[Wakefulness-promoting agents for severe fatigue: to use or not to use?] / Medicatie tegen ernstige aanhoudende vermoeidheid.

About 20% of adults experience excessive daytime sleepiness or severe fatigue. Causes include somatic conditions, psychiatric disorders, and medication or drug use. Treatment depends on the underlying cause. If sleepiness persists despite optimal treatment of the underlying condition, exclusion of other causes, and behavioral interventions, wakefulness-promoting agents may be considered. However, no established pharmacological strategy exists for symptomatic treatment. Modafinil and stimulants like methylphenidate may offer some benefit based on experiences with narcolepsy or idiopathic hypersomnia. Studies in specific patient groups (e.g., multiple sclerosis, Parkinson's disease, traumatic brain injury, cancer-related fatigue) show variable results. The use of wakefulness-promoting agents is discouraged for addressing unexplained fatigue, as seen in the context of chronic fatigue syndrome.

Discontinuation of psychotropic medication: a synthesis of evidence across medication classes.

Pharmacotherapy is an effective treatment modality across psychiatric disorders. Nevertheless, many patients discontinue their medication at some point. Evidence-based guidance for patients, clinicians, and policymakers on rational discontinuation strategies is vital to enable the best, personalized treatment for any given patient. Nonetheless, there is a scarcity of guidelines on discontinuation strategies. In this perspective, we therefore summarize and critically appraise the evidence on discontinuation of six major psychotropic medication classes: antidepressants, antipsychotics, benzodiazepines, mood stabilizers, opioids, and stimulants. For each medication class, a wide range of topics pertaining to each of the following questions are discussed: (1) Who can discontinue (e.g., what are risk factors for relapse?); (2) When to discontinue (e.g., after 1 year or several years of antidepressant use?); and (3) How to discontinue (e.g., what's the efficacy of dose reduction compared to full cessation and interventions to mitigate relapse risk?). We thus highlight how comparing the evidence across medication classes can identify knowledge gaps, which may pave the way for more integrated research on discontinuation.

[Insomnia: a persistent problem without optimal pharmacological approach]. / Slapeloosheid: een hardnekkig probleem zonder optimale medicamenteuze strategie.

Insomnia is a highly prevalent disorder in the Netherlands, with an estimated prevalence of 7-22%. The use of pharmacological interventions should be restricted, nevertheless, medications for insomnia are often prescribed. The use of off-label pharmacological interventions is increasing, although supporting evidence for these strategies is limited. In order to understand the use of certain on- and off-label strategies, we describe the pathophysiology of insomnia and the clinical pharmacology of various on- and off-label drugs.

Prednisone vs methotrexate in treatment naïve cardiac sarcoidosis.

BACKGROUND: Side effects limit the long-term use of glucocorticoids in cardiac sarcoidosis (CS), and methotrexate has gained attention as steroid sparing agent although the supporting evidence is poor. This study compared prednisone monotherapy, methotrexate monotherapy or a combination of both, in the reduction of myocardial Fluorine-18 fluorodeoxyglucose (FDG) uptake and clinical stabilization of CS patients. METHODS AND RESULTS: In this retrospective cohort study, 61 newly diagnosed and treatment naïve CS patients commenced treatment with prednisone (N = 21), methotrexate (N = 30) or prednisone and methotrexate (N = 10) between January 2010 and December 2017. Primary outcome was metabolic response on FDG PET/CT and secondary outcomes were treatment patterns, major adverse cardiovascular events, left ventricular ejection fraction, biomarkers and side effects. At a median treatment duration of 6.2 [5.7-7.2] months, 71.4% of patients were FDG PET/CT responders, and the overall myocardial maximum standardized uptake value decreased from 6.9 [5.0-10.1] to 3.4 [2.1-4.7] (P < 0.001), with no significant differences between treatment groups. During 24 months of follow-up, 7 patients (33.3%; prednisone), 6 patients (20.0%; methotrexate) and 1 patient (10.0%; combination group) experienced at least one major adverse cardiovascular event (P = 0.292). Left ventricular ejection fraction was preserved in all treatment groups. CONCLUSIONS: Significant suppression of cardiac FDG uptake occurred in CS patients after 6 months of prednisone, methotrexate or combination therapy. There were no significant differences in clinical outcomes during follow-up. These results warrant further investigation of methotrexate treatment in CS patients.

Randomised, placebo-controlled trial of dexamethasone for quality of life in pulmonary sarcoidosis.

