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Closed system transfer devices (CSTDs) are a major challenge for drug manufacturers to assess and assure drug compatibility and acceptable dosing accuracy for a range of clinical administration strategies. In this article, we systematically investigate parameters affecting the loss of product during transfer by CSTDs from vials to infusion bags. We show that liquid volume loss increases with vial size, vial neck diameter, and solution viscosity - while dependent on stopper design. We further compared CSTDs' performance with a traditional syringe transfer and learned that loss is larger for CSTDs than for syringe transfer. Based on experimental data, a statistical model was developed to predict drug loss upon transfer by CSTDs. The model predicted that, for single dose vials with USP<1151> conforming overfill, a complete extraction and transfer of the full dose can be assured for a broad range of CSTDs, product viscosities, and vial types (2R, 6R, 10R, 20R) if a flush (of syringe, syringe adaptor, bag spike) is performed. The model also predicted that complete transfer cannot be achieved for fill volumes ≤ 2.0 mL. For multi-dose vials and pooling of several vials, respectively, the effective dose transfer (i.e., ≥ 95%) for all CSTDs tested was predicted to be achieved if a minimum of 5.0 mL is transferred. [ABSTRACT FROM AUTHOR]

Aims: We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke. Methods: The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke. Results: At stroke onset, an off-label daily dose was prescribed in 61 (25.5%) of 239 NOAC patients with known AF and CHA2DS2-VASc score ≥ 1, of which 52 (21.8%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95% CI 1.05–7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95% CI 1.04–10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2%) of 61 patients. Overall, 79 (13.7%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95% CI 1.24–9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95% CI 0.01–0.47, P < 0.01; n = 56], CHA2DS2-VASc score [OR per point 1.47, 95% CI 1.08–2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95% CI 1.28–2.84, P < 0.01]. Conclusion: At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge. Clinical trial registration: NCT02306824. [ABSTRACT FROM AUTHOR]

Background: Artemisinin-based combination therapy (ACT) introduced in the mid-1990s has been recommended since 2005 by the World Health Organization as first-line treatment against Plasmodium falciparum in all endemic countries. In 2010, the combination dihydroartemisinin-piperaquine (DP) was recommended for the treatment of uncomplicated P. falciparum malaria. DP is one of the first-line treatments used by the French army since 2013. Case presentation: A case of P. falciparum clinical failure with DP at day 20 was described in a 104 kg French soldier deployed in Djibouti. He was admitted to hospital for supervision of oral treatment with DP [40 mg dihydroartemisinin (DHA) plus 320 mg piperaquine tetraphosphate (PPQ)]. This corresponded to a cumulative dose of 4.6 mg/kg DHA and 37 mg/kg PPQ in the present patient, which is far below the WHO recommended ranges. No mutation was found in the propeller domain of the Kelch 13 (k13) gene, which is associated with artemisinin resistance in Southeast Asia. Pfmdr1 N86, 184F, S1034 and N1042 polymorphisms and haplotype 72-76 CVIET for the pfcrt gene were found in the present case. There was no evidence of resistance to DP. Conclusion: This case confirms the risk of therapeutic failure with dihydroartemisinin-piperaquine by under-dosing in patients weighing more than 100 kg. This therapeutic failure with DP by under-dosing highlighted the importance of appropriate dosing guidelines and the need of research data (efficacy, pharmacokinetics and pharmacodynamics) in over-weight patient group. [ABSTRACT FROM AUTHOR]

The strategy of under-dosing coagulant was firstly applied in a coagulation–ultrafiltration (UF) process for treatment of humic-rich water in this study. When polyaluminum chloride (PACl) dosage was set as 0.025 mM (as alum), the removal efficiency of organic matter and residual turbidity were slightly inferior to 0.1 mM (as alum), but four times dosage lowered than the optimal-dosing. Although permeate flux of ultrafiltration membrane was larger at the optimal-doing than that of under-dosing, the less proportion of irreversible fouling and large proportion of reversible fouling were proved that under-dosing strategy has more meaningful engineering application value for deep investigation. The impacts of Ca 2+ on coagulation and ultrafiltration performance are also investigated under different coagulant doses. Removal of humic-like substance, floc size and incompactness were appreciably enhanced at under-dose with increasing Ca 2+ concentration, but did not distinctly change at the optimal-dosing. Besides, lower positive charge of flocs produced at under-dosing hindered the foulants transport to membrane surface. The interactions between humic substance, positively-charged coagulants, and structure of cake layer firstly systemically investigated the impacts on the performance of ultrafiltration in our study. The results shown that the technology of under-dosing with addition of Ca 2+ has dramatically increased the UV 254 removal efficiency, formed loose and porous flocs still outside of the critical electrostatic distance of membrane surface, which significantly remit the membrane fouling and improve the reversibility of membrane fouling. [ABSTRACT FROM AUTHOR]

