The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Robert J Linhardt - One of the best experts on this subject based on the ideXlab platform.
-
engineered Heparins as new anticoagulant drugs
Bioengineering & translational medicine, 2017Co-Authors: Deepika Vaidyanathan, Jonathan S. Dordick, Asher Williams, Mattheos A G Koffas, Robert J LinhardtAbstract:Heparin is an anionic polysaccharide that is widely used as a clinical anticoagulant. This glycosaminoglycan is prepared from animal tissues in metric ton quantities. Animal-sourced heparin is also widely used in the preparation of low molecular weight Heparins that are gaining in popularity as a result of their improved pharmacological properties. The recent contamination of pharmaceutical heparin together with concerns about increasing demand for this life saving drug and the fragility of the heparin supply chain has led the scientific community to consider other potential sources for heparin. This review examines progress toward the preparation of engineered Heparins through chemical synthesis, chemoenzymatic synthesis, and metabolic engineering.
-
Heparin and anticoagulation.
Frontiers in bioscience (Landmark edition), 2016Co-Authors: Akihiro Onishi, St Ange K, Jonathan S. Dordick, Robert J LinhardtAbstract:Heparin, a sulfated polysaccharide, has been used as a clinical anticoagulant for over 90 years. Newer anticoagulants, introduced for certain specialized applications, have not significantly displaced heparin and newer heparin-based anticoagulants in most medical procedures. This chapter, while reviewing anticoagulation and these newer anticoagulants, focuses on heparin-based anticoagulants, including unfractionated heparin, low molecular weight Heparins and ultra-low molecular weight Heparins. Heparin's structures and its biological and therapeutic roles are discussed. Particular emphasis is placed on heparin's therapeutic application and its adverse effects. The future prospects are excellent for new Heparins and new heparin-based therapeutics with improved properties.
-
comparison of low molecular weight Heparins prepared from bovine lung heparin and porcine intestine heparin
Journal of Pharmaceutical Sciences, 2016Co-Authors: Yudong Guan, Robert J Linhardt, Xinyue Liu, Anran Sheng, Lan Jin, Lianli ChiAbstract:Currently porcine intestine is the only approved source for producing pharmaceutical heparin in most countries. Enoxaparin, prepared by benzylation and alkaline depolymerization from porcine intestine heparin, is prevalent in the anticoagulant drug market. It is predicted that porcine intestine heparin-derived enoxaparin (PIE) will encounter shortage, and expanding its production from Heparins obtained from other animal tissues may, therefore, be inevitable. Bovine lung heparin is a potential alternative source for producing enoxaparin. Critical processing parameters for producing bovine lung heparin-derived enoxaparin (BLE) are discussed. Three batches of BLEs were prepared and their detailed structures were compared with PIEs using modern analytical techniques, including disaccharide composition, intact chain mapping by liquid chromatography-mass spectrometry and 2-dimensional nuclear magnetic resonance spectroscopy. The results suggested that the differences between PIEs and BLEs mainly result from N-acetylation differences derived from the parent Heparins. In addition, bioactivities of BLEs were about 70% of PIEs based on anti-factor IIa and Xa chromogenic assays. We conclude that BLE has the potential to be developed as an analogue of PIE, although some challenges still remain.
-
structural characterization of pharmaceutical Heparins prepared from different animal tissues
Journal of Pharmaceutical Sciences, 2013Co-Authors: Bo Yang, Fuming Zhang, Akihiro Onishi, Peilong Sun, Robert J LinhardtAbstract:Although most pharmaceutical heparin used today is obtained from porcine intestine, heparin has historically been prepared from bovine lung and ovine intestine. There is some regulatory concern about establishing the species origin of heparin. This concern began with the outbreak of mad cow disease in the 1990s and was exacerbated during the heparin shortage in the 2000s and the heparin contamination crisis of 2007-2008. Three Heparins from porcine, ovine, and bovine were characterized through state-of-the-art carbohydrate analysis methods with a view profiling their physicochemical properties. Differences in molecular weight, monosaccharide and disaccharide composition, oligosaccharide sequence, and antithrombin III-binding affinity were observed. These data provide some insight into the variability of Heparins obtained from these three species and suggest some analytical approaches that may be useful in confirming the species origin of a heparin active pharmaceutical ingredient.
