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Low Molecular Weight Heparins, Biological Drugs close to Non-Biological Complex Drugs

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Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 20))

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Abstract

Low molecular weight heparins (LMWHs) are drug substances widely used as anticoagulants after parenteral administration. They are biological substances obtained from mammalian tissues and they are closely related to non-biological complex drugs because of their heterogeneity and their complex characterization. LMWHs are highly sulfated glycosaminoglycans obtained by partial chemical or enzymatic depolymerization of unfractionated heparin, which is prepared usually by purification from porcine mucosa. Their heterogeneity and polydispersity is the result of the biosynthetic route and of the manufacturing process. Regulatory requirements and control methods are in place in Europe and in the United States to guarantee the quality and safety of these products. LMWHs interfere with the coagulation cascade mainly by interacting through a specific pentasaccharide sequence with antithrombin (AT), and accelerating the inhibition of factor Xa and, to a lesser extent, thrombin (factor IIa). Attempts to produce chemically or enzymatically synthesised LMWHs have not succeeded to displace the currently used LMWH of natural origin.

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Abbreviations

ACS:

Acute Coronary Syndromes

ACT:

Activated Clotting Time

AEMPS:

Spanish Agency for Medicines and Medical Devices

aPTT:

Activated Partial Thromboplastin Time

ASMF:

Active Substance Master File

AT/AT III:

Antithrombin/Antithrombin III

BID:

Twice Daily

CE:

Capillary Electrophoresis

CEP(s):

Certificate(s) of Suitability

CHO:

Chinese Hamster Ovary

CMDh:

Coordination Group for Mutual Recognition and Decentralised Procedures, human

CS:

Chondroitin Sulfate

DS:

Dermatan Sulfate

DVT:

Deep Venous Thrombosis

EDQM:

European Directorate for the Quality of Medicines and Health Care

ELISA:

Enzyme-Linked ImmunoSorbent Assay

EMA:

European Medicines Agency

EMEA:

European Agency for the Evaluation of Medicinal Products

EU:

European Union

FDA:

Food and Drugs Administration

GAG:

Glycosaminoglycan

GMP:

Good Manufacturing Practice

h:

hours

HIT:

Heparin Induced Thrombocytopenia

HPIC:

High Performance Ion Chromatography

HPLC:

High Performance Liquid Chromatography

HPMCP:

Hydroxypropyl methylcellulose phtalate

HPSEC:

High Performance Size Exclusion Chromatography

HS3st1:

Heparan Sulfate 3-O-sulfotransferase 1

IU:

International Units

IUBMB:

International Union of Biochemistry and Molecular Biology

IV:

Intravenously

LMWH(s):

Low Molecular Weight Heparin(s)

MI:

Miocardial Infarction

min:

Minutes

Mn:

Number average molecular weight

Mw:

Weight average molecular weight

NCBD(s):

Non-Biological Complex Drug(s)

NDST:

N-deacetylase/N-sulfotransferase

NIBSC:

National Institute for Biological Standards and Control

NMR:

Nuclear Magnetic Resonance

NSTEACS:

Non-ST-Elevation-ACS

OD:

Once-Daily

OMCL:

Official Medicines Control Laboratory

OSCS:

Oversulfated Chondroitin Sulfate

OSTs:

2-, 6-, and 3-O-sulfotransferases

PCI:

Percutaneous Coronary Intervention

PCR:

Polymerase Chain Reaction

PD:

Pharmacodynamic

PF4:

Platelet factor 4

Ph. Eur.:

European Pharmacopoeia

RI:

Refractive index

SAX-HPLC:

Strong Anion Exchange-High Perfomance Liquid Chromatography

SC:

Subcutaneously

STEMI:

ST-Elevation-MI

TFPI:

Tissue Factor Pathway Inhibitor

THR:

Total Hip Replacement

TID:

Thrice Daily

TKR:

Total Knee Replacement

Tmax:

Time to maximum concentration

UFH:

Unfractionated Heparin

US:

United States

USP:

United States Pharmacopeial Convention

USP-NF:

United States Pharmacopeia Convention and National Formulary

UV:

Ultraviolet

VTE:

Venous Thromboembolism

WHO:

