Abstract Background: Propofol may result in hypotension, bradycardia, and loss of protective reflexes, especially in elderly patients, while esketamine, a N-methyl-D-aspartate receptor antagonists, has analgesic, anaesthetic and sympathomimetic properties and is known to cause less cardiorespiratory depression. We hypothesized that esketamine may reduce the median effective concentration (EC50) of propofol and cause more stable haemodynamic responses during gastrointestinal endoscopy in elderly patients. Methods: Ninety elderly patients, aged 65-89 years, undergoing gastrointestinal endoscopy were randomly assigned into three groups: SK0.25 group (0.25 mg/kg esketamine), SK0.5 group (0.5 mg/kg esketamine) and saline control group. Anaesthesia was achieved by target-controlled infusion of propofol with an initial plasma concentration of 2.5 μg/ml with different bolus doses of esketamine during gastrointestinal endoscopy. The EC50 of propofol for gastrointestinal endoscopy was determined by using an up-and-down method of Dixon with an adjacent concentration gradient at 0.5μg/mL to prohibit purposeful movements. Cardiovascular parameters were also measured and recorded. Results: Propofol EC50 and its 95% confidence interval for gastrointestinal endoscopy in elderly patients were 1.71 (1.15-2.27) μg/mL in SK0.5 group, 2.45 (1.85-3.05) μg/mL in SK0.25 group and 3.69 (2.59-4.78) μg/mL in control group respectively (P < 0.05). The average percent change to baseline mean arterial pressure (MBP) was -19.7 (7.55), -15.2 (7.14) and -10.1 (6.73) with P＜0.001, in the control group, the SK0.25 group and the SK0.5 group, respectively. Conclusions: Combination medication of propofol with esketamine reduced the propofol EC50 during gastrointestinal endoscopy in elderly patients and caused more stable haemodynamic responses compared with single administration of propofol.

AIM: Influenza infection poses a severe threat to pregnant mothers, and antiviral treatment is recommended. However, the safety of neuraminidase-inhibitor antiviral medications during pregnancy has not been well described. METHODS: A systematic review and meta-analysis were performed to evaluate the adverse neonatal outcomes associated with exposure to neuraminidase inhibitors during pregnancy. The PubMed, Embase, and Cochrane Library databases were searched to identify potential studies for inclusion. RESULTS: Nine cohort studies that estimated adverse neonatal outcomes associated with exposure to neuraminidase-inhibitor medication during pregnancy were included. Exposure to a neuraminidase inhibitor during pregnancy was not associated with an increased risk of congenital malformation (odds ratio [OR] 0.9, 95% confidence interval [CI] 0.72–1.12, P = 0.341), low Apgar score (OR 0.96, 95% CI 0.77–1.2, P = 0.733), or preterm birth (OR 0.99, 95% CI 0.89–1.09, P = 0.771) compared with no exposure. However, exposure to a neuraminidase inhibitor was associated with a reduced risk of low birth weight (OR 0.79, 95% CI 0.68–0.92, P = 0.002) and giving birth to a small-for-gestational-age infant (OR 0.78, 95% CI 0.69–0.88, P < 0.001). Further analyses limited to oseltamivir exposure were consistent with the overall results. CONCLUSION: Exposure to neuraminidase-inhibitor medication during pregnancy does not appear to be associated with adverse neonatal outcomes. We recommend further studies to investigate this association, which will help clinicians determine whether to prescribe a neuraminidase inhibitor during pregnancy.

