Aim This study aimed to describe the levels of exposure to different forms of prednisolone in children with asthma or asthma-like symptoms, ages six months to seventeen years old, treated with crushed tablets, oro-dispersible tablets, a liquid suspension, or whole tablets. Methods Participants were randomised to received two out of four different formulations on successive days using a single-center, open-label, two-period, cross-over design. Saliva samples were collected to measure prednisolone concentrations, and a population pharmacokinetic model was used to analyse the data. The bioequivalence of the test drug to the whole tablet was determined using the 90% confidence interval of the ratios of area under the curve (AUC) and maximum concentration (Cmax). Results This study enrolled 41 children, with a mean age of 4.9 years ± 3.7 and a mean weight of 21.8 kg ± 10.9; 61% were boys. The pharmacokinetic data were best described by a two-compartment model using plasma concentrations calculated from saliva. The population mean clearance was 317±156 ml/min/70kg, with a mean half-life of 5.3 ± 3.2 hours and a volume of distribution of 141 L/70kg. The liquid suspension demonstrated bioequivalence to the control (whole tablets) in terms of AUC. However, none of the tested formulations were bioequivalent regarding to Cmax. Conclusion The tested formulations did not exhibit bioequivalence (AUC and Cmax) when compared to the whole tablet. Using different prednisolone formulations interchangeably may be challenging, especially in a paediatric population where inter-individual and residual variability in the pharmacokinetics seemed to have significant impact on exposure.

Aims: To describe the medication changes implemented during physician-led medication reviews that resulted in improved health-related quality of life; and to explore factors that could identify patients with overprescription.Methods: Post-hoc analyses of data from a pragmatic, non-blinded, randomized clinical trial investigating a medication review intervention (NCT03911934) in 408 geriatric outpatients taking \(\geq\)9 medicines.Results: The most frequent medicine change in the medication review group (n=196) was discontinuation (26% of the medicines) due to lack of indication (72% of the discontinuations). After 13 months, 82% of the discontinued medicines were persistently discontinued. The medicines most often discontinued in the medication review group compared with usual care included: metoclopramide (11/5=73% discontinued vs 1/12=8% in usual care), acetylsalicylic acid (20/48=42% vs 2/47=4%), simvastatin (18/48=38% vs 2/58=3%), zopiclone (23/59=39% vs 4/54=7%), quinine (9/14=64% vs 6/16=38%), citalopram (4/18=22% vs 0/20=0%), and tramadol (18/37=49% vs 8/30=27%). Factors associated with the number of overprescribed medicines included: number of prescribed medicines (8% increase per medicine), Drug Burden Index (15% increase per 1 increase), and patient motivation for medicine changes (26% less if not motivated). Prescriptions of metoclopramide, iron preparations, antidepressants other than SSRIs, NSAIDs, or drugs for urinary incontinence were associated with a higher number of overprescribed medicines.Conclusion: Medication reviews can be used to persistently discontinue overprescribed medicines in older polypharmacy patients. Motivation for having their medicine changed, treatment with a higher number of medicines, and a higher burden of sedative and anticholinergic drugs characterized patients most likely to benefit from physician-led medication reviews.

