BackgroundDesmopressin increases plasma factor VIII and von Willebrand factor levels in persons with nonsevere hemophilia A. Patients’ perspectives on desmopressin are relevant to increase and... Show moreBackgroundDesmopressin increases plasma factor VIII and von Willebrand factor levels in persons with nonsevere hemophilia A. Patients’ perspectives on desmopressin are relevant to increase and optimize its suboptimal use. However, patients’ views on desmopressin are not reported.ObjectivesTo evaluate the perspectives of persons with nonsevere hemophilia A on desmopressin use, barriers for its use, side effects, and their knowledge about desmopressin’s efficacy and side effects.MethodsPersons with nonsevere hemophilia A were included in a cross-sectional, national, multicenter study. Questionnaires were filled out by adult patients and children aged ≥12 years themselves. Caretakers filled out questionnaires for children aged <12 years.ResultsIn total, 706 persons with nonsevere hemophilia A were included (544 mild, 162 moderate, [age range, 0–88 years]). Of 508 patients, 234 (50%) patients reported previous desmopressin use. Desmopressin was considered as at least moderately effective in 171 of 187 (90%) patients. Intranasal administration was the modality of choice for 138 of 182 (76%) patients. Flushing was the most reported side effect in 54 of 206 (26%) adults and 7 of 22 (32%) children. The most frequently reported advantage and disadvantage were the convenience of intranasal, out-of-hospital administration by 56% (126/227) and side effects in 18% (41/227), respectively. Patients’ self-perceived knowledge was unsatisfactory or unknown in 28% (63/225).ConclusionOverall, desmopressin was most often used intranasally and considered effective, with flushing as the most common side effect. The most mentioned advantage was the convenience of intranasal administration and disadvantage was side effects. More information and education on desmopressin could answer unmet needs in patients with current or future desmopressin treatment. Show less
To compare EEG-patterns after instillation of cyclopentolate versus placebo eye drops. Prospective, randomized, placebo-controlled, and observational pilot study is presented. Ophthalmology... Show moreTo compare EEG-patterns after instillation of cyclopentolate versus placebo eye drops. Prospective, randomized, placebo-controlled, and observational pilot study is presented. Ophthalmology outpatient clinic Dutch metropolitan hospital. Healthy 6- to 15-year-old volunteers with normal or low BMI requiring a cycloplegic refraction/retinoscopy. Randomized; 1 visit 2 drops cyclopentolate-1% and 1 visit 2 drops placebo (saline-0.9%). Single-blind: conducting researcher. Double blind: subjects, parents, clinical-neurophysiology staff, neurologist, and statistician. A 10-min baseline EEG-recording, drop-application, and follow-up to at least 45 min. Primary outcome: Detection of CNS changes, i.e. EEG-pattern changes, following two drops of cyclopentolate-1%. Secondary outcome: Determination of the extent of these pattern changes. Thirty-six cyclopentolate-1% saline-0.9% EEG registrations were made in 33 subjects; 18 males and 15 females. Three subjects were tested twice (interval 7 months). Nine out of fourteen (64%) of the 11- to 15-year-old children reported impaired memory, attention, alertness, as well as mind wandering following cyclopentolate. Drowsiness and sleep were seen in EEG-recordings of 11 subjects (33%) following cyclopentolate. We observed no drowsiness nor sleep during placebo recordings. The mean time to drowsiness was 23 min. Nine subjects arrived in stage-3 sleep but none arrived in REM-sleep. In subjects without sleep (N=24), significant changes compared to placebo-EEG were present for many leads and parameters. The main findings during awake eye-open recording were as follows: 1) a significant increase of temporal Beta-1,2 and 3-power, and 2) a significant decrease in: a) the parietal and occipital Alpha-2-power, b) the frontal Delta-1-power, c) the frontal total power, and d) the occipital and parietal activation synchrony index. The former finding reflects cyclopentolate uptake in the CNS, and the latter findings provide evidence for CNS suppression. Cyclopentolate-1% eye drops can affect the CNS and may cause altered consciousness, drowsiness, and sleep with concomitant EEG results in both young children and children in puberty. There is evidence that cyclopentolate has the potency to act as a short acting CNS depressant. Nevertheless, however, cyclopentolate-1% can safely be used in children and young adolescents. Show less
