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Background: Regional citrate anticoagulation (RCA) is the preferred continuous kidney replacement therapy (CKRT) anticoagulation strategy for children in the USA. Nafamostat mesilate (NM), a synthetic serine protease, is used widely for CKRT anticoagulation in Japan and Korea. We compared the safety and efficacy of NM to RCA for pediatric CKRT. Methods: Starting June 2019, the most recent 100 medical records of children receiving CKRT with either RCA or NM were reviewed retrospectively, at one children's hospital in Japan (NM) and one in the USA (RCA). The number of hours a single CKRT filter was in use, was the primary outcome. Safety was assessed by bleeding complications for the NM group and citrate toxicity leading to RCA discontinuation or electrolyte imbalance in the RCA group. Results: Eighty patients received NM and 78 patients received RCA. Median filter life was longer for the NM group (NM: 38 [22, 74] vs. RCA: 36 [17, 66] h, p = 0.02). When filter life was censored for discontinuation other than clotting, the 60-h survival rate was higher for RCA (71% vs. 54%). The hazard ratio comparing NM over RCA varied over time (HR 0.7; 0.2–1.5, p = 0.33 at 0 h to HR 5.5; 1.3–23.7, p = 0.334 at 72 h). The lack of difference in filter survival persisted controlling for filter surface area, catheter diameter, and pre-CKRT platelet count. Major bleeding rates did not differ between groups (NM: 5% vs. RCA: 9%). Conclusions: RCA and NM provide satisfactory anticoagulation for CKRT in children with no difference in major bleeding rates. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

Dabigatran etexilate (Pradaxa) is approved in the EU for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) and one or more risk factors. Dabigatran etexilate is a prodrug of dabigatran, a direct inhibitor of thrombin. In patients with NVAF in the phase III RE-LY trial, dabigatran etexilate dosages of 110 and 150 mg twice daily were noninferior to warfarin with regard to the risk of stroke or systemic embolism (primary efficacy endpoint). The higher dosage was associated with a significantly lower risk of stroke or systemic embolism than warfarin, with no significant between-group difference in the risk of major bleeding (primary safety endpoint). Both dosages of dabigatran etexilate were associated with significantly lower rates of haemorrhagic stroke, intracranial bleeding and life-threatening major bleeding than warfarin. Dabigatran etexilate was also effective and generally well tolerated across various patient subgroups. The efficacy and tolerability of dabigatran etexilate was maintained for up to 6.7 years in the RELY-ABLE extension study. Routine anticoagulation monitoring is not required in patients receiving dabigatran etexilate, and it is currently the only non-vitamin K antagonist oral anticoagulant (NOAC) with a specific reversal agent available. Although direct comparisons with other NOACs would be beneficial, dabigatran etexilate is a useful option for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. [ABSTRACT FROM AUTHOR]

Background: Pharmaceuticals are usually granted a marketing authorisation on the basis of randomised controlled trials (RCTs). Occasionally the efficacy of a treatment is assessed without a randomised comparator group (either active or placebo).Objective: To identify and develop a taxonomic account of economic modelling approaches for pharmaceuticals licensed without RCT data.Methods: We searched PubMed, the websites of UK health technology assessment bodies and the International Society for Pharmacoeconomics and Outcomes Research Scientific Presentations Database for assessments of treatments granted a marketing authorisation by the US Food and Drug Administration or European Medicines Agency from January 1999 to May 2014 without RCT data (74 indications). The outcome of interest was the approach to modelling efficacy data.Results: Fifty-one unique models were identified in 29 peer-reviewed articles, 30 health technology appraisals, and 15 International Society for Pharmacoeconomics and Outcomes Research abstracts concerning 30 indications (44 indications had not been modelled). We noted the high rate of non-submission to health technology assessment agencies (28/98). The majority of models (43/51) were based on 'historical controls'-comparisons to previous meta-analysis or pooling of trials (5), individual trials (16), registries/case series (15), or expert opinion (7). Other approaches used the patient as their own control, performed threshold analysis, assumed time on treatment was added to overall survival, or performed cost-minimisation analysis.Conclusions: There is considerable variation in the quality and approach of models constructed for drugs granted a marketing authorisation without a RCT. The most common approach is of a naive comparison to historical data (using other trials/registry data as a control group), which has considerable scope for bias. [ABSTRACT FROM AUTHOR]

Tricaine methanesulfonate (TMS) is an anesthetic that is approved for provisional use in some jurisdictions such as the United States, Canada, and the United Kingdom (UK). Many hatcheries and research studies use TMS to immobilize fish for marking or transport and to suppress sensory systems during invasive procedures. Improper TMS use can decrease fish viability, distort physiological data, or result in mortalities. Because animals may be anesthetized by junior staff or students who may have little experience in fish anesthesia, training in the proper use of TMS may decrease variability in recovery, experimental results and increase fish survival. This document acts as a primer on the use of TMS for anesthetizing juvenile salmonids, with an emphasis on its use in surgical applications. Within, we briefly describe many aspects of TMS including the legal uses for TMS, and what is currently known about the proper storage and preparation of the anesthetic. We outline methods and precautions for administration and changes in fish behavior during progressively deeper anesthesia and discuss the physiological effects of TMS and its potential for compromising fish health. Despite the challenges of working with TMS, it is currently one of the few legal options available in the USA and in other countries until other anesthetics are approved and is an important tool for the intracoelomic implantation of electronic tags in fish. [ABSTRACT FROM AUTHOR]

To encourage the development of drugs for rare diseases, orphan drug legislation has been introduced in the USA (1983) and in the EU (2000). Recent literature discusses factors that may influence the development of new orphan medicinal products in the EU. This study aims to identify predictors for successful marketing authorisation of potential orphan drugs in the EU. A comparison between randomly selected authorised and a matched sample of not-yet-authorised orphan drug designations has been performed. Determinants in the study included characteristics of the indication, of the product and of the sponsor. Data were collected from the public domain only. Orphan drug approval was strongly associated with previous experience of the sponsor in obtaining approval for another orphan drug (OR = 17.3, 95% CI = 5.6–53.1). Furthermore, existing synthetic entities compared to biotechnology products tended to have a higher likelihood of reaching approval status (OR = 3.9, 95% CI = 0.9–16.6). This study showed that experience of a company in developing orphan drugs is an important predictor for subsequent authorisation of other orphan drugs. The same applies for existing (synthetic) molecules, for which much knowledge is available. Further research should be directed towards studying the quality of the clinical development program of those designated orphan medicinal products not reaching approval status. [ABSTRACT FROM AUTHOR]