World Health Organization

References

  • Achour O, Bridiau N, Godhbani A et al (2013) Ultrasonic-assisted preparation of a low molecular weight heparin (LMWH) with anticoagulant activity. Carbohydr Polym 97:684–689

    CAS  PubMed  Google Scholar 

  • Akl EA, Barba M, Rohilla S et al (2008) Low-molecular-weight heparins are superior to vitamin K antagonists for the long term treatment of venous thromboembolism in patients with cancer: a Cochrane systematic review. J Exp Clin Cancer Res 27:21

    PubMed Central  PubMed  Google Scholar 

  • Al Dieri R., Wagenvoord R, van Dedem GW et al (2003). The inhibition of blood coagulation by heparins of different molecular weight is caused by a common functional motif–the C-domain. J Thromb Haemost 1:907–914

    CAS  PubMed  Google Scholar 

  • Alam F, Al-Hilal TA, Chung SW et al (2014) Oral delivery of a potent anti-angiogenic heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid. Biomaterials 35:6543–6552

    CAS  PubMed  Google Scholar 

  • Anon (2014a) Heparins, low-molecular-mass. In: European Pharmacopoeia, 8.0 (ed), European Directorate For The Quality of Medicines and Healthcare, Strasbourg, 2392–2394

    Google Scholar 

  • Anon (2014b) Heparin sodium. In: European Pharmacopoeia, 8.0 (ed), European Directorate for the Quality of Medicines and HealthCare, Strasbourg, 2390–2391

    Google Scholar 

  • Anon (2014c) Heparin calcium. In: European Pharmacopoeia, 8.0 (ed), European Directorate for the Quality of Medicines and HealthCare, Strasbourg, 2388–2389

    Google Scholar 

  • Anon (2014d) USP 37 <208> Anti-factor Xa and anti-factor IIa assays for unfractionated and low molecular weight heparins. In: United States Pharmacopeia and National Formulary (USP 37-NF 32), The United States Pharmacopeial Convention, Rockville (MD), 152–155

    Google Scholar 

  • Anon (2014e) USP 38 <209> Low molecular weight heparin molecular weight determinations. In: United States Pharmacopeia and National Formulary (USP 38), The United States Pharmacopeial Convention, Rockville (MD), p. -in press

    Google Scholar 

  • Arora N, Goldhaber SZ (2006) Anticoagulants and transaminase elevation. Circulation 113:e698–e702

    PubMed  Google Scholar 

  • Auguste C, Dereux S, Rousset M, Anger P (2012) Validation of quantitative polymerase chain reaction methodology for monitoring DNA as a surrogate marker for species material contamination in porcine heparin. Anal Bioanal Chem 404:43–50

    CAS  PubMed  Google Scholar 

  • Baik JY, Wang CL, Yang B et al (2012) Toward a bioengineered heparin: challenges and strategies for metabolic engineering of mammalian cells. Bioengineered 3:227–231

    PubMed Central  PubMed  Google Scholar 

  • Bergqvist D, Nilsson B, Hedner U et al (1985) The effects of heparin fragments of different molecular weight in experimental thrombosis and haemostasis. Thromb Res 38:589–601

    CAS  PubMed  Google Scholar 

  • Bertini S, Bisio A, Torri G et al (2005). Molecular weight determination of heparin and dermatan sulfate by size exclusion chromatography with a triple detector array. Biomacromolecules 6:168–173

    PubMed  Google Scholar 

  • Beyer T, Diehl B, Randel G et al (2008) Quality assessment of unfractionated heparin using 1H nuclear magnetic resonance spectroscopy. J Pharm Biomed Anal 48:13–19

    CAS  PubMed  Google Scholar 

  • Bhaskar U, Sterner E, Hickey AM et al (2012) Engineering of routes to heparin and related polysaccharides. Appl Microbiol Biotechnol 93:1–16

    PubMed Central  PubMed  Google Scholar 

  • Buzzega D, Maccari F, Volpi N (2008) Fluorophore-assisted carbohydrate electrophoresis for the determination of molecular mass of heparins and low-molecular-weight (LMW) heparins. Electrophoresis 29:4192–4202

