Zusammenfassung
Im Mai 2014 wurde im Gesetzblatt der EU die Verordnung Nr. 536/2014 vom 16. April 2014 zu klinischen Prüfungen mit Arzneimitteln veröffentlicht, die zukünftig die bestehende ...Richtlinie 2001/20/EC (Clinical Trials Directive) ersetzen wird. Diese trat mit der 12. AMG-Novelle am 6. August 2004 in Deutschland in Kraft. Aufgrund ihrer Komplexität wird die neue Verordnung, die in allen EU-Mitgliedsstaaten direkt gilt, wohl erst ab Oktober 2018 mit dann ca. 2,5 Jahren Verspätung in Kraft treten. Eines der zentralen Anliegen der neuen Verordnung, ein umfassenderer Zugang zu klinischen Studiendaten, wird allerdings schon in diesem Herbst Realität.
Abstract Aim This article reviews outcomes of marketing authorization applications for anticancer drugs in the EU and outlines factors and hurdles of impact. Methods Procedures for initial approval ...of anticancer and non-cancer drugs were analyzed and compared to anticancer drug approvals in the USA and Japan for the same period. Results From 2006 to 2011, the regulatory review of 46 marketing authorization applications resulted in 29 new cancer drug approvals. The overall approval probability (63%) lagged behind the probability for non-cancer drugs (73%). Longer median active review times in line with additional clock-stop and EU Commission decision-making times as well as submission delays contribute to the 7.2 months median time-to-market delay 95% CI 4.7–15.0 months compared to the USA; Japanese patients had to wait an additional 25.1 months 95% CI 6.2–34.1 months. Conclusion Marketing authorization applications for anticancer drugs in the EU are associated with modest approval success. Patients in the USA get access to new products earlier, fostered by the more frequent use of expedited review procedures. So far, both procedures were used in the EU for applications claiming a major public health interest, characterized by pivotal clinical trial hazard ratios below 0.70.
The historical development of ice nucleating particle concentrations (NINP) is still unknown. Here, we present for the first time NINP from the past 500 years at two Arctic sites derived from ice ...core samples. The samples originate from the EUROCORE ice core (Summit, Central Greenland) and from the Lomo09 ice core (Lomonosovfonna, Svalbard). No long‐term trend is obvious in the measured samples, and the overall range of NINP is comparable to present‐day observations. We observe that the short‐term variations in NINP is larger than the long‐term variability, but neither anthropogenic pollution nor volcanic eruptions seem to have influenced NINP in the measured temperature range. Shape and onset temperature of several INP spectra suggest that INP of biogenic origin contributed to the Arctic INP population throughout the past.
Key Points
No obvious trend of Arctic INP concentrations over the past 500 years is observed
Short‐term variability in INP concentrations is larger than long‐term variation
A contribution of biological sources to the Arctic INP population is likely
Reversible cross-linking is a method of enhancing the mechanical properties of polymeric materials. The inspiration for this kind of cross-linking comes from nature, which uses this strategy in a ...large variety of biological materials to dramatically increase their toughness. Recently, first attempts were made to transfer this principle to technological applications. In this study, Monte Carlo simulations are used to investigate the effect of the number and the topology of reversible cross-links on the mechanical performance of a simple model system. Computational cyclic loading tests are performed, and the work to fracture and the energy dissipation per cycle are determined, which both increase when the density of cross-links is increased. Furthermore, a different topology of the bonds may increase the work to fracture by a factor of more than 2 for the same density. This dependence of the mechanical properties on the topology of the bonds has important implications on the self-healing properties of such systems, because only a fast return of the system to its unloaded state after release of the load ensures that the optimal topology may form.
