Abstract: Substances comprising disaccharides and substances comprising carboxylated and/or sulfated oligosaccharides in substantially purified form, and methods of using same, are disclosed for the regulation of cytokine activity in a host. For instance, the secretion of active Tumor Necrosis Factor Alpha (TNF-.alpha.) can be either inhibited or augmented selectively by administration to the host of an effective amount of a substance of the invention. Thus, the present invention also relates to pharmaceutical compositions and their use for the prevention and/or treatment of pathological processes involving the induction of active cytokine secretion, such as TNF-.alpha.. The invention also relates to the initiation of a desirable immune system-related response by the host to the presence of activators, including pathogens. The substances and pharmaceutical compositions of the present invention may be administered daily, at very low effective doses, typically below 0.

Abstract: Novel polysaccharide compounds are disclosed for decorating biomolecular surfaces to increase isotropic size and mask antigenicity. The oligosaccharides may be synthesized as repeating disaccharide units, or may be derived by acid hydrolysis of naturally occurring polysaccharides. Such natural sources include chondroitins obtained from shark cartilage, or hyaluronic acid. The polyanionic sulfate groups contained in the sugar moieties impart negative charges which repel the molecules from the negatively charged wall of capillaries, to lengthen retention times of decorated drug molecules, such as crosslinked hemoglobin, in the peripheral circulation.

Abstract: The present invention provides compositions and methods for the treatment of cardiovascular diseases. More particularly, the present invention relates to modifying thrombus formation by administering an agent which, inter alia, is capable of (1) selectively inactivating thrombin which is bound either to fibrin in a clot or to some other surface, but which has only minimal inhibitory activity against free thrombin, i.e., fluid-phase thrombin; (2) inhibiting the assembly of the intrinsic tenase complex, thereby inhibiting the activation of Factor X by Factor IXa; and (3) inhibiting the activation of Factor IX by Factor XIa.

Abstract: The invention relates to a method for the quantification of coagulation factor VIIa (F VIIa) in FVIIa- or FVII/FVIIa-containing solutions by means of selective binding to immobilized soluble thromboplastin.

Abstract: The invention features a method for the selection and expansion of bone marrow stromal cells. The method includes the steps of obtaining bone marrow stromal cells; introducing the stromal cells into a vessel pre-coated on an inner surface with a gelatin, and containing a culture medium including an acidic fibroblast growth factor ("aFGF") polypeptide; and expanding the stromal cells in the culture medium under conditions and for a time sufficient to obtain an increased number of bone marrow stromal cells. The culture medium additionally can include heparin, and the vessel additionally can be precoated with fetal bovine serum.

Abstract: Process for the preparation of polysaccharides having a high iduronic acid content comprising:a) N-deacetylation of the polysaccharide K5 from E. coli or of the heparan sulfate or O-desulfation of heparin or heparan sulfate;b) N-sulfation of the product obtained from the stage a);c) epimerization in presence of the C5 epimerase enzyme;d) sulfation of at least some free hydroxy groups, wherein the stage c) is carried out in a reaction medium constituted by a classical buffer solution formed by HEPES, potassium chloride, EDTA and TRITON X-100 to which a suitable additive is added.

Abstract: The present invention provides an anti-thrombogenic coating composition for blood-contacting surfaces. The coating comprises a covalent complex of from 1 to 30 hydrophobic silyl moieties of Formula I: ##STR1## wherein R.sub.1 is a C.sub.1-8 alkyl or C.sub.6-32 aryl group, each R.sub.2 is independently selected from the group consisting of C.sub.1-8 alkyl and C.sub.6-32 aryl, R.sub.3 is N or O, and n is a number from 1 to 10, directly bound to a heparin molecule via covalent bonding.

Abstract: Heparin compositions having an antithrombotic activity and virtually no hemorrhagic activity are presented. The object of the invention is to eliminate the risk of bleeding associated with heparins while retaining their main properties. The compositions of the invention (S1, S2, S3) therefore consist of heparin moieties such as those obtainable by the in vitro neutralization of a heparin with a protamine. The invention also concerns a method for the preparation of these compositions which are useful in preparing medicaments.

Abstract: A method and medicament for the inhibition of neutrophil elastase and cathepsin G in mammals comprising administering a treatment effective amount of 2-O-desulfated heparin to a mammal in need thereof. The medicament preferably is administered by aerosolization or by intravenous (IV) injection. Preferably, the 2-O-desulfated heparin medicament includes a physiologically acceptable carrier which may be selected from the group consisting of physiologically buffered saline, normal saline, and distilled water. Additionally provided is a method of synthesizing 2-O-desulfated heparin.