BACKGROUND: Many patients with pulmonary sarcoidosis experience reduced quality of life. Although oral corticosteroids are the most common agents used in sarcoidosis, very little is known on the effects on quality of life. METHODS: In this double-blind, placebo-controlled trial, newly diagnosed patients without an indication for high dose immunosuppressive therapy were randomised to once-daily dexamethasone 1 mg (6.5 mg prednisone equivalent) or placebo for 6 months. The primary study parameter was the subscale physical functioning of the 36-item Short Form health survey (SF-36). Secondary parameters included five other patient reported outcome measures, disease activity markers and plasma cytokine profiles. RESULTS: A total of 16 patients was randomised to dexamethasone (n = 7) and placebo (n = 9). During follow-up no significant difference for physical functioning was measured (p = 0.18). Dexamethasone treated patients showed a decrease in fatigue score (Checklist Individual Strength) from 106 (baseline) to 88 (3 months; p = 0.03); 86 (6 months; p = 0.05); 79 (9 months; p = 0.04); 90 (12 months; p = 0.03). Placebo treated patients showed no change: 96 (baseline) to 105 (3 months; p = 0.16); 91 (6 months; p = 0.48); 92 (9 months; p = 0.61); 95 (12 months; p = 0.90). During treatment with dexamethasone significant improvements in the SF-36 subscales vitality and pain, and a significant reduction in serum angiotensin-converting enzyme, soluble interleukin 2 receptor levels and serum cytokines and chemokines were measured. CONCLUSIONS: Low-dose dexamethasone results in a reduction of the inflammatory profile and has the potential to improve quality of life parameters and fatigue.

The effects of pharmacological interventions on quality of life and fatigue in sarcoidosis: a systematic review.

AIMS: Many sarcoidosis patients experience a reduction in health-related quality of life (HRQoL) and a majority of patients report fatigue. Historically, drug trials in sarcoidosis have focused on changes in chest radiographs, lung function parameters and biomarkers, while HRQoL and fatigue have not been the main outcomes examined. We performed a systematic review of the literature to evaluate the existing evidence on the effects of pharmacological interventions on HRQoL and fatigue outcomes. METHODS: The systematic search was performed in Medline and Embase and yielded 15 records covering seven randomised controlled trials and seven single-arm open label studies, which were included in a qualitative synthesis (the results of one study were included in two publications). 12 studies evaluated immunosuppressive and/or immunomodulatory therapies and two studies evaluated stimulants. RESULTS: Nine out of the 14 studies observed positive treatment effects from the interventions on HRQoL and/or fatigue, exceeding the minimal important difference. The risk of bias was generally high with only three studies rated as having a low risk of bias. The results suggest a potential for improvement in HRQoL and/or fatigue in patients with active disease who are either untreated or treated but not yet fully stabilised or therapy refractory. CONCLUSION: More randomised, double-blind and placebo-controlled trials are needed to expand the evidence base on these important outcome parameters.

99mTc-anti-TNF-α antibody for the imaging of disease activity in pulmonary sarcoidosis.

Infliximab, a monoclonal antibody directed against tumour necrosis factor (TNF)-α, is used in the treatment of refractory sarcoidosis. However, the clinical response is variable and a tool to select responders beforehand is highly desirable. In this study we evaluated scintigraphy with technetium-99m ((99m)Tc)-labelled infliximab for the imaging of disease activity in patients with pulmonary sarcoidosis.10 patients were studied using single photon emission computed tomography/computed tomography (CT) 6 h and 20 h after intravenous administration of 370 MBq of(99m)Tc-infliximab. Correlation analysis was performed between tissue accumulation of(99m)Tc-infliximab and laboratory parameters (including soluble interleukin-2 receptor and angiotensin-converting enzyme), lung function parameters (including forced expiratory volume in 1 s and the diffusing capacity of the lung for carbon monoxide) and(18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT.Analysis showed selective and variable accumulation of(99m)Tc-infliximab in the target tissue. Accumulation correlated positively with all four laboratory parameters and negatively with all four lung function parameters, yielding better correlations than serum TNF-α levels or(18)F-FDG PET/CT.(99m)Tc-infliximab accumulation reflects thein situTNF-α expression in an individual patient and therefore provides valuable information on the presence of the biological target for anti-TNF-α therapy.

GMP-compliant (68)Ga radiolabelling in a conventional small-scale radiopharmacy: a feasible approach for routine clinical use.

