{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:23:17Z","timestamp":1792678997605,"version":"4.5.0"},"reference-count":51,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2016,12,9]],"date-time":"2016-12-09T00:00:00Z","timestamp":1481241600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Psychopharmacol"],"published-print":{"date-parts":[[2017,2]]},"abstract":"<jats:p>\n                    A pharmacologic challenge model with a nicotinic antagonist could be an important tool not only to understand the complex role of the nicotinic cholinergic system in cognition, but also to develop novel compounds acting on the nicotinic acetylcholine receptor. The objective was to develop a pharmacokinetic\u2013pharmacodynamic (PKPD) model using nonlinear mixed effects (NLME) methods to quantitate the pharmacokinetics of three oral mecamylamine doses (10, 20 and 30 mg) and correlate the plasma concentrations to the pharmacodynamic effects on a cognitive and neurophysiologic battery of tests in healthy subjects. A one-compartment linear kinetic model best described the plasma concentrations of mecamylamine. Mecamylamine\u2019s estimated clearance was 0.28 \u00b1 0.015 L min\n                    <jats:sup>\u22121<\/jats:sup>\n                    . The peripheral volume of distribution (291 \u00b1 5.15 L) was directly related to total body weight. Mecamylamine impaired the accuracy and increased the reaction time in tests evaluating short term working memory with a steep increase in the concentration-effect relationship at plasma concentrations below 100 \u03bcg L\n                    <jats:sup>\u22121<\/jats:sup>\n                    . On the other hand, mecamylamine induced a decrease in performance of tests evaluating visual and fine motor coordination at higher plasma concentrations (EC\n                    <jats:sub>50<\/jats:sub>\n                    97 \u03bcg L\n                    <jats:sup>\u22121<\/jats:sup>\n                    ). Systolic and diastolic blood pressure decreased exponentially after a plasma mecamylamine concentration of 80 \u03bcg L\n                    <jats:sup>\u22121<\/jats:sup>\n                    , a known effect previously poorly studied in healthy subjects. The developed mecamylamine PKPD model was used to quantify the effects of nicotinic blockade in a set of neurophysiological tests in humans with the goal to provide insight into the physiology and pharmacology of the nicotinic system in humans and the possibility to optimize future trials that use mecamylamine as a pharmacological challenge.\n                  <\/jats:p>","DOI":"10.1177\/0269881116681417","type":"journal-article","created":{"date-parts":[[2016,12,7]],"date-time":"2016-12-07T21:42:11Z","timestamp":1481146931000},"page":"192-203","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":5,"title":["Pharmacokinetics and pharmacodynamics of oral mecamylamine \u2013 development of a nicotinic acetylcholine receptor antagonist cognitive challenge test using modelling and simulation"],"prefix":"10.1177","volume":"31","author":[{"given":"Ricardo","family":"Alvarez-Jimenez","sequence":"first","affiliation":[{"name":"Centre for Human Drug Research, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Catrien","family":"Baakman","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper","family":"Stevens","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan C","family":"Goulooze","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research, Leiden, the Netherlands"},{"name":"Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen 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