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Pickering, Gisèle; Loriot, Marie‐Anne; Libert, Frédéric; Eschalier, Alain; Beaune, Philippe; Dubray, Claude
Clinical pharmacology and therapeutics, April 2006, Letnik: 79, Številka: 4Journal Article
Objectives Preclinical studies have suggested that the mechanism of the analgesic action of acetaminophen (INN, paracetamol) is linked to the serotonergic system and that it is inhibited by tropisetron, a 5‐hydroxytryptamine type 3 antagonist. The aim of this study was to confirm these findings in humans. Methods Twenty‐six rapid metabolizers of tropisetron were included in this double‐blind crossover study. After ethical approval, at weekly intervals, the subjects took a single oral dose of 1 g acetaminophen combined with either intravenous tropisetron (5 mg), granisetron (3 mg), or placebo (saline solution). For each session, the analgesic effect of acetaminophen was assessed by use of a pain self‐evaluation instrument, the Pain Matcher. The pain detection threshold was determined 5 times over the period of the 4 postdosing hours. The area under the curve (0–4 hours) (mean ± SD) of acetaminophen/tropisetron and the area under the curve of acetaminophen/granisetron were compared with the effect of acetaminophen/placebo. Blood samples for acetaminophen concentration measurements were taken to evaluate a pharmacokinetic interaction. Results The analgesic effect of acetaminophen/placebo (expressed as the area under the curve of the percentage of the individual pain score reported at baseline along time % · min) (2145 ± 2901 % · min) was totally inhibited by both tropisetron (89 ± 1747 % · min, P = .007) and granisetron (45 ± 2020 % · min, P = .002). Acetaminophen concentration was not significantly different when associated with tropisetron (P = .919) or granisetron (P = .309). Conclusion These results clearly show for the first time in humans that the coadministration of tropisetron or granisetron with acetaminophen completely blocks the analgesic effect of acetaminophen. They support the hypothesis that the mechanism of the analgesic action of acetaminophen might involve the serotonergic system. Furthermore, they demonstrate a pharmacodynamic interaction between these 2 types of drugs, which are frequently coadministered, especially in cancer patients. Clinical Pharmacology & Therapeutics (2006) 79, 371–378; doi: 10.1016/j.clpt.2005.12.307
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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