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Non-anticoagulant derivatives of heparin for the management of asthma : distant dream or close reality?

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Shastri, MD (2015) Non-anticoagulant derivatives of heparin for the management of asthma : distant dream or close reality? PhD thesis, University of Tasmania.

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Abstract

Unfractionated heparin (UFH) belongs to a class of linear, highly sulfated, acidic polysaccharides known as glycosaminoglycans. Low-molecular-weight heparins (LMWHs) are modified heparin fragments with a molecular weight range of 2000 to 8000 Da. LMWHs are prepared by either chemical or enzymatic depolymerisation of UFH. In clinical practice, UFH is largely replaced by LMWHs because of their improved pharmacokinetic profiles as decreased risk of side effects. Heparins (UFH and LMWHs) are comprised of heterogeneous mixture of anticoagulant and non-anticoagulant fractions. Much recently, these polysaccharides have shown to possess anti-inflammatory effects and such effects are strongly influenced by degree of sulfation, distribution of sulfate groups and chain length. Interestingly, the potential anti-inflammatory activities of heparins, such seen in asthma, are reported to be because of the interactions between their non-anticoagulant molecules and various biological molecules. Numerous studies highlight the role of heparins in the management of inflammatory disorders including asthma. Asthma is a common chronic inflammatory condition of the conducting airways. It is estimated that approximately 300 million people worldwide suffer from asthma and it is associated with severe morbidity, and sometimes even mortality. Asthma is known to be driven by various inflammatory cytokines including interleukin-(IL)-4, IL-5, IL-6, IL-8, IL-13 and tumor necrosis factor-alpha (TNF-α). The current drug modalities used for the management of asthma are reported to have a number of drawbacks and it is also estimated that up to 10% asthmatic patients have difficult-to-treat asthma that is often resistant to first line treatment with inhaled corticosteroids. Some recent in vivo studies have confirmed that heparins possess significant anti-asthmatic activity. However, the use of heparins for the management of asthma is hindered by the risk of bleeding associated with their anticoagulant fractions. For example, in one study, administration of LMWH resulted in massive haemorrhage in a patient with inflammation. Apart from this, the investigation of anti-inflammatory effects of LMWH is challenging because these activities are expressed with high LMWH concentrations where the anticoagulant effects predominate. Therefore, the overall aim of the study was to confirm that a LMWH (e.g. enoxaparin and dalteparin) can inhibit various inflammatory mediators involved in the pathogenesis of asthma with a view of identifying non-anticoagulant fraction(s) of the parent LMWH responsible for its anti-asthmatic effect.

Item Type: Thesis (PhD)
Keywords: Heparin, Low-molecular-weight-heparin, Enoxaparin, Anticoagulant Oligosaccharides, Bleeding, Non-anticoagulant Oligosaccharides, Anti-inflammatory, Asthma
Copyright Information:

Copyright 2015 the author

Additional Information:

Chapter 1 appears to be the equivalent of an Accepted Manuscript of an article published by Taylor & Francis in Expert opinion on investigational drugs on 3/1/2014, available online: http://www.tandfonline.com/10.1517/13543784.2014.866092

Chapter 2 appears to be the equivalent of a post-print version of an article published as: Shastri, M. D., Stewart, N., Eapen, M., Peterson, G. M., Zaidi, S. T., Guven, N., Sohal, S. S., Patel, R. P., 2015.Opposing effects of low molecular weight heparins on the release of inflammatory cytokines from peripheral blood mononuclear cells of asthmatics. PLoS one, 10(3), 1-196, e0118798. Copyright: © 2015 Shastri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Chapter 3 appears to be the equivalent of a post-print version of an article published as: Shastri, M. D., Johns, C., Hutchinson, J. P. et al., 2013. Ion exchange chromatographic separation and isolation of oligosaccharides of intact low-molecular-weight heparin for the determination of their anticoagulant and anti-inflammatory properties, Analytical and Bioanalytical Chemistry, 405(18), 6043-6052. The final publication is available at Springer via https://doi.org/10.1007/s00216-013-6996-9

Chapter 4 appears to be the equivalent of a post-print version of an article published as: Shastri, M. D., Stewart, N., Horne, J., Zaidi, S. T. R., Sohal, S. S., Peterson, G. M. et al., 2015. Non-aticoagulant fractions of enoxaparin supress inflammatory cytokine release from peripheral blood mononuclear cells of allergic asthmatic individuals, PLoS one, 10(6), 1-21, e0128803. Copyright: © 2015 Shastri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Chapter 5 appears to be the equivalent of a post-print version of an article published as: Shastri, M. D., Stewart, N., Horne, J., Peterson, G. M., Gueven, N., Sohal, S. S. et al., 2015. In-vitro supression of IL-6 and IL-8 release from human pulmonary epithelial cells by non-anticoagulant fraction of enoxaparin., PLOS one, 10(5), 1-23, e0126763. Copyright: © 2015 Shastri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Date Deposited: 17 Nov 2016 03:18
Last Modified: 18 Sep 2017 03:01
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