Low-Molecular-Weight Derivative of Heparin that is Orally Active in Mice

Lasker, Sigmund E.

doi:10.1007/978-1-4684-0946-8_10

Cited by 10 publications

(5 citation statements)

References 12 publications

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“…However, these results are consistent with the results in large numbers of mice that were given heparin by mouth and in which intestinal or stomach absorption occurred. 14 The present data do not permit a critical examination of the structural feature of the administered polysaccharide responsible for the presence of circulating anti-Xa activity or to suggest mechanisms for the transport of a highly charged macromolecule across a mucosal membrane.…”

Section: Preparation Of Some Low Molecular Weight Fractionsmentioning

confidence: 56%

“…22,23 A study in 1964 failed to detect absorption by a variety of routes, including inhalation, installation into the small intestine, and sublingual administration in dogs, rabbits and man. 31 In view of the recent reports of intestinal absorption 4,14,27 of derivatives and low-molecular weight fractions, the inconsistent earlier data may reflect the vagarities of the preparations of commercial heparins in use. The wide molecular weight dispersity of commercial heparins has been reported 1,8,12,[16][17][18] and the molecular weight dependence of intestinal absorption recognized.…”

Section: Absorption From Intestinal Mucosamentioning

confidence: 99%

“…The wide molecular weight dispersity of commercial heparins has been reported 1,8,12,[16][17][18] and the molecular weight dependence of intestinal absorption recognized. 4,14,18,27 Separation of the lowest molecular weight fractions from commercial heparins for this purpose could be clinically useful. Since some of the activities of the low molecular weight fractions-below 5000 -appear to be critically sensitive to molecular weight, assessing the absorption behavior in this range requires careful fractionation.…”

Section: Absorption From Intestinal Mucosamentioning

confidence: 99%

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Low Molecular Weight Heparin-Like Preparations with Oral Activity

Lasker¹

1985

Semin Thromb Hemost

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Section: Preparation Of Some Low Molecular Weight Fractionsmentioning

confidence: 56%

Section: Absorption From Intestinal Mucosamentioning

confidence: 99%

Section: Absorption From Intestinal Mucosamentioning

confidence: 99%

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Low Molecular Weight Heparin-Like Preparations with Oral Activity

Lasker¹

1985

Semin Thromb Hemost

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“…This was done and proved, but was not of commercial interest, primarily because of cost. 14 All of the past work was performed before antithrombin III and activated factor X (factor Xa) assumed importance. It had been known that factor Xa was inhibited by a heparin cofactor identical with antithrombin III.…”

Section: From Heparin To Heparin Fractions and Derivativesmentioning

confidence: 99%

From Heparin to Heparin Fractions and Derivatives

Coyne¹

1985

Semin Thromb Hemost

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After 40 years of commercial availability, heparin is still one of the most interesting pharmaceuticals in use today. It is one of the few agents that has continued to provoke intense interest after many years of use. The biologic activities, and the concepts of the chemical structure have been constantly changing over the years. Heparin is no longer thought of as a simple compound delaying the coagulation of blood by whatever means. It does have multiple and varied effects. 17 Commercial heparin today, as in the past, is not a compound and does not have a uniform molecular structure. It is a mixture of polymers of varying size and slight differences exist between the polymers and in the individual sugars within a particular polymer grouping. 18 A semiofficial designation says that it is composed of alternating derivatives of D-glucosamine (N-sulfated or N-acetylated) and uronic acid (L-iduronic acid with varying sulfate or D-glucuronic acid) joined by glycosidic linkages. Molecular weights can range from 1000 to 50,000 daltons. Structural differences comprise degree of sulfation and placement of sulfate groups, whether they be ester sulfate (o-sulfate) or amine sulfate (n-sulfate), and also the presence or absence of acetyl groups, aside from the chain length size.Being a mixture of active and so-called inactive principles, heparin has always been fractionated during the extraction and purification stages. These procedures are carried out not just to remove unwanted protein and peptide contaminants, but to enhance activity. The fractionations are primarily separations through charge, such as a gradient of differing salt elution concentrations, either from quaternary ammonium compound complexes or from ion exchange resins. This is the most common method of carrying out separations. 4 However, charge density separation cannot be considered a molecular sizing operation. The highest charged material can have the highest anticoagulant potency, but there are differences in activities using different types of assays. These activities can take place within a particular molecular weight species. 10 Nonaqueous water miscible solvent separations are usually carried out in the final steps of a purification. These separations, to a great degree, can be considered molecular weight separations, for varying amounts of solvent are added for individual isolations to obtain different activities. There can be as much as four precipitations from a mixture using different volumes of solvent. Some heparin-like compounds can be coprecipitated, also. 5 Gel permeation separations have rarely been carried out on a commercial scale. This procedure, performed properly, does give a true molecular weight separation. 2,11 Unfortunately to a degree, the fractionations that had taken place in the past, and even today, were almost always aimed at gaining a higher anticoagulant activity based on compendial requirements and the global assays being used. Little attention was paid to other effects of the heparins, or of the extraneous factors, with t...

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“…Heparin represents a heterogenous mixture of polysaccharides and oligosaccharides with a molecular weight range of 1200 to 40,000 daltons with a mean molecular weight of approximately 15,000 daltons. 31,42,46,47 Depending upon the source and method of manufacturing, 10 to 30 molecular species may be present in a given heparin preparation. 20,40,50,57 The heterogeneity in molecular structure of heparin presents a complex problem to pharmacologists in that the conventional phar- Chemically and physically modified heparin preparations Naturally occurring (plant or animal) and synthetic analogues of heparin macologic concepts are not applicable to the study of heparin.…”

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confidence: 99%

Studies on the Antithrombotic Effects and Pharmacokinetics of Heparin Fractions and Fragments

Fareed¹,

Walenga²,

Williamson³

et al. 1985

Semin Thromb Hemost

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The pharmacokinetics of heparin differ markedly from those of its fractions both in man and in experimental animal models. The route of administration determines the relative availability of different molecular species that exert the anti-Xa, anti-IIa, fibrinopeptide A generation inhibiting actions and the release of tissue plasminogen activator-like activity from the endothelial cell lining. The bioavailability of heparin fractions has proved to be much greater than heparin after subcutaneous or intraperitoneal administration. Most of the low molecular weight heparin fractions exhibit sustained antiprotease and antithrombotic actions. The pharmacokinetics of the specific anti-IIa and anti-Xa actions of heparin and its fractions is dependent on the molecular composition of these agents. Even if the fractions are standardized for identical potencies by the in vitro assays, the elimination rate of anti-Xa and anti-IIa actions are significantly different for each fraction. The antithrombotic actions of heparin and its fractions also vary widely in the rabbit stasis thrombosis model. Different fractions show variable antithrombotic actions against defined thrombogenic challenges. Moreover, selection and potency of a thrombogenic agent is of crucial importance in these studies. The primate (Macaca mulatta) model offers a useful preclinical model for the pharmacologic evaluation of the low molecular heparin fractions. Since the coagulation system and heparinizability index of this model approximate a human response, the data may be used to reflect therapeutic and prophylactic responses, as well as to assess toxic effects, such as bleeding.

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Low-Molecular-Weight Derivative of Heparin that is Orally Active in Mice

Cited by 10 publications

References 12 publications

Low Molecular Weight Heparin-Like Preparations with Oral Activity

Low Molecular Weight Heparin-Like Preparations with Oral Activity

From Heparin to Heparin Fractions and Derivatives

Studies on the Antithrombotic Effects and Pharmacokinetics of Heparin Fractions and Fragments

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