    CAS  PubMed  Google Scholar 

  • Carlsson P, Kjellén L (2012) Heparin biosynthesis. Handb Exp Pharmacol 207:23–41

    CAS  PubMed  Google Scholar 

  • Carter C, Kelton J, Hirsh J et al (1982) The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparins in rabbits. Blood 59:1239–1245

    CAS  PubMed  Google Scholar 

  • Chen J, Avci FY, Muñoz EM et al (2005) Enzymatic redesigning of biologically active heparan sulfate. J Biol Chem 280:42817–42825

    CAS  PubMed Central  PubMed  Google Scholar 

  • Choay J, Petitou M, Lormeau JC et al (1983) Structure-activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochem Biophys Res Commun 116:492–499

    CAS  PubMed  Google Scholar 

  • CMDh (2007) Overview of Biological Active Substances of Non-Recombinant Origin, CMDh, June 2007. http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/Compilation_Biological_Active_Substance_non-recombinant_origin.pdf. Accessed 12 Sept 2014

  • CMDh (2012) CMDh questions and answers biologicals. CMDh/269/2012, Rev0. http://www.hma.eu/20.html. Accessed 11 July 2014

  • Concannon SP, Wimberley PB, Workman WE (2011) A quantitative PCR method to quantify ruminant DNA in porcine crude heparin. Anal Bioanal Chem 399(2):757–62

    CAS  PubMed Central  PubMed  Google Scholar 

  • Datta P, Li G, Yang B et al (2013) Bioengineered Chinese hamster ovary cells with Golgi-targeted 3-O-sulfotransferase-1 biosynthesize heparan sulfate with an antithrombin-binding site. J Biol Chem 288:37308–37318

    CAS  PubMed Central  PubMed  Google Scholar 

  • De Caterina R, Husted S, Wallentin L et al (2013) Parenteral anticoagulants in heart disease: current status and perspectives (Section II). Position paper of the ESC working group on thrombosis-task force on anticoagulants in heart disease. Thromb Haemost 109:769–786

    PubMed  Google Scholar 

  • Dentali F, Douketis JD, Gianni M et al (2007) Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 146:278–288

    PubMed  Google Scholar 

  • Edens RE, Al-Hakim A, Weiler JM et al (1992) Gradient polyacrylamide gel electrophoresis for determination of molecular weights of heparin preparations and low-molecular-weight heparin derivatives. J Pharm Sci 81:823–827

    CAS  PubMed  Google Scholar 

  • Editorial Nature Biotechnology (2010) The identity problem. Nat Biotech 28:877

    Google Scholar 

  • EDQM (2009) The EDQM position on CEP Applications for Biological Substances. PA/PH/CEP (09) 152 rev 01 (EN). https://www.edqm.eu/site/cep_the_edqm_position_on_cep_applications_for_biolpdf-en-18486-2.html. Accessed 12 Sept 2014

  • Eikelboom JW, Quinlan DJ, Douketis JD (2001) Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet 358:9–15

    CAS  PubMed  Google Scholar 

  • EMA (2008) European Medicines Agency, London, 5 June 2008, Questions and Answers on Heparins, Doc. Ref. EMEA/276814/2008

    Google Scholar 

  • EMA (2013a) EMA/CHMP/BWP/429241/2013, Committee for Medicinal Products for Human Use (CHMP).Guideline on the use of starting materials and intermediates collected from different sources in the manufacturing of non-recombinant biological medicinal products. http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500145739&mid=WC0b01ac058009a3dc. Accessed 11 July 2014

  • EMA (2013b) EMEA/CHMP/BMWP/118264/2007 Rev. 1, Committee for Medicinal products for Human (CHMP). Guideline on non-clinical and clinical development of similar biological medicinal products containing low molecular-weight-heparins Draft. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/01/WC500138309.pdf. Accessed 12 Sept 2014

  • Ernst S, Rhomberg AJ, Biemann K, Sasisekharan R (1998) Direct evidence for a predominantly exolytic processive mechanism for depolymerization of heparin-like glycosaminoglycans by heparinase I. Proc Natl Acad Sci U S A 95:4182–4187

    CAS  PubMed Central  PubMed  Google Scholar 

  • Falck-Ytter Y, Francis CW, Johanson NA et al (2012) Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 141(Suppl 2):e278S–e325S

