especially cardiotoxicity is the major concern for the high drug attrition rate. The pharmaceutical industry is looking for high throughput, high content analysis based novel assays that would be fast, efficient, reproducible, and cost-effective; would address toxicity, the safety of lead molecules and complement currently used cell-based assays in preclinical testing. The zebrafish embryo development is fast and all vital organs like heart, liver, brain, pancreas, kidneys in zebrafish are functional within 96-120 hours post-fertilization. The maintenance cost of zebrafish is reasonably low as compared to mammalian systems. The functional and developmental features of zebrafish heart are quite similar to the human heart. Due to these features, zebrafish have arisen as a potential experimental screening model in lead identification and validation in the drug development process. We aim to evaluate the impact of drug treatment on cardiac physiology when zebrafish embryos exposed to a different class of cardiovascular drugs. The treatment with amlodipine (calcium channel blocker), atenolol (class II anti-arrhythmia drug), and amiodarone (class III antiarrhythmic) attenuated heart rate in zebrafish embryos at different concentrations depending upon their pharmacokinetic profile and mechanism of action. Among three compounds, amiodarone showed a dose-dependent decrease in heart rate (0.001-100 µM concentration) along with atria ventricle block (10 µM concentration onward) and liver toxicity. The different classes of cardiovascular drugs showed a differential pattern of cardiac effect. Furthermore, the mice treated with these drugs showed a similar pattern as observed in zebrafish. In conclusion, we showed that the zebrafish model is more appealing, amenable to investigate the cardiac risk assessment in the early phase of drug discovery due to its high throughput nature and other advantageous features.

Keywords: cardiovascular drugs, drug safety, zebrafish, cardiac risk assessment

JEL Classification: 100

Suggested Citation

Kamthe, Dipanjali and Takawale, Rohan and Nikam, Vandana, Differential Cardiac Effect With Different Cardiovascular Drugs in Zebrafish: A Predictive Tool in Cardiac Risk Assessment (February 7, 2020). Proceedings of International Conference on Drug Discovery (ICDD) 2020, Available at SSRN: https://ssrn.com/abstract=3533859

Dipanjali Kamthe (Contact Author)

affiliation not provided to SSRN

Rohan Takawale

Smt. N. M. Padalia Pharmacy College ( email )

PUNE, 411048
India

Vandana Nikam

Smt. N. M. Padalia Pharmacy College ( email )

PUNE, 411048
India

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