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      The effects of sulodexide on both clinical and molecular parameters in patients with mixed arterial and venous ulcers of lower limbs

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          Abstract

          Background

          Mixed venous and arterial ulcers account for approximately 15%–30% of all venous leg ulcerations. Several studies have shown that matrix metalloproteinases (MMPs) and neutrophil gelatinase-associated lipocalin (NGAL) play a central role in the pathophysiology of venous and arterial diseases. Some studies have shown the efficacy of glycosaminoglycans, such as sulodexide (SDX), in treating patients with leg ulcers. The aim of this study was to evaluate clinical effects of SDX and its correlation with MMPs and NGAL expression in patients with mixed arterial and venous leg ulcers.

          Methods

          Patients eligible for this study were of both sexes, older than 20 years, and with a clinical and instrumental diagnosis of mixed ulcer.

          Results

          Fifty-three patients of both sexes were enrolled and divided into two groups by means of randomization tables. Group A (treated group) comprised 18 females and ten males (median age: 68.7 years) treated with standard treatment (compression therapy and surgery) + SDX (600 lipoprotein lipase-releasing units/day intramuscularly) for 15 days followed by SDX 250 lipase-releasing units every 12 hours day orally for 6 months as adjunctive treatment. Group B (control group) comprised 17 females and eight males (median age: 64.2 years) treated with standard treatment only (compression therapy and surgery). The type of surgery was chosen according to anatomical level of vein incompetence: superficial venous open surgery and/or subfascial endoscopic perforating surgery. In all enrolled patients, blood samples were collected in order to evaluate the plasma levels of MMPs and NGAL through enzyme-linked immunosorbent assay. These results were compared to another control group (Group C) of healthy individuals. Moreover, biopsies of ulcers were taken to evaluate the tissue expression of MMPs and NGAL through Western blot analysis. Our results revealed that SDX treatment is able to reduce both plasma levels and tissue expression of MMPs improving the clinical conditions in patients with mixed ulcers.

          Conclusion

          Inhibition of MMPs could represent a possible therapeutic intervention to limit the progression of leg ulceration. In particular, our findings demonstrate the efficacy of SDX in patients with mixed arterial and venous chronic ulcers of the lower limbs.

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          Most cited references 56

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          Matrix metalloproteinases (MMPs) in health and disease: an overview.

          Matrix metalloproteinases (MMPs) are members of an enzyme family that require a zinc ion in their active site for catalytic activity. MMPs are critical for maintaining tissue allostasis. MMPs are active at neutral pH and can therefore catalyze the normal turnover of extracellular matrix (ECM) macromolecules such as the interstitial and basement membrane collagens, proteoglycans such as aggrecan, decorin, biglycan, fibromodulin and versican as well as accessory ECM proteins such as fibronectin. Members of the MMP family include the "classical" MMPs, the membrane-bound MMPs (MT-MMPs) the ADAMs (a disintegrin and metalloproteinase; adamlysins) and the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif). There are more than 20 members in the MMP and ADAMTS family including the collagenases, gelatinases, stromelysins, some elastases and aggrecanases. Adamlysins are membrane-bound MMPs that also degrade aggrecan, but more importantly, one ADAM family member (i.e.ADAM-17) is a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE) that activates pro-TNF-alpha. Most of the MMPs are synthesized as inactive latent enzymes. Conversion to the active enzyme is generally mediated by activator systems that include plasminogen activator or the pro-hormone convertase, furin. MMP activity is regulated by a group of endogenous proteins, called, tissue inhibitor of metalloproteinases (TIMPs) that bind to active and alternative sites of the activated MMP. Significant advances have occurred in the understanding of the regulation of MMPs, ADAMs and ADAMTSs gene expression. In addition, development of MMP inhibitors to study MMP structure/function relationships spawned many studies to determine the effectiveness of MMP inhibitors in regulating abnormal connective tissue turnover. In addition, development of MMP null mice carrying specific MMP deletions has provided an opportunity to explore the role of MMPs in normal development as well as in such diverse conditions and diseases as skeletal dysplasias, coronary artery and heart disease, arthritis, cancer, and brain disorders.
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            Validity and responsiveness of EuroQol-5 dimension (EQ-5D) versus Short Form-6 dimension (SF-6D) questionnaire in chronic pain