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fan B, Xing Y, Zheng Y et al (2014) pH-responsive thiolated chitosan nanoparticles for oral low-molecular weight heparin delivery: in vitro and in vivo evaluation. Drug Deliv 28:1–10

    CAS  Google Scholar 

  • FDA (2013) Guidance for Industry. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), Center for Devices and Radiological Health (CDRH). Heparin for Drug and Medical Device Use: Monitoring Crude Heparin for Quality. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291390.pdf. Accessed 11 July 2014

  • FDA (2014) Guidance for Industry. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) Immunogenicity-Related Considerations for the Approval of Low Molecular Weight Heparin for NDAs and ANDAs. DRAFT GUIDANCE. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM392194.pdf. Accessed 11 July 2014

  • Fisher WD, Agnelli G, George DJ et al (2013) Extended venous thromboembolism prophylaxis in patients undergoing hip fracture surgery—the SAVE-HIP3 study. Bone Joint J 95-B:459–466

    CAS  PubMed  Google Scholar 

  • FRISC study group (1996) Low-molecular-weight heparin during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Lancet 347:561–568

    Google Scholar 

  • Garcia DA, Baglin TP, Weitz JI et al (2012) Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 141(Suppl 2):e24S–e43S

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gasimli L, Glass CA, Datta P et al (2014) Bioengineering murine mastocytoma cells to produce anticoagulant heparin. Glycobiology 24:272–280

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gómez-Outes A, Suárez-Gea ML, Lecumberri R et al (2011) New parenteral anticoagulants in development. Ther Adv Cardiovasc Dis 5:33–59

    PubMed  Google Scholar 

  • Gómez-Outes A, Suárez-Gea ML, Calvo-Rojas G et al (2012) Discovery of anticoagulant drugs: a historical perspective. Curr Drug Discov Technol 9:83–104

    PubMed  Google Scholar 

  • Gray E, Mulloy B (2009) Biosimilar low molecular weight heparin products. J Thromb Haemost 7:1218–1221

    CAS  PubMed  Google Scholar 

  • Gray E, Mulloy B, Barrowcliffe TW (2008) Heparin and low-molecular-weight heparin. Thromb Haemost 99:807–818

    CAS  PubMed  Google Scholar 

  • Gray E, Hogwood J, Mulloy B (2012) The anticoagulant and antithrombotic mechanisms of heparin. Handb Exp Pharmacol 207:43–61 (Heparin—A century of Progress, R. Lever et al. (eds))

    CAS  PubMed  Google Scholar 

  • Guerrini M, Beccati D, Shriver Z et al (2008) Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events. Nat Biotechnol 26:669–675

    CAS  PubMed Central  PubMed  Google Scholar 

  • Guerrini M, Elli S, Gaudesi D et al (2010) Effects on molecular conformation and anticoagulant activities of 1,6-anhydrosugars at the reducing terminal of antithrombin-binding octasaccharides isolated from low-molecular-weight heparin enoxaparin. J Med Chem 53:8030–8040

    CAS  PubMed  Google Scholar 

  • Harenberg J, Devries JX, Waibel S, Zimmermann R (1983) High-performance size exclusion liquid-chromatography of heparins. Thromb Haemost 50:103

    Google Scholar 

  • Higashi K, Hosoyama S, Ohno A et al (2012) Photochemical preparation of a novel low molecular weight heparin. Carbohydr Polym 67:1737–1743

    PubMed Central  PubMed  Google Scholar 

  • Hirsh J, Levine MN (1992) Low molecular weight heparin. Blood 79:1–17

    CAS  PubMed  Google Scholar 

  • Houiste C, Auguste C, Makrez C et al (2009) Quantitative PCR and disaccharide profiling to characterize the animal origin of low-molecular-weight heparins. Clin Appl Thromb Hemost 15:50–58

    CAS  PubMed  Google Scholar 

  • Huang Q, Xu T, Wang GY et al (2012) Species-specific identification of ruminant components contaminating industrial crude porcine heparin using real-time fluorescent qualitative and quantitative PCR. Anal Bioanal Chem 402:1625–1634

    CAS  PubMed  Google Scholar 

  • Hull RD, Schellong SM, Tapson VF et al (2010) Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 153:8–18

