{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T10:39:02Z","timestamp":1777718342335,"version":"3.51.4"},"reference-count":12,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Milestone Pharmaceuticals Inc"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Int J Toxicol"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>\n                    Paroxysmal supraventricular tachycardia (PSVT) is a common cardiac arrhythmia associated with substantial health care burden. Etripamil, a fast-acting non-dihydropyridine calcium channel blocker developed for intranasal self-administration, is currently under investigation for acute treatment of PSVT episodes. A novel two-phase study design was used to test a series of five doses of intravenous etripamil (0, 0.025, 0.05, 0.15, and 0.3\u00a0mg\/kg) in conscious cynomolgus monkeys. The cardiovascular effects (e.g., blood pressure and ECG recordings) were assessed during the first phase, and the pharmacokinetic profile was characterized during the second phase. Animals were dosed remotely to avoid the stress of intranasal dosing and minimize the impact of dose administration on measurements. Results were compared with findings from subsequent intranasal studies in cynomolgus monkeys and humans. Etripamil decreased systolic blood pressure and increased heart rate proportionately in a dose-dependent manner. Etripamil also induced dose-dependent increases in the PR interval. At a dose of 0.3\u00a0mg\/kg (the highest dose), the mean highest PR prolongation from baseline during 20\u00a0minutes after dosing was 27.38%. Systemic exposure to etripamil increased in a dose-dependent manner. Mean area under the curve from administration to when drug was no longer present (AUC\n                    <jats:sub>0\u2013\u221e<\/jats:sub>\n                    ) values ranged from 179 to 2364\u00a0ng \u2022 min\/mL, peak plasma concentration ranged from 13.2 to 176\u00a0ng\/mL, and mean half-life ranged from 12.3 to 20.8\u00a0minutes (Figure 1). Results were consistent with data from subsequent intranasal preclinical and clinical studies. Intravenous etripamil demonstrated the desired targeted pharmacokinetic and pharmacodynamic profiles in conscious cynomolgus monkeys.\n                  <\/jats:p>","DOI":"10.1177\/10915818251327963","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T13:40:55Z","timestamp":1743514855000},"page":"287-296","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cardiovascular and Pharmacokinetic Profiles of Intravenous Etripamil in Conscious Telemetered Cynomolgus Monkeys"],"prefix":"10.1177","volume":"44","author":[{"given":"Alexis","family":"Ascah","sequence":"first","affiliation":[{"name":"Charles River, Laval, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Pierre","family":"Moreau","sequence":"additional","affiliation":[{"name":"Recherche Continuum Research, Rigaud, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Authier","sequence":"additional","affiliation":[{"name":"Charles River, Laval, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9125-3090","authenticated-orcid":false,"given":"David B.","family":"Bharucha","sequence":"additional","affiliation":[{"name":"Milestone Pharmaceuticals Inc, Charlotte, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3608-3228","authenticated-orcid":false,"given":"Douglas","family":"Wight","sequence":"additional","affiliation":[{"name":"Milestone Pharmaceuticals Inc, Montreal, QC, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2025,4]]},"reference":[{"issue":"14","key":"e_1_3_5_2_2","first-page":"e471","article-title":"2015 ACC\/AHA\/HRS guideline for the management of adult patients with supraventricular tachycardia: executive summary: a report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society","volume":"133","author":"Page RL","year":"2016","unstructured":"Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC\/AHA\/HRS guideline for the management of adult patients with supraventricular tachycardia: executive summary: a report of the American College of Cardiology\/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2016;133(14):e471-505.","journal-title":"Circulation"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1197\/j.aem.2007.01.013"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/jce.15109"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/XCE.0000000000000208"},{"key":"e_1_3_5_6_2","unstructured":"Niehues LJ Klovenski V. Vagal maneuver [Updated 2023 Jul 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK551575\/."},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jemermed.2019.06.008"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz467"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2018.04.082"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00776-6"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.1383"},{"issue":"1","key":"e_1_3_5_12_2","first-page":"95","article-title":"P522: preclinical safety evaluation of etripamil nasal spray in cynomolgus macaques (Macaca fascicularis) supports its safe use in PSVT patients","volume":"42","author":"Pion J","year":"2023","unstructured":"Pion J, Mendez CL, Moreau J-P, Wight D. P522: preclinical safety evaluation of etripamil nasal spray in cynomolgus macaques (Macaca fascicularis) supports its safe use in PSVT patients. Int J Toxicol. 2023;42(1):95.","journal-title":"Int J Toxicol"},{"key":"e_1_3_5_13_2","unstructured":"Wight DYS Nguyen D Francis Plat F. Safety tolerability pharmacokinetics and pharmacodynamics of intranasal etripamil in healthy Japanese and non-Japanese adults. Paper Presented at: 71st Annual Scientific Session at the American College of Cardiology 2022; April 2-4 2022; Washington DC."}],"container-title":["International Journal of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10915818251327963","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/10915818251327963","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10915818251327963","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:24:54Z","timestamp":1777458294000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/10915818251327963"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4]]},"references-count":12,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1177\/10915818251327963"],"URL":"https:\/\/doi.org\/10.1177\/10915818251327963","relation":{},"ISSN":["1091-5818","1092-874X"],"issn-type":[{"value":"1091-5818","type":"print"},{"value":"1092-874X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4]]}}}