THE POTENTIAL THERAPEUTIC ROLE OF MONTELUKAST AND NEW HYBRID AGENTS, TXA2 ANTAGONIST-COX-2 INHIBITORS IN CARDIOVASCULAR EVENTS

The main target of my PhD research project was to explore new alternatives to reduce the cardiovascular (CV) risk targeting the arachidonic acid metabolites. Hence, I have been part of two different projects, one studying multitarget compounds with balanced COXIB and TP receptor antagonist properties, and the other evaluating the potential role of a leukotriene (LT) antagonist drug such as montelukast in improving the CV outcome. In reference to the first project, new multitarget compounds were synthesized at the University of Turin, by substituting the carboxylic function of Lumiracoxib. This strategy led to several new compounds, of which we have analyzed the platelet aggregation, total inositol phosphate production, COX-1 and COX-2 inhibitory activity. Out of all the studied compounds compound 18, the terazole derivative as well as compound 20 were the most active, with a decent balanced activity as COXIB and TP antagonist . Whereas, compound 32, displaying a functional group of terutroban did not accomplish our expectation to be a more potent TP antagonist with respect to compounds 7,18,20. Our main goal is to obtain new molecules with higher TP antagonist properties but at the same time retaining the COXIB activity. It is important to highlight that the therapeutic effect of these new compounds depend on the balance of two pharmacological profiles. The results we obtained demostrate that it is possible to have new chemical entities with higher TP antagonist potencies, and better balanced COX-2 selectivity. This approach will provide further benefits for patients with chronic pain taking a COXIB, and in patients with higher CV risk, like diabetics and hopefully can lead to a new generation of safer non steroidal antiinflammatory drugs. The second project of my PhD was focused on a LT antagonist drug such as montelukast, which is a pharmacological alternative for patients suffering asthma, allergic rhinites and urticaria. We performed a retrospective study including patients exposed or not to montelukast for a total of eight hundred asthmatic patients to assess the potential role of montelukast in primary and secondary prevention of major CV events as ischemic stroke (IS) or myocardial infarction (MI). Each of the two subjects sample was further classified in patients with or without MI or IS based on their diagnosis according to the International Classification of Diseases (ICD). The myocardial infarction event rate was almost 6 fold higher in asthmatic patients not taking montelukast and 9 fold higher for ischemic stroke events. Drug used in these patients were also monitored in order to exclude potential confounders of the results. Overall, our results suggest a reduction of CV events by montelukast, including both MI and IS eventhough the study should be expanded to a larger number of subjects. Given their association with the inflammatory onset and amplification, LTs synthesis inhibitors or LT receptor antagonists such as montelukast could be consider as potential approach for CV diseases. The results obtained during this three years of PhD cycle have shown that new innovative strategies targeting arachidonic acid metabolites can be implied to improve the CV outcome. There is still an unmet need for an anti-inflammatory treatment to reduce the CV risk, and these strategies can lead to new pharmacological approaches

Fireworks-related Injuries during New Year celebrations in Kosovo: A comparison of the years 2008 and 2009

Background: Fireworks related injuries in children occur in Kosovo particularly during New Year celebrations.Aim: To report the pattern of fireworks- related injuries in childrenup to 16 years of age treated at the Emergency Center and Plastic Surgery,University Clinical Centre of Kosovo during the 2008 and 2009 New Year celebrations.Methods: Retrospective review of hospital recordsResults: During the New Year celebrations in 2008, a total of 65 caseswere admitted, 32 (49.2%) of who were children injured by fireworks. The ages of the children ranged from 5 to 16 years with a mean of 10.5years. The modal age affected was the 10 – 14 year-old group (53.6%). Boys constituted 93.8% of patients and girls 6.3%. During the 2009 New Year celebration, 17 cases were admitted with fireworks injuries, 12 (70.58%) of who were children ranging in age from 8 to 15 years (mean 11.5 years) with a modal age group of 10 – 14 years (66.7%). Boys accounted for 88.3% and girls for 16.7% of patients.Conclusions: The frequency of fireworks injuries reduced appreciablyafter introduction of laws restricting sales of fireworks devices and banningtheir use by children.Recommendations: It is recommended that parents play a greaterrole in controlling the activities of their children during festivities. Thegovernment and police should also ensure compliance with the law onthe use of fireworks during the holidays.Key words: fireworks injury, epidemiology, wounds, prevention

Intestinal barrier tightening by a cell-penetrating antibody to Bin1, a candidate target for immunotherapy of ulcerative colitis.

