{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T15:15:25Z","timestamp":1793286925109,"version":"4.5.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T00:00:00Z","timestamp":1678233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["ACT210083"],"award-info":[{"award-number":["ACT210083"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Chronopharmacology of arterial hypertension impacts the long-term cardiovascular risk of hypertensive subjects. Therefore, clinical and computational studies have proposed optimizing antihypertensive medications\u2019 dosing time (Ta). However, the causes and mechanisms underlying the Ta-dependency antihypertensive effect have not been elucidated. Here we propose using a Ta- dependent effect model to understand and predict the antihypertensive effect of valsartan and aspirin throughout the day in subjects with grade I or II essential hypertension. The model based on physiological regulation mechanisms includes a periodic function for each parameter that changes significantly after treatment. Circadian variations of parameters depending on the dosing time allowed the determination of regulation mechanisms dependent on the circadian rhythm that were most relevant for the action of each drug. In the case of valsartan, it is the regulation of vasodilation and systemic vascular resistance. In the case of aspirin, the antithrombotic effect generates changes in the sensitivity of systemic vascular resistance and heart rate to changes in physical activity. Dosing time-dependent models predict a more significant effect on systemic vascular resistance and blood pressure when administering valsartan or aspirin at bedtime. However, circadian dependence on the regulation mechanisms showed different sensitivity of their circadian parameters and shapes of functions, presenting different phase shifts and amplitude. Therefore, different mechanisms of action and pharmacokinetic properties of each drug can generate different profiles of Ta-dependence of antihypertensive effect and optimal dosing times.<\/jats:p>","DOI":"10.3389\/fendo.2023.1110459","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T01:05:24Z","timestamp":1678237524000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Understanding the dosing-time-dependent antihypertensive effect of valsartan and aspirin through mathematical modeling"],"prefix":"10.3389","volume":"14","author":[{"given":"Javiera","family":"Cort\u00e9s-R\u00edos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Rodriguez-Fernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/HR.2015.142","article-title":"Chronotherapy with conventional blood pressure medications improves management of hypertension and reduces cardiovascular and stroke risks","volume":"39","author":"Hermida","year":"2016","journal-title":"Hypertens Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehz754","article-title":"Bedtime hypertension treatment improves cardiovascular risk reduction: the hygia chronotherapy trial","volume":"41","author":"Hermida","year":"2019","journal-title":"Eur Heart J"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/S11906-018-0897-4","article-title":"Chronotherapy for hypertension","volume":"20","author":"Bowles","year":"2018","journal-title":"Curr Hypertens Rep"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/J.ADDR.2021.01.013","article-title":"Ingestion-time differences in the pharmacodynamics of hypertension medications: Systematic review of human chronopharmacology trials","volume":"170","author":"Hermida","year":"2021","journal-title":"Adv Drug Delivery Rev"},{"key":"B5","doi-asserted-by":"publisher","first-page":"101454","DOI":"10.1016\/J.SMRV.2021.101454","article-title":"Extent of asleep blood pressure reduction by hypertension medications is ingestion-time dependent: Systematic review and meta-analysis of published human trials","volume":"59","author":"Hermida","year":"2021","journal-title":"Sleep Med Rev"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/J.JACC.2004.08.071","article-title":"Aspirin administered at bedtime, but not on awakening, has an effect on ambulatory blood pressure in hypertensive patients","volume":"46","author":"Hermida","year":"2005","journal-title":"J Am Coll Cardiol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2011.08.752","article-title":"Effect of administration of low-dose aspirin before bedtime on blood pressure in hypertensive patients: A meta-analysis","volume":"152","author":"Ruan","year":"2011","journal-title":"Int J Cardiol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1007\/S00228-020-02997-8\/FIGURES\/3","article-title":"The impact of acetylsalicylic acid dosed at bedtime on circadian rhythms of blood pressure in the high-risk group of cardiovascular patients\u2013a randomized, controlled trial","volume":"77","author":"Krasi\u0144ska","year":"2021","journal-title":"Eur J Clin Pharmacol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.4.2.175","article-title":"The influence of circadian rhythms on the kinetics of drugs in humans","volume":"4","author":"Baraldo","year":"2008","journal-title":"Expert Opin Drug Metabol Toxicol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2020.1825681","article-title":"Ingestion-time \u2013 relative to circadian rhythms \u2013 differences in the pharmacokinetics and pharmacodynamics of hypertension medications","volume":"16","author":"Hermida","year":"2020","journal-title":"Expert Opin Drug Metabol Toxicol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59259-978-3_17","author":"Lemmer","year":"2007","journal-title":"\u201cChronobiology and chronopharmacology of hypertension. 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