{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T05:36:50Z","timestamp":1782193010845,"version":"3.54.5"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":398,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100031829","name":"Ceva Sante Animale","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100031829","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Open access funding provided by the Iowa State University Library."}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Benazepril exhibits a dose-dependent effect on biomarkers of the circulating renin-angiotensin-aldosterone system (RAAS) in dogs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Hypothesis\/Objectives<\/jats:title>\n                    <jats:p>To characterize the dose-exposure-response relationship of a fixed-dose combination product including benazepril and spironolactone (CARDALIS\u00ae) on RAAS biomarkers in dogs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Animals<\/jats:title>\n                    <jats:p>Eighteen purpose-bred healthy beagle dogs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Three groups of 6 dogs received different doses of CARDALIS\u00ae for 14\u2009days following induction of RAAS activation by feeding a low-sodium diet: (a) benazepril 0.25\u2009mg\/kg\u2009+\u2009spironolactone 2\u2009mg\/kg PO q24h (label dose); (b) benazepril 0.25\u2009mg\/kg\u2009+\u2009spironolactone 2\u2009mg\/kg PO q12h; or (c) benazepril 0.5\u2009mg\/kg\u2009+ spironolactone 4\u2009mg\/kg PO q12h. Blood samples were collected at baseline and serial time intervals after CARDALIS\u00ae dosing to measure serum RAAS biomarkers and plasma concentrations of active drug metabolites. Time-weighted averages for serum RAAS biomarkers after CARDALIS\u00ae dosing at steady state were compared between dosage groups using Wilcoxon rank-sum testing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Compared to the label dose, the highest dose of CARDALIS\u00ae was associated with a 30% decrease in angiotensin II (P\u2009=\u2009.03), 94% increase in angiotensin 1-7 (P\u2009=\u2009.03), 71% decrease in surrogate activity of ACE (P\u2009=\u2009.002), and 116% increase in circulating aldosterone (P\u2009=\u2009.02). CARDALIS\u00ae was well-tolerated at all doses with no clinically relevant changes in renal values or serum electrolytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Clinical Importance<\/jats:title>\n                    <jats:p>The combined CARDALIS\u00ae product leads to dose-dependent alterations of RAAS metabolites. These results could help inform clinical trials in dogs with heart disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jvim.17255","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T07:42:21Z","timestamp":1732693341000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dose-exposure-response of CARDALIS\u00ae (benazepril\/spironolactone) on the classical and alternative arms of the renin-angiotensin-aldosterone system in healthy dogs"],"prefix":"10.1093","volume":"39","author":[{"given":"Elizabeth","family":"Manson","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Iowa State University Department of Veterinary Clinical Sciences, , Ames, Iowa,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9153-7916","authenticated-orcid":false,"given":"Jessica L.","family":"Ward","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Iowa State University Department of Veterinary Clinical Sciences, , Ames, Iowa,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Merodio","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Iowa State University Department of Veterinary Clinical Sciences, , Ames, Iowa,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6892-4176","authenticated-orcid":false,"given":"Emilie","family":"Guillot","sequence":"additional","affiliation":[{"name":"Ceva Sant\u00e9 Animale, Companion Animal Franchise , Libourne,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Blondel","sequence":"additional","affiliation":[{"name":"Ceva Sant\u00e9 Animale , Pharma Research & Development, Libourne,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Allenspach","sequence":"additional","affiliation":[{"name":"SMART Pharmacology, College of Veterinary Medicine, The University of Georgia Precision One Health Initiative, Department of Veterinary Pathology, , Athens, Georgia,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Domenig","sequence":"additional","affiliation":[{"name":"Attoquant Diagnostics , Vienna,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan P.","family":"Mochel","sequence":"additional","affiliation":[{"name":"SMART Pharmacology, College of Veterinary Medicine, The University of Georgia Precision One Health Initiative, Department of Veterinary Pathology, , Athens, Georgia,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,1,1]]},"reference":[{"key":"2026020302391218800_jvim17255-bib-0001","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jvc.2022.02.001","article-title":"The longitudinal outcome of canine (K9) myxomatous mitral valve disease (LOOK-Mitral) registry: baseline treatment characteristics","volume":"41","author":"Franchini","year":"2022","journal-title":"J Vet Cardiol"},{"key":"2026020302391218800_jvim17255-bib-0002","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1111\/jvim.15488","article-title":"ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs","volume":"33","author":"Keene","year":"2019","journal-title":"J Vet Intern Med"},{"key":"2026020302391218800_jvim17255-bib-0003","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1111\/j.1939-1676.1995.tb01074.x","article-title":"Acute and short-term hemodynamic, echocardiographic, and clinical effects of enalapril maleate in dogs with naturally acquired heart failure: results of the Invasive Multicenter PROspective Veterinary Evaluation of Enalapril study. 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