polybrene), 11–14 peptides, 11,15 and nanoparticles 16,17 have been designed and evaluated in vitro and/or in vivo.
8,9 During the past two decades, a variety of different UFH neutralizers including small molecules, 10 cationic polymers ( e.g.
8ĭiscovering and developing new heparin neutralizers has been a popular area of research. 5–7 Given these issues, there has been a medical need for alternative, safe UFH neutralizers that can specifically counteract UFH without causing serious adverse effects. 5 When overdosed, protamine may further impair the intricate balance in the blood and cause coagulopathy. 1,5 However, due to its non-specific interactions, protamine sulfate often causes various adverse effects such as bradycardia, hypotension and pulmonary hypertension, as well as allergic reactions including life-threatening anaphylactic reactions in some patients. Thus, electrostatic interactions are the major driving force in the formation of a UFH–protamine complex, leading to the neutralization and deactivation of UFH. Protamine sulfate, the only FDA-approved neutralizer of UFH, possesses a highly positive charge density due to its polymeric nature and rich arginine residues. 1 Scheme of heparin reversal by GC4AOEG in the circulatory system. 4 Therefore, the neutralization of heparin has been a topic of significant research interest in the biomedical field.įig. At the end of surgery, excess heparin often needs to be deactivated by using a heparin neutralizer otherwise patients have risks of low blood pressure and a slow heart rate, and may develop internal bleeding. open-heart surgery) and extracorporeal therapies such as kidney dialysis. 2,3 Systemic heparinization is the most common anticoagulation procedure in surgical practice ( e.g. 1 It is currently a gold-standard life-saving drug to overcome blood coagulation by activating antithrombin-III to impede the coagulation process. Heparin sodium, often referred to as unfractionated heparin (UFH, also known as heparin), is a well-known anionic glycosaminoglycan consisting of long, helical, unbranched chains of repeating sulfonated disaccharide units ( Fig. Taken together, GC4AOEG, as a strategically designed, biocompatible artificial receptor with strong recognition affinity towards UFH, may have significant clinical potential as an alternative UFH reversal agent. Additionally, no adverse effects were observed during these treatments in vivo. As a consequence, UFH-induced excessive bleeding was significantly alleviated by GC4AOEG in different mouse bleeding models. GC4AOEG and UFH exhibited a strong binding affinity, ensuring specific recognition and neutralization of UFH by GC4AOEG in vitro and in vivo.
Herein, we designed a highly biocompatible, oligoethylene glycol functionalized guanidinocalixarene (GC4AOEG) as an antidote against UFH. However, the most common UFH neutralizer, protamine sulfate, often causes various adverse effects, some of which are life-threatening. When overdosed or used in sensitive patients, UFH may cause various risks and a UFH neutralizer needs to be administered immediately to reverse heparinization. Unfractionated heparin (UFH), a naturally occurring anionic polysaccharide, is widely used as an anticoagulant agent in clinical practice.
0 kommentar(er)