Aim A robust and user-friendly software tool was developed for the prediction of dopamine D2 receptor occupancy (RO) in patients with schizophrenia treated with either olanzapine or risperidone. This tool can facilitate clinician exploration of the impact of treatment strategies on RO using sparse plasma concentration measurements. Methods Previously developed population pharmacokinetic (PPK) models for olanzapine and risperidone were combined with a PD model for D2 receptor occupancy (RO) and implemented in the R programming language. MAP Bayesian estimation was used to provide predictions of plasma concentration and receptor occupancy and based on sparse PK measurements. Results The average (standard deviation) response times of the tools were 2.8 (3.1) and 5.3 (4.3) seconds for olanzapine and risperidone, respectively. The mean error (95% confidence interval) and root mean squared error (RMSE, 95% CI) of predicted versus observed concentrations were 3.73 ng/mL (-2.42 – 9.87) and 10.816 (6.71 – 14.93) for olanzapine, and 0.46 ng/mL (-4.56 – 5.47) and 6.68 (3.57 – 9.78) for risperidone and its active metabolite (9-OH risperidone). Mean error and RMSE of RO were -1.47% (-4.65 – 1.69) and 5.80 (3.89 – 7.72) for olanzapine and -0.91% (-7.68 – 5.85) and 8.87 (4.56 – 13.17) for risperidone. Conclusion Treatment of schizophrenia with antipsychotics offers unique challenges and requires careful monitoring to establish the optimal dosing regimen. Our monitoring software predicts RO in a reliable and accurate form.

Identifying the optimal treatment based on specific aetiology of each patient is the main promise of precision medicine. In order to realize this promise researches and physicians must first identify the underlying cause; over the last 10 years, advances in genetics have made this possible for several monogenic epilepsies. At present through next generation techniques we can reach the precise genetic aetiology in 30 to 50% of genetic epilepsies beginning in the paediatric age. While committed in such gene hunting, progresses in the study of experimental models of epilepsy have also provided a better understanding of the mechanisms underlying the condition. Such impressive advances is already being translated into improving care, management and treatment of some patients. Identification of a precise genetic etiology can already direct physicians to prescribe treatments correcting specific metabolic defects avoid antiseizure medicines that can aggravate the pathogenic defect or select the drug that counteract the functional disturbance caused by the gene mutation. Personalized, tailored treatments should not just focus on how to stop seizures but possibly preventing their onset and cure the disorder often consisting of epilepsy and its comorbidities including cognitive, motor and behavior deficiencies. This review discusses the therapeutic implications following a specific genetic diagnosis and the correlation between genetic findings, pathophysiological mechanism and tailored seizure treatment emphasizing the impact on current clinical practice.

Chagas cardiomyopathy is the most prevalent non-ischemic cardiomyopathy in Latin America, with high morbidity and mortality even today. Treatment of these patients is based on the use of medications for heart failure. This study evaluated a cohort of patients with Chagas heart disease who used sacubitril valsartan at a referral hospital for the disease in Brazil. After six months, there was a symptomatic improvement in these individuals assessed by the NYHA classification, with a 44.3% reduction in the absolute number of patients classified as III-IV in the period (p 0.035), but without changes in the parameters on the echocardiogram for reverse ventricular remodeling and still high mortality rate and hospitalization. These results emphasize the importance of studying the use of sacubitril valsartan in chagas heart disease to better describe its effectiveness taking into account the peculiarities of these individuals.

Since the beginning of the COVID-19 pandemic, industry and healthcare providers have investigated methodologies to manage infection of SARS-CoV-2. One treatment breakthrough has been the introduction of monoclonal antibodies to prevent worsening SARS-CoV-2 infection in non-hospitalized patients diagnosed with COVID-19. These monoclonal antibodies, like bamlanivimab, bind to the SARS-CoV-2 spike protein and prevent its ability to binding to human ACE2 receptors. This is a case of a 91 year-old man with no prior seizure history who developed new-onset seizures after bamlanivimab infusion.

Improved global access to novel age-appropriate formulations for paediatric subsets, either of new chemical entities or existing drugs, is a priority to ensure that medicines meet the needs of these patients. However, despite regulatory incentives, the introduction to the market of paediatric formulations still lags behind adult products. This is mainly caused by additional complexities associated with the development of acceptable age-appropriate paediatric medicines. This position paper proposes the use of a paediatric Quality Target Product Profile (pQTPP) as an efficient tool to facilitate early planning and decision making during the children-centric formulation design for new chemical entities, or to repurpose/reformulate off-patent drugs. Essential key attributes of a paediatric formulation are suggested and described. Moreover, greater collaboration between formulation experts and clinical colleagues, including healthcare professionals, is advocated to lead to safe and effective, age-appropriate medicinal products. Acceptability testing should be a secondary endpoint in paediatric clinical trials to ensure post-marketing adherence is not compromised by a lack of acceptability. Not knowing the indications and the related age groups and potential dosing regimens early enough is still a major hurdle for efficient paediatric formulation development; however the proposed pQTPP could be a valuable collaborative tool for planning and decision making to expedite paediatric product development.

