{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T18:57:10Z","timestamp":1790449030686,"version":"4.1.0"},"reference-count":24,"publisher":"SAGE Publications","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2021,5,4]]},"abstract":"<jats:p>Background: Bradycardia is a physiological condition characterized by a decrease in heart rate and is a side effect of many drug classes. Bradycardia has been reported as an adverse event for patients receiving donepezil for Alzheimer\u2019s disease (AD) treatment. Objective: The purpose of the paper is to systematically investigate the association between the occurrence of bradycardia in adults and the usage of donepezil using clinical data derived from the FDA Adverse Event Reporting System (FAERS) database. Methods: The risk of bradycardia in patients who only took donepezil was compared with those of patients who only took over-the-counter medications, multiple arrhythmia drugs, or other medications for AD treatment. In addition, this study sought to determine if this heightened bradycardia risk was influenced by sex, age, and dosage. Results: The results indicated that there was a significant greater likelihood of reporting bradycardia in patients administered donepezil than most of the drugs investigated. There was no significant association between age or the dosage of donepezil and the likelihood of reporting bradycardia. However, males were found to be more likely than females to report bradycardia as an adverse event. Tumor necrosis factor inhibition and the stimulation of endothelial nitric oxide synthase were proposed to be the primary mechanism of actions which confer elevated bradycardia risk when using donepezil. Conclusion: These findings identified strong association between the usage of donepezil and bradycardia in adults as well as provided insight into the underlying molecular mechanisms that induce bradycardia by donepezil.<\/jats:p>","DOI":"10.3233\/jad-201551","type":"journal-article","created":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T14:16:20Z","timestamp":1616508980000},"page":"297-307","source":"Crossref","is-referenced-by-count":21,"title":["Bradycardia Due to Donepezil in Adults: Systematic Analysis of FDA Adverse Event Reporting System"],"prefix":"10.1177","volume":"81","author":[{"given":"Robert","family":"Morris","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Science, Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hunter","family":"Luboff","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science, Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul P.","family":"Jose","sequence":"additional","affiliation":[{"name":"Muma College of Business, University of South Florida, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Eckhoff","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Microbiology and Molecular Biology, College of Art and Science, University of South Florida, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Bu","sequence":"additional","affiliation":[{"name":"Department of Mathematics & Statistics, College of Art and Science, University of South Florida, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh","family":"Pham","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, College of Engineering, University of South Florida, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dekai","family":"Rohlsen-Neal","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science, Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science, Taneja College of Pharmacy, University of South Florida, Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"key":"10.3233\/JAD-201551_ref1","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1037\/tps0000124","article-title":"Alterations in hippocampal activity and Alzheimer\u2019s disease","volume":"3","author":"Setti","year":"2017","journal-title":"Transl Issues Psychol Sci"},{"key":"10.3233\/JAD-201551_ref2","doi-asserted-by":"crossref","first-page":"961","DOI":"10.3390\/brainsci10120961","article-title":"The association between the usage of non-steroidal anti-inflammatory drugs and cognitive status: Analysis of longitudinal and cross-sectional studies from the global Alzheimer\u2019s Association interactive network and transcriptomic data","volume":"10","author":"Morris","year":"2020","journal-title":"Brain Sci"},{"key":"10.3233\/JAD-201551_ref3","doi-asserted-by":"crossref","unstructured":"(2020) 2020 Alzheimer\u2019s disease facts and figures.heimers Dement}. Alz{- 16, 391\u2013460.","DOI":"10.1002\/alz.12068"},{"key":"10.3233\/JAD-201551_ref4","doi-asserted-by":"crossref","first-page":"391","DOI":"10.2174\/18715273113126660166","article-title":"Current acetylcholinesterase-inhibitors: A neuroinformatics perspective","volume":"13","author":"Shaikh","year":"2014","journal-title":"CNS Neurol Disord Drug Targets"},{"issue":"Suppl 2","key":"10.3233\/JAD-201551_ref5","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/jnc.14052","article-title":"Cholinergic modulation of the hippocampal region and memory function","volume":"142","author":"Haam","year":"2017","journal-title":"J Neurochem"},{"key":"10.3233\/JAD-201551_ref6","doi-asserted-by":"crossref","first-page":"101","DOI":"10.2174\/1570159X13666150716165726","article-title":"Alzheimer\u2019s disease: Targeting the Cholinergic System","volume":"14","author":"Ferreira-Vieira","year":"2016","journal-title":"Curr Neuropharmacol"},{"key":"10.3233\/JAD-201551_ref7","doi-asserted-by":"crossref","first-page":"77","DOI":"10.32607\/20758251-2013-5-4-77-82","article-title":"Depolarization-induced calcium-independent synaptic vesicle exo- and endocytosis at frog motor nerve terminals","volume":"5","author":"Abdrakhmanov","year":"2013","journal-title":"Acta Naturae"},{"key":"10.3233\/JAD-201551_ref8","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1111\/bph.12359","article-title":"Neuronal AChE splice variants