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Glutathione (GSH<\/jats:styled-content>) plays a pivotal role in APAP<\/jats:styled-content> metabolism as it allows the detoxification of a toxic metabolite. N\u2010Acetylcysteine (NAC<\/jats:styled-content>) is APAP<\/jats:styled-content> antidote, is also largely used as a mucoactive drug and is often associated with APAP<\/jats:styled-content>. This study aims at evaluating if 1\u2010 NAC<\/jats:styled-content> modifies APAP<\/jats:styled-content> pain efficacy and 2\u2010 NAC<\/jats:styled-content> prevents glutathione depletion with APAP<\/jats:styled-content> at therapeutic doses. This double\u2010blind randomized controlled study (NCT<\/jats:styled-content>02206178) was carried out in 24 healthy volunteers. APAP<\/jats:styled-content> was given for 4 days (1 g \u00d74 daily) with NAC<\/jats:styled-content> or with placebo. Thermal pain tests, whole blood GSH<\/jats:styled-content>, and hepatic enzymes (ASAT<\/jats:styled-content>, ALAT<\/jats:styled-content>) were measured before (D0) and after (D4) oral APAP<\/jats:styled-content>\u2010NAC<\/jats:styled-content> or APAP<\/jats:styled-content>\u2010placebo intake. anova<\/jats:sc> for repeated measures adapted to cross\u2010overdesign was performed and a two\u2010tailed type I error was fixed at 5%. The primary endpoint was the area under the curve (0\u2013240 min) of pain intensity (Numerical Scale) after thermal pain stimulation using Pathway\u2010Medoc\u00ae<\/jats:sup>. APAP<\/jats:styled-content> antinociceptive effect was similar in both groups. GSH<\/jats:styled-content> was maintained to its baseline value in the APAP<\/jats:styled-content>\/NAC<\/jats:styled-content> group but diminished in the APAP<\/jats:styled-content>\/placebo group (P<\/jats:italic> = 0.033). This study shows for the first time that APAP<\/jats:styled-content> antinociceptive effectiveness is not influenced by NAC<\/jats:styled-content>. It also shows that the effect of APAP<\/jats:styled-content> at therapeutic dosage on GSH<\/jats:styled-content> may be counteracted by NAC<\/jats:styled-content>. These issues are particularly important for patients as APAP<\/jats:styled-content> is often prescribed for years as a first\u2010line pain treatment and further trials in patients are now warranted.<\/jats:p>","DOI":"10.1111\/fcp.12437","type":"journal-article","created":{"date-parts":[[2018,11,24]],"date-time":"2018-11-24T16:19:34Z","timestamp":1543076374000},"page":"303-311","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["N\u2010acetylcysteine prevents glutathione decrease and does not interfere with paracetamol antinociceptive effect at therapeutic dosage: a randomized double\u2010blind controlled trial in healthy subjects"],"prefix":"10.1111","volume":"33","author":[{"given":"Gis\u00e8le","family":"Pickering","sequence":"first","affiliation":[{"name":"Centre de Pharmacologie Clinique CIC Inserm 1405 CHU Clermont\u2010Ferrand Clermont\u2013Ferrand Auvergne 63000 France"},{"name":"Inserm 1107 Universit\u00e9 Clermont Auvergne Neurodol Clermont\u2013Ferrand Auvergne 63000 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2964-8444","authenticated-orcid":false,"given":"Nicolas","family":"Macian","sequence":"additional","affiliation":[{"name":"Centre de Pharmacologie Clinique CIC Inserm 1405 CHU Clermont\u2010Ferrand Clermont\u2013Ferrand Auvergne 63000 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Papet","sequence":"additional","affiliation":[{"name":"INRA UNH Unit\u00e9 de Nutrition Humaine CRNH Universit\u00e9 Clermont Auvergne Clermont\u2010Ferrand Auvergne 63000 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Dual\u00e9","sequence":"additional","affiliation":[{"name":"Centre de Pharmacologie Clinique CIC Inserm 1405 CHU Clermont\u2010Ferrand Clermont\u2013Ferrand Auvergne 63000 France"},{"name":"Inserm 1107 Universit\u00e9 Clermont Auvergne Neurodol Clermont\u2013Ferrand Auvergne 63000 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Coudert","sequence":"additional","affiliation":[{"name":"Pharmacie centrale CHU Clermont\u2010Ferrand Clermont\u2013Ferrand Auvergne 63000 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Pereira","sequence":"additional","affiliation":[{"name":"DRCI CHU Clermont\u2010Ferrand Clermont\u2010Ferrand Auvergne 63000 France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,1,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-013-0172-x"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.3109\/03602532.2010.527984"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.176"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1987.50"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12802"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.296.1.87"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2006.05.002"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.02.065"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2006.02.004"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2006.10.008"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12990-015-0009-2"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(02)00414-1"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.16m11101"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1183\/09059180.00003510"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2014.09.015"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(13)70286-8"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrtlng.2016.12.004"},{"key":"e_1_2_7_19_1","first-page":"CD003124","article-title":"Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho\u2010pulmonary disease","volume":"1","author":"Duijvestijn Y.C.","year":"2009","journal-title":"Cochrane Database Syst. 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