Алфавитный указатель тома 12 за 2007 г.

Liposomes have proven to be well tolerated drug delivery vehicles that offer the possibility of drug delivery for a wide range of therapeutic agents, for instance for the treatment of rheumatoid arthritis. Optimal liposomal physicochemical properties depend on the administration route: large-sized liposomes show good retention upon local injection, while small-sized liposomes are better suited to achieve passive targeting upon intravenous infusion. PEGylation reduces the uptake of the liposomes by liver and spleen, and increases the circulation time (so-called ‘long-circulating liposomes’), resulting in increased localization at the inflamed sites. The phenomenon of ‘passive targeting’ to pathological sites can be attributed to locally enhanced permeability of the vascular endothelium, allowing long-circulating small-sized PEG-liposomes to extravasate and accumulate in the extravascular tissue, known as the ‘enhanced permeability and retention’ (EPR) effect. Additionally, targeting ligands can be attached to the liposomal surfaces to achieve selective delivery of the encapsulated drug to specific target cells, referred to as ‘active targeting’. Glucocorticoids have proven to be powerful drugs in the treatment of rheumatic diseases.However, the use of glucocorticoids is hampered by unfavorable pharmacokinetic behavior, which necessitates high and frequent dosing to maintain therapeutic levels at sites of inflammation, thereby increasing the risk for severe adverse effects. To improve their therapeutic index, glucocorticoids can be encapsulated in long-circulating liposomes. The work presented in this thesis aims to show that these liposomal glucocorticoids can effectively and safely be used as intravenous targeted drug delivery vehicles for the treatment of rheumatoid arthritis. Selective delivery of a drug to the inflamed joints improved the efficacy, while the systemic exposure of the drug was reduced. As a result of the long-circulating and targeting properties of PEGylated liposomes, the dose level and dosing frequency can likely be reduced dramatically. Optimization of the liposomal glucocorticoid formulation was performed at the level of the encapsulated drug to start with, by selecting glucocorticoids with a high clearance rate to minimize the occurrence of side effects. Second, an attempt was made to reduce the occurrence of hypersensitivity reactions upon infusion of PEGylated liposomes, by changing the PEG profile at the liposomal surface. All formulations tested caused mild activation of the complement system in vitro. One particular formulation, however, wherein the PEG is anchored to cholesterol, turned out to be an extremely strong activator of the complement cascade. Further study of this phenomenon might be useful to elucidate the mechanism behind complement activation by liposomal formulations in general. Lastly, the stability of the liposomal formulation was improved by spray-drying or freeze-drying the formulation, using hydroxypropyl-β-cyclodextrin to stabilize the liposomal membranes during the drying process. The in vivo performance of a liposomal formulation is critically dependent on its physicochemical characteristics. Typically, small changes in one of these characteristics can have a huge impact on the in vivo behavior of the administered liposomes. Therefore, the characterization of the liposomal formulation is of major importance. The work presented in this thesis shows that the characterization procedures and regulation of liposomal drug products leave some room for improvement

Initial properdin binding contributes to alternative pathway activation at the surface of viable and necrotic cells

Transplantation and autoimmunit

Blood and Imaging Biomarkers in the Long-term Follow-up of Bicuspid Aortic Valve Patients

Background: Bicuspid aortic valve (BAV) is a common congenital heart defect. Patients with BAV are at risk for long-term complications such as valve stenosis and regurgitation. This study aimed to investigate sex differences in blood and imaging biomarkers and to describe the long-term prognostic value of blood and echocardiographic biomarkers. Methods:Patients were included from 2 prospective observational cohort studies; they underwent venous blood sampling and transthoracic echocardiography including speckle tracking. Analyzed blood biomarkers were red-cell distribution width (RDW), creatinine, C-reactive protein (CRP), troponin T, N-terminal pro B-type natriuretic peptide (NT-proBNP), and transforming growth factor-beta (TGF-β). Sex differences were analyzed at baseline. Associations between biomarkers and arrhythmia-free and intervention-free survival were determined by Cox regression, adjusted for age and sex. Results:A total of 182 patients with BAV were included: median age 34; interquartile range [IQR]: 23-46 years; 55.5% male. CRP, NT-proBNP, and RDW were higher in women, whereas creatinine, troponin T and TGF-β were higher among men. After a median follow-up time of 6.9 (IQR: 6.5-9.9) years, arrhythmia-free and intervention-free survival was, 81.0% and 73.1%, respectively. NT-proBNP was associated with both arrhythmia-free and intervention-free survival (hazard ratio [HR], 1.94, P = 0.005 and HR, 2.06, P = 0.002, respectively). On echocardiography higher left atrial (LA) size, left ventricular end-diastolic diameter (LVEDD), left ventricular (LV) mass index and E/e’ ratio were associated with lower arrhythmia-free survival, whereas higher LA size, LV mass index, aortic valve peak velocity, and aortic regurgitation were associated with lower intervention-free survival. Conclusions: Differences were observed in blood biomarkers between men and women with BAV. Besides LV systolic parameters, diastolic LV function and NT-proBNP should have a more prominent role as prognostic markers in clinical care.</p