Pharmakokinetik und Pharmakodynamik von Fumarsäureestern

Das Nutzen/Risiko-Verhältnis von Fumarsäureestern zur Therapie der Psoriasis wird als sehr gut eingestuft. Sowohl die Pharmakokinetik als auch die Pharmakodynamik der Substanzen sind aber bis heute noch nicht vollständig verstanden. Es stellte sich heraus, dass Fumarsäuredimethylester (DMF) der essentielle Bestandteil zur Erzielung des antipsoriatischen Effektes ist. Aufgrund der Tatsache, dass nur das Hydrolyseprodukt Fumarsäuremonomethylester (MMF) im humanem Plasma nach oraler Gabe von DMF nachgewiesen werden konnte, wurde bezüglich der Pharmakokinetik von DMF angenommen, dass es schon im Milieu des Dünndarms vollständig zu MMF verstoffwechselt wird. Mercaptursäure-Derivate sind Abbauprodukte von Glutathion-Konjugaten. Da sowohl DMF als auch MMF als elektrophile Substanzen an Glutathion addieren können, war ein Vorkommen ihrer Mercaptursäuren in vivo möglich. Im Rahmen der vorliegenden Arbeit konnte der Nachweis erbracht werden, dass die Mercaptursäuren von DMF und MMF in humanem Urin auftreten. Die Ergebnisse lassen darauf schließen, dass DMF oral absorbiert wird, im Pfortaderblut anflutet und zum Teil in Form von N-Acetyl-S (1,2 dimethoxy- carbonylethyl)cystein über die Nieren ausgeschieden wird. Die Bindung eines Teils von DMF an intrazelluläres Glutathion unter Bildung von S (1,2 Dimethoxycarbonylethyl)glutathion erfolgt wahrscheinlich schon in den Blutzellen des Pfortaderblutes. Der andere Teil des anflutenden DMF wird zu MMF hydrolysiert, das in vivo zu detektieren ist. Durch diese zwei konkurrierenden Reaktionen wird DMF komplett verstoffwechselt, was wiederum zu nicht detektierbaren Konzentrationen im Plasma führt. Da gezeigt werden konnte, dass DMF in vitro wesentlich stärkere Effekte als MMF induziert, kann auf eine Hauptwirkung von DMF durch dessen Einfluß auf den Glutathiongehalt von Immunzellen des Pfortaderblutes geschlossen werden

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations

Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-Adjusted life-years for 29 cancer groups, 1990 to 2017 : A systematic analysis for the global burden of disease study

Importance: Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. Objective: To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. Evidence Review: We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-Adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. Findings: In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572000 deaths and 15.2 million DALYs), and stomach cancer (542000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601000 deaths and 17.4 million DALYs), TBL cancer (596000 deaths and 12.6 million DALYs), and colorectal cancer (414000 deaths and 8.3 million DALYs). Conclusions and Relevance: The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care. © 2019 American Medical Association. All rights reserved.Peer reviewe