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Agency: European Commission | Branch: H2020 | Program: RIA | Phase: PHC-17-2014 | Award Amount: 6.77M | Year: 2015

While Cardiovascular diseases (CVD) are the main cause of death worldwide, they are responsible for half of all deaths in Europe. The overall ageing of the European population and improving survival of patients with coronary heart disease has created a large population of older adults eligible for secondary prevention. Despite the established efficacy of cardiovascular medications, suboptimal adherence reduces their effectiveness and is the primary reason for suboptimal clinical benefit, contributing significantly to worsening of diseases and deaths at the population level. SECURE will be the first trial testing the efficacy of a fixed dose combination (FDC) polypill for secondary cardiovascular prevention in the elderly population ( 65 years old). The main objective is to evaluate the potential benefit of the FDC as a component of a cost-effective, globally available and comprehensive treatment strategy for secondary prevention of cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, stroke, and hospitalisation requiring revascularisation) as compared to standard therapy (the three components of the polypill given separately). As part of the secondary endpoints, SECURE will compare the effect of both strategies on adherence and intermediate measures of risk factor control such as lipids and blood pressure. Importantly, it will also measure the pharmacoeconomic impact of the FDC intervention as well as regional differences in all outcomes. The five-year project will thus involve subjects from seven different countries: Spain, Italy, France, Germany, Hungary, Poland and the Czech Republic. The findings and conclusions obtained in SECURE will allow the drafting of clinical guidelines and recommendations that will provide useful guidance and will serve as a reference framework for all stakeholders involved in tackling major challenges related to secondary prevention and treatment of chronic diseases in the elderly population.

Patients with cardiovascular risk factors, e.g. hypertension and obesity are at risk of developing heart failure with preserved ejection fraction (HFpEF), a highly prevalent disease in the elderly, mostly women population. There is currently no specific, defined treatment for HFpEF, beyond control of risk factors. Activation of cardiac and vascular Beta3-adrenergic receptors (B3AR) represents a new concept and a novel target for structural cardiac disease. B3AR expression and coupling were demonstrated in human myocardium and vasculature. In pre-clinical models with expression of the human receptor, its activation attenuates myocardial remodelling, i.e. decreases hypertrophy and fibrosis in response to neurohormonal or hemodynamic stress. Mirabegron is a new agonist of B3AR available for human use, that was recently introduced for a non-cardiovascular indication (overactive bladder disease). The primary objective of the project is to design and implement a multi-centric, prospective, randomized, placebo-controlled clinical trial testing the additional beneficial effect of mirabegron, versus placebo over 12 months on top of standard treatment of patients carrying structural cardiac disease without overt heart failure (stage B of AHA classification); the co-primary end-point will be the quantitative change in myocardial hypertrophy measured by cardiac MRI; and in diastolic ventricular function, measured by Doppler echocardiography (E/E); in addition, exercise tolerance (peak VO2) will be measured as well as circulating biomarkers reflecting both myocardial remodeling and function. In addition, we will test the effect of mirabegron on beige/brown fat activation and metabolism. Our proposal therefore combines a major conceptual advance and repurposing of an original drug to validate pre-clinical discoveries in the context of a major health problem.

Kosmala W.,Wroclaw Medical University | Kosmala W.,University of Tasmania | Jellis C.L.,Cleveland Clinic | Marwick T.H.,University of Tasmania
Journal of the American College of Cardiology | Year: 2015

Background Stage B heart failure (SBHF) describes asymptomatic ventricular disease that may presage the development of heart failure (HF) symptoms. This entity has been largely defined by structural changes; the roles of sensitive indicators of nonischemic left ventricular (LV) dysfunction, such as LV strain, are undefined. Objectives This study sought to define the association of exercise capacity with left ventricular hypertrophy (LVH) and systolic/diastolic dysfunction in asymptomatic patients with HF risk factors. Methods We used echocardiography to study 510 asymptomatic patients (age 58 ± 12 years) with type 2 diabetes mellitus, hypertension, or obesity. The results of cardiopulmonary exercise testing in patients with structural evidence of SBHF were compared with those in patients with subclinical dysfunction, defined by reduced LV strain (>-18%) or increased LV filling pressure (E/e′ >13). Results Compared with healthy subjects, groups with LV abnormalities differed in terms of oxygen uptake (peak VO2): 25.5 ± 8.2 versus 21.0 ± 8.2 for strain >-18% (p < 0.001); 26.4 ± 8.0 versus 19.0 ± 7.2 for E/e′ >13 (p < 0.0001); and 26.0 ± 7.7 versus 15.9 ± 6.9 ml/kg/min for LVH (p < 0.0001). SBHF, defined as ≥1 imaging variable present, was associated with lower peak VO2 (beta = -0.20; p < 0.0001) and metabolic equivalents (beta = -0.21; p < 0.0001), independent of higher body mass index and insulin resistance, older age, male sex, and treatment with beta-blockers. Conclusions LVH, elevated LV filling pressure, and abnormal myocardial deformation were independently associated with impaired exercise capacity. Including functional markers may improve identification of SBHF in nonischemic heart disease. © 2015 American College of Cardiology Foundation.