Background: Adverse late health outcomes after multimodal treatment for pediatric cancer are diverse and of prime interest. Currently available evidence and survivorship care guidelines are largely... Show moreBackground: Adverse late health outcomes after multimodal treatment for pediatric cancer are diverse and of prime interest. Currently available evidence and survivorship care guidelines are largely based on studies addressing side-effects of two dimensional planned radiotherapy. Aims: The Dutch pediatric 3D-planned radiotherapy (3D-RT) study aims to gain insight in the long-term health outcomes among children who had radiotherapy in the 3D era. Here, we describe the study design, data-collection methods, and baseline cohort characteristics. Methods and Results: The 3D-RT study represents an expansion of the Dutch Childhood Cancer Survivor study (DCCSS) LATER cohort, including pediatric cancer patients diagnosed during 2000-2012, who survived at least 5 years after initial diagnosis and 2 years post external beam radiotherapy. Individual cancer treatment parameters were obtained from medical files. A national infrastructure for uniform collection and archival of digital radiotherapy files (Computed Tomography [CT]-scans, delineations, plan, and dose files) was established. Health outcome information, including subsequent tumors, originated from medical records at the LATER outpatient clinics, and national registry-linkage. With a median follow-up of 10.9 (interquartile range [IQR]: 7.9-14.3) years after childhood cancer diagnosis, 711 eligible survivors were identified. The most common cancer types were Hodgkin lymphoma, medulloblastoma, and nephroblastoma. Most survivors received radiotherapy directed to the head/cranium only, the craniospinal axis, or the abdominopelvic region. Conclusion: The 3D-RT study will provide knowledge on the risk of adverse late health outcomes and radiation-associated dose-effect relationships. This information is valuable to guide follow-up care of childhood cancer survivors and to refine future treatment protocols. Show less
Immune checkpoint blocking therapy is a promising cancer treatment modality, though it has limitations such as systemic toxicity, which can often be traced to uncontrolled antibody spread.... Show moreImmune checkpoint blocking therapy is a promising cancer treatment modality, though it has limitations such as systemic toxicity, which can often be traced to uncontrolled antibody spread. Controlling antibody release with delivery systems is, therefore, an attractive approach to reduce systemic antibody spread and potentially mitigate the side effects of checkpoint immunotherapy. Here, bacterial cellulose (BC) was produced and investigated as a delivery system for optimizing checkpoint-blocking antibody delivery. BC was produced in 24-well plates, and afterward, the edges were removed to obtain square-shaped BC samples with a surface of similar to 49 mm(2). This customization was necessary to allow smooth in vivo implantation. Scanning electron microscopy revealed the dense cellulose network within BC. Human IgG antibody was included as the model antibody for loading and release studies. IgG antibody solution was injected into the center of BC samples. In vitro, all IgG was released within 24 to 48 h. Cell culture experiments demonstrated that BC neither exerted cytotoxic effects nor induced dendritic cell activation. Antibody binding assays demonstrated that BC does not hamper antibody function. Finally, antibody-loaded BC was implanted in mice, and serum measurements revealed that BC significantly reduced IgG and anti-CTLA-4 spread in mice. BC implantation did not induce side effects in mice. Altogether, BC is a promising and safe delivery system for optimizing the delivery and release of checkpoint-blocking antibodies. Show less
Berghuis, D.; Lambregts, M.M.C.; Boer, M.G.J. de 2021
