Quantification of Acetaminophen and Its Metabolites in Plasma Using UPLC-MS: Doors Open to Therapeutic Drug Monitoring in Special Patient Populations

Item does not contain fulltextBACKGROUND: Acetaminophen (APAP, paracetamol) is the most commonly used drug for pain and fever in both the United States and Europe and is considered safe when used at registered dosages. Nevertheless, differences between specific populations lead to remarkable changes in exposure to potentially toxic metabolites. Furthermore, extended knowledge is required on metabolite formation after intoxication, to optimize antidote treatment. Therefore, the authors aimed to develop and validate a quick and easy analytical method for simultaneous quantification of APAP, APAP-glucuronide, APAP-sulfate, APAP-cysteine, APAP-glutathione, APAP-mercapturate, and protein-derived APAP-cysteine in human plasma by ultraperformance liquid chromatography-electrospray ionization-tandem mass spectrometry. METHODS: The internal standard was APAP-D4 for all analytes. Chromatographic separation was achieved with a reversed-phase Acquity ultraperformance liquid chromatography HSS T3 column with a runtime of only 4.5 minutes per injected sample. Gradient elution was performed with a mobile phase consisting of ammonium acetate, formic acid in Milli-Q ultrapure water or in methanol at flow rate of 0.4 mL/minute. RESULTS: A plasma volume of only 10 muL was required to achieve both adequate accuracy and precision. Calibration curves of all 6 analytes were linear. All analytes were stable for at least 48 hours in the autosampler; the high quality control of APAP-glutathione was stable for 24 hours. The method was validated according to the U.S. Food and Drug Administration guidelines. CONCLUSIONS: This method allows quantification of APAP and 6 metabolites, which serves purposes for research, as well as therapeutic drug monitoring. The advantage of this method is the combination of minimal injection volume, a short runtime, an easy sample preparation method, and the ability to quantify APAP and all 6 metabolites

RET codon 609 mutations: a contribution for better clinical managing

Medullary thyroid carcinoma currently accounts for 5–8% of all thyroid cancers. The clinical course of this disease varies from extremely indolent tumors that can go unchanged for years to an extremely aggressive variant that is associated with a high mortality rate. As many as 75% of all medullary thyroid carcinomas are sporadic, with an average age at presentation reported as 60 years, and the remaining 25% are hereditary with an earlier age of presentation, ranging from 20 to 40 years

Training of a New Generation of Talents Capable of Working Across Borders and Sectors, with an Inclusive Approach of Food Innovation: the Case of FIPDes, the ERASMUS Mundus Joint Master’s Degree in Food Innovation and Product Design.

Training of a new generation of talents capable of working across borders and sectors, with an inclusive approach of food innovation: the case of FIPDes, the ERASMUS mundus joint master’s degree in food innovation and product design. Food innovation applied to sustainable growth is driven by different needs and constraints. Sensory and nutritional aspects of food, as well as convenience are individual needs that cannot ignore the societal needs such as population growth and safety, as well as the urgent demand to ensure the availability of natural resources and reduce the impacts on environment. Innovation of products, processes, marketing strategies and organizations is the core approach to create incremental or breakthrough solutions for the food sector challenges. Innovation is always a transversal process and involves, in different manners and at different levels, the Research & Development, the Marketing, the Quality Management, and the Supplier and the Production departments. Recently, it has been shown that an integrative approach of these levels accelerates innovation at three different stages: the generation of ideas, development of concepts and prototypes, and the development of processes and products (Bertoluci, 2011). Companies of different size and organisation (from multinationals to start-ups) need skilled and versatile professionals to improve their innovation potential. However, worldwide there is still a lack of trained international food professionals and entrepreneurs that embrace and merge the multidisciplinary aspects of food innovation and product design as a whole. The Erasmus Mundus Joint Master Degree in Food Innovation and Product Design (FIPDes) has been created to meet this emerging need and bring a European solution to the global challenges of sustainable design, production and consumption of food. The competences of four recognized European Higher Education Institutions have been merged together to offer a deeply innovative learning approach, integrating technical and horizontal skills. The presentation will show how FIPDes is pinpointing the global training needs of innovation towards sustainable food systems

Frequency and significance of Ras, Tert promoter, and Braf mutations in cytologically indeterminate thyroid nodules: A monocentric case series at a tertiary-level Endocrinology unit

PurposeThe management of thyroid nodules of indeterminate cytology is controversial. Our study aimed to establish the frequency and significance of H-,K-,N-RAS, TERT promoter, and BRAF gene mutations in thyroid nodes of indeterminate cytology and to assess their potential usefulness in clinical practice.MethodsH-,K-,N-RAS, TERT promoter and BRAF gene mutations were examined in a series of 199 consecutive nodes of indeterminate cytology referred for surgical excision.Results69/199 (35%) were malignant on histopathological review. RAS mutations were detected in 36/199 (18%), and 19/36 cases (53%) were malignant on histological diagnosis. TERT promoter mutations were detected in 7/199 (4%) nodules, which were all malignant lesions. BRAF mutations were detected in 15/199 (8%), and a BRAF K601E mutation was identified in 2 follicular adenomas and 1 noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Altogether, this panel was able to identify 48% of the malignant lesions, achieving a specificity, positive predictive value, and negative predictive value for malignancy of 85, 62, and 75%, respectively.ConclusionThe residual malignancy risk in mutation-negative nodes is 25%. These nodes still need to be resected, but mutation analysis could help to orient the appropriate surgical strategy

Ustekinumab trough levels in children with Crohn’s disease refractory to anti-tumor necrosis factor agents: a prospective case series of off-label use

