Pharmacokinetic profile of nomegestrol acetate and 17β-estradiol after multiple and single dosing in healthy women

BackgroundThe pharmacokinetics of the monophasic oral contraceptive nomegestrol acetate (NOMAC) plus 17β-estradiol (E₂) were investigated after a single dose and multiple dosing.Study designNOMAC/E₂ (2.5 mg/1.5 mg) was administered daily to healthy women (18–50 years, n= 23) for 24 days; blood samples for pharmacokinetic analysis were obtained on Day 24 and again, after a 10-day pill-free interval, on Day 35 after a single dose.ResultsNOMAC reached steady state after 5 days with mean ± standard deviation (SD) trough NOMAC concentration (C_av) of 4.4±1.4 ng/mL. On Day 24, mean±SD peak NOMAC concentration (C_max, 12.3±3.5 ng/mL) was reached in mean 1.5 h (t_max); the mean±SD elimination half-life (t_½) was 45.9±15.3 h. After a single dose, NOMAC mean±SD C_max was 7.2±2.0 ng/mL and mean±SD t_½ was 41.9±16.2 h. On Day 24, E₂ mean±SD C_av was 50.3±25.7 pg/mL; mean±SD C_max was 86.0±51.3 pg/mL. After a single dose, mean±SD E₂ C_max was 253±179 pg/mL.ConclusionsThese data demonstrate that NOMAC/E₂ has a pharmacokinetic profile consistent with once-daily dosing.     

Schulungsmaterial zur Minimierung von Arzneimittelrisiken

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Schulungsmaterial für Heilberufler und Patienten stellt eine wichtige Hilfe bei der sicheren Anwendung bestimmter...     

Glutathionylated Lipid Aldehydes Are Products of Adipocyte Oxidative Stress and Activators of Macrophage Inflammation

Obesity-induced insulin resistance has been linked to adipose tissue lipid aldehyde production and protein carbonylation. Trans-4-hydroxy-2-nonenal (4-HNE) is the most abundant lipid aldehyde in murine adipose tissue and is metabolized by glutathione S-transferase A4 (GSTA4), producing glutathionyl-HNE (GS-HNE) and its metabolite glutathionyl-1,4-dihydroxynonene (GS-DHN). The objective of this study was to evaluate adipocyte production of GS-HNE and GS-DHN and their effect on macrophage inflammation. Compared with lean controls, GS-HNE and GS-DHN were more abundant in visceral adipose tissue of ob/ob mice and diet-induced obese, insulin-resistant mice. High glucose and oxidative stress induced production of GS-HNE and GS-DHN by 3T3-L1 adipocytes in a GSTA4-dependent manner, and both glutathionylated metabolites induced secretion of tumor necrosis factor-α from RAW 264.7 and primary peritoneal macrophages. Targeted microarray analysis revealed GS-HNE and GS-DHN induced expression of inflammatory genes, including C3, C4b, c-Fos, igtb2, Nfkb1, and Nos2. Transgenic overexpression of GSTA4 in mouse adipose tissue led to increased production of GS-HNE associated with higher fasting glucose levels and moderately impaired glucose tolerance. These results indicated adipocyte oxidative stress results in GSTA4-dependent production of proinflammatory glutathione metabolites, GS-HNE and GS-DHN, which may represent a novel mechanism by which adipocyte dysfunction results in tissue inflammation and insulin resistance.     

Risikostratifizierung und Therapie kardialer Amyloidosen

Cardiac amyloidoses are a heterogeneous group of cardiomyopathies that are resistant to treatment and are associated with a poor outcome. Standard heart failure treatment is usually not well tolerated and the underlying disease remains unaffected. The clinical picture is uncharacteristic. Cardiac amyloidosis is often associated with dysfunction of additional organs. Early cardiac amyloid involvement usually reveals left ventricular hypertrophy, impairment of longitudinal shortening and diastolic ventricular function. Without adequate therapy (bi-)ventricular hypertrophy will progress to severe systolic ventricular function decrease. The combination of low voltage pattern, left ventricular hypertrophy and granular sparkling is characteristic for advanced cardiac amyloid involvement. Cardiac magnetic resonance imaging and scintigraphy yield further information on the pattern and severity of cardiac involvement. In unclear cases (left ventricular) endomyocardial biopsy is necessary. Detection of early cardiac involvement and proper identification of patients at high risk for sudden cardiac death due to rapid progressive amyloidosis is still incompletely defined. Referral to specialized centers is strongly recommended.     

Platelet factor 4 (PF-4)-induced neutrophil adhesion is controlled by src-kinases, whereas PF-4-mediated exocytosis requires the additional activation of p38 MAP kinase and phosphatidylinositol 3-kinase

Among the various chemokines that are functionally active on neutrophils, platelet factor 4 (PF-4; CXCL4) appears to have a specialized role. Lacking typical chemokine activities, PF-4 stimulates neutrophils to undergo firm adhesion to endothelial cells and, in the presence of an appropriate costimulus like tumor necrosis factor (TNF), PF-4 induces exocytosis of secondary granule contents. Analyzing the individual contribution of PF-4 and its costimuli in the control of these functions at the signaling level, we demonstrate that TNF-induced activation of p38 mitogen-activated protein (MAP) kinase (but not extracellular regulated kinase [Erk] kinases) acts as general and essential costimulatory signal in PF-4-dependent neutrophil exocytosis. This was shown by the use of a specific inhibitor (SB203580), by biologic (lipopolysaccharide, N-formyl-methionyl-leucyl-phenylalanine) and pharmacologic (anisomycin) activators of p38 MAP kinase, and by phosphorylation studies. Furthermore, TNF-mediated activation of phosphatidylinositol 3-kinase (PI 3-kinase) represents an additional essential signaling component in this process as demonstrated by studies with its inhibitor wortmannin as well as by analysis of the phosphorylation of AKT kinase. PF-4, however, directly activates src-kinases and PF-4-induced adherence as well as PF-4/TNF-mediated exocytosis was inhibited by an src-kinase inhibitor PP1. Taken together, neutrophil exocytosis and adherence are regulated on p38 MAP kinase, PI 3-kinase, and src-kinase activation.