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Low Molecular Weight Heparins and Their Clinical Applications

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Low Molecular Weight Heparins and Their Clinical Applications CHAPTER TWO Low molecular weight heparins and their clinical applications Cui Haoa,*, Mojian Sunb, Hongmei Wangc, Lijuan Zhanga, Wei Wangd aSystems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China bDepartment of Medical Records, Affiliated Hospital of Qingdao University, Qingdao, China cRespiratory Department, Affiliated Hospital of Qingdao University, Qingdao, China dKey Laboratory of Marine Drugs, Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience & Glycoengineering, Ocean University of China, Qingdao, China *Corresponding author: e-mail address: [email protected] Contents 1. Introduction 22 2. Structure of LMWHs 23 3. Clinical uses of LMWHs 25 4. Update on the LMWHs under clinic trials and its potential applications 27 4.1 Anti-tumor 27 4.2 Anti-viral 30 4.3 Anti-inflammation 30 4.4 Anti-diabetes-associated complications 31 4.5 Other applications 32 5. Concluding remarks 32 Acknowledgments 33 References 34 Abstract Heparin is an anticoagulant medication that was discovered in 1917 and used in clinic since 1935. Low molecular weight heparins (LMWHs) represent a refined use of heparin as anticoagulant medications that were developed in 1980s. LMWHs are obtained by cleaving heparin with different chemical or enzymatic methods. Eight chemically distinct and officially approved LMWHs are Bemiparin, Certoparin, Dalteparin, Enoxaparin, Nadroparin, Parnaparin, Reviparin, and Tinzaparin. LMWHs are mainly used for preventing blood clots, for treating deep vein thrombosis and pulmonary embolism, and for treating myocardial infarction. LMWHs have advantages over heparin in that they can be used at home with good predictability, dose-dependent plasma levels, a long half-life, less bleeding for a given antithrombotic even, smaller risk of osteoporosis in long-term use, and smaller risk of heparin-induced thrombocytopenia and thrombo- sis, a potential side effect of heparin. However, heparin is reversible with protamine sulfate while LMWHs have no antidote. Moreover, LMWHs have less of an effect on inhibiting thrombin activity than heparin. Furthermore, patients with end-stage renal # Progress in Molecular Biology and Translational Science, Volume 163 2019 Elsevier Inc. 21 ISSN 1877-1173 All rights reserved. https://doi.org/10.1016/bs.pmbts.2019.02.003 22 Cui Hao et al. diseases have to use heparin because LMWHs are dependent on functioning kidney for their clearance but heparin is primarily cleared in the liver. We will review the recent progress made on the clinically approved and under clinical trialed LMWHs and their potential medical applications. In particular, we will provide an update on the chemical characteristics and clinical use of different branded LMWHs. In addition, the potential clinical applications of LMWHs in other therapeutic area will also be discussed. 1. Introduction Low molecular weight heparins (LMWHs) are derived from unfrac- tioned heparin that are isolated from either porcine intestinal mucosa or bovine lungs. The medical grade unfractioned heparin has an average molec- ular weight of 12–16,000 Da.1,2 LMWHs were developed as anticoagulant/ – antithrombotic drugs since 1980s3 7 and defined as heparin salts having an average molecular weight of less than 8000 Da and for which at least 60% of all chains have a molecular weight less than 8000 Da.8 LMWHs represent a refined use of heparin and have several advantages over heparin in that they have longer half-life in the blood circulation, more predictable effects after a given dose, require less blood tests to check for their effectiveness and side effects, and do not have to be given in the hospital settings that is required for heparin.9 Eight chemically distinct and officially approved LMWHs are Bemiparin, Certoparin, Dalteparin, Enoxaparin, Nadroparin, Parnaparin, Reviparin, and Tinzaparin. LMWHs are originally developed and used for preventing blood clots and for treating myocardial infarction. Many clinical trials are currently conducting to expand the medical applications of LMWHs to other diseases. Each LMWH is a pleiotropic biological agent with its own chemical, biochem- ical, biophysical, and biological characteristics. Each LMWH also displays unique pharmacodynamic and pharmacokinetic profiles.8 Moreover, each LMWH is independently studied in preclinical assays or in clinical trials during their development.10 Thus, therapeutic interchange is regarded as inap- propriate among different LMWHs on the basis of differences in the biochem- ical and pharmacologic profiles and clinical effect identified in clinical trials.11 This review presents an overview of