Background: Ustekinumab is used off-label in pediatric Crohn’s disease refractory to anti-tumor necrosis factor. Data on optimal dosing, target trough levels, and potential benefit of therapeutic drug monitoring in children treated with ustekinumab are limited.Materials and Methods: We describe a series of six adolescents who consented to be treated with ustekinumab. We measured their trough levels, C-reactive protein, and fecal calprotectin before every administration.Results: Standard adult dosing was effective to achieve biochemical remission (fecal calprotectin < 250 mg/kg) in one patient and clinical remission (resolution of symptoms) in another. The other four patients failed to respond on standard dosing and underwent intravenous re-induction and interval shortening to increase ustekinumab trough levels. This resulted in biochemical remission in one patient and clinical remission in another, suggesting an exposure–response relationship. The remaining two patients had no therapeutic benefit, and ustekinumab was discontinued.Conclusion: In this report, we show that ustekinumab can induce remission in pediatric patients with anti-tumor necrosis factor refractory Crohn’s disease. It is worth escalating the dose before abandoning the drug as ineffective. Prospective studies in children are needed to determine long-term efficacy of ustekinumab, usefulness of therapeutic drug monitoring strategies, and, if applicable, optimal target trough levels

Pharmacokinetics of the most commonly used antihypertensive drugs throughout pregnancy methyldopa, labetalol, and nifedipine:a systematic review

Purpose Antihypertensive drugs are among the most prescribed drugs during pregnancy. Methyldopa, labetalol, and nifedipine have been perceived safe to use during pregnancy and are therefore recommended in international guidelines for treatment of hypertension. In this review, we provide a complete overview of what is known on the pharmacokinetics (PK) of the antihypertensive drugs methyldopa, labetalol, and nifedipine throughout pregnancy. Methods A systematic search was performed to retrieve studies on the PK of methyldopa, labetalol, and nifedipine used throughout pregnancy. The search was restricted to English and original studies. The systematic search was conducted on July 27, 2021, in Embase, Medline Ovid, Web of Science, Cochrane Library, and Google Scholar. Keywords were methyldopa, labetalol, nifedipine, pharmacokinetics, pregnancy, and placenta. Results A total of 1459 unique references were identified of which title and abstract were screened. Based on this screening, 67 full-text papers were assessed, to retain 30 PK studies of which 2 described methyldopa, 12 labetalol, and 16 nifedipine. No fetal accumulation is found for any of the antihypertensive drugs studied. Conclusion We conclude that despite decades of prescribing methyldopa, labetalol, and nifedipine throughout pregnancy, descriptions of their PK during pregnancy are hampered by a large heterogeneity in the low number of available studies. Aiming for evidence-based and personalized dosing of antihypertensive medication in the future, further studies on the relationship of both PK and pharmacodynamics (including the optimal blood pressure targeting) during pregnancy and pregnancy-related pathology are urgently needed to prevent undertreatment, overtreatment, and side effects

Variabiliteit in farmacokinetiek van intraveneuze paracetamol bij gezonde ouderen

BACKGROUND and OBJECTIVE: Paracetamol is the most used analgesic in older people. The physiological changes occurring with ageing influence the pharmacokinetics of paracetamol and its variability. A population pharmacokinetic analysis to describe the pharmacokinetics of intravenous paracetamol in fit older people was performed. Thereafter, simulations were conducted to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg q6h, q8h) using steady-state concentration (Cssmean) of 10 mg/L as target for effective analgesia. DESIGN and METHODS: A population pharmacokinetic-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age = 77.3 years [61.8- 88.5], body weight = 79 kg [60-107]). All had received an intravenous paracetamol dose of 1000 mg – over 15 min – after elective knee surgery. RESULTS: A two-compartment pharmacokinetic-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css-mean of 9.2 mg/L (q6h) and 7.2 mg/L (q8h). Variability in paracetamol pharmacokinetics resulted in a Css-mean above 5.4 (q6h) and 4.1 mg/L (q8h) in 90%, and above 15.5 (q6h) and 11.7 mg/L (q8h) in 10% of the population. CONCLUSION: The target concentration was achieved in the average patient with 1000 mg q6h, while q8h resulted in underdosing for the majority of the population. Due to large unexplained interindividual variability in paracetamol pharmacokinetics a relevant proportion of the fit older people remained either under- or overexposed

Current practice for the treatment of acute paracetamol intoxication with N-acetylcysteine in Dutch hospitals

Background Nationally and internationally a discussion is ongoing on the effectiveness, the dose required and the treatment duration of N-acetylcysteine to treat acute paracetamol intoxication. Objective In this paper we present the results of a national survey among hospital pharmacists. In this research the present treatment duration and dosing of N-acetylcysteine is reviewed. Design and methods An electronic survey consisting of 15 questions on the treatment of acute paracetamol intoxications in hospitals has been sent to hospital pharmacists. Results Hospital pharmacists of 67 of the 69 Dutch hospitals (97%) have responded. The majority (52 centres, 78%) indicated to treat acute paracetamol intoxications according to the treatment guideline of the NVZA/NVKFB on toxicologie.org. 64 centres (96%) used the dosing regimen of the above-mentioned treatment guideline, namely 150 mg/kg in 1 hour, followed by 450 mg/kg in 24 hours. The toxicologie.org treatment guideline of 150 mg/L at 4 hours after intake, (or 75 mg/L at 4 hours after intake for sensitive patients) to start N-acetylcysteine therapy, is used by 61 centres (91%). 30% of the centres indicate that there are differences in the treatment of an acute paracetamol intoxication in children and adults. In general, in these centres, it is preferred to start early with N-acetylcysteine in children. Conclusion Despite local differences, in the majority of the hospitals acute paracetamol intoxications are treated according to the toxicologie.org treatment guideline. Because of this, toxicologie.org is an appropriate medium to implement possible future adaptations in the N-acetylcysteine dosing regime in Dutch hospitals.</p