Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno... Show moreIntravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dos-ing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative con-ditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, high-est 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 mg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg x h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two addi-tional alkylators (63.7%, n = 444), cumulative busulfan exposure (<78 and >78 mg x h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan expo-sure did not further increase this risk. Show less
Background The Screening Tool of Older Persons' Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START) instrument is used to evaluate the appropriateness of medication in older... Show moreBackground The Screening Tool of Older Persons' Prescriptions (STOPP)/Screening Tool to Alert to Right Treatment (START) instrument is used to evaluate the appropriateness of medication in older people. STOPP/START criteria have been converted into software algorithms and implemented in a clinical decision support system (CDSS) to facilitate their use in clinical practice. Objective Our objective was to determine the frequency of CDSS-generated STOPP/START signals and their subsequent acceptance by a pharmacotherapy team in a hospital setting. Design and Methods Hospitalised older patients with polypharmacy and multimorbidity allocated to the intervention arm of the OPERAM (OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly) trial underwent a CDSS-assisted structured medication review in four European hospitals. We evaluated the frequency of CDSS-generated STOPP/START signals and the subsequent acceptance of these signals by a trained pharmacotherapy team consisting of a physician and pharmacist after evaluation of clinical applicability to the individual patient, prior to discussing pharmacotherapy optimisation recommendations with the patient and attending physicians. Multivariate linear regression analysis was used to investigate potential patient-related (e.g. age, number of co-morbidities and medications) and setting-related (e.g. ward type, country of inclusion) determinants for acceptance of STOPP and START signals. Results In 819/826 (99%) of the patients, at least one STOPP/START signal was generated using a set of 110 algorithms based on STOPP/START v2 criteria. Overall, 39% of the 5080 signals were accepted by the pharmacotherapy team. There was a high variability in the frequency and the subsequent acceptance of the individual STOPP/START criteria. The acceptance ranged from 2.5 to 75.8% for the top ten most frequently generated STOPP and START signals. The signal to stop a drug without a clinical indication was most frequently generated (28%), with more than half of the signals accepted (54%). No difference in mean acceptance of STOPP versus START signals was found. In multivariate analysis, most patient-related determinants did not predict acceptance, although the acceptance of START signals increased in patients with one or more hospital admissions (+ 7.9; 95% confidence interval [CI] 1.6-14.1) or one or more falls in the previous year (+ 7.1; 95% CI 0.7-13.4). A higher number of co-morbidities was associated with lower acceptance of STOPP (- 11.8%; 95% CI - 19.2 to - 4.5) and START (- 11.0%; 95% CI - 19.4 to - 2.6) signals for patients with more than nine and between seven and nine co-morbidities, respectively. For setting-related determinants, the acceptance differed significantly between the participating trial sites. Compared with Switzerland, the acceptance was higher in Ireland (STOPP: + 26.8%; 95% CI 16.8-36.7; START: + 31.1%; 95% CI 18.2-44.0) and in the Netherlands (STOPP: + 14.7%; 95% CI 7.8-21.7). Admission to a surgical ward was positively associated with acceptance of STOPP signals (+ 10.3%; 95% CI 3.8-16.8). Conclusion The involvement of an expert team in translating population-based CDSS signals to individual patients is essential, as more than half of the signals for potential overuse, underuse, and misuse were not deemed clinically appropriate in a hospital setting. Patient-related potential determinants were poor predictors of acceptance.Future research investigating factors that affect patients' and physicians' agreement with medication changes recommended by expert teams may provide further insight for implementation in clinical practice. Registration ClinicalTrials.gov Identifier: NCT02986425. Show less
