Heparinoids, preparation

It is very difficult to remove the last traces of such material from heparin, yet this can be pharmacologically active. The histamine found in heparin after acid hydrolysis, as in the determination of normal blood histamine, probably arises from such peptides. Heparinoids prepared from natural... 

Heparinoid polysaccharides such as heparan sul te and heparin are able to interact with numerous proteins and influence vital biological processes. Heparinoid mimetics were prepared to reduce the structural complexity of heparinoids and to obtain selectivities. This artide summarizes the development of heparinoid mimetics of different classes including representative syntheses and biological activities. Largely simplified compounds with regard to structure and synthetic access are described which maintain or exceed the activity of heparinoid polysaccharides. One of the recipes to increase binding or modify pharmacokinetic parameters was the introduction of hydrophobic groups. 

The work on the first sulfated oligosaccharides was based on investigations of the polymeric heparinoids derivatives of heparin had been prepared to obtain information on the structural requirements of heparin for SMC antiproliferative activity. A clue for further studies was brought about by carboxyl-reduced sulfated heparin (CRS-heparin, 9) in which all carboxyl groups were reduced and... 

Lauenstein, Friedrich and Haberland investigated the effects of the parenteral administration of heparin, sodium polyethylene sulphonate and a number of other sulphated polysaccharides on oedema of the rat-foot produced by Zymosan . Two heparin preparations were almost inactive but a heparinoid derived from fungal mycelium exhibited marked effects unaltered by adrenalectomy. These authors conclude that it is unlikely that the anti-inflammatory effects of heparinoids are dependent on anticoagulant activity. 

Heparinoids are sulphated polysaccharides, prepared semi-synthetically by sulphation of partially degraded polysaccharides or occurring naturally in plant or animal tissue. They possess the properties described for heparin mucopolysaccharide. 

Heparins and heparinoids are grouped in Table 3.2. Some are naturally occurring compounds, whilst others are derivatives prepared from heparins or from mucopolysaccharides. Semi-synthetic compounds have been prepared by degradation of natural polysaccharides followed by sulphation with chlorsulphonic acid or methyl sulphate . The common activities shown by the heparins and heparinoids—complexing with organic bases and proteins, antilipaemic activity and anticoagulant activity—are also shown by various sulphonic acid dyes and by polyphosphates. The table is completed with a list of those preparations that have been issued to provide depot preparations of heparins and heparinoids. 

Having considered the complexes which heparin (and heparinoids and mucopolysaccharides) form, we can ask the question whether such complexes are present in the materials as prepared. It is self-evident that such complexes must be present and this immediately explains why heparin usually occurs as a multi-component system. 

Sodium salt has a special connotation in describing these substances. The almost universal practice in analyses of heparin preparations is to bum a sample moistened with sulphuric acid in oxygen, weigh the ash, and calculate from the sulphated ash the equivalent sodium. This is evidently a questionable practice. The metal cations bound must be identified. As heparin and heparinoids complex with ions, there is interference with various colour and precipitation reactions for ions unless the heparin sample is first subjected to combustion. Flame analyses of Boots and Evans heparin for... 

Heparin and heparinoids are absorbed in only trace amounts when given in large doses orally . EDTA increases the absorption . Subcutaneous and intramuscular injection of various depot heparin preparations have not been found very satisfactory. They fail to give satisfactory blood levels and they increase Sensitization. With subcutaneous injection, the ability of heparin to become fixed to protein becomes a factor modifying absorption. One of the basic difficulties in deciding on the value of subcutaneous or intramuscular injections of heparin is that there has been no quantitative comparison made of the blood levels of heparin administered in these two ways, to determine how much appears in the circulation in active form. It is possible that much heparin never reaches the circulation. This is to be expected when it is remembered that heparin released by mast cells does not reach the circulation. Depository forms of heparin have been replaced by the use of concentrated heparin solutions (40 gm per cent), so that volumes of 0-2 to 0-4 ml. ean be injected into subcutaneous fat tissue or intramuscularly. 

Sulfated amino (sulfoamino) groups occur naturally in heparin, and are readily produced synthetically by sulfation of amino groups. Such a reaction has been employed in the preparation of heparinoids, in the radio-labelling of heparin by lV-resulfation, and in the °S-sulfa-tion of nitrogen atoms of chitosan. ... 

Polymers that are structurally related to heparin and that possess certain of its biological properties, such as anticoagulant activity, are commonly called heparinoids. Non-heparin glycosaminoglycans having anti-coagulant/antithrombotic activities are sometimes classified as heparinoids. Heparinoids are also prepared by modification of naturally occurring polysaccharides, by the total synthesis of heparin-like polymers, and most recently by the synthesis of small sulfated heparin-like oligomers. 

The subject of the present review stems from the discoveries of A. Fischer and E. Jorpes. Fischer demonstrated that heparin binds or complexes with proteins and other bases and so modifies their biological activity. As a result, hef>arin is able to release or activate enzymes such as lifK)protein lipase, to inhibit hormones such as cortisone and aldosterone , to detoxify toxic agents , and to bind histamine in body cells . Jorpes discovered that heparin is a highly sulphated polysaccharide and that it gives a specific colour reaction with dyes the metachromatic reaction. This resulted in (i) the association of heparin with the naturally occurring mucofK)lysaccharides (ii) the preparation of other sulphated px>lysaccharides, heparinoids (iii) the identification of the mast cells as heparinocytes. 

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