Jutel M.,Wroclaw Medical University | Akdis C.A.,University of Zürich
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2011

The studies on the mechanisms of specific immunotherapy (SIT) point out its targets that decide on the efficacy of SIT and hence might be used for its further improvement. Several mechanisms have been proposed to explain the beneficial effects of immunotherapy. The knowledge of the mechanisms underlying allergic diseases and curative treatment possibilities has experienced exciting advances over the last three decades. Studies in several clinical trials in allergen-SIT have demonstrated that the induction of a tolerant state against allergens in many ways represents a key step in the development of a healthy immune response against allergens. Several cellular and molecular mechanisms have been demonstrated: allergen-specific suppressive capacities of both inducible subsets of CD4 + CD25 + forkhead box P3 + T-regulatory and IL-10-secreting type 1 T-regulatory cells increase in peripheral blood; suppression of eosinophils, mast cells, and basophils; Ab isotype change from IgE to IgG4. This review aims at the better understanding of the observed immunological changes associated with allergen SIT. © 2011 John Wiley & Sons A/S.

Galezowska J.,Wroclaw Medical University | Gumienna-Kontecka E.,Wrocław University
Coordination Chemistry Reviews | Year: 2012

This review provides a summary of the coordination chemistry of mono-, bis- and polyphosphonates, as well as of their functionalized analogues. Specific interactions with various metal ions will be discussed in the context of their biological, biomedical and nanotechnological applications. Several complexes will be shown to reveal a spectacular spectrum of possibilities, which the phosphonate moiety gives to coordination chemistry.We would like to show a link between coordination properties and unique functionality of particular phosphonate complexes which were developed and successfully applied in different branches of biological science. © 2011 Elsevier B.V.

Worldwide, approximately 2 billion people are chronically infected with Toxoplasma gondii with largely yet unknown consequences. Patients with autism spectrum disorders (ASD) similarly as mice with chronic toxoplasmosis have persistent neuroinflammation, hypercytokinemia with hypermetabolism associated with enhanced lipid peroxidation, and extreme changes in the weight resulting in obesity or wasting. Data presented in this review suggest that environmental triggering factors such as pregnancy, viral/bacterial infections, vaccinations, medications, and other substances caused reactivation of latent cerebral toxoplasmosis because of changes in intensity of latent central nervous system T. gondii infection/inflammation and finally resulted in development of ASD. Examples of such environmental factors together with their respective biomarker abnormalities are: pregnancy (increased NO, IL-1β, TNF-α, IL-6, IL-10, prolactin; decreased IFN-γ, IL-12), neuroborreliosis (increased IL-1β, sIL-1R2, TNF-α, IFN-γ, IL-6, IL-10, IL-12, IL-18, transforming growth factor-β1 (TGF-β1)), viral infections (increased IL-1β, IL-6, IL-8, TNF-α, IFN-γ/α/β, TGF-β1), thimerosal (increased IL-5, IL-13; decreased IFN-γ, TNF-α, IL-6, IL-12p70, NOS), and valproic acid (increased NO, reactive oxygen species; decreased TNF-α, IL-6, IFN-γ). The imbalances in pro- and antiinflammatory processes could markedly hinder host defense mechanisms important for immune control of the parasite, such as the production of NO, cytokines, and reactive oxygen/nitrogen species, tryptophan degradation by indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase, limitation of the availability of intracellular iron to T. gondii, and the mechanisms mediated by an IFN-γ responsive gene family. These fluctuations could result in a recurrent profuse multiplication of T. gondii in the brain associated with persistent neuroinflammation, chronic overproduction of pro- and antiinflammatory cytokines, and NO causing increased oxidative stress, and significantly depressed activity of several enzymes including cytochrome P450 monooxygenase family responsible for metabolism of physiological substrates and xenobiotics, such as steroids, fatty acids, prostaglandins, drugs, pollutants, and carcinogens, finally leading to development of ASD. This reasoning may be supported by such abnormal metabolic events as: (1) patients with ASD have significantly decreased melatonin levels caused by marked deficit in acetylserotonin methyltransferase activity, possibly resulting from maternal and/or fetal/postnatal overproduction of NO, characteristic for this clinical entity; (2) thimerosal inhibited both insulin-like growth factor-1- and dopamine-stimulated methylation reactions, and depressed methionine synthase activity, the metabolic events important for promoting normal neurodevelopment; (3) valproic acid, a strong histone deacetylase inhibitor, have potent anti-T. gondii activity. Thus, patients with ASD should be tested for T. gondii infection. © 2009 Elsevier Ltd. All rights reserved.