    PubMed  Google Scholar 

  • Iverius PH (1971) Coupling of glycosaminoglycans to agarose beads (sepharose 4B) Biochem J 124:677–683

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jandik KA, Gu K, Linhardt RJ (1994) Action pattern of polysaccharide lyases on glycosaminoglycans. Glycobiology 4:289–296

    CAS  PubMed  Google Scholar 

  • Johnson EA, Kirkwood TBL, Stirling Y et al (1976) Four heparin preparations: anti-Xa potentiating effect of heparin after subcutaneous injection. Thromb Haemost 35:586–591

    CAS  PubMed  Google Scholar 

  • Jones CJ, Beni S, Limtiaco JF et al (2011) Heparin characterization: challenges and solutions. Annu Rev Anal Chem (Palo Alto Calif) 4:439–465

    CAS  Google Scholar 

  • Jongen P, de Kaste D (2011) Heparins and changing regulatory requirements in the EU. Pharmaeuropa 23:1

    Google Scholar 

  • Kane TA, White CL, DeAngelis PL (2006) Functional characterization of PmHS1, a Pasteurella multocida heparosan synthase. J Biol Chem 281:33192–33197

    CAS  PubMed  Google Scholar 

  • Kearon C, Akl EA, Comerota AJ et al (2012) Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 141(Suppl 2):e419S–e494S

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kellenbach E, Sanders K, Michiels PJ, Girard FC (2011) (1)H NMR signal at 2.10 ppm in the spectrum of KMnO(4)-bleached heparin sodium: identification of the chemical origin using an NMR-only approach. Anal Bioanal Chem 399:621–628

    CAS  PubMed  Google Scholar 

  • Kishimoto TK, Viswanathan K, Ganguly T et al (2008) Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med 358:2457–2467

    CAS  PubMed Central  PubMed  Google Scholar 

  • Knobloch JE, Shaklee PN (1997) Absolute molecular weight distribution of low-molecular-weight heparins by size-exclusion chromatography with multiangle laser light scattering detection. Anal Biochem 245:231–241

    CAS  PubMed  Google Scholar 

  • Komatsu H, Yoshii K, Ishimitsu S et al (1993) Molecular mass determination of low-molecular-mass heparins. Application of wide collection angle measurements of light scattering using a high-performance gel permeation chromatographic system equipped with a low-angle laser light-scattering photometer. J Chromatogr 644:17–24

    CAS  PubMed  Google Scholar 

  • Kristensen HI, Tromborg EM, Nielsen JR et al (1991) Development and validation of a size exclusion chromatography method for determination of molecular masses and molecular mass distribution in low molecular weight heparin. Thromb Res 64:131–141

    CAS  PubMed  Google Scholar 

  • Kuberan B, Beeler DL, Lech M et al (2003a) Chemoenzymatic synthesis of classical and non-classical anticoagulant heparan sulfate polysaccharides. J Biol Chem 278:52613–52621

    CAS  PubMed  Google Scholar 

  • Kuberan B, Lech MZ, Beeler DL et al (2003b) Enzymatic synthesis of antithrombin III-binding heparan sulfate pentasaccharide. Nat Biotechnol 21:1343–1346

    CAS  PubMed  Google Scholar 

  • Lassen MR, Dahl OE, Mismetti P (2009) AVE5026, a new hemisynthetic ultra-low-molecular-weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery–TREK: a dose-ranging study. J Thromb Haemost 7:566–572

    CAS  PubMed  Google Scholar 

  • Laurencin CT, Nair L (2008) The FDA and safety—beyond the heparin crisis. Nat Biotechnol 26:621–623

    CAS  PubMed  Google Scholar 

  • Lawson F, Turpie AG, SAVE-ONCO Investigators (2012) Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 366:601–609

    PubMed  Google Scholar 

  • Lee S, Raw A, Yu L et al (2013) Scientific considerations in the review and approval of generic enoxaparin in the United States. Nat Biotechnol 31:220–6

    CAS  PubMed  Google Scholar 

  • Levieux A, Rivera V, Levieux D (2002) Immunochemical control of the species origin of porcine crude heparin and detection of ovine and caprine materials. J Pharm Biomed Anal 27:305–313

