Pharmacokinetic properties of remimazolam in subjects with hepatic or renal impairment

BACKGROUND: Remimazolam is a new benzodiazepine for procedural sedation and general anaesthesia. The aim of this study was to characterise its pharmacokinetic properties and safety in renally and hepatically impaired subjects. METHODS: Two separate trials were conducted in patients with hepatic (n=11) or renal impairment (n=11) compared with matched healthy subjects (n=9 and n=12, respectively). The hepatic impairment trial was an open-label adaptive 'Reduced Design' trial, using a single bolus of remimazolam 0.1 mg kg-1 i.v., whereas the renal impairment trial was an open-label trial of a single bolus dose of remimazolam 1.5 mg i.v. Remimazolam plasma concentrations over time were analysed by population pharmacokinetic modelling. RESULTS: Remimazolam pharmacokinetic properties were adequately described by a three-compartment, recirculatory model. Exposure in subjects with severe hepatic impairment was 38.1% higher (i.e. clearance was 38.1% lower) compared with healthy volunteers. This increase caused a slightly delayed recovery (8.0 min for healthy, 12.1 min for moderate, and 16.7 min for severe hepatic impairment). With renal impairment, plasma clearance was comparable with that measured in healthy subjects. Simulations of Cmax after a bolus dose of 10 mg showed no relevant impact of hepatic or renal impairment. The overall incidence of adverse events was low, and all adverse events were mild. CONCLUSIONS: As Cmax after a remimazolam bolus i.v. was not affected by hepatic or renal impairment, no dose adjustments are required. No unexpected adverse events related to remimazolam were seen in subjects with renal or hepatic impairment. CLINICAL TRIAL REGISTRATION: Hepatic impairment trial: ClinicalTrials.gov, NCT01790607 (https://clinicaltrials.gov/ct2/show/NCT01790607). Renal impairment trial: EudraCT Number: 2014-004575-23

The trade-off between taxi time and fuel consumption in airport ground movement

Environmental impact is a very important agenda item in many sectors nowadays, which the air transportation sector is also trying to reduce as much as possible. One area which has remained relatively unexplored in this context is the ground movement problem for aircraft on the airport’s surface. Aircraft have to be routed from a gate to a runway and vice versa and it is still unknown whether fuel burn and environmental impact reductions will best result from purely minimising the taxi times or whether it is also important to avoid multiple acceleration phases. This paper presents a newly developed multi-objective approach for analysing the trade-off between taxi time and fuel consumption during taxiing. The approach consists of a combination of a graph-based routing algorithm and a population adaptive immune algorithm to discover different speed profiles of aircraft. Analysis with data from a European hub airport has highlighted the impressive performance of the new approach. Furthermore, it is shown that the trade-off between taxi time and fuel consumption is very sensitive to the fuel-related objective function which is used

Towards policies that capture the expected value of biomolecular diversity for drug discovery, human health, and well-being

This paper aims to help policy makers with a characterization of the intrinsic value of biodiversity and its role as a critical foundation for sustainable development, human health, and well-being. Our objective is to highlight the urgent need to overcome economic, disciplinary, national, cultural, and regional barriers, in order to work out innovative measures to create a sustainable future and prevent the mutual extinction of humans and other species. We emphasize the pervasive neglect paid to the cross-dependency of planetary health, the health of individual human beings and other species. It is critical that social and natural sciences are taken into account as key contributors to forming policies related to biodiversity, conservation, and health management. We are reaching the target date of Nagoya treaty signatories to have accomplished measures to prevent biodiversity loss, providing a unique opportunity for policy makers to make necessary adjustments and refocus targets for the next decade. We propose recommendations for policy makers to explore novel avenues to halt the accelerated global loss of biodiversity. Beyond the critical ecological functions biodiversity performs, its enormous untapped the repertoire of natural molecular diversity is needed for solving accelerating global healthcare challenges

Chronic kidney disease and neurological disorders: are uraemic toxins the missing piece of the puzzle?