Prandota J.,Wroclaw Medical University
American Journal of Alzheimer's Disease and other Dementias | Year: 2014

Toxoplasma gondii is an intracellular protozoan infecting 30% to 50% of global human population. Recently, it was suggested that chronic latent neuroinflammation caused by the parasite may be responsible for the development of several neurodegenerative diseases manifesting with the loss of smell. Studies in animals inoculated with the parasite revealed cysts in various regions of the brain, including olfactory bulb. Development of behavioral changes was paralleled by the preferential persistence of cysts in defined anatomic structures of the brain, depending on the host, strain of the parasite, its virulence, and route of inoculation. Olfactory dysfunction reported in Alzheimer's disease, multiple sclerosis, and schizophrenia was frequently associated with the significantly increased serum anti-T gondii immunoglobulin G antibody levels. Damage of the olfactory system may be also at least in part responsible for the development of depression because Tgondii infection worsened mood in such patients, and the olfactory bulbectomized rat serves as a model of depression. © The Author(s) 2014.

Multidrug resistance (MDR) of cancer cells poses a serious obstacle to successful chemotherapy. The overexpression of multispecific ATP-binding cassette transporters appears to be the main mechanism of MDR. A search for MDR-reversing agents able to sensitize resistant cells to chemotherapy is ongoing in the hope of their possible clinical use. Studies of MDR modulators, although they have not produced clinically beneficial effects yet, may greatly enrich our knowledge about MDR transporters, their specificity and mechanism of action, especially substrate and/or inhibitor recognition. In the present review, interactions of three groups of modulators: phenothiazines, flavonoids and stilbenes with both P-glycoprotein and MRP1 are discussed. Each group of compounds is likely to interact with the MDR transporters by a different mechanism. Phenothiazines probably interact with drug binding sites, but they also could indirectly affect the transporter's activity by perturbing lipid bilayers. Flavonoids mainly interact with ABC proteins within their nucleotide-binding domains, though the more hydrophobic flavonoids may bind to regions within transmembrane domains. The possible mechanism of MDR reversal by stilbenes may result from their direct interaction with the transporter (possibly within substrate recognition sites) but some indirect effects such as stilbene-induced changes in gene expression pattern and in apoptotic pathways should also be considered. Literature data as well as some of our recent results are discussed. Special emphasis is put on cases when the interactions of a given compound with both P-glycoprotein and MRP1 have been studied simultaneously.

Ksiadzyna D.,Wroclaw Medical University
European Journal of Internal Medicine | Year: 2011

Background: With the growing number of pharmacological agents available nowadays, the gastrointestinal drug-induced side effects become more common than ever. However, drug-induced pancreatitis belongs to rather seldom reported adverse drug reactions, probably because of the difficulty in proving the relationship between an inflammation of the pancreas and the pharmacotherapy with a certain drug. Aim: The aim of this review is to draw attention to an infrequent but real problem of drug-induced acute pancreatitis associated with medications commonly used in the treatment of gastrointestinal disorders. Methodology: For the purpose of that the PubMed database was searched using the keywords "drug-induced pancreatitis", "drug-associated pancreatitis", "acute pancreatitis", "pancreatitis" in various combinations and relevant literature was reviewed. Results: A substantial number of drugs commonly prescribed for gastrointestinal disorders are known to cause acute pancreatitis. Case reports and review articles published so far draw attention to medications already known to cause drug-induced pancreatic damage as well as implicate new drugs. Generally, the etiopathological mechanisms involved in drug-induced pancreatitis remain unclear. It is difficult to establish or rule out definitely such unwanted event, especially in patients taking numerous medications prescribed for multiple comorbidities. Conclusion: Pharmacological agents are among etiologic factors that should be considered in all patients presenting with signs and symptoms consistent with acute pancreatitis. The diagnosis of drug-induced AP is often difficult to established. Therefore a high index of suspicion and thorough drug history are crucial for making the final diagnosis. © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

University of Limerick, Wroclaw University of Technology and Wroclaw Medical University | Date: 2012-03-16

The present invention relates to a polymeric material having one or more nanoparticles embedded within the surface layer of a single side of the material. In some embodiments, the nanoparticles are microbiocidal nanoparticles which impart antimicrobial characteristics to the polymeric material within which they sprayed and pushed by are embedded.

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