Pharmacokinetics and safety of intravitreally delivered etanercept

Background The anti-inflammatory drug etanercept may be an effective therapeutic agent in diabetic retinopathy. In order to further evaluate its potential, the pharmacokinetics and safety of this drug after intravitreal delivery were investigated.Methods After intravitreal administration of etanercept in rabbits, clinical examination, electroretinography (ERG), visually evoked potentials (VEP) and histology were evaluated. The pharmacokinetics and distribution of etanercept were analyzed using fluorescence-coupled protein at 0, 2, 4, and 8 weeks after injection in vitreous, retina, and choroid.Results No adverse effects and signs of toxicity were found. Etanercept showed peak concentrations after 4 weeks in the retina and choroid.Conclusions Intravitreally delivered etanercept is safe and results in high concentrations in the retina and choroid over a long period of time.     

Effectiveness of Scapular Stabilization Versus Non-Stabilization Stretching on Shoulder Range of Motion,a Randomized Clinical Trial

BackgroundPrevious research has demonstrated the benefits of both stabilization and non-stabilization of the scapula during stretching in individuals with posterior shoulder tightness, but limited evidence exists in patients with shoulder pain.Hypothesis/PurposeThe aim of this study was to determine the effect of stabilized scapular stretching on patients with shoulder pain. The primary hypothesis of this study is that stabilized scapular stretching will improve glenohumeral motion and pain compared to non-stabilized stretch program. A secondary hypothesis of this study is that stabilized scapular stretching will produce greater improvement in function compared to the non-stabilized stretching program.Study DesignRandomized Clinical TrialMethodsSixteen patients with sub-acromial pain associated with tendinopathy and associated pathologies presenting to physical therapy were randomized into two groups (stabilized or non-stabilized scapular stretching). Baseline pain and range of motion were measured prior to and following each treatment session for three visits that occurred over the course five to seventeen days depending on the patients availability. The dependent measurements were stabilized horizontal adduction, stabilized internal rotation, stabilized shoulder flexion, non-stabilized shoulder flexion, and current pain level.ResultsPatients in the scapular stabilization stretching group increased horizontal adduction 40° (CI₉₅ 31, 48°) compared to the non-stabilization stretching group increase of 8° (CI₉₅ 0, 17°) over the course of the three treatments (p<0.001). Similarly, the stabilized stretching group increased internal rotation 48° (CI₉₅ 26, 69°) compared to the non-stabilized stretching group increase of 26° (CI₉₅ 4, 48°) (p=0.001). Pain decreased in the stabilized stretching group by 1.4 points (CI₉₅ -0.4, 3.2) but increased slightly in non-stabilized group by -0.5 points (CI₉₅ -2.3, 1.3) which was not a clinically meaningful change. (p=0.03)ConclusionStabilized scapular stretching was more effective than non-stabilized stretching at gaining shoulder mobility in patients with shoulder pain. Benefits were immediate and sustained between treatment sessions. Stretching interventions improved range of motion but had limited effect on shoulder pain.Level of Evidence2     

Endovascular treatment of traumatic aortic rupture using iliac extension stent-grafts in patients with small aortic diameters

