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      Novel pharmacological approaches in abdominal aortic aneurysm

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          Abstract

          Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is no medical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA.

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          Of Mice and Not Men: Differences between Mouse and Human Immunology

          Mice are the experimental tool of choice for the majority of immunologists and the study of their immune responses has yielded tremendous insight into the workings of the human immune system. However, as 65 million years of evolution might suggest, there are significant differences. Here we outline known discrepancies in both innate and adaptive immunity, including: balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets, the B cell (BLNK, Btk, and lambda5) and T cell (ZAP70 and common gamma-chain) signaling pathway components, Thy-1, gammadelta T cells, cytokines and cytokine receptors, Th1/Th2 differentiation, costimulatory molecule expression and function, Ag-presenting function of endothelial cells, and chemokine and chemokine receptor expression. We also provide examples, such as multiple sclerosis and delayed-type hypersensitivity, where complex multicomponent processes differ. Such differences should be taken into account when using mice as preclinical models of human disease.
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            Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.

            Selective inhibition of cyclooxygenase-2 (COX-2) may be associated with an increased risk of thrombotic events, but only limited long-term data have been available for analysis. We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term, multicenter, randomized, placebo-controlled, double-blind trial designed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas. A total of 2586 patients with a history of colorectal adenomas underwent randomization: 1287 were assigned to receive 25 mg of rofecoxib daily, and 1299 to receive placebo. All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee. A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008). The increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. There was earlier separation (at approximately five months) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio for the comparison of the rofecoxib group with the placebo group, 4.61; 95 percent confidence interval, 1.50 to 18.83). Overall and cardiovascular mortality was similar in the two groups. Among patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk. Copyright 2005 Massachusetts Medical Society.
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              Is there new hope for therapeutic matrix metalloproteinase inhibition?

              Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that form a family of 24 members in mammals. Evidence of the pathological roles of MMPs in various diseases, combined with their druggability, has made them attractive therapeutic targets. Initial drug discovery efforts focused on the roles of MMPs in cancer progression, and more than 50 MMP inhibitors have been investigated in clinical trials in various cancers. However, all of these trials failed. Reasons for failure include the lack of inhibitor specificity and insufficient knowledge about the complexity of the disease biology. MMPs are also known to be involved in several inflammatory processes, and there are new therapeutic opportunities for MMP inhibitors to treat such diseases. In this Review, we discuss the recent advances made in understanding the role of MMPs in inflammatory diseases and the therapeutic potential of MMP inhibition in those conditions.
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                Author and article information

                Contributors
                Role: Writing—original draftRole: Writing—review & editing
                Role: Writing—original draftRole: Writing—review & editing
                Role: Writing—original draftRole: Writing—review & editing
                Role: Writing—original draftRole: Writing—review & editing
                Role: Writing—original draftRole: Writing—review & editing
                Role: ConceptualizationRole: ResourcesRole: Funding acquisitionRole: Writing—original draftRole: Writing—review & editing
                Role: ConceptualizationRole: ResourcesRole: Funding acquisitionRole: Writing—original draftRole: Writing—review & editing
                Journal
                Clin Sci (Lond)
                Clin Sci (Lond)
                cs
                Clinical Science (London, England : 1979)
                Portland Press Ltd.
                0143-5221
                1470-8736
                August 2023
                10 August 2023
                : 137
                : 15
                : 1167-1194
                Affiliations
                [1 ]Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain
                [2 ]CIBER de Enfermedades Cardiovasculares, ISCIII, Madrid, Spain
                [3 ]Department of Pharmacology, Therapeutics and Toxicology, School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
                [4 ]Neuroscience Institute, Universitat Autònoma de Barcelona, Barcelona, Spain
                [5 ]Departamento de Angiología y Cirugía Vascular del Hospital Universitari General de Granollers, Granollers, Barcelona, Spain
                [6 ]Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain
                [7 ]Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Barcelona, Spain
                Author notes
                Correspondence: José Martínez-González ( jose.martinez@ 123456iibb.csic.es ) or Cristina Rodríguez ( crodriguezs@ 123456santpau.cat )
                [*]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-9034-2041
                https://orcid.org/0000-0002-4758-8388
                https://orcid.org/0000-0002-3894-7166
                Article
                CS20220795
                10.1042/CS20220795
                10415166
                37559446
                e02795c5-9ed2-44b1-8b9b-862a3c57b916
                © 2023 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND).

                History
                : 05 May 2023
                : 05 July 2023
                : 28 July 2023
                Page count
                Pages: 28
                Categories
                Cardiovascular System & Vascular Biology
                Molecular Bases of Health & Disease
                Pharmacology & Toxicology
                Translational Science
                Review Articles

                Medicine
                abdominal aortic aneurysm,clinical trials,therapeutic target
                Medicine
                abdominal aortic aneurysm, clinical trials, therapeutic target

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