Posttraumatic stress disorder (PTSD) is an often chronic condition for which currently available medications have limited efficacy. Medical cannabis is increasingly used to treat patients with PTSD... Show morePosttraumatic stress disorder (PTSD) is an often chronic condition for which currently available medications have limited efficacy. Medical cannabis is increasingly used to treat patients with PTSD; however, evidence for the efficacy and safety of cannabinoids is scarce. To learn more about patients' opinions on and experiences with medical cannabis, we organized a focus group discussion among military veterans (N = 7) with chronic PTSD who were treated with medical cannabis. Afterwards, some of their partners (N = 4) joined the group for an evaluation, during which they shared their perspective on their partner's use of medical cannabis. Both sessions were audio-recorded, transcribed verbatim, and analyzed by means of qualitative content analysis. Five overarching themes were identified. The first four themes related to the different phases of medical cannabis use - namely, 1) Consideration; 2) Initiation; 3) Usage; and 4) Discontinuation. The fifth theme related to several general aspects of medical cannabis use. Patients used medical cannabis to manage their symptoms and did not experience an urge to "get high." They used a variety of different cannabis strains and dosages and reported several therapeutic effects, including an increased quality of sleep. Furthermore, discussions about the experienced stigma surrounding cannabis generated insights with implications for the initiation of medical cannabis use. These results underscore the value of qualitative research in this field and are relevant for the design of future clinical trials on the use of medical cannabis for the treatment of PTSD. (c) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/) Show less
Favie, L.M.A.; Peeters-Scholte, C.M.P.C.D.; Bakker, A.; Tjabbes, H.; Egberts, T.C.G.; Bel, F. van; ... ; Groenendaal, F. 2020
BACKGROUND: Neonatal encephalopathy following perinatal asphyxia is a leading cause for neonatal death and disability, despite treatment with therapeutic hypothermia. 2-Iminobiotin is a promising... Show moreBACKGROUND: Neonatal encephalopathy following perinatal asphyxia is a leading cause for neonatal death and disability, despite treatment with therapeutic hypothermia. 2-Iminobiotin is a promising neuroprotective agent additional to therapeutic hypothermia to improve the outcome of these neonates.METHODS: In an open-label study, pharmacokinetics and short-term safety of 2-iminobiotin were investigated in neonates treated with therapeutic hypothermia. Group A (n = 6) received four doses of 0.16 mg/kg intravenously q6h. Blood sampling for pharmacokinetic analysis and monitoring of vital signs for short-term safety analysis were performed. Data from group A was used to determine the dose for group B, aiming at an AUC(0-48 h) of 4800 ng*h/mL.RESULTS: Exposure in group A was higher than targeted (median AUC(0-48 h) 9522 ng*h/mL); subsequently, group B (n = 6) received eight doses of 0.08 mg/kg q6h (median AUC(0-48 h) 4465 ng*h/mL). No changes in vital signs were observed and no adverse events related to 2-iminobiotin occurred.CONCLUSION: This study indicates that 2-iminobiotin is well tolerated and not associated with any adverse events in neonates treated with therapeutic hypothermia after perinatal asphyxia. Target exposure was achieved with eight doses of 0.08 mg/kg q6h. Optimal duration of therapy for clinical efficacy needs to be determined in future clinical trials. Show less
Favie, L.M.A.; Peeters-Scholte, C.M.P.C.D.; Bakker, A.; Tjabbes, H.; Egberts, T.C.G.; Bel, F. van; ... ; Groenendaal, F. 2020
Background: Sialorrhea affects approximately 75% of patients with Parkinson disease (PD). Sialorrhea is often treated with anticholinergics, but central side effects limit their usefulness.... Show moreBackground: Sialorrhea affects approximately 75% of patients with Parkinson disease (PD). Sialorrhea is often treated with anticholinergics, but central side effects limit their usefulness. Glycopyrrolate (glycopyrronium bromide) is an anticholinergic drug with a quaternary ammonium structure not able to cross the blood-brain barrier in considerable amounts. Therefore, glycopyrrolate exhibits minimal central side effects, which may be an advantage in patients with PD, of whom a significant portion already experience cognitive deficits. Objective: To determine the efficacy and safety of glycopyrrolate in the treatment of sialorrhea in patients with PD. Methods: We conducted a 4-week, randomized, double-blind, placebo-controlled, crossover trial with oral glycopyrrolate 1 mg 3 times daily in 23 patients with PD. The severity of the sialorrhea was scored on a daily basis by the patients or a caregiver with a sialorrhea scoring scale ranging from 1 (no sialorrhea) to 9 (profuse sialorrhea). Results: The mean (SD) sialorrhea score improved from 4.6 (1.7) with placebo to 3.8 (1.6) with glycopyrrolate (p = 0.011). Nine patients (39.1%) with glycopyrrolate had a clinically relevant improvement of at least 30% vs 1 patient (4.3%) with placebo (p = 0.021). There were no significant differences in adverse events between glycopyrrolate and placebo treatment. Conclusions: Oral glycopyrrolate 1 mg 3 times daily is an effective and safe therapy for sialorrhea in Parkinson disease. Classification of evidence: This study provides Class I evidence that glycopyrrolate 1 mg 3 times daily is more effective than placebo in reducing sialorrhea in patients with Parkinson disease during a 4-week study. Neurology (R) 2010;74:1203-1207 Show less
Arbouw, M. el; Guchelaar, H.J.; Egberts, T.C.G. 2010