Abstract: The present invention relates to pharmaceutical compositions for the prevention and/or treatment of pathological processes involving the induction of TNF-.alpha. secretion comprising a pharmaceutically acceptable carrier and a low molecular weight heparin (LMWH). In the pharmaceutical compositions of the present invention, the LMWH is present in a low effective dose and is administered at intervals of about 5-8 days. Furthermore, the LMWH is capable of inhibiting in vitro TNF-.alpha. secretion by resting T cells and/or macrophages in response to T cell-specific antigens, mitogens, macrophage activators, disrupted extracellular matrix (dECM), laminin, fibronectin, and the like.

Abstract: The invention relates to a method for promoting the healing of dermal wounds by applying a composition containing chitosan and the polysaccharide, heparin or heparan sulfate. Heparin or heparan sulfate can be immobilized to chitosan by ionic or covalent bonds, and the degree of N-acetylation of chitosan can range from 25% to 90%. The composition can include a cellulose derivative as an additional polysaccharide to increase the viscosity of the composition. The combination of chitosan and polysaccharide, when applied to a wound site, effectively stimulates and accelerates wound healing.

Abstract: Disclosed are fibroblast growth factor (FGF) binding and FGF receptor activation, and a method of identifying small molecular weight compounds that interact with FGF to modulate its activity such as, e.g., activators and inhibitors. Illustrative small oligosaccharides, namely di- and tri-saccharides, are shown to be effective modulators of FGF binding and FGF receptor activation.

Abstract: The invention relates to carbohydrate derivatives having the formula I, ##STR1## wherein R.sup.1 is H or CH.sub.2 OSO.sub.3.sup.-, R.sup.2 and R.sup.3 are independently H, (1-6C)alkyl or SO.sub.3.sup.- ; R.sup.4 is OSO.sub.3.sup.- or NHSO.sub.3.sup.- ; n is 0 or 1; p is 1 or 2; or a pharmaceutically acceptable salt thereof The compounds of the invention have antithrombotic activity and may be used for inhibiting smooth muscle cell proliferation.

Abstract: Use of a polysaccharide selected from the group consisting of sulfated acid mucopolysaccharides and sulfated dextrans, and physiologically acceptable salts thereof for prophylaxis or treatment of inflammations, particularly an adult respiratory distress syndrome (ARDS), ischemic heart diseases, ischemic cerebral diseases, chronic articular rheumatism, atopic dermatitis, and infiltration after organ implantation.

Abstract: This invention relates to mixtures of sulfated oligosaccharides which possess antithrombotic properties and are useful for the treatment and prevention of venous and arterial thrombosis, prevention of arterial thrombotic accidents, and in the prevention of thrombosis in surgical equipment, to pharmaceutical compositions including such mixtures, to processes for preparing such mixtures, and to the use of such mixtures in the prevention of thrombosis in surgical equipment.

Abstract: An oligosaccharide having an affinity for fibroblast growth factor, which is composed of 8 to 18 monosaccharide residues, wherein a principal disaccharide unit comprising L-iduronic acid 2-sulfate and N-sulfo-D-glucosamine and a process for producing the oligosaccharide comprising digesting heparan sulfate.

Abstract: The present invention, using a readily available sulfated chitin as an adsorbent, can permit platelet factor-4 to be recovered through specific adsorption from a solution containing the same factor, in by far increased yields as compared with the conventional process utilizing a heparin-immobilized affinity column, and provides the process for isolating, through purification platelet factor-4 which is suited for a commercial-scale, mass production process, wherein there can be offered the advantages of utilization of more readily available sulfated chitin, simplified procedure and improved production yields for the objective substance.

Abstract: This invention provides novel methods and reagents for specifically delivering biologically active compounds to phagocytic mammalian cells. The invention also relates to specific uptake of such biologically active compounds by phagocytic cells and delivery of such compounds to specific sites intracellularly. The invention specifically relates to methods of facilitating the entry of antiviral and antimicrobial drugs and other agents into phagocytic cells and for targeting such compounds to specific organelles within the cell. The invention specifically provides compositions of matter and pharmaceutical embodiments of such compositions comprising conjugates of such antimicrobial drugs and agents covalently linked to particulate carriers generally termed microparticles. In particular embodiments, the antimicrobial drug is covalently linked to a microparticle via an organic linker molecule which is the target of a microorganism-specific protein having enzymatic activity.