    CAS  PubMed  Google Scholar 

  • Li L, Zhang F, Zaia J, Linhardt RJ (2012) Top-down approach for the direct characterization of low molecular weight heparins using LC-FT-MS. Anal Chem 84:8822–8829

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lim W, Cook DJ, Crowther MA (2004) Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-stage renal failure: a meta-analysis of randomized trials. J Am Soc Nephrol 15:3192–3206

    PubMed  Google Scholar 

  • Lindahl U, Thunberg L, Backstrom G et al (1984) Extension and structural variability of the antithrombin-binding sequence in heparin. J Biol Chem 259:12368–12376

    CAS  PubMed  Google Scholar 

  • Lindahl U, Li JP, Kusche-Gullberg M et al (2005) Generation of “neoheparin” from E. coli K5 capsular polysaccharide. J Med Chem 48:349–52

    CAS  PubMed  Google Scholar 

  • Linhardt RJ, Dordick PL, Deangelis PL, Liu J (2007) Enzymatic synthesis of glycosaminoglycan heparin. Semin Thromb Hemost 33:453–465.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liu H, Zhang Z, Linhardt RJ (2009) Lessons learned from the contamination of heparin. Nat Prod Rep 26:313–321

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liu Z, Ji S, Sheng J, Wang F (2014) Pharmacological effects and clinical applications of ultra low molecular weight heparins. Drug Discov Ther 8(1):1–10

    CAS  PubMed  Google Scholar 

  • Lord MS, Whitelock JM (2014) Bioengineered heparin. Is there a future for this form of the successful therapeutic? Bioengineered 5(4):1–5 (July/August 2014 (in press))

    Google Scholar 

  • Ludwig RJ (2009) Therapeutic use of heparin beyond anticoagulation. Curr Drug Discov Technol 6:281–289

    CAS  PubMed  Google Scholar 

  • Martínez-González J, Rodríguez C (2010) New challenges for a second-generation low-molecular-weight heparin: focus on bemiparin. Expert Rev Cardiovasc Ther 8:625–634

    PubMed  Google Scholar 

  • McEwen I, Mulloy B, Hellwig E et al (2008) Determination of oversulfated chondroitin sulfate and dermatan sulfate in unfractionated heparin by 1H NMR. Collaborative study for quantification and analytical determination of LoD. Pharmaeuropa Bio 2008(1):31–39

    CAS  Google Scholar 

  • Mintz CS, Liu JL (2013) China’s heparin revisited: what went wrong and has anything changed? J Commerc Biotechnol 19(1):33–39

    Google Scholar 

  • Mourier AJ, Viskov C (2004) Chromatographic analysis and sequencing approach of heparin oligosaccharides using cetylmethylammonium dynamically coated stationary phases. Anal Biochem 332:299–313

    CAS  PubMed  Google Scholar 

  • Mourier PA, Guichard OY, Herman F, Viskov C (2011) Heparin sodium compliance to the new proposed USP monograph: elucidation of a minor structural modification responsible for a process dependent 2.10 ppm NMR signal. J Pharm Biomed Anal 54:337–344

    CAS  PubMed  Google Scholar 

  • Mourier PA, Guichard OY, Herman F, Viskov C (2012) Heparin sodium compliance to USP monograph: structural elucidation of an atypical 2.18 ppm NMR signal. J Pharm Biomed Anal 67–68:169–174

    PubMed  Google Scholar 

  • Mulloy B (2012) Structure and physicochemical characterisation of heparin. Handb Exp Pharmacol 207:77–98

    CAS  PubMed  Google Scholar 

  • Mulloy B, Gee C, Wheeler SF et al (1997) Molecular weight measurements of low molecular weight heparins by gel permeation chromatography. Thromb Haemost 77:668–674

    CAS  PubMed  Google Scholar 

  • Mulloy B, Gray E, Barrowcliffe TW (2000) Characterization of unfractionated heparin: comparison of materials from the last 50 years. Thromb Haemost 84:1052–1056

    CAS  PubMed  Google Scholar 

  • Mulloy B, Heath A, Behr-Gross ME (2007) Establishment of replacement batches for heparin low-molecular-mass for calibration CRS, and the International Standard Low Molecular Weight Heparin for Calibration. Pharmeuropa Bio 2007:29–48