Background: Population-based self-reported data on off-label medicine use independent from health care provisions are lacking. The purpose of this study is to investigate off-label medicine use in children and adolescents in Germany in a non-clinical setting and to identify prevalence, determinants and spectrum of off-label medicine use. Methods: Data were obtained from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) conducted by the Robert Koch Institute (2003-2006). 17,450 randomly selected children aged 0-17 years took part in the drug interviews. Of those, 8,899 took at least one medicine during the 7 days preceding the interview. Off-label medicine use was defined as the discrepancy between actual use and the intended use described in the summary of product characteristics. Off-label medicine use was stratified into off-label indication, off-label age, off-label over-dosing, and off-label under-dosing. Results: The prevalence rate of off-label medicine use among those who used medicines amount of is 40.2%. The prevalence rate is significantly higher in boys (41.4%), in children aged 3 to 6 years (48.7%), without migration background (40.9%), with high social status (42.5%), living in small (42.0%) and medium sized cities (41.6%), and with a poor parents rated health status (41.7%). 12,667 preparations (attributable in respect to off-label use) were taken by 8,899 children. 30% of the medicines have been used off-label. Off-label medicine use was highest in preparations of the ATC-class "C00 Cardiovascular System". In all origins of medicine, all age groups and all ATC-classes under-dosing was the most frequent reason for off-label medicine use. Conclusions: There is a considerable level of self-reported off-label medicines use in the general paediatric population. Further investigations are needed to examine in how far off-label medicine use is based on lack of knowledge or on empiricism in paediatric pharmacotherapy. Attention also needs to be paid to under-dosing which potentially exposes drug users to risks of side effects without the benefit of a therapeutic effect. Clinical trials for licensing of paediatric medicines, education of health care professionals, but also of parents and carers are needed to ensure the rational use of medicines. [ABSTRACT FROM AUTHOR]

Like other areas of speech-language pathology, the behavioural management of voice disorders lacks precision regarding optimal dose-response relationships. In voice therapy, dosing can presumably vary from no measurable effect (i.e., no observable benefit or adverse effect), to ideal dose (maximum benefit with no adverse effects), to doses that produce toxic or harmful effects on voice production. Practicing specific vocal exercises will inevitably increase vocal load. At ideal doses, these exercises may be non-toxic and beneficial, while at intermediate or high doses, the same exercises may actually be toxic or damaging to vocal fold tissues. In pharmacology, toxicity is a critical concept, yet it is rarely considered in voice therapy, with little known regarding 'effective' concentrations of specific voice therapies vs 'toxic' concentrations. The potential for vocal fold tissue damage related to overdosing on specific vocal exercises has been under-studied. In this commentary, the issue of dosing will be explored within the context of voice therapy, with particular emphasis placed on possible 'overdosing'. [ABSTRACT FROM AUTHOR]

Background: intravenous (IV) drugs are administered widely and under-dosing can result in therapy failure. The aim of this study was to quantify frequency, volume and dose of drug discarded within administration sets in the clinical setting. Methods: residual volume for 24 different administration sets was measured under controlled conditions in a laboratory. Clinical assessment of current practice regarding post-infusion flushing occurred in 6 departments of one teaching hospital in the UK over 7 days. Details of drug last infused, (concentration, diluent and volume) and type and brand of administration set were collected. Results: 74% of administration sets were not flushed. Non-flushing exceeded 90% and 61% for gravity and pump infusions respectively (p<0.001) in all areas excluding oncology. Oncology was the only area where flushing was standard practice for all infusions (p<0.001). Mean residual volume of the administration sets was 13.1 ml and 16.7 ml for gravity and pump sets respectively. Antibiotics were commonly infused and up to 21% of antibiotic dose was frequently discarded. Conclusions: the findings suggest disposal of substantial volumes of drugs occurs frequently in general hospital areas. Without clear national and local policies this unrecognised under-dosing will continue. [ABSTRACT FROM AUTHOR]