Chronic kidney disease (CKD) perturbs the crosstalk with others organs, with the interaction between the kidneys and the heart having been studied most intensively. However, a growing body of data indicates that there is an association between kidney dysfunction and disorders of the central nervous system. In epidemiological studies, CKD is associated with a high prevalence of neurological complications, such as cerebrovascular disorders, movement disorders, cognitive impairment and depression. Along with traditional cardiovascular risk factors (such as diabetes, inflammation, hypertension and dyslipidaemia), non-traditional risk factors related to kidney damage (such as uraemic toxins) may predispose patients with CKD to neurological disorders. There is increasing evidence to show that uraemic toxins, for example indoxyl sulphate, have a neurotoxic effect. A better understanding of factors responsible for the elevated prevalence of neurological disorders among patients with CKD might facilitate the development of novel treatments. Here, we review (i) the potential clinical impact of CKD on cerebrovascular and neurological complications, (ii) the mechanisms underlying the uraemic toxins' putative action (based on pre-clinical and clinical research) and (iii) the potential impact of these findings on patient care

Acidosis, cognitive dysfunction and motor impairments in patients with kidney disease

Metabolic acidosis, defined as a plasma or serum bicarbonate concentration <22 mmol/L, is a frequent consequence of chronic kidney disease (CKD) and occurs in ~10-30% of patients with advanced stages of CKD. Likewise, in patients with a kidney transplant, prevalence rates of metabolic acidosis range from 20% to 50%. CKD has recently been associated with cognitive dysfunction, including mild cognitive impairment with memory and attention deficits, reduced executive functions and morphological damage detectable with imaging. Also, impaired motor functions and loss of muscle strength are often found in patients with advanced CKD, which in part may be attributed to altered central nervous system (CNS) functions. While the exact mechanisms of how CKD may cause cognitive dysfunction and reduced motor functions are still debated, recent data point towards the possibility that acidosis is one modifiable contributor to cognitive dysfunction. This review summarizes recent evidence for an association between acidosis and cognitive dysfunction in patients with CKD and discusses potential mechanisms by which acidosis may impact CNS functions. The review also identifies important open questions to be answered to improve prevention and therapy of cognitive dysfunction in the setting of metabolic acidosis in patients with CKD

Measurements of molecular-frame Auger electron angular distributions at the CO C 1s(-1) 2 pi* resonance with high energy resolution

The molecular-frame Auger electron angular distributions (MFAEADs) of resonantly excited CO 1s -> pi molecules in the gas phase were determined with high energy resolution using a novel experimental approach. We investigated the process of excitation, Auger decay and fragmentation in unprecedented detail. We confirmed theoretical predictions for the different MFAEADs of close lying Auger final states. By examining the dependence of the MFAEADs on the vibrational state of the excitation and on the fragmentation energy we found that the measured MFAEADs can be considered independent of the vibrational excitation and the fragmentation process. The method used to obtain molecular-frame angular distributions of Auger electrons is based on electron-ion coincidence measurements using two high-resolution electron spectrometers with limited acceptance angles mounted at fixed positions

Science and Management of Intermittent Rivers and Ephemeral Streams (SMIRES)

More than half of the global river network is composed of intermittent rivers and ephemeral streams (IRES), which are expanding in response to climate change and increasing water demands. After years of obscurity, the science of IRES has bloomed recently and it is being recognised that IRES support a unique and high biodiversity, provide essential ecosystem services and are functionally part of river networks and groundwater systems. However, they still lack protective and adequate management, thereby jeopardizing water resources at the global scale. This Action brings together hydrologists, biogeochemists, ecologists, modellers, environmental economists, social researchers and stakeholders from 14 different countries to develop a research network for synthesising the fragmented, recent knowledge on IRES, improving our understanding of IRES and translating this into a science-based, sustainable management of river networks. Deliverables will be provided through i) research workshops synthesising and addressing key challenges in IRES science, supporting research exchange and educating young researchers, and ii) researcher-stakeholder workshops translating improved knowledge into tangible tools and guidelines for protecting IRES and raising awareness of their importance and value in societal and decision-maker spheres. This Action is organized within six Working Groups to address: (i) the occurrence, distribution and hydrological trends of IRES; (ii) the effects of flow alterations on IRES functions and services; (iii) the interaction of aquatic and terrestrial biogeochemical processes at catchment scale; (iv) the biomonitoring of the ecological status of IRES; (v) synergies in IRES research at the European scale, data assemblage and sharing; (vi) IRES management and advocacy training