    CAS  PubMed  Google Scholar 

  • Mulloy B, Heath A, Shriver Z et al (2014) USP compendial methods for analysis of heparin: chromatographic determination of molecular weight distributions for heparin sodium. Anal Bioanal Chem 406:4815–4823

    CAS  PubMed  Google Scholar 

  • Murphy SA, Gibson CM, Morrow DA et al (2007) Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis. Eur Heart J 28:2077–2086

    CAS  PubMed  Google Scholar 

  • Navarese EP, De Luca G, Castriota F et al (2011) Low-molecular-weight heparins vs unfractionated heparin in the setting of percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis. J Thromb Haemost 9:1902–1915

    Google Scholar 

  • NC-IUBMB (2014) Nomenclature committee of the international union of biochemistry and molecular biology. Enzyme Nomenclature. Recommendations. http://www.chem.qmul.ac.uk/iubmb/enzyme/EC4/2/2/. Accessed 12 Sept 2014

  • Nielsen JI (1992) A convenient method for molecular mass determination of heparin. Thromb Haemost 68:478–480

    CAS  PubMed  Google Scholar 

  • Paty I, Trellu M, Destors JM et al (2010) Reversibility of the anti-FXa activity of idrabiotaparinux (biotinylated idraparinux) by intravenous avidin infusion. J Thromb Haemost 8:722–729

    CAS  PubMed  Google Scholar 

  • Peters SM, Jones YL, Perrella F et al (2014) Development of a multiplex real-time PCR assay for the detection of ruminant DNA in raw materials used for monitoring crude heparin for quality. Draft. http://www.fda.gov/AnimalVeterinary/ScienceResearch/ToolsResources/ucm350289.htm. Accessed 11 July 2014

  • Petitou M, van Boeckel CAA (2004) A synthetic antithrombin III binding pentasaccharide is now a drug! What comes next? Angew Chem Int Ed Engl 43:3118–3133

    CAS  PubMed  Google Scholar 

  • Petitou M, Jacquinet JC, Choay J et al (1989) Process for the organic synthesis of oligosaccharides and derivatives thereof. US Patent 4,818,816

    Google Scholar 

  • Petitou M, Herault JP, Bernat A et al (1999) Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 398:417–422

    CAS  PubMed  Google Scholar 

  • Rico S, Antonijoan RM, Gich I et al (2011) Safety assessment and pharmacodynamics of a novel ultra low molecular weight heparin (RO-14) in healthy volunteers-a first-time-in-human single ascending dose study. Thromb Res 127:292–298

    CAS  PubMed  Google Scholar 

  • Rivera V, Levieux A, Levieux D (2002) Immunochemical characterisation of species-specific antigens in bovine crude heparin. J Pharm Biomed Anal 29:431–441

    CAS  PubMed  Google Scholar 

  • Rosenberg RD, Damus PS (1973) The purification and mechanism of action of human antithrombin-heparin cofactor. J Biol Chem 248:6490–6505

    CAS  PubMed  Google Scholar 

  • Savi P, Herault JP, Duchaussoy P et al (2008) Reversible biotinylated oligosaccharides: a new approach for a better management of anticoagulant therapy. J Thromb Haemost 6:1697–1706

    CAS  PubMed  Google Scholar 

  • Schroeder M, Hogwood J, Gray E et al (2011) Protamine neutralisation of low molecular weight heparins and their oligosaccharide components. Anal Bioanal Chem 399:763–771

    CAS  PubMed  Google Scholar 

  • Senior M (2013) Biosimilars battle rages on, Amgen fights both sides. Nat Biotechnol 31:269–270

    CAS  PubMed  Google Scholar 

  • Shastri MD, Peterson GM, Stewart N et al (2014) Non-anticoagulant derivatives of heparin for the management of asthma: distant dream or close reality? Expert Opin Investig Drugs 23:357–373

    CAS  PubMed  Google Scholar 

  • Shriver Z, Sundaram M, Venkataraman G et al (2000) Cleavage of the antithrombin III binding site in heparin by heparinases and its implication in the generation of low molecular weight heparin. Proc Nat Acad Sci U S A 97:10365–10370