Up to 10% of hospitalized patients have an antibiotic allergy label in their medical file, most frequently concerning penicillins. However, the vast majority of reported allergies to antibiotics... Show moreUp to 10% of hospitalized patients have an antibiotic allergy label in their medical file, most frequently concerning penicillins. However, the vast majority of reported allergies to antibiotics does not represent a "true" allergy but are due to drug intolerance, idiosyncratic reactions or symptoms of the concurrent infectious disease. Since antibiotic allergy labels result in deviation from first-choice antimicrobial therapy, tackling the issue of incorrect antibiotic allergy labelling, already at young age, is a core element of antibiotic stewardship. In this article, we describe the structured approach to the patient with a presumed antibiotic allergy with emphasis on key elements of allergy-specific history taking and the limited risk of cross-allergic reactions between beta-lactam subclasses. Show less
Westrhenen, R. van; Schaik, R.H.N. van; Gelder, T. van; Birkenhager, T.K.; Bakker, P.R.; Houwink, E.J.F.; ... ; Weelden-Hulshof, M.J.M. van 2021
Effective pharmacologic treatments for psychiatric disorders are available, but their effect is limited due to patients' genetic heterogeneity and low compliance-related to frequent adverse events.... Show moreEffective pharmacologic treatments for psychiatric disorders are available, but their effect is limited due to patients' genetic heterogeneity and low compliance-related to frequent adverse events. Only one third of patients respond to treatment and experience remission. Pharmacogenetics is a relatively young field which focusses on genetic analyses in the context of the metabolism and outcome of drug treatment. These genetic factors can, among other things, lead to differences in the activity of enzymes that metabolize drugs. Recently, a clinical guideline was authorized by the Dutch Clinical Psychiatric Association (NVvP) on the clinical use of pharmacogenetics in psychiatry. The main goal was to provide guidance, based on current evidence, on how to best use genotyping in clinical psychiatric practice. A systematic literature search was performed, and available publications were assessed using the GRADE methodology. General recommendations for psychiatric clinical practice were provided, and specific recommendations per medication were made available. This clinical guideline for caregivers prescribing psychotropic drugs is the product of a broad collaboration of professionals from different disciplines, making use of the information available at the Dutch Pharmacogenetics Working Group (DPWG) and the Clinical Pharmacogenetics Implementation Consortium (CPIC) so far. We summarize the relevant literature and all recommendations in this article. General recommendations are provided and also detailed recommendations per medication. In summary we advise to consider genotyping, when there are side effects or inefficacy for CYP2C19 and CYP2D6. When genotype information is available use this to select the right drug in the right dose for the right patient. Show less
Dahan, A.; Boon, M.; Velzen, M. van; Niesters, M. 2020
Introduction: Gln-1062 (MEMOGAIN) is an intranasally administered lipophilic prodrug of galantamine. Based on high brain-to-blood concentrations observed in preclinical studies, Gln-1062 is... Show moreIntroduction: Gln-1062 (MEMOGAIN) is an intranasally administered lipophilic prodrug of galantamine. Based on high brain-to-blood concentrations observed in preclinical studies, Gln-1062 is expected to have superior cognitive efficacy compared to oral galantamine.Methods: Forty-eight healthy elderly subjects were randomized 12:4 to Gln-1062 (5.5, 11, or 22 mg, b.i.d., for 7 days) or placebo. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed repeatedly. Pharmacokinetics were compared with 16 mg oral galantamine.Results: Gln-1062 up to 22 mg, b.i.d., was well tolerated. Gln-1062 plasma concentrations increased immediately following dosing (median T-max of 0.5 hour [range 0.5-1.0]). C-max and AUC(0-last) increased in a dose-linear manner over all three dose levels. Gln-1062 was rapidly cleaved into galantamine. Gln-1062 significantly improved adaptive tracking (sustained attention) with 1.95% (95% confidence interval [CI] 0.630-3.279, P = 0.0055) compared to placebo after correction for individual baseline performance.Discussion: Gln-1062 was considered to be safe and caused fewer gastrointestinal side effects than oral galantamine. Gln-1062 behaved pharmacokinetically as expected and improved performance on cognitive tests. Show less
