Abstract
Heparin is a centennial anticoagulant drug broadly employed for treatment and prophylaxis of thromboembolic conditions. Although unfractionated heparin (UFH) has already been shown to have remarkable pharmacological potential for treating a variety of diseases unrelated with thromboembolism, including cancer, atherosclerosis, inflammation, and virus infections, its high anticoagulant potency makes the doses necessary to exert non-hemostatic effects unsafe due to an elevated bleeding risk. Our group recently developed a new low-anticoagulant bovine heparin (LABH) bearing the same disaccharide building blocks of the UFH gold standard sourced from porcine mucosa (HPI) but with anticoagulant potency approximately 85% lower (approximately 25 and 180 Heparin International Units [IU]/mg). In the present work, we investigated the pharmacokinetics profile, bleeding potential, and anticancer properties of LABH administered subcutaneous into mice. LABH showed pharmacokinetics profile similar to HPI but different from the low-molecular weight heparin (LMWH) enoxaparin and diminished bleeding potential, even at high doses. Subcutaneous treatment with LABH delays the early progression of Lewis lung carcinoma, improves survival, and brings beneficial health outcomes to the mice, without the advent of adverse effects (hemorrhage/mortality) seen in the animals treated with HPI. These results demonstrate that LABH is a promising candidate for prospecting new therapeutic uses for UFH.
Highlights
Unfractionated heparin (UFH) obtained from animal tissues has been massively exploited as anticoagulant agent for almost a century, which makes it one of the oldest extant biologic drugs[1]
We evaluated the in vitro anticoagulant activity of low-anticoagulant bovine heparin (LABH) based on the anti-FIIa and anti-FXa activities and compared the effect with those of HPI and low-molecular-weight heparins (LMWHs)
LMWH showed potent anti-FXa but low anti-FIIa activities (~100 IU/mg and ~25 IU/mg; Fig. 2), as previously established elsewhere . 22-24 its low potency had already been determined by Tovar et al 201918, the distinct profile of LABH seen in these anticoagulant assays indicates that this heparin may have different therapeutic effects than HPI and LMWH on non-hemostatic pathological conditions
Summary
Unfractionated heparin (UFH) obtained from animal tissues has been massively exploited as anticoagulant agent for almost a century, which makes it one of the oldest extant biologic drugs[1]. In addition to anticoagulant activity, UFH exerts many other biological effects, including modulation of different proteases and components of the extracellular matrix and binding to cytokines and growth factors[3]. The high anticoagulant potency of UFH makes the doses commonly necessary to achieve satisfactory effects on therapeutic targets related to cancer or other non-thromboembolic diseases unsafe due to an elevated risk of hemorrhage incidents[7]. In addition to this serious adverse effect, UFH is clinically employed by intravenous route, making it unfeasible for long term outpatient treatments[8]. LMWHs and some UFH mimetics obtained through extensive chemical/enzymatic processes have already proven to be effective and pose reduced risk of bleeding, different stakeholders involved in the production and research of heparins still looking for new and more feasible UFH derivatives that somehow preserve the physicalchemical features required for aiming new therapeutic targets but with decreased anticoagulant activity [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
