{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:21:13Z","timestamp":1760239273225,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T00:00:00Z","timestamp":1604361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Although nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the main types of drugs used to treat pain, they have several adverse effects, and such effects can be reduced by combining two analgesic drugs. The aim of this study was to evaluate the nociceptive activity of methyleugenol combined with either diclofenac or ketorolac, and determine certain parameters of pharmacokinetics. For the isobolographic analysis, the experimental effective dose 30 (ED30) was calculated for the drugs applied individually. With these effective doses, the peak plasma concentration (Cmax) was found and the other parameters of pharmacokinetics were established. Methyleugenol plus diclofenac and methyleugenol plus ketorolac decreased licking behavior in a dose-dependent manner in phase II, with an efficacy of 32.9 \u00b1 9.3 and 39.8 \u00b1 9.6%, respectively. According to the isobolographic analysis, the experimental and theoretical ED30 values were similar for methyleugenol plus diclofenac, suggesting an additive effect, but significantly different for methyleugenol plus ketorolac (3.6 \u00b1 0.5 vs. 7.7 \u00b1 0.6 mg\/kg, respectively), indicating a probable synergistic interaction. Regarding pharmacokinetics, the only parameter showing a significant difference was Cmax for the methyleugenol plus diclofenac combination. Even with this difference, the combinations studied may be advantageous for treating inflammatory pain, especially for the combination methyleugenol plus ketorolac.<\/jats:p>","DOI":"10.3390\/molecules25215106","type":"journal-article","created":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T20:46:52Z","timestamp":1604436412000},"page":"5106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Antinociceptive Interaction and Pharmacokinetics of the Combination Treatments of Methyleugenol Plus Diclofenac or Ketorolac"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3199-5683","authenticated-orcid":false,"given":"H\u00e9ctor Isaac","family":"Rocha-Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Elena","family":"S\u00e1nchez-Mendoza","sequence":"additional","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leticia","family":"Cruz-Antonio","sequence":"additional","affiliation":[{"name":"Facultad de Estudios Superiores Zaragoza, UNAM, Av. Guelatao No. 66, Colonia Ej\u00e9rcito de Oriente, Iztapalapa, Ciudad de M\u00e9xico 09230, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco Javier","family":"Flores-Murrieta","sequence":"additional","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"},{"name":"Unidad de Investigaci\u00f3n en Farmacolog\u00eda, Instituto Nacional de Enfermedades Respiratorias Ismael Cosi\u00f3 Villegas, Secretar\u00eda de Salud, Ciudad de M\u00e9xico 14080, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xochilt Itzel","family":"Cornelio-Huerta","sequence":"additional","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2928-744X","authenticated-orcid":false,"given":"Jes\u00fas","family":"Arrieta","sequence":"additional","affiliation":[{"name":"Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Colonia Casco de Santo Tom\u00e1s, Miguel Hidalgo, Ciudad de M\u00e9xico 11340, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1097\/j.pain.0000000000000613","article-title":"Updating the definition of pain","volume":"157","author":"Williams","year":"2016","journal-title":"Pain"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Mickle, A.D., Shepherd, A.J., and Mohapatra, D.P. 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