Approval of direct-acting oral anticoagulants (DOACs) for stroke prevention in atrial fibrillation (AF) was an important milestone, providing widened treatment choices along with the possibility for inter-drug switching after initiation. In addition to improved utilisation of oral anticoagulants (OACs) for stroke prevention, reports of switching among OACs are growing in the literature. Switching may influence clinical outcomes, healthcare costs and patient satisfaction. This review aimed to summarise the current literature on the pattern of OAC switching in patients with AF, including reasons for switching and clinical consequences following switching. We included articles published after 2013, following the introduction of apixaban; searched on June 27, 2020 from PubMed, Scopus and Embase. The review found that switching among OACs was common in clinical practice, significantly varying with the type of OAC. Studies reporting the reason for switching and clinical outcomes were comparatively limited. The reasons were often related to safety issues, poor anticoagulation control and ease of use. Factors that can increase the risk of bleeding and stroke were found to be associated with switching from vitamin K antagonists, but less for DOAC switching. Findings regarding bleeding outcomes following switching were inconsistent, possibly confounded with the type of OAC, reasons for switching and switching protocol. Despite the limited number of studies included and their relatively short follow-up periods, our review revealed that switching had minimal impact on stroke and other related thrombotic outcomes. Further prospective studies are needed to better understand possible reasons for switching and its influence on clinical outcomes.

Aim Antimicrobial resistance is an evolving phenomenon with alarming public health consequences. Antibiotic cycling is a widely known antimicrobial stewardship initiative which encompasses periodical shifts in empirical treatment protocols with the aim to limit selective pressures on bacterial populations. Nonetheless, mathematical models have challenged its presumable efficacy by favouring a higher heterogeneity in antibiotic administration. We present a review of the evidence regarding the actual impact of antimicrobial cycling on bacterial resistance control within hospitals. Methods A systematic literature review was conducted using the PubMed/MedLine, Embase, CINAHL Plus and Global Health databases. Results A systematic search process retrieved a sole randomised study, and so we broadened inclusion criteria to encompass quasi-experimental designs. Fifteen studies formed our dataset including seven prospective trials and eight before-and-after studies. Nine studies evaluated cycling versus a control group and produced conflicting results whilst three studies compared cycling with antibiotic mixing, with none of the strategies appearing superior. The rest evaluated resistance dynamics of each of the on-cycle antibiotics with contradictory findings. Research protocols differed in parameters such as the cycle length, the choice of antibiotics, the opportunity to de-escalate to narrow-spectrum agents and the measurement of indicators of collateral damage. This limited our ability to evaluate the replicability of findings and the overall policy effects. Conclusions Dearth of robust designs and standardised protocols limits our ability to reach safe conclusions. Nonetheless, in view of the available data we find no reason to believe that cycling should be expected to improve antibiotic resistance rates within hospitals.

A document by Teun van Gelder. Click on the document to view its contents.

Pregnant, or potentially pregnant women have historically been excluded from clinical trials of new medications. However, it is increasingly recognised that it is imperative to generate evidence from the population in whom the drugs are likely to be used in order to inform safe, evidence-based shared clinical decision making. Reluctance by researchers and regulators to perform such studies often relates to concerns about risk, particularly to the fetus. However, this must be offset against the risk of untreated disease or using a drug in pregnancy where safety, efficacy and dosing information are not known. This review summarises the historical perspective, the ethical and legal frameworks which inform the conduct of such research, then highlights examples of innovative practice which have enabled high quality, ethical research to proceed to inform the evidence-based use of medication in pregnancy.

A document by Emma Magavern. Click on the document to view its contents.

