{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T20:22:08Z","timestamp":1787775728179,"version":"build-2784847793"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>OBJECTIVE:<\/jats:title>\n                    <jats:p>Our study investigated the impact of various cardiovascular drug on the cardiac physiology of zebrafish embryos and validated these findings in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Cardiotoxicity has significantly contributed to the high drug attrition rate over the last two decades, underscoring the cardiac risk assessment in drug discovery and development. Although regulatory authority\u2019s guidelines specified the cell-based assays for the safety assessment of drugs, the current requirements fall short due to a lack of\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      biology. The use of zebrafish experimental system has surged in developmental and pathophysiological investigation due to their striking resemblance to mammals. Hence, we used the zebrafish model system for cardiovascular drug studies and validated it in the mice model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>MATERIALS AND METHODS:<\/jats:title>\n                    <jats:p>The zebrafish embryos of 72 hours post-fertilization (hpf) were exposed to different CVS drug and, recorded their heart rate, and further validated in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>We observed that exposure to amlodipine (a calcium channel blocker), atenolol (a class II antiarrhythmic), and amiodarone (a class III antiarrhythmic) led to dose-dependent reductions in heart rate in zebrafish embryos, with effects varying based on drug concentration and mechanism of action. Specifically, amiodarone treatment resulted in a dose-dependent decrease in heart rate (0.001\u2013100 \u03bcM) and atrioventricular block starting at a 10 \u03bcM concentration. Each class of cardiovascular drug demonstrated unique cardiac effects in zebrafish embryos, reflecting similar patterns in mice treated with these drugs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our findings highlight the zebrafish model\u2019s utility for early-phase cardiac risk assessment in drug discovery due to its high throughput capabilities and other beneficial features.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.4103\/ijp.ijp_566_24","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T21:05:33Z","timestamp":1746479133000},"page":"12-20","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Cardiac physiological changes induced by cardiovascular drugs from different chemical classes in zebrafish mirrored in mice: A predictive tool for comprehensive risk assessment"],"prefix":"10.4103","volume":"57","author":[{"given":"Rohan","family":"Takawale","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Smt. Kashibai Navale College of Pharmacy, Savitribai Phule Pune University, Pune, Maharashtra, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deeksha","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Smt. Kashibai Navale College of Pharmacy, Savitribai Phule Pune University, Pune, Maharashtra, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandana S.","family":"Nikam","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Smt. Kashibai Navale College of Pharmacy, Savitribai Phule Pune University, Pune, Maharashtra, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,5,6]]},"reference":[{"key":"R1-20250506","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.pharmthera.2013.03.005","article-title":"Drug attrition during pre-clinical and clinical development: Understanding and managing drug-induced cardiotoxicity","volume":"138","author":"Ferri","year":"2013","journal-title":"Pharmacol Ther"},{"key":"R2-20250506","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/nbt.2786","article-title":"Clinical development success rates for investigational drugs","volume":"32","author":"Hay","year":"2014","journal-title":"Nat Biotechnol"},{"key":"R3-20250506","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/nrd4309","article-title":"Lessons learned from the fate of AstraZeneca's drug pipeline: A five-dimensional framework","volume":"13","author":"Cook","year":"2014","journal-title":"Nat Rev Drug Discov"},{"key":"R4-20250506","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1021\/acs.chemrestox.5b00407","article-title":"Toxicology strategies for drug discovery: Present and future","volume":"29","author":"Blomme","year":"2016","journal-title":"Chem Res Toxicol"},{"key":"R5-20250506","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1080\/01926230701419063","article-title":"Aretrospective analysis of toxicogenomics in the safety assessment of drug candidates","volume":"35","author":"Foster","year":"2007","journal-title":"Toxicol Pathol"},{"key":"R6-20250506","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.vascn.2013.03.005","article-title":"A history of the role of the hERG channel in cardiac risk assessment","volume":"68","author":"Rampe","year":"2013","journal-title":"J Pharmacol Toxicol Methods"},{"key":"R7-20250506","doi-asserted-by":"crossref","first-page":"11316","DOI":"10.1073\/pnas.0702724104","article-title":"Zebrafish model for human long QT syndrome","volume":"104","author":"Arnaout","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R8-20250506","doi-asserted-by":"crossref","first-page":"H1152","DOI":"10.1152\/ajpheart.00870.2002","article-title":"Functional and morphological evidence for a ventricular conduction system in zebrafish and Xenopus hearts","volume":"284","author":"Sedmera","year":"2003","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"R9-20250506","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1242\/dev.119.1.31","article-title":"Cardiovascular development in the zebrafish. I. Myocardial fate map and heart tube formation","volume":"119","author":"Stainier","year":"1993","journal-title":"Development"},{"key":"R10-20250506","first-page":"13","article-title":"Advances in the study of heart development and disease using zebrafish","volume":"3","author":"Brown","year":"2016","journal-title":"J Cardiovasc Dev Dis"},{"key":"R11-20250506","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.taap.2003.07.012","article-title":"Zebrafish embryos express an orthologue of