Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns : impact of design optimisation

Purpose: There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. Methods: A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a first-in-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. Results: Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. Conclusions: The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population

Coronary Vascular (DYS) Function and Invasive Physiology Assessment:Insights into Bolus and Continuous Thermodilution Methods

A considerable number of patients with angina or myocardial ischemia have no significant coronary artery disease on invasive angiography. In recent years, several steps towards a better comprehension of the pathophysiology of these conditions, angina or ischemia with non-obstructive coronary arteries (ANOCA/INOCA), have been made. Nevertheless, several gaps in knowledge still remain. This review is intended to provide a comprehensive overview of ANOCA and INOCA, with a particular focus on pathophysiology, recent diagnostic innovations, gaps in knowledge and treatment modalities.</p

Coronary Vascular (DYS) Function and Invasive Physiology Assessment:Insights into Bolus and Continuous Thermodilution Methods

A considerable number of patients with angina or myocardial ischemia have no significant coronary artery disease on invasive angiography. In recent years, several steps towards a better comprehension of the pathophysiology of these conditions, angina or ischemia with non-obstructive coronary arteries (ANOCA/INOCA), have been made. Nevertheless, several gaps in knowledge still remain. This review is intended to provide a comprehensive overview of ANOCA and INOCA, with a particular focus on pathophysiology, recent diagnostic innovations, gaps in knowledge and treatment modalities.</p

Modulating local airway immune responses to treat allergic asthma: lessons from experimental models and human studies

With asthma affecting over 300 million individuals world-wide and estimated to affect 400 million by 2025, developing effective, long-lasting therapeutics is essential. Allergic asthma, where Th2-type immunity plays a central role, represents 90% of child and 50% of adult asthma cases. Research based largely on animal models of allergic disease have led to the generation of a novel class of drugs, so-called biologicals, that target essential components of Th2-type inflammation. Although highly efficient in subclasses of patients, these biologicals and other existing medication only target the symptomatic stage of asthma and when therapy is ceased, a flare-up of the disease is often observed. Therefore, it is suggested to target earlier stages in the inflammatory cascade underlying allergic airway inflammation and to focus on changing and redirecting the initiation of type 2 inflammatory responses against allergens and certain viral agents. This focus on upstream aspects of innate immunity that drive development of Th2-type immunity is expected to have longer-lasting and disease-modifying effects, and may potentially lead to a cure for asthma. This review highlights the current understanding of the contribution of local innate immune elements in the development and maintenance of inflammatory airway responses and discusses available leads for successful targeting of those pathways for future therapeutics

Everolimus- and sirolimus-eluting stents in patients with and without ST-segment elevation myocardial infarction

Aims Everolimus-eluting stents (EES) were superior to sirolimus-eluting stents (SES) in a dedicated myocardial infarction trial, a finding that was not observed in trials with low percentages of ST-elevation myocardial infarction (STEMI). Therefore, this study sought to investigate the influence of clinical presentation on outcome after EES and SES implantation. Methods A pooled population of 1602 randomised patients was formed from XAMI (acute MI trial) and APPENDIXAMI (all-comer trial). Primary outcome was cardiac mortality, MI and target vessel revascularisation at 2 years. Secondary endpoints included definite/probable stent thrombosis (ST). Adjustment was done using Cox regression. Results In total, 902 EES and 700 SES patientswere included, of which 44%STEMI patients (EES 455; SES 257) and 56% without STEMI (EES 447; SES 443). In the pooled population, EES and SES showed similar outcomes during followup. Moreover, no differences in the endpoints were observed after stratification according to presentation. Although a trend toward reduced early definite/probable ST was observed in EES compared with SES in STEMI patients, long-term ST rates were low and comparable. Conclusions EES and SES showed a similar outcome during 2-year follow-up, regardless of clinical presentation. Longterm safety was excellent for both devices, despite wide inclusion criteria and a large sub-population of STEMI patients

Second-Generation Everolimus-Eluting Stents Versus First-Generation Sirolimus-Eluting Stents in Acute Myocardial Infarction 1-Year Results of the Randomized XAMI (XienceV Stent vs. Cypher Stent in Primary PCI for Acute Myocardial Infarction) Trial

ObjectivesThe goal of this study was to compare the efficacy and safety of second-generation everolimus-eluting stents (EES) with first-generation sirolimus-eluting stents (SES) in primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI).BackgroundDrug-eluting stents (DES) in AMI are still feared for possible late and very late stent thrombosis (ST). Newer-generation DES, with more hemocompatible polymers and improved healing, may show promise regarding increased efficacy of DES with improved safety. However, no randomized trials in AMI are available.MethodsA total of 625 patients with AMI were randomized (2:1) to receive EES or SES in the XAMI (XienceV Stent vs Cypher Stent in Primary PCI for Acute Myocardial Infarction) trial. Primary endpoint was major adverse cardiac events (MACE) at 1 year consisting of cardiac death, nonfatal AMI, or any target vessel revascularization. The study was powered for noninferiority of EES. Secondary endpoints comprised ST rates and MACE rate up to 3 years.ResultsThe MACE rate was 4.0% for EES and 7.7% for SES; the absolute difference was −3.7% (95% confidence interval: −8.28 to −0.03; p = 0.048) and relative risk was 0.52 (95% confidence interval: 0.27 to 1.00). One-year cardiac mortality was low at 1.5% for EES versus 2.7% for SES (p = 0.36), and 1-year incidence of definite and/or probable ST was 1.2% for EES versus 2.7% for SES (p = 0.21).ConclusionsIn this all-comer, randomized, multicenter AMI trial, second-generation EES was noninferior to SES, and superiority for MACE was suggested. ST rate in EES at 1-year was low, but long-term follow-up and larger studies will have to show whether very late ST rates will also be improved in newer DES. (XienceV Stent vs Cypher Stent in Primary PCI for Acute Myocardial Infarction [XAMI]; NTR1123