“…37 Nevertheless, several episodes of post-surgical bleeding related to inadequate protamine neutralization of HBI were reported in Brazilian Hospitals in the late 2000s. 38,39 The mass-mass nature of the protamine neutralization reaction and the uneven inactivation of the distinct chains component of HBI may have been the cause of these incidents. 27,28 The current protocols based on monitoring the coagulant state of patients during the protamine-neutralization procedures are effective to evaluate the inactivation of the HBI chains with enhanced anionic strength and anticoagulant activity.…”
Unfractionated heparin (UFH) and their low-molecular-weight derivatives are sourced almost exclusively from porcine mucosa (HPI); however, a worldwide introduction of UFH from bovine mucosa (HBI) has been recommended to reinforce the currently unsteady supply chain of heparin products. Although HBI has different chemical composition and about half of the anticoagulant potency of HPI (∼100 and ∼180 international unit [IU]/mg, respectively), they have been employed as interchangeable UFHs in some countries since the 1990s. However, their use as a single drug provoked several bleeding incidents in Brazil, which precipitated the publication of the first monographs exclusive for HBI and HPI by the Brazilian Pharmacopoeia. Nevertheless, we succeed in producing with high-resolution anion-exchange chromatography a novel HBI derivative with anticoagulant potency (200 IU/mg), disaccharide composition (enriched in N,6-disulfated α-glucosamine) and safety profile (bleeding and heparin-induced thrombocytopaenia potentials and protamine neutralization) similar to those seen in the gold standard HPI. Therefore, we show that it is possible to equalize the composition and pharmacological characteristics of these distinct UFHs by employing an easily implementable improvement in the HBI manufacturing.
“…37 Nevertheless, several episodes of post-surgical bleeding related to inadequate protamine neutralization of HBI were reported in Brazilian Hospitals in the late 2000s. 38,39 The mass-mass nature of the protamine neutralization reaction and the uneven inactivation of the distinct chains component of HBI may have been the cause of these incidents. 27,28 The current protocols based on monitoring the coagulant state of patients during the protamine-neutralization procedures are effective to evaluate the inactivation of the HBI chains with enhanced anionic strength and anticoagulant activity.…”
Unfractionated heparin (UFH) and their low-molecular-weight derivatives are sourced almost exclusively from porcine mucosa (HPI); however, a worldwide introduction of UFH from bovine mucosa (HBI) has been recommended to reinforce the currently unsteady supply chain of heparin products. Although HBI has different chemical composition and about half of the anticoagulant potency of HPI (∼100 and ∼180 international unit [IU]/mg, respectively), they have been employed as interchangeable UFHs in some countries since the 1990s. However, their use as a single drug provoked several bleeding incidents in Brazil, which precipitated the publication of the first monographs exclusive for HBI and HPI by the Brazilian Pharmacopoeia. Nevertheless, we succeed in producing with high-resolution anion-exchange chromatography a novel HBI derivative with anticoagulant potency (200 IU/mg), disaccharide composition (enriched in N,6-disulfated α-glucosamine) and safety profile (bleeding and heparin-induced thrombocytopaenia potentials and protamine neutralization) similar to those seen in the gold standard HPI. Therefore, we show that it is possible to equalize the composition and pharmacological characteristics of these distinct UFHs by employing an easily implementable improvement in the HBI manufacturing.
“…These issues have led researchers and regulatory agencies to consider alternative supplies of heparins, either the development of bioengineered heparins, synthetic heparins, or the reintroduction of bovine heparin into the pharmaceutical market . Bovine lung heparin was successfully used in the U.S. until the 1990s when it was voluntarily withdrawn following the outbreak of bovine spongiform encephalopathy (BSE) in Europe, and BI mucosa heparin has been more recently used in South America. ,, …”
Section: Introductionmentioning
confidence: 99%
“…18 Bovine lung heparin was successfully used in the U.S. until the 1990s when it was voluntarily withdrawn following the outbreak of bovine spongiform encephalopathy (BSE) in Europe, 18 and BI mucosa heparin has been more recently used in South America. 14,16,26 Recently, our laboratory 11,13,15,27 and others 12,14,16,17 have been examining the physicochemical, biological, and pharmacological differences in heparins prepared from different tissues of food animals. Moreover, there have even been efforts reported to prepare low molecular weight heparin products from bovinederived heparins.…”
Unlike USP porcine heparin, bovine intestinal heparin (BIH) has a low anticoagulant activity. Treatment with 6-OST-1, -3, and/or 3-OST-1 afforded two remodeled heparins that met USP heparin activity and Mw specifications. We explored the pharmacodynamics and pharmacokinetics in a rabbit model. We conclude that a modest increase in the content of 3-O-sulfo groups in BIH increases the number of antithrombin III binding sites, making remodeled BIH behave similarly to pharmaceutical heparin.
“…Although only porcine intestinal heparin is currently used in the United States, bovine lung and intestinal heparins have been used in South America and in the Middle East, and ovine intestinal and porcine lung heparins have been used in Asia. Heparins derived from different organisms and tissues display different physical–chemical properties (i.e., molecular weight properties, disaccharide composition, and antithrombin III pentasaccharide binding sites (Fig.…”
The assessment of provenance of heparin is becoming a major concern for the pharmaceutical industry and its regulatory bodies. Batch-specific [carbon (δ13C), nitrogen (δ15N), oxygen (δ18O), sulfur (δ34S), and hydrogen (δD)] stable-isotopic compositions of five different animal-derived heparins were performed. Measurements readily allowed their differentiation into groups and/or subgroups based on their isotopic provenance. Principle component analysis showed that a bivariate plot of δ13C and δ18O is the best single, bivariate plot that results in the maximum discrimination ability when only two stable isotopes are used to describe the variation in the data set. Stable-isotopic analyses revealed that (i) stable-isotope measurements on these highly-sulfated polysaccharide (MW ~15 kDa) natural products (“biologics”) were feasible; (ii) in bivariate plots, the δ13C versus δ18O plot reveals a well-defined relationship for source differentiation of hogs raised in the US from hogs raised in Europe and China; (iii) the δD versus δ18O plot revealed the most well-defined relationship for source differentiation based on the hydrologic-environmental isotopes of water (D/H and 18O/16O), and (iv) the δ15N versus δ18O and δ34S versus δ18O relationships are both very similar, possibly reflecting the food sources used by the different heparin producers.
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