Patients afflicted with ulcerative colitis (UC) are at increased risk of colorectal cancer. While its causes are not fully understood, UC is associated with defects in colonic epithelial barriers that sustain inflammation of the colon mucosa caused by recruitment of lymphocytes and neutrophils into the lamina propria. Based on genetic evidence that attenuation of the bridging integrator 1 (Bin1) gene can limit UC pathogenicity in animals, we have explored Bin1 targeting as a therapeutic option. Early feasibility studies in the dextran sodium sulfate mouse model of experimental colitis showed that administration of a cell-penetrating Bin1 monoclonal antibody (Bin1 mAb 99D) could prevent lesion formation in the colon mucosa in part by preventing rupture of lymphoid follicles. In vivo administration of Bin1 mAb altered tight junction protein expression and cecal barrier function. Strikingly, electrophysiology studies in organ cultures showed that Bin1 mAb could elevate resistance and lowe

Rules and regulations for the safeguard of water resources: examples from European, Italian and Albanian experiences

Water is a vital and precious resource for people and for ecosystems. We should make each possible effort to protect water resources and increase people’s access to clean and sufficient water. To pursue these purposes many efforts have been realised in terms of technical rules and national laws. This contribution describes the approach of the European Union, Italy and Albania, considering also some local government initiatives concerning the protection of water resources, in terms of availability and quality, and of ecosystems. Attention is given also to the effect of the whole water cycle management in terms of environmental protection and reduction of water-related natural disaster

On the stability and spectrum of non-supersymmetric AdS(5) solutions of M-theory compactified on Kahler-Einstein spaces

Eleven-dimensional supergravity admits non-supersymmetric solutions of the form AdS(5)xM(6) where M(6) is a positive Kahler-Einstein space. We show that the necessary and sufficient condition for such solutions to be stable against linearized bosonic supergravity perturbations can be expressed as a condition on the spectrum of the Laplacian acting on (1,1)-forms on M(6). For M(6)=CP(3), this condition is satisfied, although there are scalars saturating the Breitenlohner-Freedman bound. If M(6) is a product S(2)xM(4) (where M(4) is Kahler-Einstein) then there is an instability if M(4) has a continuous isometry. We show that a potential non-perturbative instability due to 5-brane nucleation does not occur. The bosonic Kaluza-Klein spectrum is determined in terms of eigenvalues of operators on M(6).Comment: 21 pages. v2: Includes SU(4) quantum numbers for CP3 case, typos fixed, refs adde

Co-crystallisation of cytosine with 1,10-phenanthroline: computational screening and experimental realisation

Attempts to co-crystallise the nucleobases adenine, thymine, guanine, and cytosine with 1,10-phenanthroline by ball milling and solvent evaporation methods are described. A 1:1 co-crystal of cytosine and 1,10-phenanthroline can be obtained by grinding or by solvent evaporation. The structure contains two crystallographically independent cytosine and two independent 1,10-phenanthroline molecules (Z′ = 2). The cytosine molecules form two similar but crystallographically independent hydrogen-bonded chains, while the 1,10-phenanthroline molecules are arranged in π-stacks. Between the chains of cytosine and the π-stacks exist N-H⋯N and C-H⋯N interactions. Crystal structure prediction (CSP) calculations were applied to all four systems to assess their potential for co-crystallisation as well as the likely structures and intermolecular interactions that could result from co-crystallisation. Calculations on the cytosine system demonstrate that co-crystallisation results in a lower energy than the crystalline forms of the two starting materials, in line with the co-crystal formation observed. For the systems which did not form a co-crystal, CSP was used to explore potential packing arrangements, but found none which were lower in energy than that of the pure crystalline forms. In these cases there is significant disruption to the nucleobase hydrogen bonding between the pure compound and the hypothetical co-crystal. For pure adenine and guanine, the hydrogen-bonded ribbons form sheets which must be broken, whereas for thymine, the lack of hydrogen bond donors does not allow the hydrogen bonding present for pure thymine to be maintained while forming thymine-1,10-phenanthroline hydrogen bonds