Comment on “The changing face of paracetamol toxicity and new regimens for an old antidote acetylcysteine”Dear Editor,We have with interest read the recently published commentary by Isbister and Chiew1 in which current approaches for the treatment of paracetamol (PCM) poisoning with N-acetylcysteine (NAC) were described. While we appreciate the authors’ valuable comments on the challenges in managing this common poisoning, we noticed the omission of the Danish NAC regimen.NAC has been established as a highly efficient antidote in preventing PCM-induced hepatotoxicity when administered within 8 h of PCM ingestion.2 Treatment delays because of pending laboratory results do not harmfully affect the outcome if NAC is administered within 8 h. However, it is frequent occurring that patients get treated beyond that time in e.g. the UK,3 thus potentially decreasing the efficacy of NAC.In Denmark a 20-hour two-bag regime has been used for more than seven years.4 All patients suspected of poisoning with more than 6 g PCM are treated with NAC without risk stratification according to a nomogram. Patients deliberately poisoning themselves with PCM may not report reliable information of the time of ingestion and dose of PCM. If a nomogram is used without an accurate time of ingestion, the estimation of the risk of hepatotoxicity is unreliable. It is well documented that patients have been withheld treatment with NAC due to misinterpretation of the nomogram resulting in hepatotoxicity.5Concomitant overdosing of several drugs that delay the time to peak PCM concentration is common and may result in crossing from below to above the treatment line5 leaving line crossers who required treatment untreated. The same is relevant in cases of massive PCM overdosing alone (drug bezoar) or poisonings with extended-release PCM formulations (late PCM peak).6 Furthermore, it is well-known that the half-life of PCM in liver injury exceeds the expected 4 h used for treatment decision in the nomogram, thus further questioning the reliability of the nomogram as a risk stratification tool for patients suffering from liver diseases. Although the Danish regime further reduces the risk of hepatoxicity, because of incorrectly withheld or delayed NAC treatment compared to other regimes based on a nomogram, it comes at a cost of more patients being treated.We believe that all approaches deserve mention in order to identify the most effective and safe approach to this poisoning. Therefore, we should consider the effectiveness, duration and safety of choice of treatment including the incidence of anaphylactoid reactions to NAC while assuring that nobody is wrongly withhold NAC treatment. Not to mention, that the abovementioned approach is associated with a comparable incidence of anaphylactoid reactions when compared to other approaches.4,7 It is worth mentioning that the primary factor limiting a faster delivery of the antidote is the development of anaphylactoid reactions. It is to be shown if pre-administrations of antihistamines can reduce the dose-dependent side-effect leading to development of faster NAC regimes7.We declare no competing interests.Alaa Daoud (orcid: 0000-0002-8714-4028)a,b, Kim Peder Dalhoffa,b, Tonny Studsgaard Petersen (orcid: 0000-0002-9974-2738)a,baDepartment of Clinical Medicine, Faculty of Health and Medical science, Copenhagen University, Copenhagen, DenmarkbDepartment of Clinical Pharmacology and The Danish Poison Information Centre, Bispebjerg and Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark*Correspondence to Alaa Daoud, [email protected]. Isbister GK, Chiew A. The changing face of paracetamol toxicity and new regimens for an old antidote acetylcysteine. British Journal of Clinical Pharmacology . n/a(n/a). doi:10.1111/bcp.144952. Prescott LF, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. Br Med J . 1979;2(6198):1097-1100. doi:10.1136/bmj.2.6198.10973. The College of Emergency Medicine. Paracetamol Overdose Clinical Audit 2013-14. Accessed September 7, 2020. https://www.rcem.ac.uk/docs/Previous%20Audits/CEM8120-Paracetamol%20Overdose%20national%20report.pdf4. Daoud A, Dalhoff KP, Christensen MB, Bøgevig S, Petersen TS. Two-bag intravenous N-acetylcysteine, antihistamine pretreatment and high plasma paracetamol levels are associated with a lower incidence of anaphylactoid reactions to N-acetylcysteine. Clinical Toxicology . 2020;58(7):698-704. doi:10.1080/15563650.2019.16758865. Mutsaers A, Green JP, Sivilotti MLA, et al. Changing nomogram risk zone classification with serial testing after acute acetaminophen overdose: a retrospective database analysis. Clinical Toxicology . 2019;57(6):380-386. doi:10.1080/15563650.2018.15293206. Bizovi KE, Aks SE, Paloucek F, Gross R, Keys N, Rivas J. Late Increase in Acetaminophen Concentration After Overdose of Tylenol Extended Relief. Annals of Emergency Medicine . 1996;28(5):549-551. doi:10.1016/S0196-0644(96)70119-17. Mullins ME, Yu M, O’Grady L, Khan S, Schwarz ES. Adverse reactions in patients treated with the one-bag method of N-acetylcysteine for acetaminophen ingestion. Toxicology Communications . 2020;4(1):49-54. doi:10.1080/24734306.2020.1770498