Carbohydrates, originating from marine microorganisms, enter the atmosphere as part of sea spray aerosol (SSA) and can influence fog and cloud microphysics as cloud condensation nuclei (CCN) or ...ice-nucleating particles (INP). Particularly in the remote Arctic region, significant knowledge gaps persist about the sources, the sea-to-air transfer mechanisms, atmospheric concentrations, and processing of this substantial organic group. In this ship-based field study conducted from May to July 2017 in the Fram Strait, Barents Sea, and central Arctic Ocean, we investigated the sea-to-air transfer of marine combined carbohydrates (CCHO) from concerted measurements of the bulk seawater, the sea surface microlayer (SML), aerosol particles and fog. Our results reveal a wide range of CCHO concentrations in seawater (22–1070 µg L−1), with notable variations among different sea-ice-related sea surface compartments. Enrichment factors in the sea surface microlayer (SML) relative to bulk water exhibited variability in both dissolved (0.4–16) and particulate (0.4–49) phases, with the highest values in the marginal ice zone (MIZ) and aged melt ponds. In the atmosphere, CCHO was detected in super- and submicron aerosol particles (CCHOaer,super: 0.07–2.1 ng m−3; CCHOaer,sub: 0.26–4.4 ng m−3) and fog water (CCHOfog,liquid: 18–22 000 µg L−1; CCHOfog,atmos: 3–4300 ng m−3). Enrichment factors for sea–air transfer varied based on assumed oceanic emission sources. Furthermore, we observed rapid atmospheric aging of CCHO, indicating both biological/enzymatic processes and abiotic degradation. This study highlights the diverse marine emission sources in the Arctic Ocean and the atmospheric processes shaping the chemical composition of aerosol particles and fog.
OBJECTIVESPatients with type-2 diabetes mellitus (T2DM) have increased risk for bone fractures which points towards impaired bone quality. METHODSWe measured bone mineralization density distribution ...(BMDD) and osteocyte lacunae section (OLS) characteristics based on quantitative backscattered electron images of transiliac biopsy samples from n=26 premenopausal women with T2DM. Outcomes were compared to those from reference cohorts as well as between T2DM subgroups defined by clinical characteristics. RESULTSComparison to references did not reveal any differences in BMDD (all p>0.05) but a lowered OLS-density in cancellous bone in T2DM (-14.9%, p<0.001). Neither BMDD nor OLS-characteristics differed in T2DM subgroups defined by HbA1c (<7% versus >7%). The average degree of bone mineralization (CaMean) was higher (0.44 wt%Ca in T2DM, 0.30 wt%Ca in reference) and consistently the calcium concentration between the tetracycline double labels (CaYoung) was higher (0.76 wt%Ca, all p<0.001) in cancellous versus cortical bone. CONCLUSIONSOur findings suggest that bone matrix mineralization was neither affected by the presence nor by the glycemic control of T2DM in our study cohort. The intra-individual differences between cancellous and cortical bone mineralization gave evidence for differences in the time course of the early mineralization process in these compartments in general.
Aims/hypothesis
The metabolic syndrome is a cluster of risk correlates that can progress to type 2 diabetes. The present study aims to evaluate a novel molecule with a dual action against the ...metabolic syndrome and type 2 diabetes.
Methods
We developed and tested a novel dual modulator, RB394, which acts as a soluble epoxide hydrolase (sEH) inhibitor and a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist in rat models of the metabolic syndrome—the obese spontaneously hypertensive (SHROB) rat and the obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat. In SHROB rats we studied the ability of RB394 to prevent metabolic syndrome phenotypes, while in ZSF1 obese diabetic rats we compared RB394 with the ACE inhibitor enalapril in the treatment of type 2 diabetes and associated comorbid conditions. RB394 (10 mg/kg daily) and enalapril (10 mg/kg daily) were administered orally for 8 weeks.
Results
RB394 blunted the development of hypertension, insulin resistance, hyperlipidaemia and kidney injury in SHROB rats and reduced fasting blood glucose and HbA
1c
, improved glucose tolerance, reduced blood pressure and improved lipid profiles in obese ZSF1 rats. A reduction in liver fibrosis and hepatosteatosis was evident in RB394-treated obese ZSF1 rats. Unlike RB394, enalapril did not demonstrate any positive effects in relation to diabetes, hyperlipidaemia or liver dysfunction in obese ZSF1 rats. RB394 ameliorated diabetic nephropathy by reducing renal interstitial fibrosis and renal tubular and glomerular injury in obese diabetic ZSF1 rats. Intriguingly, enalapril demonstrated a weaker action against diabetic nephropathy in obese ZSF1 rats.
Conclusions/interpretation
These findings demonstrate that a novel sHE inhibitor/PPAR-γ agonist molecule targets multiple risk factors of the metabolic syndrome and is a glucose-lowering agent with a strong ability to treat diabetic complications.
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