Aims: No study has evaluated the BET pharmacokinetics in twin pregnancies separated by chorionicity. The aim this study is to describe and compare the BET pharmacokinetic parameters in singleton, dichorionic (DC) and monochorionic (MC) twin pregnancies in the third trimester of pregnancy. Methods: Twenty-six pregnant women received an intramuscular dose of 6 mg of BET sodium phosphate plus 6 mg BET acetate. Serial blood samples were collected for 24 hours after the first intramuscular BET esters dose. BET plasma concentrations were quantified using a validated HPLC analytical method. BET pharmacokinetic parameters were obtained employing a non-compartment model, and were compared using ANOVA’s test with Tukey’s multiple comparisons test. Correlations between clinical features and pharmacokinetic parameters were analyzed using Pearson’s correlation. Preliminary data on the BET placental transfer were also presented. Results: The geometric mean (IC 95%) of AUC0-∞ 670.0 (504.3-805.2) vs 434.9 (311.2-539.6) ng.h/mL and the CL/F 18.38 (13.84-22.65) vs 29.40 (21.17-36.69) were significantly lower and higher, respectively, in DC twin pregnancies compared to singleton. Others pharmacokinetic parameters did not differ among the groups. Conclusions: Data from this study suggest that the presence of two fetoplacental units may increase the BET metabolism by CYP3A4 enzyme and increase its elimination. Pharmacokinetic-pharmacodynamic clinical studies are needed to investigate whether this BET pharmacokinetic changes have clinical repercussions for the newborns and require dose adjustment in DC twin pregnancies.

Objectives: To assess the effectiveness of dimethyl fumarate (DMF) on annual rate of relapse (ARR) and disability progression in multiple sclerosis (MS) compared to injectable immunomodulators (IMM), teriflunomide (TERI) and fingolimob (FTY), in real life setting. Methods: A population-based cohort study was conducted using data of the French nationwide claims database, SNDS. All patients initiating IMM, TERI, FTY or DMF between July 1, 2015 and December 12, 2017, with 4.5 years of database history and 1 to 3.5 years of follow-up were included in this study. DMF patients were 1:1 matched to IMM, TERI or FTY using a high dimensional Propensity Score. Negative binomial regression and a logistic regression models were used to estimate the relative risk (RR ± [95% CI]) of ARR and the Odds Ratio (OR ± [95% CI]) of disability progression, respectively. Results: Overall, 9 304 subjects were identified: 29.0% initiated DMF, 33.2% TERI, 5.6% FTY and 32.2% an IMM. The matched cohorts consisted of 1779 DMF- IMM, patients, 1679 DMF-TERI patients, and 376 DMF-FTY patients. DMF significantly reduced ARR compared to IMM (RR 0.72 [0.61 - 0.86]) and TERI (0.81 [0.68 - 0.96]) and did not show any significant difference when compared with FTY The risk of the progression of MS specific disability was not significantly different for any matched cohorts. Interpretation: DMF is associated with lower risk of relapse for patients with RRMS than other first-line RRMS agents (TERI and IIM).

Aim: The Norwegian Association for Clinical Pharmacology in their National Guidelines decreased therapeutic range (TR) of topiramate (TPM) from 5-20 mg/L to 2-10 mg/L. The objective of this study is to ascertain which TR produces better clinical outcomes. Methods: Data source were request forms for routine therapeutic drug monitoring of TPM. Concentration dependent adverse drug reactions (ADRs) were evaluated in 1,721 samples taken pre-dose. Seizure frequency analysis was performed in 294 samples of monotherapy. Statistics: Prism 5.0, GraphPad Instatt: Mann–Whitney U test for median plasma level (PL). χ2-test for seizure frequency and for distribution of PL according to TR 5-20 mg/L and intervals <2, 2-5, 5-10, 10-20, >20 mg/L. Results: Better seizure control was found in children both in whole cohort (without seizure 49% vs 37% adults), as well as in monotherapy (56% vs 44%), in children with PL 5-20 mg/L vs 5 mg/L (65% vs 44%) and in children with PL 5-10 mg/L vs <2 mg/L. Seizure-free children had higher PL than those with seizure yearly: median (lower, upper quartile) [mg/L]: 5.5 (3.4-6.5) vs 4.7 (4.3-7.95). No difference was found in adults. Seizure control was poorer in all patients with PL <2 mg/L compared to 5-10 mg/L; and 10-20 mg/L; further in PL within 5-10 mg/L vs 10-20 mg/L; and in the period 2003-2005. ADRs reported in 38 samples (2.8%) were without relation to PL. Conclusions: Change of TR is not recommended.