-
chemoenzymatic synthesis of homogeneous ultralow molecular weight Heparins
Science, 2011Co-Authors: Sayaka Masuko, Robert J Linhardt, Majde Takieddin, Renpeng Liu, Juliana Jing, Shaker A Mousa, Jian LiuAbstract:Ultralow molecular weight (ULMW) Heparins are sulfated glycans that are clinically used to treat thrombotic disorders. ULMW Heparins range from 1500 to 3000 daltons, corresponding from 5 to 10 saccharide units. The commercial drug Arixtra (fondaparinux sodium) is a structurally homogeneous ULMW heparin pentasaccharide that is synthesized through a lengthy chemical process. Here, we report 10- and 12-step chemoenzymatic syntheses of two structurally homogeneous ULMW Heparins (MW = 1778.5 and 1816.5) in 45 and 37% overall yield, respectively, starting from a simple disaccharide. These ULMW Heparins display excellent in vitro anticoagulant activity and comparable pharmacokinetic properties to Arixtra, as demonstrated in a rabbit model. The chemoenzymatic approach is scalable and shows promise for a more efficient route to synthesize this important class of medicinal agent.
Graham F. Pineo - One of the best experts on this subject based on the ideXlab platform.
-
Low molecular weight heparin
Handbook of experimental pharmacology, 1999Co-Authors: Graham F. Pineo, Russell D. HullAbstract:Unfractionated heparin is used widely for the prevention of venous thromboembolism in medical patients or in patients undergoing various surgical procedures. Furthermore, unfractionated heparin, given by a continuous intravenous infusion with laboratory monitoring using the activated partial thromboplastin time (APTT), with warfarin starting on day 1 or day 2 and continued for 3 months, has been the standard treatment of established venous thromboembolism. Heparin is used in a number of other clinical settings and constitutes one of the most frequently used agents in hospital medicine. Over the past 15 years, various low molecular weight Heparins have been evaluated against a number of different controls, including unfractioned heparin for many of these clinical problems. In a number of countries, the low molecular weight Heparins have replaced unfractioned heparin for both the prevention and treatment of venous thromboembolism. The low molecular weight Heparins have also been used in clinical trials for the prevention and treatment of arterial thrombosis. In this chapter, we review the problems related to the use of unfractioned heparin, compare the low molecular weight Heparins with unfractioned heparin, and discuss their role in the prevention and treatment of venous thromboembolism, as well as in arterial thrombosis.
-
Treatment of Venous Thromboembolism with Low-Molecular-Weight Heparin.
Journal of Thrombosis and Thrombolysis, 1995Co-Authors: Russell D. Hull, Graham F. PineoAbstract:There is now ample evidence to indicate that certain low-molecular-weight Heparins given subcutaneously can replace continuous intravenous unfractionated heparin for the initial treatment of venous thromboembolism. The low-molecular-weight Heparins have a predictably high absorption rate when given subcutaneously and a prolonged duration of action, permitting them to be given by a once or twice daily injection for the prevention or treatment of venous thrombosis. Furthermore, treatment does not require laboratory monitoring, thus eliminating the need for continuous IV infusion and permitting the early discharge of patients with venous thromboembolism. This should eventually lead to the outpatient treatment of venous thromboembolism. Studies to date indicate that low-molecular-weight heparin is more cost-effective than unfractionated heparin in the treatment of venous thromboembolism and the cost effectiveness will be increased by out-of-hospital treatment. At the present time, the findings associated with any individual lowmolecular-weight heparin preparation cannot be extrapolated to different low-molecular-weight Heparins, and therefore each must be evaluated in separate clinical trials. The information to date is that low-molecular-weight heparin is safer and more effective than continuous intravenous unfractionated heparin in the treatment of proximal venous thrombosis. The decreased mortality rate seen in two clinical trials, particularly in patients with metastatic cancer, was quite unexpected. This requires further confirmation in larger prospective randomized trials.
