Polymorphisms in CYP2C9 can significantly interfere with the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen. The present research aimed to study the PK/PD parameters of naproxen and its metabolite, 6-O-desmethylnaproxen, associated with allelic variations of CYP2C9. In our study, a rapid, selective, and sensitive Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) method was developed and validated for the determination of naproxen and its main metabolite, 6-O-desmethylnaproxen, in oral fluid. Naproxen and its main metabolite were separated using a Shim-Pack XR-ODS 75L × 2.0 column and C18 pre-column at 40 °C using a mixture of methanol and 10 mM ammonium acetate (70:30, v/v), with an injection flow of 0.3 mL/min. The total analytical run time was 3 min. The volunteers, previously genotyped for CYP2C9 (16 ancestral—CYP2C9 *1 and 12 with the presence of polymorphism—CYP2C9 *2 or *3), had their oral fluids collected sequentially before and after taking a naproxen tablet (500 mg) at the following times: 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6 8, 11, 24, 48, 72 and 96 h. Significant differences in the PK parameters (* p < 0.05) of naproxen in the oral fluid were: Vd/F (L): 98.86 (55.58–322.07) and 380.22 (261.84–1097.99); Kel (1/h): 0.84 (0.69–1.34) and 1.86 (1.09–4.06), in ancestral and mutated CYP2C9 *2 and/or *3, respectively. For 6-O-desmethylnaproxen, no PK parameters were significantly different between groups. The analysis of prostaglandin E2 (PGE2) proved to be effective and sensitive for PD parameters analysis and showed higher levels in the mutated group (p < 0.05). Both naproxen and its main metabolite, 6-O-desmethylnaproxen, and PGE2 in oral fluid can be effectively quantified using LC-MS/MS after a 500 mg oral dose of naproxen. Our method proved to be effective and sensitive to determine the lower limit of quantification of naproxen and its metabolite, 6-O-desmethylnaproxen, in oral fluid (2.4 ng/mL). All validation data, such as accuracy, precision, and repeatability intra- and inter-assay, were less than 15%. Allelic variations of CYP2C9 may be considered relevant in the PK of naproxen and its main metabolite, 6-O-desmethylnaproxen.

After performing liquid-liquid extraction with ethyl acetate and HCl, samples from 12 volunteers who performed sequential collections after taking a tablet of naproxen alone (n = 6) or associated with esomeprazole (n = 6) were analyzed in a triple quadrupole mass spectrometer 8040 LC MS/MS Shimadzu. Separation of naproxen and its main metabolite 6-O-desmethylnaproxen was performed in a Shim-Pack XR-ODS 75Lx2.0 column and C18 pre-column at 40°C using a mixture of methanol and ammonium acetate 10 mM (70:30, v/v) with an injection rate of 0.3 ml/min. The total analytical run time for each sample was 5 min. The association of naproxen with esomeprazole take considerably longer time to reach the maximum concentration [Tmax 0.17 h (interquartile range, 0.13–1.95) for naproxen alone and 13.18*h (interquartile range, 10.12–27.15) for naproxen with esomeprazole, p = 0.002], also to be eliminated [T1/2 0.12 h (interquartile range, 0.09–1.35) for naproxen alone and 9.16*h (interquartile range, 7.16–41.40) for naproxen with esomeprazole, p = 0.002] and lower maximum concentrations (Cmax 4.6 ± 2.5 ug/mL for naproxen alone and 2.04 ± 0.78* μg/mL, p = 0.038). The association of naproxen with esomeprazole showed increased values of AUC0-t [82.06* h*μg/mL (interquartile range, 51.90–157.00) with esomeprazole and 2.97 h*μg/mL (interquartile range, 1.82–7.84) naproxen alone, p = 0.002] in drug concentrations in relation to the naproxen tablet alone, probably, such differences are due to the delay in the absorption of naproxen when it is associated with the drug proton pump inhibitor, esomeprazole. As well as reduced values of full clearance when naproxen is combined with esomeprazole (0.07* μg/h (interquartile range, 0.005–0.01) with esomeprazole and 7.29 μg/h (interquartile range, 3.17–16.23) in naproxen alone, p = 0.002). Both naproxen and 6-O-desmethylnaproxen in saliva samples can be effectively quantified using LC-MS/MS, this methodology proved to be rapid, sensitive, accurate and selective for each drug and allows for the analysis of their pharmacokinetic parameters, in both situations.

The aim of this study was to carry out a systematic investigation and analysis of different drug extraction methods, specifically non-steroidal anti-inflammatory drugs in biological fluid samples, for Liquid Chromatography in Mass Spectrometry assays (LC-MS/MS). A search was carried out in the main databases between 1999 and 2021, following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. Data were obtained through PubMed, Lilacs, Embase, Scopus, and Web of Science databases using the Boolean operators AND and OR. Studies were pre-selected by title and abstract by two independent reviewers. The selected texts were read in full, and only those that were complete and compatible with the inclusion and exclusion criteria were eligible for this research. A total of 248 references were obtained in the databases. After removing the duplicates and analyzing the titles and abstracts, 79 references were evaluated and passed to the next phase, which comprised the complete reading of the article. A total of 39 publications were eligible for this study. In 52% of the studies, the authors used the liquid–liquid extraction method (LLE), while in 41%, the solid-phase extraction method (SPE) was used. A total of 5% used microextraction methods and 2% used less-conventional techniques. The literature on the main methods used, the LLE and SPE methods, is extensive and consolidated; however, we found other studies that reported modifications of these traditional techniques, which were equally validated for use in LC-MS/MS. From this review, it is concluded that the diversity of techniques, reliability, and practical information about each analytical method used in this study can be adapted to advances in LC-MS/MS techniques; however, more ecological, economic, and sustainable approaches should be explored in the future.

This systematic review aimed to analyze the clinicopathological profile and relevant prognostic factors of head and neck rhabdomyosarcoma in pediatric patients. The search was carried out in the electronic search portals PubMed, Lilacs, Embase, Scopus, and Web of Science. The search yielded studies that were then analyzed regarding study topic, data extraction, and risk of bias using the STROBE (Strengthening the Reporting of Observational Studies) guidelines. Finally, three studies were included for qualitative analysis. Most of the cases involved embryonic and alveolar rhabdomyosarcoma. Expression of MYOD1 was highly correlated with diagnosis of spindle cell/sclerosing rhabdomyosarcoma, which appears to have a poor prognosis in children. Furthermore, tumor size <5 cm and absence of metastasis accompanied by complete resection and administration of adjuvant therapies such as chemotherapy and radiotherapy favored a better prognosis.

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