    CAS  Google Scholar 

  • Thunberg L, Bäckström G, Lindahl U (1982) Further characterization of the antithrombin-binding sequence in heparin. Carbohydr Res 100:393–410

    CAS  PubMed  Google Scholar 

  • Tumolo T, Angnes L, Baptista MS (2004) Determination of the refractive index increment (dn/dc) of molecule and macromolecule solutions by surface plasmon resonance. Anal Biochem 333:273–279

    CAS  PubMed  Google Scholar 

  • van Dedem GW, Nielsen JI (1991) Determination of the molecular mass of low molecular mass (LMM) heparin. Pharmeuropa 3:202–218

    Google Scholar 

  • van Gogh Investigators, Buller HR, Cohen AT et al (2007) Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 357:1094–104

    Google Scholar 

  • Vignoli A, Marchetti M, Russo L et al (2011) LMWH bemiparin and ULMWH RO-14 reduce the endothelial angiogenic features elicited by leukemia, lung cancer, or breast cancer cells. Cancer Invest 29:153–161

    CAS  PubMed  Google Scholar 

  • Viskov C, Bouley E, Hubert P et al (2009a) Isolation and characterization of contaminants in recalled unfractionated heparin and low-molecular-weight heparin. Clin Appl Thromb Hemost 15:395–401

    CAS  PubMed  Google Scholar 

  • Viskov C, Just M, Laux V et al (2009b) Description of the chemical and pharmacological characteristics of a new hemisynthetic ultra-low-molecular-weight heparin, AVE5026. J Thromb Haemost 7:1143–1151

    CAS  PubMed  Google Scholar 

  • WHO (2014) WHO International biological reference preparations. http://www.who.int/biologicals/reference_preparations/en/. Accessed 12 Sept 2014

  • Xu Y, Masuko S, Takieddin M et al (2011) Chemoenzymatic synthesis of structurally homogeneous ultra-low molecular weight heparins. Science 334:498–501

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xu Y, Cai C, Chandarajoti K et al (2014) Homogeneous low-molecular-weight heparins with reversible anticoagulant activity. Nat Chem Biol 10:248–250

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang Z, Weïwer M, Li B et al (2008) Oversulfated chondroitin sulfate: Impact of a heparin impurity, associated with adverse clinical events, on low-molecular-weight heparin preparation. J Med Chem 51:5498–5501

    CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Biological Products and Biotechnology Division Medicines for Human Use Department, Spanish Agency for Medicines and Medical Devices (AEMPS), C/Campezo 1, Edificio 8, 28022, Madrid, Spain

    Dr. Isabel Rodrigo, Dr. Sofía Caruncho & Dr. Concepción Alonso

  2. Pharmacology and Clinical Evaluation Division, Medicines for Human Use Department, Spanish Agency for Medicines and Medical Devices (AEMPS), C/Campezo 1, Edificio 8, 28022, Madrid, Spain

    Dr. Antonio Gómez-Outes

  3. Institute of Pharmaceutical Science, King’s College London, Franklin Wilkins Building, 150 Stamford Street, Waterloo Campus, SE1 9NH, London, UK

    Dr. Barbara Mulloy

Authors
  1. Dr. Isabel Rodrigo
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  2. Dr. Sofía Caruncho
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  3. Dr. Concepción Alonso
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  4. Dr. Antonio Gómez-Outes
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  5. Dr. Barbara Mulloy
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Corresponding author

Correspondence to Isabel Rodrigo .

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Editors and Affiliations

  1. Utrecht University, Utrecht, Utrecht, The Netherlands

    Daan J.A. Crommelin

  2. Top Institute Pharma NBCD Working Group, Leiden, The Netherlands

    Jon S. B. de Vlieger

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Rodrigo, I., Caruncho, S., Alonso, C., Gómez-Outes, A., Mulloy, B. (2015). Low Molecular Weight Heparins, Biological Drugs close to Non-Biological Complex Drugs. In: Crommelin, D., de Vlieger, J. (eds) Non-Biological Complex Drugs. AAPS Advances in the Pharmaceutical Sciences Series, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-319-16241-6_9

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