-
Low-molecular-weight Heparins for the Treatment of Venous Thromboembolism
Annals of Medicine, 1993Co-Authors: Russell D. Hull, Graham F. PineoAbstract:Recent studies have indicated that certain low-molecular-weight Heparins given subcutaneously may replace continuous intravenous unfractionated heparin for the treatment of venous thromboembolism. Low-molecular-weight Heparins have a predictably high absorption rate when given subcutaneously and they do not require laboratory monitoring. These characteristics of low-molecular-weight heparin therapy raise the possibility of treating uncomplicated patients with deep venous thrombosis or pulmonary embolism in the outpatient setting. The advantages to the patient of avoiding in-hospital care and its associated hazards are obvious. Outpatient lowmolecular-weight heparin will likely prove to be highly cost-effective. At the present time, the findings associated with an individual low-molecular-weight heparin preparation cannot be extrapolated to different low-molecular-weight Heparins and each must be evaluated in separate clinical trials. Recent randomized clinical trials indicate that low-molecular-weight hep...
Russell D. Hull - One of the best experts on this subject based on the ideXlab platform.
-
Low molecular weight heparin
Handbook of experimental pharmacology, 1999Co-Authors: Graham F. Pineo, Russell D. HullAbstract:Unfractionated heparin is used widely for the prevention of venous thromboembolism in medical patients or in patients undergoing various surgical procedures. Furthermore, unfractionated heparin, given by a continuous intravenous infusion with laboratory monitoring using the activated partial thromboplastin time (APTT), with warfarin starting on day 1 or day 2 and continued for 3 months, has been the standard treatment of established venous thromboembolism. Heparin is used in a number of other clinical settings and constitutes one of the most frequently used agents in hospital medicine. Over the past 15 years, various low molecular weight Heparins have been evaluated against a number of different controls, including unfractioned heparin for many of these clinical problems. In a number of countries, the low molecular weight Heparins have replaced unfractioned heparin for both the prevention and treatment of venous thromboembolism. The low molecular weight Heparins have also been used in clinical trials for the prevention and treatment of arterial thrombosis. In this chapter, we review the problems related to the use of unfractioned heparin, compare the low molecular weight Heparins with unfractioned heparin, and discuss their role in the prevention and treatment of venous thromboembolism, as well as in arterial thrombosis.
-
Treatment of Venous Thromboembolism with Low-Molecular-Weight Heparin.
Journal of Thrombosis and Thrombolysis, 1995Co-Authors: Russell D. Hull, Graham F. PineoAbstract:There is now ample evidence to indicate that certain low-molecular-weight Heparins given subcutaneously can replace continuous intravenous unfractionated heparin for the initial treatment of venous thromboembolism. The low-molecular-weight Heparins have a predictably high absorption rate when given subcutaneously and a prolonged duration of action, permitting them to be given by a once or twice daily injection for the prevention or treatment of venous thrombosis. Furthermore, treatment does not require laboratory monitoring, thus eliminating the need for continuous IV infusion and permitting the early discharge of patients with venous thromboembolism. This should eventually lead to the outpatient treatment of venous thromboembolism. Studies to date indicate that low-molecular-weight heparin is more cost-effective than unfractionated heparin in the treatment of venous thromboembolism and the cost effectiveness will be increased by out-of-hospital treatment. At the present time, the findings associated with any individual lowmolecular-weight heparin preparation cannot be extrapolated to different low-molecular-weight Heparins, and therefore each must be evaluated in separate clinical trials. The information to date is that low-molecular-weight heparin is safer and more effective than continuous intravenous unfractionated heparin in the treatment of proximal venous thrombosis. The decreased mortality rate seen in two clinical trials, particularly in patients with metastatic cancer, was quite unexpected. This requires further confirmation in larger prospective randomized trials.