Open in a separate window OBJECTIVESTo evaluate outcomes after thoracic endovascular aortic repair in young patients sustaining traumatic blunt aortic injury (BAI) using iliac extension stent-grafts because of small aortic diameters measuring <24 mm.METHODSRetrospective analysis regarding clinical presentation, trauma management, endovascular techniques and outcome of patients with a small descending aorta involving an iliac extension stent-graft to treat traumatic BAI.RESULTSAmong 48 patients who suffered a BAI and underwent thoracic endovascular aortic repair, 7 received iliac extension stent-grafts. They were 27.4/[standard deviation (SD): −13.1] years old and 6 out of 7 were male. The iliac extension stent-graft was used as distal stent-graft, and a thoracic stent-graft was used in most patients as proximal extension. We achieved overall technical success in all patients during a procedure lasting 92.6 (SD: 54.9) min. One patient died 2 days after the endovascular procedure of hypoxic brain injury, and another died after 17 days of liver failure. That patient had also suffered a spinal cord injury following the procedure, as the stent-graft had been deployed in Ishimaru Zone 2, and the carotid to subclavian bypass had to be omitted because of his critical condition. Control computed tomographic angiographs was available in 6 patients after 7.7 (SD: 5.1) days and showed no endoleak. The surviving patients were discharged after 18.4 (SD: 13.4) days.CONCLUSIONSTreating traumatic BAI using iliac extension stent-grafts in young patients with small aortic diameters is feasible. We observed no mortality caused by the BAI or related to endovascular therapy within this small patient cohort.     

Characterization of Healthcare-Associated and Community-Associated Clostridioides difficile Infections among Adults,Canada, 2015–2019

We investigated epidemiologic and molecular characteristics of healthcare-associated (HA) and community-associated (CA) Clostridioides difficile infection (CDI) among adult patients in Canadian Nosocomial Infection Surveillance Program hospitals during 2015–2019. The study encompassed 18,455 CDI cases, 13,735 (74.4%) HA and 4,720 (25.6%) CA. During 2015–2019, HA CDI rates decreased by 23.8%, whereas CA decreased by 18.8%. HA CDI was significantly associated with increased 30-day all-cause mortality as compared with CA CDI (p<0.01). Of 2,506 isolates analyzed, the most common ribotypes (RTs) were RT027, RT106, RT014, and RT020. RT027 was more often associated with CDI-attributable death than was non-RT027, regardless of acquisition type. Overall resistance C. difficile rates were similar for all drugs tested except moxifloxacin. Adult HA and CA CDI rates have declined, coinciding with changes in prevalence of RT027 and RT106. Infection prevention and control and continued national surveillance are integral to clarifying CDI epidemiology, investigation, and control.     

How we make choices and sacrifices in medical education during the COVID-19 pandemic

Abstract

In this commentary, we highlight some of the pressing choices and sacrifices we must make in medical education during the COVID-19 pandemic.     

Value of non-clinical cardiac repolarization assays in supporting the discovery and development of safer medicines

Non-clinical QT-related assays aligned to the pharmaceutical drug discovery and development phases are used in several ways. During the early discovery phases, assays are used for hazard identification and wherever possible for hazard elimination. The data generated enable us to: (i) establish structure–activity relationships and thereby; (ii) influence the medicinal chemistry design and provide tools for effective decision making; and provide structure–activity data for in silico predictive databases; (iii) solve problems earlier; (iv) provide reassurance for compound or project to progress; and (v) refine strategies as scientific and technical knowledge grows. For compounds progressing into pre-clinical development, the ‘core battery’ QT-related data enable an integrated risk assessment to: (i) fulfil regulatory requirements; (ii) assess the safety and risk–benefit for compound progression to man; (iii) contribute to defining the starting dose during the phase I clinical trials; (iv) influence the design of the phase I clinical trials; (v) identify clinically relevant safety biomarkers; and (vi) contribute to the patient risk management plan. Once a compound progresses into clinical development, QT-related data can be applied in the context of risk management and risk mitigation. The data from ‘follow-up’ studies can be used to: (i) support regulatory approval; (ii) investigate discrepancies that may have emerged within and/or between non-clinical and clinical data; (iii) understand the mechanism of an undesirable pharmacodynamic effect; (iv) provide reassurance for progression into multiple dosing in humans and/or large-scale clinical trials; and (v) assess drug–drug interactions. Based on emerging data, the integrated risk assessment is then reviewed in this article, and the benefit–risk for compound progression was re-assessed. Project examples are provided to illustrate the impact of non-clinical data to support compound progression throughout the drug discovery and development phases, and regulatory approval.This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010