{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T12:21:38Z","timestamp":1763468498682,"version":"build-2065373602"},"reference-count":29,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,11,17]],"date-time":"2018-11-17T00:00:00Z","timestamp":1542412800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2010\/08967\u20100","2014\/00474\u20105","2014\/50265\u20103","2017\/01425\u20106"],"award-info":[{"award-number":["2010\/08967\u20100","2014\/00474\u20105","2014\/50265\u20103","2017\/01425\u20106"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["beva.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Equine Veterinary Journal"],"published-print":{"date-parts":[[2019,7]]},"abstract":"Summary<\/jats:title>\n \n Background<\/jats:title>\n \n Pharmacokinetic (\n PK<\/jats:styled-content>\n )\/pharmacodynamic (\n PD<\/jats:styled-content>\n ) modelling offers new insights to design protocols for sedation and analgesia in standing horses.\n <\/jats:p>\n <\/jats:sec>\n \n Objectives<\/jats:title>\n To evaluate the parameters and interactions between detomidine and methadone when given alone or combined in standing horses.<\/jats:p>\n <\/jats:sec>\n \n Study design<\/jats:title>\n Randomised, placebo\u2010controlled, blinded, crossover.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Eight adult healthy horses were given six treatments intravenously: saline (\n SAL<\/jats:styled-content>\n ); detomidine (5\u00a0\u03bcg\/kg bwt;\n DET<\/jats:styled-content>\n ); methadone (0.2\u00a0mg\/kg bwt;\n MET<\/jats:styled-content>\n ) alone or combined with detomidine (2.5 [\n MLD<\/jats:styled-content>\n ], 5 [\n MMD<\/jats:styled-content>\n ] or 10 [\n MHD<\/jats:styled-content>\n ] \u03bcg\/kg bwt). Venous blood samples were obtained at predetermined times between 0 and 360\u00a0min after drug administration. Plasma detomidine and methadone were measured using a single, liquid\/liquid extraction technique by liquid chromatography coupled with a triple quadrupole mass spectrometer (\n LC<\/jats:styled-content>\n \u2010\n MS<\/jats:styled-content>\n \/\n MS<\/jats:styled-content>\n ). Sequential\n PK<\/jats:styled-content>\n \/\n PD<\/jats:styled-content>\n modelling compared rival models, with and without\n PK<\/jats:styled-content>\n and\n PD<\/jats:styled-content>\n interaction between drugs, to fit the\n PD<\/jats:styled-content>\n data including height of the head above the ground (\n HHAG<\/jats:styled-content>\n ), a visual analogue scale for sedation (\n VAS<\/jats:styled-content>\n ), electrical (\n ET<\/jats:styled-content>\n ), thermal (\n TT<\/jats:styled-content>\n ) and mechanical (\n MT<\/jats:styled-content>\n ) nociceptive thresholds and gastrointestinal motility (\n GIM<\/jats:styled-content>\n )\u00a0[1].\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Two and three compartment models best described the\n PK<\/jats:styled-content>\n of detomidine and methadone, respectively. Detomidine decreased its own clearance as well as the clearance of methadone. The interaction of methadone on the effect of detomidine revealed an infra\u2010additive (partial antagonism) effect for\n HHAG<\/jats:styled-content>\n (\u03b1\u00a0=\u00a0\u22121.33),\n VAS<\/jats:styled-content>\n (\u03b1\u00a0=\u00a0\u22120.98) and\n GIM<\/jats:styled-content>\n (\u03b1\u00a0=\u00a0\u22121.05), a positive potentiation for\n ET<\/jats:styled-content>\n (pot\u00a0=\u00a00.0041) and\n TT<\/jats:styled-content>\n (pot\u00a0=\u00a00.133) and a synergistic to additive effect for\n MT<\/jats:styled-content>\n (\u03b1\u00a0=\u00a00.78).\n <\/jats:p>\n <\/jats:sec>\n \n Main limitations<\/jats:title>\n This is a small experimental study.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Different\n PK<\/jats:styled-content>\n \/\n PD<\/jats:styled-content>\n interactions were demonstrated for each\n PD<\/jats:styled-content>\n parameter and could be modelled in\u00a0vivo. The modelling of our data will allow us to simulate and predict the effect of constant rate infusions of both drugs for future investigations.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/evj.13031","type":"journal-article","created":{"date-parts":[[2018,10,8]],"date-time":"2018-10-08T23:11:09Z","timestamp":1539040269000},"page":"517-529","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Characterisation of the in vivo interactions between detomidine and methadone in horses: Pharmacokinetic and pharmacodynamic modelling"],"prefix":"10.1111","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1391-0989","authenticated-orcid":false,"given":"M.","family":"Gozalo\u2010Marcilla","sequence":"first","affiliation":[{"name":"Department of Veterinary Surgery and Anaesthesiology School of Veterinary Medicine and Animal Science S\u00e3o Paulo State University (UNESP) Botucatu S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. P. L.","family":"Luna","sequence":"additional","affiliation":[{"name":"Department of Veterinary Surgery and Anaesthesiology School of Veterinary Medicine and Animal Science S\u00e3o Paulo State University (UNESP) Botucatu S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Moreira da Silva","sequence":"additional","affiliation":[{"name":"N\u00facleo de Pesquisas em Produtos Naturais e Sint\u00e9ticos (NPPNS) School of Pharmaceutical Sciences University of S\u00e3o Paulo (USP) Ribeir\u00e3o Preto S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N.","family":"Crosignani","sequence":"additional","affiliation":[{"name":"Department of Veterinary Surgery and Anaesthesiology School of Veterinary Medicine and Animal Science S\u00e3o Paulo State University (UNESP) Botucatu S\u00e3o Paulo Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N. 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