AI Article Synopsis
- Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) are commonly used in surgical procedures but have a risk of bleeding, making effective antidotes essential.
- Protamine is currently the only approved antidote, effectively neutralizing UFH but only partially neutralizing LMWHs and posing safety concerns.
- New research shows that multicationic small molecules can completely neutralize both UFH and LMWHs, proving to have superior neutralization activity and better safety profiles compared to protamine in various testing environments.
Article Abstract
Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) are widely applied for surgical procedures and extracorporeal therapies, which, however, suffer bleeding risk. Protamine, the only clinically approved antidote, can completely neutralize UFH, but only partially neutralizes LMWHs, and also has a number of safety drawbacks. Here, we show that caltrop-like multicationic small molecules can completely neutralize both UFH and LMWHs. In vitro and ex vivo assays with plasma and whole blood and in vivo assays with mice and rats support that the lead compound is not only superior to protamine by displaying higher neutralization activity and broader therapeutic windows but also biocompatible. The effective neutralization dose and the maximum tolerated dose of the lead compound are determined to be 0.4 and 25 mg/kg in mice, respectively, suggesting good promise for further preclinical studies.
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| http://dx.doi.org/10.1021/acs.jmedchem.3c02224 | DOI Listing |
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