HERG and are sensitive toward a range of QT-prolonging drugs inducing severe arrhythmia","volume":"193","author":"Langheinrich","year":"2003","journal-title":"Toxicol Appl Pharmacol"},{"key":"R12-20250506","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1038\/bjp.2008.249","article-title":"Zebrafish: An emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery","volume":"154","author":"Barros","year":"2008","journal-title":"Br J Pharmacol"},{"key":"R13-20250506","doi-asserted-by":"crossref","first-page":"864","DOI":"10.3390\/ijms18040864","article-title":"ZeGlobalTox: An innovative approach to address organ drug toxicity using zebrafish","volume":"18","author":"Cornet","year":"2017","journal-title":"Int J Mol Sci"},{"key":"R14-20250506","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/nature12111","article-title":"The zebrafish reference genome sequence and its relationship to the human genome","volume":"496","author":"Howe","year":"2013","journal-title":"Nature"},{"key":"R15-20250506","first-page":"e4196","article-title":"Regular care and maintenance of a zebrafish (Danio rerio) laboratory: An introduction","volume":"69","author":"Avdesh","year":"2012","journal-title":"J Vis Exp"},{"key":"R16-20250506","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1111\/j.1476-5381.2010.00872.x","article-title":"Animal research: Reporting in vivo experiments: The ARRIVE guidelines","volume":"160","author":"Kilkenny","year":"2010","journal-title":"Br J Pharmacol"},{"key":"R17-20250506","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.aquaculture.2007.04.077","article-title":"The husbandry of zebrafish (Danio rerio): A review","volume":"269","author":"Lawrence","year":"2007","journal-title":"Aquaculture"},{"key":"R18-20250506","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1093\/jac\/dkl224","article-title":"Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines","volume":"58","author":"Agwuh","year":"2006","journal-title":"J Antimicrob Chemother"},{"key":"R19-20250506","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/BF03188723","article-title":"Clinical pharmacokinetics of atenolol \u2013 A review","volume":"7","author":"Kirch","year":"1982","journal-title":"Eur J Drug Metab Pharmacokinet"},{"key":"R20-20250506","doi-asserted-by":"crossref","first-page":"136","DOI":"10.2165\/00003088-198409020-00002","article-title":"Clinical pharmacokinetics of amiodarone","volume":"9","author":"Latini","year":"1984","journal-title":"Clin Pharmacokinet"},{"key":"R21-20250506","doi-asserted-by":"crossref","first-page":"22","DOI":"10.2165\/00003088-199222010-00003","article-title":"Clinical pharmacokinetics of amlodipine","volume":"22","author":"Meredith","year":"1992","journal-title":"Clin Pharmacokinet"},{"key":"R22-20250506","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.ecoenv.2004.10.015","article-title":"Development of a zebrafish 4-day embryo-larval bioassay to assess toxicity of chemicals","volume":"63","author":"Fraysse","year":"2006","journal-title":"Ecotoxicol Environ Saf"},{"key":"R23-20250506","doi-asserted-by":"crossref","first-page":"755","DOI":"10.2131\/jts.42.755","article-title":"Evaluation system for arrhythmogenic potential of drugs using human-induced pluripotent stem cell-derived cardiomyocytes and gene expression analysis","volume":"42","author":"Higa","year":"2017","journal-title":"J Toxicol Sci"},{"key":"R24-20250506","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1161\/01.CIR.96.3.856","article-title":"Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Vasodilator-heart failure trial (V-HeFT) study group","volume":"96","author":"Cohn","year":"1997","journal-title":"Circulation"},{"key":"R25-20250506","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1056\/NEJM199610103351504","article-title":"Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective randomized amlodipine survival evaluation study group","volume":"335","author":"Packer","year":"1996","journal-title":"N Engl J Med"},{"key":"R26-20250506","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1016\/S0140-6736(04)17355-8","article-title":"Atenolol in hypertension: Is it a wise choice?","volume":"364","author":"Carlberg","year":"2004","journal-title":"Lancet"},{"key":"R27-20250506","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.jash.2017.05.001","article-title":"Comparative efficacy of ?-blockers on mortality and cardiovascular outcomes in patients with hypertension: A systematic review and network meta-analysis","volume":"11","author":"Zhang","year":"2017","journal-title":"J Am Soc Hypertens"},{"key":"R28-20250506","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.1016\/j.bmc.2005.01.028","article-title":"Synthesis and evaluation of the permeability transition inhibitory characteristics of paramagnetic and diamagnetic amiodarone derivatives","volume":"13","author":"K\u00e1lai","year":"2005","journal-title":"Bioorg Med Chem"},{"key":"R29-20250506","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1038\/srep02100","article-title":"MICE models: Superior to the HERG model in predicting torsade de pointes","volume":"3","author":"Kramer","year":"2013","journal-title":"Sci Rep"},{"key":"R30-20250506","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1093\/toxsci\/kfv180","article-title":"Bridging functional and structural cardiotoxicity assays using human embryonic stem cell-derived cardiomyocytes for a more comprehensive risk assessment","volume":"148","author":"Clements","year":"2015","journal-title":"Toxicol Sci"}],"container-title":["Indian Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.4103\/ijp.ijp_566_24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T19:40:43Z","timestamp":1787773243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.4103\/ijp.ijp_566_24"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1]]},"references-count":30,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025]]}},"URL":"https:\/\/doi.org\/10.4103\/ijp.ijp_566_24","relation":{},"ISSN":["0253-7613","1998-3751"],"issn-type":[{"value":"0253-7613","type":"print"},{"value":"1998-3751","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1]]},"assertion":[{"value":"2024-07-04","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-01","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}