Conjugation of Low-Molecular-Weight Heparin and Deoxycholic Acid for the Development of a New Oral Anticoagulant Agent

Lee, Yong-kyu; Nam, Jong Hee; Shin, Hang‐Sik; Byun, Youngro

doi:10.1161/hc5001.100627

Cited by 110 publications

(76 citation statements)

References 23 publications

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“…34,62,63 The discomfort and inconvenience associated with long-term parenteral therapies lessens enthusiasm for the prophylactic administration of heparin. Despite assertions of the lack of absorption of orally administered heparin because of its large molecular weight, strong negative charge, and hydrophilicity, 37,64 there are published reports that unfractionated heparin administered orally to laboratory animals is absorbed, binds avidly to the endothelium, and has antithrombotic activity. [65][66][67] One particular formulation of heparin with an agent that promotes its oral absorption has been reported to have antithrombotic activity and possibly to be associated with a lower incidence of heparin-associated thrombocytopenia.…”

Section: Discussionmentioning

confidence: 99%

Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin

Matsui

Varki

Embury

2002

Blood

115

110

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The adhesion of sickle erythrocytes to vascular endothelium is important to the generation of vascular occlusion. Interactions between sickle cells and the endothelium use several cell adhesion molecules. We have reported that sickle cell adhesion to endothelial cells under static conditions involves P-selectin. Others have shown that sickle cell adhesion is decreased by unfractionated heparin, but the molecular target of this inhibition has not been defined. We postulated that the adhesion of sickle cells to P-selectin might be the pathway blocked by unfractionated heparin. In this report we demonstrate that the flow adherence of sickle cells to thrombin-treated human vascular endothelial cells also uses P-selectin and that this component of adhesion is inhibited by unfractionated heparin. We also demonstrate that sickle cells adhere to immobilized recombinant P-selectin under flow conditions. This adhesion too was inhibited by unfractionated heparin, in a concentration range that is clinically attainable. These findings and the general role of P-selectin in initiating adhesion of blood cells to the endothelium suggest that unfractionated heparin may be useful in preventing IntroductionVascular occlusion is responsible for much of the morbidity associated with sickle cell disease. 1,2 Although the underlying cause of sickle cell disease is a single nucleotide mutation that directs the production of an easily polymerized hemoglobin protein, 3,4 both the erythrocyte sickling caused by hemoglobin polymerization and the interactions between a proadhesive population of sickle cells and the vascular endothelium are essential to vascular occlusion. 5,6 The correlation between sickle cell adhesiveness and the severity of vascular occlusion 7 led to extensive studies of the molecular mechanisms of adhesion. These pathways recently have been reviewed [8][9][10][11][12] and are briefly described here. Sickle red cells express adhesion molecules including integrin ␣ 4 ␤ 1 , CD36, band 3 protein, sulfated glycolipid, Lutheran protein, phosphatidylserine, and integrin-associated protein. The proadhesive sickle cells may bind to endothelial cell P-selectin, E-selectin, vascular cell adhesion molecule-1 (VCAM-1), CD36, and integrins. Activation of endothelial cells by specific agonists enhances adhesion by inducing the expression of cellular adhesion molecules and by causing cell contraction, which exposes extracellular matrix proteins, such as thrombospondin (TSP), laminin, and fibronectin. Bridging molecules from the plasma such as von Willebrand factor (VWF) and TSP also participate in certain of these adhesive interactions.Sickle cell adhesion has been studied under both static and flow conditions. 13 The relevance of both types of adhesion is suggested by in vivo observations of laminar, intermittent, and antegraderetrograde flow in the microvasculature of sickle cell subjects and sickle cell mouse models. [14][15][16] Initial events likely involve the adhesion of sickle erythrocytes to activated endothelial cells under ...

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Section: Discussionmentioning

confidence: 99%

Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin

Matsui

Varki

Embury

2002

Blood

115

110

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“…In this study, ileum segment was selected for the study at different drug concentrations, in that it exhibited higher absorption ability than duodenum, jejunum and colon segments ( Figure 3B). Lee et al (2001) and Kim et al (2011) reported that deoxycholic acid would increase the absorption of macromolecules, such as heparin, into the intestinal, through interactions with bile acid transporters expressed on the ileum membrane. However, the permeability of silybin-loaded HAadh-DOCA 10 micelles at 50, 100, 200 and 300 mg/mL was (8.26 ± 1.44) Â 10 À4 , (8.41 ± 1.11) Â 10 À4 , (8.49 ± 1.36) Â 10 À4 and (8.38 ± 0.87) Â 10 À4 cm/s, respectively, showing no significant difference among different drug concentrations (p40.05).…”

Section: Spip Study Of Silybin-loaded Micellesmentioning

confidence: 99%

Liver-targeting self-assembled hyaluronic acid-glycyrrhetinic acid micelles enhance hepato-protective effect of silybin after oral administration