and their non-hydrolytic functions: Redefining a target of AChE inhibitors?","volume":"170","author":"Zimmermann","year":"2013","journal-title":"Br J Pharmacol"},{"key":"10.3233\/JAD-201551_ref9","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3389\/fnmol.2011.00022","article-title":"Revisiting the role of acetylcholinesterase in Alzheimer\u2019s disease: Cross-talk with P-tau and beta-amyloid","volume":"4","author":"Garcia-Ayllon","year":"2011","journal-title":"Front Mol Neurosci"},{"key":"10.3233\/JAD-201551_ref10","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1006\/jmbi.1997.1245","article-title":"Acetylcholinesterase promotes the aggregation of amyloid-beta-peptide fragments by forming a complex with the growing fibrils","volume":"272","author":"Alvarez","year":"1997","journal-title":"J Mol Biol"},{"key":"10.3233\/JAD-201551_ref11","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1152\/japplphysiol.90401.2008","article-title":"Decreased maximal heart rate with aging is related to reduced beta-adrenergic responsiveness but is largely explained by a reduction in intrinsic heart rate","volume":"105","author":"Christou","year":"2008","journal-title":"J Appl Physiol (1985)"},{"key":"10.3233\/JAD-201551_ref12","doi-asserted-by":"crossref","first-page":"e1000157","DOI":"10.1371\/journal.pmed.1000157","article-title":"Cholinesterase inhibitors and hospitalization for bradycardia: A population-based study","volume":"6","author":"Park-Wyllie","year":"2009","journal-title":"PLoS Med"},{"key":"10.3233\/JAD-201551_ref13","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1097\/WAD.0b013e3181b7642b","article-title":"Donepezil-associated bradyarrhythmia in a patient with dementia with Lewy bodies (DLB)","volume":"24","author":"Rosenbloom","year":"2010","journal-title":"Alzheimer Dis Assoc Disord"},{"key":"10.3233\/JAD-201551_ref14","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1111\/j.1532-5415.2009.02488.x","article-title":"Cholinesterase inhibitors and incidence of bradycardia in patients with dementia in the veterans affairs new England healthcare system","volume":"57","author":"Hernandez","year":"2009","journal-title":"J Am Geriatr Soc"},{"key":"10.3233\/JAD-201551_ref15","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1007\/s40264-018-00792-0","article-title":"A comon study of algorithms to detect drug-adverse event associations: Frequentist, Bayesian, and machine-learning approaches","volume":"42","author":"Pham","year":"2019","journal-title":"Drug Saf"},{"key":"10.3233\/JAD-201551_ref16","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1002\/pds.677","article-title":"Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports","volume":"10","author":"Evans","year":"2001","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"10.3233\/JAD-201551_ref17","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1002\/1097-0258(20001130)19:22<3127::AID-SIM784>3.0.CO;2-M","article-title":"A simple method for converting an odds ratio to effect size for use in meta-analysis","volume":"19","author":"Chinn","year":"2000","journal-title":"Stat Med"},{"key":"10.3233\/JAD-201551_ref18","doi-asserted-by":"crossref","first-page":"101441","DOI":"10.1016\/j.redox.2020.101441","article-title":"An emerging perspective on sex differences: Intersecting S-nitrosothiol and aldehyde signaling in the heart","volume":"31","author":"Casin","year":"2020","journal-title":"Redox Biol"},{"key":"10.3233\/JAD-201551_ref20","first-page":"250","article-title":"Influence of sildenafil and donepezil administration on the serum redox balance in experimentally induced lower limb critical ischemia","volume":"86","author":"Constantinescu","year":"2013","journal-title":"Clujul Med"},{"key":"10.3233\/JAD-201551_ref21","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.brainres.2018.12.044","article-title":"Differential roles of hippocampal nNOS and iNOS in the control of baroreflex function in conscious rats","volume":"1710","author":"Almeida","year":"2019","journal-title":"Brain Res"},{"key":"10.3233\/JAD-201551_ref22","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1161\/CIRCULATIONAHA.110.981738","article-title":"Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease","volume":"123","author":"Stasch","year":"2011","journal-title":"Circulation"},{"key":"10.3233\/JAD-201551_ref23","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.3389\/fimmu.2018.01849","article-title":"Tumor necrosis factor receptor-associated factor regulation of nuclear factor kappaB and mitogen-activated protein kinase pathways","volume":"9","author":"Shi","year":"2018","journal-title":"Front Immunol"},{"key":"10.3233\/JAD-201551_ref24","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1161\/01.ATV.18.11.1796","article-title":"NO inhibits cytokine-induced iNOS expression and NF-kappaB activation by interfering with phosphorylation and degradation of IkappaB-alpha","volume":"18","author":"Katsuyama","year":"1998","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"10.3233\/JAD-201551_ref25","doi-asserted-by":"crossref","first-page":"17357","DOI":"10.1038\/srep17357","article-title":"A novel algorithm for analyzing drug-drug interactions from MEDLINE literature","volume":"5","author":"Lu","year":"2015","journal-title":"Sci Rep"}],"container-title":["Journal of Alzheimer's Disease"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JAD-201551","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T10:05:30Z","timestamp":1777370730000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JAD-201551"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,4]]},"references-count":24,"journal-issue":{"issue":"1"},"URL":"https:\/\/doi.org\/10.3233\/jad-201551","relation":{},"ISSN":["1387-2877","1875-8908"],"issn-type":[{"value":"1387-2877","type":"print"},{"value":"1875-8908","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,4]]}}}