Elsevier

Cardiovascular Surgery

Volume 9, Issue 3, June 2001, Pages 211-218
Cardiovascular Surgery

Invited Review
Development of oral heparin therapy for prophylaxis and treatment of deep venous thrombosis

https://doi.org/10.1016/S0967-2109(00)00144-7Get rights and content

Abstract

Objective: To review the current research and published literature regarding the development of oral heparin therapy for the prophylaxis and treatment of deep venous thrombosis.

Background: Currently, the accepted practice of prophylaxis and/or treatment of acute deep venous thrombosis (DVT) is intravenous or subcutaneous (SQ) heparin followed by oral warfarin or SC low molecular weight heparin (LMWH) therapy followed by warfarin. Both of which are less than ideal. More recently, advances have been made towards an effective oral heparin preparation that would resolve many of the drawbacks to the current therapies.

Methods: A review of the current and relevant English literature identified via a search of the Medline database from January 1990 to present.

Results: Initial oral heparin therapy for DVT was unsuccessful due to presumed inadequate intestinal absorption as a result of heparin's molecular and structural characteristics. The development of oral heparin therapy, based on combining heparin with the carrier molecule Sodium N-(8[2-hydroxybenzoyl]amino) caprylate (SNAC) to enhance its intestinal absorption and bioavailability for the prophylaxis and treatment of DVT has been demonstrated to be effective in animal models. More recent efforts have been aimed at human trials.

Conclusion: Recent advances in prophylaxis and treatment of DVT have stimulated great interest among researchers to develop an effective, convenient, and well tolerated oral therapy. An effective oral heparin therapy may represent an ideal method of prophylaxis and treatment of DVT.

Introduction

Heparin therapy has been shown to be a potent and safe therapy in the prevention and treatment of deep venous thrombosis (DVT) [1]. The evolution of treatment strategies has been on-going for over 35 years and recently has accelerated with the development of new pharmacological agents. DVT continues to be responsible for significant morbidity and mortality, affecting approximately 250,000 patients annually [2]. This large patient population translates to an estimated 300,000 to 600,000 hospitalizations and 50,000 deaths per year [3]. Classically, acute DVT has been treated with hospitalization for intravenous heparin followed by outpatient warfarin therapy for six months [1]. More recently, outpatient therapy with low molecular weight heparin (LMWH) has gained acceptance in many centers across the country in an effort to decrease cost and reduce hospitalization. The primary disadvantages of these treatments include in-patient hospitalization, serial laboratory tests, home heath care nursing, multiple painful injections, and the inherent risks of warfarin therapy. Ultimately, the cost and resource utilization for DVT treatment approaches $2.5 billion per year [4].

In an effort to make therapy more easily tolerated by patients, oral heparin therapy may represent a new method of outpatient prophylaxis and treatment of acute DVT. The emphasis of this article is to briefly review the development of DVT treatment until present, focusing on the development of oral heparin therapy.

Section snippets

Pharmacology of heparin

The anticoagulant properties of heparin are due to the accelerated neutralization of serine proteases XIIa, XIa, IXa, Xa, and thrombin by antithrombin III (ATIII) after binding with heparin [5]. Its major therapeutic action is due to specific binding of ATIII by a unique pentasaccaride found in only one third of heparin molecules. Following binding with heparin, ATIII undergoes a conformational change that enhances its ability to bind intrinsic and extrinsic clotting factors thereby greatly

Oral heparin therapy

The disadvantages of intravenous heparin/warfarin and LMWH therapy for DVT include: in-patient hospitalization (IV heparin), multiple laboratory tests (aPTT, PT/INR) multiple painful injections (SQ LMWH), home health surveillance, risk of hemorrhage, and teratogenecity. Efforts aimed at developing an oral heparin regiment have been on going for over 60 years. Presumably due to heparin's large size and negative ionic charge, it is not absorbed efficiently across the mucosa of the

Animal studies

The initial investigation of an oral heparin preparation combined with a delivery agent (SNAC) was performed in 1998 [11]. The goal of this study was to demonstrate the efficacy of SNAC:heparin in preventing DVT in a rat model. The physiologic model of DVT was based on induced thrombus in the rat internal jugular vein [12]. In this model, the internal jugular vein was isolated and bathed in a sclerosant mixture of 10% formalin and absolute ethanol for 2 min. The internal jugular veins were

Human studies

The initial human study of oral heparin therapy reported in the literature was designed to evaluate the effect of increasing doses of oral heparin in combination with SNAC. In a randomized, double-blinded format, researchers focused on changes in coagulation parameters (aPTT, anti-factor IIa, Xa, and TFPI) as well as adverse events in response to oral dosing of SNAC:heparin in healthy volunteers [15].

In the first part of this study, healthy volunteers were assigned to one of three treatment

Conclusion

This article was intended as a review of the current and relevant literature regarding the development of oral heparin in the prevention and treatment of acute DVT. The studies discussed have established the groundwork for the development of a clinically useful preparation of oral heparin. These studies have shown that efficient enteric absorption of heparin is possible when combined with an appropriate carrier molecule. Also, that this combination is as effective as intravenous heparin or SQ

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