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Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): In vitro evaluation of efficacy and toxicity

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Abstract

Patients undergoing anticoagulation with heparin or low molecular weight heparin (LMWH) require a superior antidote that possesses more selective biological actions and a better safety profile than protamine. We had previously developed 2 low molecular weight protamine (LMWP) fractions (TDSP4 and TDSP5) from thermolysin-digested protamine as potential nontoxie, heparin-neutralizing agents. In this, the second article in this series, studies focused on in vitro evaluation of heparin/LMWH-neutralizing efficacy and putative toxicity. These LMWP fractions, particularly TDSP5, were effective and fully capable of neutralizing a broad spectrum of heparin-induced anticoagulant activities (ie, aPTT, anti-Xa, and anti-IIa activities). Additionally, these LMWP fractions could neutralize the activities of commercial LMWH. As assessed by the anti-Xa assay, TDSP5 was as effective as, although less potent than, protamine in reversing the activity of Mono-Embolex (molecular weight 5000–7000) and 2 other different sizes (molecular weight of 3000 and 5000 d) of LMWH preparations. Furthermore, compared with protamine, TDSP5 exhibited a much-reduced toxicity and thus an improved safety profile, as reflected by its reduced ability to activate the complement system and cross-react with the antiprotamine antibodies, which are 2 primary indices of protamine toxicity.

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Authors and Affiliations

  1. School of Pharmacy, National Defense Medical Center, Taipei, Taiwan

    Li-Chien Chang

  2. College of Pharmacy, The University of Michigan, 428 Church Street Ann Arbor, 48109-1065, Ann Arbor, MI

    Jun Feng Liang, Hsiao-Feng Lee, Lai Ming Lee & Victor C Yang

Authors
  1. Li-Chien Chang
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  2. Jun Feng Liang
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  3. Hsiao-Feng Lee
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  4. Lai Ming Lee
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  5. Victor C Yang
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Corresponding author

Correspondence to Victor C Yang.

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Published: July 11, 2001

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Chang, LC., Liang, J.F., Lee, HF. et al. Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): In vitro evaluation of efficacy and toxicity. AAPS PharmSci 3, 18 (2001). https://doi.org/10.1208/ps030318

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  • DOI: https://doi.org/10.1208/ps030318

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