Pharmaceutical industry and drugs advertisement is sometimes accused of “creating diseases”. This article assesses and describes the role of that industry in fostering medicalization. First, the notions of medicalization and pharmaceuticalization are defined. Then, the problem of distinguishing between harmful overmedicalization and well-founded medicalization is presented. Next, the phenomenon of disease mongering is explained and illustrated by the case analysis of medicalizing pain and suffering in three contexts: 1) the general idea of medicalizing physical pain, 2) the medicalization of grief, and 3) disease mongering of pseudoaddiction - a condition promoted in order to increase the demand for opioid pain relievers.

Aims: The objective of this retrospective cohort study was to provide an overview of the utilization of originator and biosimilar infliximab in the Netherlands. Methods: All infliximab dispensings were selected from the PHARMO In-patient Pharmacy Database from 2002-2018. Descriptive analyses were performed in order to characterise initiators and to describe switching patterns over time. Results: Overall, 3,840 patients with 61,274 infliximab dispensings were identified. 2,496 patients initiated an originator infliximab and 777 patients initiated a biosimilar infliximab. Overall, 57% of the patients was female and mean age was 43.2 years. Both originators and biosimilars were mostly prescribed by gastroenterologists, followed by internists and rheumatologists. After market authorization of the first biosimilar the proportion of new patients initiating the biosimilar increased from 39% in 2015 to 91% in 2018. Out of 704 patients eligible for switching 34% switched. Among switchers, the proportion of females was 60% and mean age at index was 45.1 years. Among non-switchers, 55% was female and mean age was 39.8 years. The median time to switch was 1.7 years and switchers were most frequently initiated on infliximab by a rheumatologist (42%), while non-switchers were most frequently initiated by a gastroenterologist (42%). Conclusions: The results of this large population-based cohort show an increase in biosimilar initiation in daily clinical practice. The number of switchers remains relatively low as non-medical switch is not encouraged in the Netherlands.

Aim: To analyze the appropriateness of DOAC dosing and determinants for under-and overdosing as well as acceptance and implementation rates of interventions by clinical pharmacists. Methods: Cross-sectional study from January 2019-December 2019 in a tertiary hospital in hospitalized patients with atrial fibrillation on DOACs (n=1688). Primary outcome was the proportion of patients with inappropriate DOAC prescribing with identification of determinants for under-and overdosing. Secondary outcomes included acceptance and implementation rates of pharmacists’ advices and determination of reasons for non-acceptance/non-implementation. Results: In 16.9% of patients, inappropriate prescribing was observed. For all DOACs considered together, body weight<60 kg(OR 0.46 [0.27-0.77]), edoxaban use(OR 0.42 [0.24-0.74]), undergoing surgery(OR 0.57 [0.37-0.87]) and being DOAC naïve(OR 0.45 [0.29-0.71]) were associated with a significantly lower odds of underdosing. Bleeding history(OR 1.86 [1.24-2.80]) and narcotic use(OR 1.67 [1.13-2.46]) were associated with a significantly higher odds for underdosing. Determinants with a significantly higher odds of overdosing were renal impairment(OR 11.29 [6.23-20.45]) and body weight<60 kg(OR 2.34 [1.42-3.85]), whereas the use of dabigatran(OR 0.24 [0.08-0.71]) and apixaban(OR 0.18 [0.10-0.32]) were associated with a significantly lower odds of overdosing compared to rivaroxaban. Physicians accepted the pharmacists’ advice in 179 cases (79.2%) consisting of 92 (51.4%) advices for underdosing, 82 (45.8%) for overdosing and 5 (2.8%) for contraindications. The advices were effectively implemented for 75 (81.5%) underdosed, 69 (84.1%) overdosed and 4 (80.0%) contraindicated cases. Conclusion: Inappropriate DOAC prescribing remains common. Clinical services led by pharmacists helps physicians to reduce the number of inadequate prescriptions for high risk medications such as DOACs.