Pharmacokinetics and short-term safety of the selective NOS inhibitor 2-iminobiotin in asphyxiated neonates treated with therapeutic hypothermia

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 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.Neurolog

Cost-effectiveness of a transitional pharmaceutical care program for patients discharged from the hospital

Background To improve continuity of care at hospital admission and discharge and to decrease medication errors pharmaceutical care programs are developed. This study aims to determine the cost-effectiveness of the COACH program in comparison with usual care from a societal perspective. Methods A controlled clinical trial was performed at the Internal Medicine department of a general teaching hospital. All admitted patients using at least one prescription drug were included. The COACH program consisted of medication reconciliation, patient counselling at discharge, and communication to healthcar

Medicatiescreening met Beers-criteria en STOPP/START-criteria bij de oudere patiënt: associatie tussen potentieel ongewenst geneesmiddelengebruik en geneesmiddelgerelateerde ziekenhuisopnamen

OBJECTIVE To assess the risk of medication-related hospital admissions associated with inappropriate medication use applying the Beers and the STOPP/START criteria. There are multiple screening methods to detect and reduce potentially inappropriate medication [PIM] and prescribing omissions (PPOs). Whether this will result in less medication-related hospitalisations is unknown. DESIGN A nested case-control study was conducted with a subset of patients of the Hospital Admissions Related to Medication (HARM) study. METHODS Cases were defined as patients ≥65 years with a potentially preventable medication-related hospital admission. For each case one control was selected, matched on age and sex. The primary determinant was defined as the presence of one or more PlMs and/or PPOs according to the Beers 2012 and the STOPP/START criteria. The strength of the association between a PIM/PPO and a medication-related hospital admission was evaluated with multivariate logistic regression and expressed as odds ratios with 95% confidence intervals (Cl95). RESULTS PlMs and PPOs detected with the STOPP/START criteria are associated with medication-related hospital admissions [OR 3.47; CI95 1.70-7.09], while for the presence of PIMs according to the Beers 2012 criteria a non-significant trend was visible (ORadj 1.49; CI95 0.90-2.47). CONCLUSION Both the STOPP/START criteria and the Beers 2012 criteria can be used to identify older people at risk for medication-related problems. The choice which set of criteria should be used is more dependent on other factors (e.g. national guidelines, practical considerations) than on the association of each set with ADR-related hospital admission

Frequency and acceptance of clinical decision support system-generated STOPP/START signals for hospitalised older patients with polypharmacy and multimorbidity

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 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.Geriatrics in primary carePublic Health and primary car

Megakaryocyte lineage development is controlled by modulation of protein acetylation

Treatment with lysine deacetylase inhibitors (KDACi) for haematological malignancies, is accompanied by haematological side effects including thrombocytopenia, suggesting that modulation of protein acetylation affects normal myeloid development, and specifically megakaryocyte development. In the current study, utilising ex-vivo differentiation of human CD34+ haematopoietic progenitor cells, we investigated the effects of two functionally distinct KDACi, valproic acid (VPA), and nicotinamide (NAM), on megakaryocyte differentiation, and lineage choice decisions. Treatment with VPA increased the number of megakaryocyte/erythroid progenitors (MEP), accompanied by inhibition of megakaryocyte differentiation, whereas treatment with NAM accelerated megakaryocyte development, and stimulated polyploidisation. Treatment with bot

Association between the magnitude of intravenous busulfan exposure and development of hepatic veno-occlusive disease in children and young adults undergoing myeloablative allogeneic hematopoietic cell transplantation

Intravenous 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 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. Transplantation and immunomodulatio

Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia

Objective Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in thi

Novel insights in pharmacogenetics of drug response in Parkinson's disease

Personalised Therapeutic

Prevalence of Psychotropic Medication Use Among Dutch Military Personnel Between 2003 and 2012 and Its Comparison to the Dutch General Population

Stress-related psychiatric disorders across the life spa

Seasonal patterns of initiating antidepressant therapy in general practice in the Netherlands during 2002-2007.

Background: Studies on seasonality in antidepressant prescribing showed prescribing peaks during autumn and winter. Since then, new antidepressants have become available and indications have broadened, possibly contributing to a change inprescribing practices. This study investigates seasonal patterns of initiating antidepressant use in general practice during 2002–2007 in the Netherlands. Method: Data were obtained from the Netherlands Information Network of General Practice. The study population was composed of adult patients initiating antidepressant use from 21 December 2001 to 20 December 2007, with no antidepressant use during at least two years prior to initiation. Seasonal distribution of initiating antidepressant use was investigated for the four seasons. The difference in frequency of initiating use between the seasons, normalized for general practice contacts, was tested using Chi-square testing. Results: The majority of the study population (N=16,289) was female (64.0%) with a mean age (standard deviation (SD)) of 50.5 (18.0) years. Significant seasonal variation (pb0.01) was found in initiation of antidepressant use, with about 5–35% more patients initiating use during winter than summer. Significant (pb0.01) seasonality of initiating antidepressant use was seen in all patient groups, except within age groups 18–30 years and N60 years. Limitations: Our study investigated only general practitioner prescribing thus additional prescriptions from psychiatrists are missed. Conclusions: The seasonal influence on initiation of antidepressant drug use has not changed with the introduction of the newer antidepressants and is in line with seasonality of depression onset, with most patients initiating use during the winter and fewest during the summer. (aut. ref.