BACKGROUND: The number of routine care patient examinations with (68)Ga radiopharmaceuticals is still relatively limited, probably caused by the presumed need for large investments in hot cells, automated synthesis modules, laboratory equipment and validation efforts. Our aim was to set up the preparation of (68)Ga-DOTA-NOC in compliance with all current European Union-Good Manufacturing Practices (EU-GMP), current Good Radiopharmacy Practice (cGRPP) and European Pharmacopoeia (Ph. Eur.) guidance but without the availability of a hot cell and gas chromatography (GC), high-performance liquid chromatography (HPLC) and atomic absorption spectrometry (AAS) equipment. METHODS: A risk-based approach was applied to align preparation conditions with applicable regulations, together with a validation of a thin-layer chromatography (ITLC) method to replace HPLC as modality for examining radiochemical purity. RESULTS: Using an internally shielded labelling module for manual operation, a (68)Ga-DOTA-NOC labelling procedure was set up that meets all applicable Ph. Eur. specifications. The applied ITLC method showed very good correlation with HPLC results (r = 0.961) and was able to detect relevant deviations in radiolabelling procedures. All identified quality assurance aspects were made compliant with EU-GMP and cGRPP guidance. CONCLUSIONS: We consider the described configuration and validation approach feasible for many conventional small-scale radiopharmacies, something that could help to increase the availability of (68)Ga radiopharmaceuticals to a large number of patients.

[Not Available]. / PSMA-PET voor prostaatkanker en eventuele metastasen.

(68)Gallium (Ga)-PSMA PET/CT (PSMA stands for "prostate-specific membrane antigen") is a new diagnostic tool for patients with prostate cancer or with prostate cancer metastases. PET/CT is a combination scan which uses the physiological information of the PET scan and the anatomic information of the CT scan. The radioligand (68)Ga-PSMA is a radioactively labelled peptide that binds to the membrane protein PSMA. Prostate cancer cells in the primary tumour and in metastases express increased levels of PSMA in the plasma membrane. A number of studies have shown that (68)Ga-PSMA PET/CT is sensitive in detecting primary prostate cancer and metastases in lymph nodes and bone. In the same patient, (68)Ga-PSMA PET/CT detects more metastases in an earlier phase, i.e. at a lower PSA level, than fluorine-18 choline PET/CT. Furthermore, the (68)Ga-PSMA can be produced in the investigating hospital with a gallium generator. The expectation is that the use of (68)Ga-PSMA PET/CT will increase to a major extent over the coming years in patients with prostate cancer.

[Choosing the correct benzodiazepine: mechanism of action and pharmacokinetics]. / Kiezen voor de juiste benzodiazepine: werkingsmechanisme en farmacokinetiek.

There is a discrepancy between the recommendation for caution and daily practice in the prescription of benzodiazepines. Although there is heterogeneity in the registered indications, all benzodiazepine agonists have almost the same mechanism of action. There are, however, substantial pharmacokinetic differences between individual benzodiazepine agonists. During short-term use of benzodiazepines, the elimination half-life is no measure of duration of action. Benzodiazepine lipophilicity determines the speed of action. If a rapid effect is desired, for instance in acute anxiety or agitation, then regarding oral medication the use of a lipophilic benzodiazepine such as diazepam is a rational choice. An accumulation factor can be used to estimate benzodiazepine accumulation during chronic use. In theory, accumulation does not occur with once-daily dosage of benzodiazepines that have an elimination half-life markedly shorter than 24 h, such as oxazepam, temazepam, and lorazepam.

Implementation of asymmetric yielding in case-specific finite element models improves the prediction of femoral fractures.

Although asymmetric yielding in bone is widely shown in experimental studies, previous case-specific non-linear finite element (FE) studies have mainly adopted material behaviour using the Von Mises yield criterion (VMYC), assuming equal bone strength in tension and compression. In this study, it was verified that asymmetric yielding in FE models can be captured using the Drucker-Prager yield criterion (DPYC), and can provide better results than simulations using the VMYC. A sensitivity analysis on parameters defining the DPYC (i.e. the degree of yield asymmetry and the yield stress settings) was performed, focusing on the effect on bone failure. In this study, the implementation of a larger degree of yield asymmetry improved the prediction of the fracture location; variations in the yield stress mainly affected the predicted failure force. We conclude that the implementation of asymmetric yielding in case-specific FE models improves the prediction of femoral bone strength.