-
Low-molecular-weight Heparins for the Treatment of Venous Thromboembolism
Annals of Medicine, 1993Co-Authors: Russell D. Hull, Graham F. PineoAbstract:Recent studies have indicated that certain low-molecular-weight Heparins given subcutaneously may replace continuous intravenous unfractionated heparin for the treatment of venous thromboembolism. Low-molecular-weight Heparins have a predictably high absorption rate when given subcutaneously and they do not require laboratory monitoring. These characteristics of low-molecular-weight heparin therapy raise the possibility of treating uncomplicated patients with deep venous thrombosis or pulmonary embolism in the outpatient setting. The advantages to the patient of avoiding in-hospital care and its associated hazards are obvious. Outpatient lowmolecular-weight heparin will likely prove to be highly cost-effective. At the present time, the findings associated with an individual low-molecular-weight heparin preparation cannot be extrapolated to different low-molecular-weight Heparins and each must be evaluated in separate clinical trials. Recent randomized clinical trials indicate that low-molecular-weight hep...
S Alban - One of the best experts on this subject based on the ideXlab platform.
-
Adverse Effects of Heparin
Handbook of experimental pharmacology, 2011Co-Authors: S AlbanAbstract:All the adverse effects of Heparins are related to their wide variety of biological activities, with bleeding being the most important safety issue, resulting directly from the potency of heparin as an anticoagulant. However, it is hard to define the bleeding risk, since it depends on numerous parameters including the indication, dosage, method, and duration of heparin application, the clinical study design and definition of bleeding as well as patient characteristics and determinants of bleeding such as type of surgery and co-medication. Nonbleeding complications of Heparins are caused by binding of heparin molecules to proteins other than antithrombin and to cells, which is generally more pronounced with unfractionated heparin than with low-molecular-weight Heparins. Accordingly, heparin-induced thrombocytopenia, the most severe nonbleeding adverse reaction, occurs about 10 times less with low-molecular-weight Heparins than with unfractionated heparin. Frequent and therefore important adverse reactions of Heparins are skin lesions resulting from delayed-type hypersensitivity reactions. All the other undesirable effects are discussed as well, but they are mostly clinically irrelevant.
-
prothrombin time for detection of contaminated Heparins
The New England Journal of Medicine, 2008Co-Authors: S Alban, Susanne LuhnAbstract:These authors report on the use of prothrombin time to detect OSCS contamination in both unfractionated heparin and low-molecular-weight Heparins. At concentrations of 5 _6;g per milliliter or less, contaminated unfractionated heparin, but not unfractionated heparin, shortened the prothrombin time.
-
the ability of different forms of Heparins to suppress p selectin function in vitro correlates to their inhibitory capacity on bloodborne metastasis in vivo
Thrombosis and Haemostasis, 2006Co-Authors: Ralf Ludwig, S Alban, Roxana Bistrian, Wolfhenning Boehncke, Roland Kaufmann, Reinhard Henschler, Jens GilleAbstract:Ample evidence suggests that many of the in vivo anti-metastatic effects by Heparins reflect their actions on P-selectin-mediated binding. We hypothesized that the ability of widely used Heparins and derivatives to interfere with P-selectin-dependent tumour cell interactions under flow in vitro could be used to identify anticoagulants with advanced inhibitory functions on experimental blood-borne metastasis in vivo. To test this assumption, the impact of unfractionated heparin, the low-molecular-weight Heparins (LMWH) nadroparin and enoxaparin, and the synthetic pentasaccharide fondaparinux on P-selectin-dependent tumour interactions in vitro and metastasis formation in vivo were evaluated. Our data revealed that these commonly used anticoagulants widely differ in their potential to interfere with P-selectinmediated cell binding. Importantly, the superior inhibitory capacity on P-selectin function of unfractionated heparin and LMWH nadroparin as opposed to LMWH enoxaparin and synthetic heparin pentasaccharide fondaparinux strongly correlated to the inhibitory potency of each in inhibiting experimental lung metastasis in vivo. Hence, P-selectin inhibition may constitute a valuable feature to identify anticoagulants that are suitable for anticancer therapy.