Han

Wang

et al. 2015

Drug Delivery

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Muxin Gong (2016) Liver-targeting self-assembled hyaluronic acidglycyrrhetinic acid micelles enhance hepato-protective effect of silybin after oral administration, Drug Delivery, 23:5, 1818-1829, DOI: 10.3109/10717544.2015 AbstractIn order to enhance oral bioavailability and liver targeting delivery of silybin, two amphiphilic hyaluronic acid derivatives, hyaluronic acid-deoxycholic acid (HA-adh-DOCA) and hyaluronic acid-glycyrrhetinic acid (HA-adh-GA) conjugates, were designed and synthesized. Silybin was successfully loaded in HA-adh-DOCA and HA-adh-GA micelles with high drug-loading capacities (20.3% ± 0.5% and 20.6% ± 0.6%, respectively). The silybin-loaded micelles were spherical in shape with the average size around 130 nm. In vitro release study showed that two silybin-loaded micelles displayed similar steady continued-release pattern in simulated gastrointestinal fluids and PBS. Single-pass intestinal perfusion studies indicated that silybinloaded micelles were absorbed in the whole intestine and transported via a passive diffusion mechanism. Compared with suspension formulation, silybin-loaded HA-adh-DOCA and HA-adh-GA micelles achieved significantly higher AUC and C max level. Moreover, liver targeting drug delivery of micelles was confirmed by in vivo imaging analysis. In comparison between the two micellar formulations, HA-adh-GA micelles possessed higher targeting capacity than HA-adh-DOCA micelles, owing to the active hepatic targeting properties of glycyrrhetinic acid. In the treatment of acute liver injury induced by CCl 4 , silybin-loaded HA-adh-GA micelles displayed better effects over suspension control and silybin-loaded HA-adh-DOCA micelles. Overall, pharmaceutical and pharmacological indicators suggested that the HA-adh-GA conjugates can be successfully utilized for liver targeting of orally administered therapeutics.

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“…In a previous study, we developed a new oral delivery carrier based on bile acids, which could improve the oral bioavailability of therapeutically active peptides without damaging the tissue structure of the mucous membrane (8,9). Based on the observation that associated bile acid could increase the absorption of a poorly absorbable drug in the intestine, we prepared a positively charged carrier by simple modification of bile acid, cholic acid, with ethylenediamine for the negatively charged small organic molecules, CRO.…”

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confidence: 99%

Pharmacokinetics of a New, Orally Available Ceftriaxone Formulation in Physical Complexation with a Cationic Analogue of Bile Acid in Rats

Lee

Kim

Lee

et al. 2006

Antimicrob Agents Chemother

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Oral administration of ceftriaxone associated with a bile acid-based new oral carrier, cholylethylenediamine, in 50% propylene glycol to rats at doses of 25 and 50 mg/kg of body weight resulted in a significant increase in intestinal absorption, as evidenced by 55% improvement in the bioavailability, whereas ceftriaxone alone showed a bioavailability of less than 1%.The introduction of new oral cephalosporins, or formulation development of existing and highly promising parenteral cephalosporins, provides a possibility for follow-up oral treatment after initial parenteral treatment, thus reducing hospitalization time and costs (5,6,14). Ceftriaxone (CRO) is a widely used injectable broad-spectrum cephalosporin that exhibits potent activity against gram-positive and gram-negative bacteria (1, 2, 11, 12). However, the therapeutic utility of ceftriaxone is limited, as it requires parenteral infusion for its administration. In this respect, the development of an oral formulation of CRO would be helpful in rapid and proper step-down therapy that would lead to better patient compliance without compromising the therapeutic activity.In a previous study, we developed a new oral delivery carrier based on bile acids, which could improve the oral bioavailability of therapeutically active peptides without damaging the tissue structure of the mucous membrane (8, 9). Based on the observation that associated bile acid could increase the absorption of a poorly absorbable drug in the intestine, we prepared a positively charged carrier by simple modification of bile acid, cholic acid, with ethylenediamine for the negatively charged small organic molecules, CRO. This scheme was designed with the goal of preparing a carrier that could physically associate with the drug by ion pair interaction to improve its lipophilicity without altering the structure of the native drug. In the present study, we show that the positively charged bile acid analogue forms a complex with CRO and report the impact of this association on the oral bioavailability.Cholylethylendiamine (CEA) was synthesized by using cholic acid and ethylenediamine as precursors. A delivery agent was composed of the hydrophobic part of bile acid and the positive charge of ethylenediamine, thereby facilitating an ionpairing interaction with anionic drug, CRO. The complex formation in aqueous medium was reversible and dependent on the molar ratio between CRO and the delivery agent. Since CRO/CEA complexes showed significantly reduced solubility in water, the lyophilized drug complex was reformulated by the addition of one of the most common water-soluble solvents, propylene glycol (PG) (15), as a prototype formulation.The partition coefficients of CRO/CEA complexes were investigated in an n-octanol/water system. CRO concentrations were analyzed on a reversed-phase high-performance liquid chromatograph (RP-HPLC) (Shimadzu, Tokyo, Japan) as previously described (3). Briefly, a 50-l aliquot of supernatant was injected into an RP-HPLC fitted with an Eclipse XDB analytical column (25...

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Conjugation of Low-Molecular-Weight Heparin and Deoxycholic Acid for the Development of a New Oral Anticoagulant Agent

Cited by 110 publications

References 23 publications

Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin

Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin

Liver-targeting self-assembled hyaluronic acid-glycyrrhetinic acid micelles enhance hepato-protective effect of silybin after oral administration

Pharmacokinetics of a New, Orally Available Ceftriaxone Formulation in Physical Complexation with a Cationic Analogue of Bile Acid in Rats

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