            Background Assessments of health-related quality of life and particularly utility values are important components of health economic analyses. Several instruments have been developed to measure utilities. However no consensus has emerged regarding the most appropriate instrument within a therapeutic area such as chronic pain. The study compared two instruments – EQ-5D and SF-6D – for their performance and validity in patients with chronic pain. Methods Pooled data from three randomised, controlled clinical trials with two active treatment groups were used. The included patients suffered from osteoarthritis knee pain or low back pain. Differences between the utility measures were compared in terms of mean values at baseline and endpoint, Bland–Altman analysis, correlation between the dimensions, construct validity, and responsiveness. Results The analysis included 1977 patients, most with severe pain on the Numeric Rating Scale. The EQ-5D showed a greater mean change from baseline to endpoint compared with the SF-6D (0.43 to 0.58 versus 0.59 to 0.64). Bland–Altman analysis suggested the difference between two measures depended on the health status of a patient. Spearmans rank correlation showed moderate correlation between EQ-5D and SF-6D dimensions. Construct validity showed both instruments could differentiate between patient subgroups with different severities of adverse events and analgesic efficacies but larger differences were detected with the EQ-5D. Similarly, when anchoring the measures to a disease-specific questionnaire – Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) – both questionnaires could differentiate between WOMAC severity levels but the EQ-5D showed greater differences. Responsiveness was also higher with the EQ-5D and for the subgroups in which improvements in health status were expected or when WOMAC severity level was reduced the improvements with EQ-5D were higher than with SF-6D. Conclusions This analysis showed that the mean EQ-5D scores were lower than mean SF-6D scores in patients with chronic pain. EQ-5D seemed to have higher construct validity and responsiveness in these patients.
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              Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors.

              To assess the differences in proteolytic activity of acute and chronic wound environments, wound fluids were collected from acute surgical wounds (22 samples) and chronic wounds (25 samples) of various etiologies, including mixed vessel disease ulcers, decubiti and diabetic foot ulcers. Matrix metalloproteinase (MMP) activity measured using the Azocoll assay was significantly elevated by 30 fold in chronic wounds (median 22.8 microg MMP Eq/ml) compared to acute wounds (median 0.76 microg MMP Eq/ml) (p < 0.001). The addition of the matrix metalloproteinase inhibitor Illomostat decreased the matrix metalloproteinase activity by approximately 90% in all samples, confirming that the majority of the activity measured was due to matrix metalloproteinases. Gelatin zymograms indicated predominantly elevated matrix metalloproteinase-9 with smaller elevations of matrix metalloproteinase-2. In addition tissue inhibitor of metalloproteinase-1 levels were analyzed in a small subset of acute and chronic wounds. When tissue inhibitor of metalloproteinase-1 levels were compared to protease levels there was an inverse correlation (p = 0.02, r = - 0.78). In vitro degradation of epidermal growth factor was measured by addition of 125I labelled epidermal growth factor to acute and chronic wound fluid samples. There was significantly higher degradation of epidermal growth factor in chronic wound fluid samples (mean 28.1%) compared to acute samples (mean 0.6%). This also correlated to the epidermal growth factor activity of these wound fluid samples (p < 0. 001, r = 0.64). Additionally, the levels of proteases were assayed in wound fluid collected from 15 venous leg ulcers during a nonhealing and healing phase using a unique model of chronic wound healing in humans. Patients with nonhealing venous leg ulcers were admitted to the hospital for bed rest and wound fluid samples were collected on admission (nonhealing phase) and after 2 weeks (healing phase) when the ulcers had begun to heal as evidenced by a reduction in size (median 12%). These data showed that the elevated levels of matrix metalloproteinase activity decreased significantly as healing occurs in chronic leg ulcers (p < 0.01). This parallels the processes observed in normally healing acute wounds. This data also supports the case for the addition of protease inhibitors in chronic wounds in conjunction with any treatments using growth factors.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2014
                13 May 2014
                : 8
                : 519-527
                Affiliations
                [1 ]Interuniversity Center of Phlebolymphology (CIFL), International Research and Educational Program in Clinical and Experimental Biotechnology, University Magna Graecia of Catanzaro, Catanzaro, Italy
                [2 ]Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
                [3 ]Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy
                [4 ]Cardiovascular and Thoracic Department, University of Messina, Messina, Italy
                [5 ]Unit of Vascular Surgery, S Anna Hospital, Catanzaro, Italy
                [6 ]Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
                [7 ]Department of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy
                [8 ]Department of Experimental Medicine, Second University of Naples, Naples, Italy
                [9 ]University Campus BioMedico of Rome, Rome, Italy
                [10 ]Department of General Surgery, University of Turin, Turin, Italy
                Author notes
                Correspondence: Raffaele Serra, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Viale Europa, Germaneto 88100, Catanzaro, Italy, Tel +39 0961 364 7380; mob +39 338 707 8043, Fax +39 0961 364 7175, Email rserra@ 123456unicz.it
                [*]

                These authors contributed equally to this work

                Article
                dddt-8-519
                10.2147/DDDT.S61770
                4026398
                24872682
                © 2014 Serra et al. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Ltd, provided the work is properly attributed.

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                Original Research

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