-
fixed dosage of low molecular weight Heparins causes large individual variation in coagulability only partly correlated to body weight
Journal of Thrombosis and Haemostasis, 2006Co-Authors: Al R Dieri, S Alban, Suzette Beguin, H C HemkerAbstract:Summary. Backgrounds: Low-molecular-weight Heparins (LMWHs) are routinely given without the control of their effect on coagulation. The endogenous thrombin potential (ETP) is a sensitive detector of the heparin effect. Question: What is the interindividual variation in TG after a fixed dose of LMWH in normal volunteers, is it explained by variation in weight? Methods: Subcutaneous (s.c.) injection, in 12 healthy volunteers, of 9000 aXa-units of unfractionated heparin (UFH) and of three Heparins with narrow MW distribution around 10.5, 6.0 and 4.5 kD. Measurement of anti-thrombin (aIIa) and antifactor Xa (aXa)-activities and ETP at 11 time points over 24 h. Results: The coefficient of variation (CV) of the AUCs of aXa- and aIIa-activities is 50% for UFH and 22–37% for LMWHs. Because of the hyperbolic form of the dose–response curve, the CV of the inhibition of the ETP is lower: 32% for UFH and 13–21% for the LMWHs. Fixed dosage of LMWH caused under-dosage in 10–13% of the samples and over-dosage in 5–11%. High or low response is an individual property independent of the type of heparin injected and only partially explained by variation in body weight. Conclusion: Optimized individual dosage of LMWH is possible through recognition of high and low responders, which requires one measurement of the heparin concentration or, preferably, the heparin effect on the ETP, 2–5 h after a first injection.
Fuming Zhang - One of the best experts on this subject based on the ideXlab platform.
-
analysis of Heparins derived from bovine tissues and comparison to porcine intestinal Heparins
Clinical and Applied Thrombosis-Hemostasis, 2016Co-Authors: Kalib St Ange, Jawed Fareed, Akihiro Onishi, Jonathan S. Dordick, Fuming Zhang, Xiaojun Sun, Lei Lin, Daisuke Mori, Debra Hoppensteadt, Walter JeskeAbstract:Heparin is a widely used clinical anticoagulant. It is also a linear glycosaminoglycan with an average mass between 10 and 20 kDa and is primarily made up of trisulfated disaccharides comprised of 1,4-linked iduronic acid and glucosamine residues containing some glucuronic acid residues. Heparin is biosynthesized in the Golgi of mast cells commonly found in the liver, intestines, and lungs. Pharmaceutical heparin currently used in the United States is primarily extracted from porcine intestines. Other sources of heparin including bovine intestine and bovine lung are being examined as potential substitutes for porcine intestinal heparin. These additional sources are intended to serve to diversify the heparin supply, making this lifesaving drug more secure. The current study examines bovine Heparins prepared from both intestines and lung and compares these to porcine intestinal heparin. The structural properties of these Heparins are examined using nuclear magnetic resonance, gel permeation chromatography, ...
-
structural characterization of pharmaceutical Heparins prepared from different animal tissues
Journal of Pharmaceutical Sciences, 2013Co-Authors: Bo Yang, Fuming Zhang, Akihiro Onishi, Peilong Sun, Robert J LinhardtAbstract:Although most pharmaceutical heparin used today is obtained from porcine intestine, heparin has historically been prepared from bovine lung and ovine intestine. There is some regulatory concern about establishing the species origin of heparin. This concern began with the outbreak of mad cow disease in the 1990s and was exacerbated during the heparin shortage in the 2000s and the heparin contamination crisis of 2007-2008. Three Heparins from porcine, ovine, and bovine were characterized through state-of-the-art carbohydrate analysis methods with a view profiling their physicochemical properties. Differences in molecular weight, monosaccharide and disaccharide composition, oligosaccharide sequence, and antithrombin III-binding affinity were observed. These data provide some insight into the variability of Heparins obtained from these three species and suggest some analytical approaches that may be useful in confirming the species origin of a heparin active pharmaceutical ingredient.