recent progress on LMWHs. We will mainly focus on the chemical characteristics, biological activities, and clinical use of different branded LMWHs. Recent developments of LMWHs in other therapeutic area will also be discussed in detail. Low molecular weight heparins 23 2. Structure of LMWHs Each LMWH is made by a unique manufacturing process. The eight LMWHs can be distinguished from each other by their specific molecular – and structural differences (Table 1).12 15 TheLMWHsareusuallysodium salt except Nadroparin (Fraxiparin), which is a calcium salt. The average molecular weight of the LMWHs is usually around 4000–6000 Da (Table 1). Moreover, among them, Bemiparin has best anticoagulation activity with the ratio of anti-Xa/anti-IIa activity more than 9.0 (Table 1). Each LMWH in clinical use is derived from standard commercial grade unfractioned heparin by chemical or enzymatic depolymerization. Each preparation uses a unique, proprietary manufacturing process to produce specific structural features. For example, Oxidative depolymerization with hydrogen peroxide is used in the manufacture of Ardeparin while oxidative depolymerization with Cu2+ and hydrogen peroxide is used in the Table 1 The eight commercially available LMWHs. Trade Anti-Xa/IIa LMWH Salt name Manufacturer MW(kD) ratio Nadroparin Calcium Fraxiparin Sanofi- 4.3 3.3 Winthrop Enoxaparin Sodium Clexane, AVENTIS 4.5 3.9 Lovenox Dalteparin Sodium Fragmin Pfizer Kissei 6.0 2.5 Certoparin Sodium Sandoparin Novartis 5.4 2.4 Tinzaparin Sodium Innohep, Braun Novo/ 6.5 2.6 Logiparin Leo/Pharmiom Parnaparin Sodium Fluxum Alfa Wassermann 5.0 2.3 Reviparin Sodium Clivarin ABBOT 4.4 4.2 Bemiparin Sodium Beparine Biological Evans 3.6 9.7 Adapted from Gray E, Mulloy B, Barrowcliffe TW. Heparin and low-molecular-weight heparin. Thromb Haemost. 2008;99(5):807–818; Fareed J, Leong W, Hoppensteadt DA, Jeske WP, Walenga J, Bick RL. Development of generic low molecular weight heparins: a perspective. Hematol Oncol Clin North Am. 2005;19(1):53–68, v-vi; Mulloy B, Gee C, Wheeler SF, Wait R, Gray E, Barrowcliffe TW. Molecular weight measurements of low molecular weight heparins by gel permeation chromatography. Thromb Haemost. 1997;77(4):668–674. 24 Cui Hao et al. manufacture of Parnaparin. Deaminative cleavage with isoamyl nitrite is used in the manufacture of Certoparin. Alkaline beta-eliminative cleavage of the benzyl ester of heparin is used in the manufacture of enoxaparin. Deaminative cleavage with nitrous acid is used in the manufacture of Dalteparin, Reviparin, and Nadroparin. Beta-eliminative cleavage by the heparinase enzyme is used in the manufacture of Tinzaparin. The prep- aration of LMWHs using the different cleavage methods results in subtle structural differences among these pharmaceutical agents (Table 2 and Fig. 1).8 In summary, each LMWH is unique with specific molecular and structural signature. Table 2 Characteristics and the method of preparation of LMWHs. LMWH Characteristics Method of preparation Dalteparin Presence of 2,5-anhydro-D-mannose Nitrous acid depolymerization at reducing terminus Reviparin Presence of 2,5-anhydro-D-mannose Nitrous acid depolymerization at reducing terminus Nadroparin Presence of 2,5-anhydro-D-mannose Nitrous acid depolymerization at reducing terminus Certoparin Presence of 2,5-anhydro-D-mannose Deaminative cleavage with at reducing terminus isoamyl nitrite Enoxaparin Presence of 4,5 unsaturated uronic Benzylation followed by acid at non-reducing terminus alkaline depolymerization Bemiparin Presence of 2-O- Depolymerized heparin sulfo-4-enepyranosuronic acid obtained by alkaline structure at non-reducing terminus degradation Tinzaparin Presence of 4,5 unsaturated uronic Enzymatic depolymerization acid at non-reducing terminus with heparinase Parnaparin Presence of a 2-N,6-O-disulfo-D- Oxidative depolymerization glucosamine structure at reducing with Cu2+ and hydrogen terminus peroxide Adapted from Gray E, Mulloy B, Barrowcliffe TW. Heparin and low-molecular-weight heparin. Thromb Haemost. 2008;99(5):807–818; Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl): 188S–203S; Ingle RG, Agarwal AS. A world of low molecular weight heparins (LMWHs) enoxaparin as a promising moiety—a review. Carbohydr Polym. 15 2014;106:148–153. Low molecular weight heparins 25 Fig. 1 Structural characteristics of the LMWHs. Adapted from Fareed J, Leong W, Hoppensteadt DA, Jeske WP, Walenga J, Bick RL. Development of generic low molecular weight heparins: a perspective. Hematol Oncol Clin North Am. 2005;19(1):53–68, v–vi; Jeske WP, Walenga JM, Hoppensteadt DA, et al. Differentiating low-molecular-weight heparins based on chemical, biological, and pharmacologic properties: implications for the develop- ment of generic versions of low-molecular-weight
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