-
structural characterization of Heparins from different commercial sources
Analytical and Bioanalytical Chemistry, 2011Co-Authors: Fuming Zhang, Jonathan S. Dordick, Zhongping Xiao, Bo Yang, Kemal Solakyildirim, Zhenyu Wang, Julie M Beaudet, Amanda Y Torelli, Robert J LinhardtAbstract:Seven commercial heparin active pharmaceutical ingredients and one commercial low molecular weight from different manufacturers were characterized with a view profiling their physicochemical properties. All Heparins had similar molecular weight properties as determined by polyacrylamide gel electrophoresis (MN, 10–11 kDa; MW, 13–14 kDa; polydispersity (PD), 1.3–1.4) and by size exclusion chromatography (MN, 14–16 kDa; MW, 21–25 kDa; PD, 1.4–1.6). one-dimensional 1H- and 13C-nuclear magnetic resonance (NMR) evaluation of the heparin samples was performed, and peaks were fully assigned using two-dimensional NMR. The percentage of glucosamine residues with 3-O-sulfo groups and the percentage of N-sulfo groups and N-acetyl groups ranged from 5.8–7.9%, 78–82%, to 13–14%, respectively. There was substantial variability observed in the disaccharide composition, as determined by high performance liquid chromatography (HPLC)-mass spectral analysis of heparin lyase I–III digested Heparins. Heparin oligosaccharide mapping was performed using HPLC following separate treatments with heparin lyase I, II, and III. These maps were useful in qualitatively and quantitatively identifying structural differences between these Heparins. The binding affinities of these Heparins to antithrombin III and thrombin were evaluated by using a surface plasmon resonance competitive binding assay. This study provides the physicochemical and activity characterization necessary for the appropriate design and synthesis of a generic bioengineered heparin.
-
analysis of pharmaceutical Heparins and potential contaminants using 1h nmr and page
Journal of Pharmaceutical Sciences, 2009Co-Authors: Zhenqing Zhang, Fuming Zhang, Zhenyu Wang, Jiraporn Suwan, Haiying Liu, Barbara Mulloy, Robert J LinhardtAbstract:In 2008, heparin (active pharmaceutical ingredient, API) lots were associated with anaphylactoid-type reactions. Oversulfated chondroitin sulfate (OSCS), a semi-synthetic glycosaminoglycan (GAG), was identified as a contaminant and dermatan sulfate (DS) as an impurity. While DS has no known toxicity, OSCS was toxic leading to patient deaths. Heparins, prepared before these adverse reactions, needed to be screened for impurities and contaminants. Heparins were analyzed using high-field 1H-NMR spectroscopy. Heparinoids were mixed with a pure heparin and analyzed by 1H-NMR to assess the utility of 1H-NMR for screening heparin adulterants. Sensitivity of heparinoids to deaminative cleavage, a method widely used to depolymerize heparin, was evaluated with polyacrylamide gel electrophoresis to detect impurities and contaminants, giving limits of detection (LOD) ranging from 0.1% to 5%. Most pharmaceutical Heparins prepared between 1941 and 2008 showed no impurities or contaminants. Some contained DS, CS, and sodium acetate impurities. Heparin prepared in 2008 contained OSCS contaminant. Heparin adulterated with heparinoids showed additional peaks in their high-field 1H-NMR spectra, clearly supporting NMR for monitoring of heparin API with an LOD of 0.5–10%. Most of these heparinoids were stable to nitrous acid treatment suggesting its utility for evaluating impurities and contaminants in heparin API. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4017–4026, 2009