Abstract: The present invention provides a process for preparing a cross-linked biocompatible polysaccharide gel composition, which comprises:forming an aqueous solution of a water soluble, cross-linkable polysaccharide;initiating a cross-linking of said polysaccharide in the presence of a polyfunctional cross-linking agent therefor;sterically hindering the cross-linking reaction from being terminated before gelation occurs, an activated poly-saccharide being obtained; andreintroducing sterically unhindered conditions for said activated polysaccharide so as to continue the cross-linking thereof to a viscoelastic gel. The invention also provides a gel composition obtainable by such a process as well as gel compositions for different medical uses.

Abstract: Heparan sulfate 2-O-sulfotransferase having the following properties is obtained from, for example, CHO cells:(i) action: sulfate group is transferred from a sulfate group donor selectively to the hydroxyl group at C-2 position of iduronic acid residue of a sulfate group acceptor;(ii) substrate specificity: sulfate group is transferred to heparan sulfate or CDSNS-heparin, but sulfate group is not transferred to chondroitin, chondroitin sulfate, dermatan sulfate, and keratan sulfate;(iii) optimum reaction pH: about pH 5 to 6.5;(iv) optimum ionic strength: about 50 to 200 mM when sodium chloride is used; and(v) inhibition and activation: the activity of the enzyme is increased by protamine, the activity of the enzyme is inhibited by adenosine-3',5'-diphosphate, and the activity of the enzyme is scarcely affected by dithiothreitol at 10 mM or less.

Abstract: A drug composition comprising a mucopolysaccharide (also referred in the art as a glycosaminoglycan) and a drug which is scarcely soluble in water but soluble in a water-miscible organic solvent, wherein fine crystals or fine particles of the drug is attached on or between the particles of a mucopolysaccharide, and a process for preparing the same. The drug composition of the present invention exhibits greatly improved solubility and a dissolution rate of the drug, and thus greatly improve the drug's bioavailability.

Abstract: Absorbents of the present invention can be obtained by reacting the vicinity of the surface of (A) polysaccharide particles with a (B) crosslinking agent having at least two functional groups which can react with the polysaccharides such as polyglycidyl ether compounds, polyhydric alcohol compounds or polyamine compounds by means of treating the (A) polysaccharide particles with the (B) crosslinking agent and an aqueous solution of a (C) water soluble compound while heated. The obtained absorbents exhibit excellent absorbing ability even to a high concentrated salt solution and also are well biodegradable.

Abstract: Methods of reducing the degeneration of a tissue resulting from mobilization with or without chronic, continuous electrical stimulation by administering basic fibroblast growth factor or heparin to the tissue are provided.

Abstract: Methods of making and using, as prophylactics or therapeutics for preventing or treating certain diseases including cancer, O-desulfated heparin compositions, preferably 2-O, 3-O desulfated heparin compositions, wherein the methods permit regulating the degree of 2-O, 3-O desulfation to produce compositions that are variably desulfated upto about 99% and 75% desulfated at the 2-O and 3-O positions, respectively.

Abstract: The present invention relates to a method for purifying heparin into two subspecies of molecules, one which binds transforming growth factor-.beta. (TGF-.beta.), and another which does not. The method involves using a peptide, immobilized on a chromatography substrate, that is homologous to the heparin-binding region of TGF-.beta. and allowing the heparin to contact the immobilized peptide for a sufficient time to cause binding. The fraction of heparin which does not bind to the peptide retains its activity as an anticoagulant but is devoid of the ability to bind TGF-.beta..

Abstract: Compositions and methods of making selectively O-desulfated heparin compositions, preferably 6-O-desulfated heparin compositions, wherein the methods permit regulating the degree of 6-O-desulfation. The compositions are useful for treating various diseases, including cancer, angiogenesis, shock, ischemia reperfusion injury, inflammation, and cardiovascular diseases including restenosis.

Abstract: The present invention relates to an organic solvent-soluble mucopolysaccharide consisting of an ionic complex of at least one mucopolysaccharide (preferably heparin or heparin derivative) and a quaternary phosphonium, an antibacterial antithrombogenic composition comprising said organic solvent-soluble mucopolysaccharide and an organic polymer material, an antibacterial antithrombogenic composition comprising said organic solvent-soluble mucopolysaccharide and an antibacterial agent (preferably inorganic antibacterial agent such as silver zeolite), and to a medical material comprising said organic solvent-soluble mucopolysaccharide.

Abstract: The present invention relates to a method of treating in a mammal certain cancers, other cell proliferative diseases, and/or angiogenesis by using a salt or complex of a sulfated saccharide. The invention also relates to the use of mutant heparin binding growth factors that bind to the growth factor receptor, but not to heparin. The invention also provides pharmaceutical compositions for such methods.

Abstract: The invention discloses a starch graft poly(meth)acrylate blast media which is effective in paint removal. The media is superior to a physical blend of the components (i.e., starch and acrylic polymers) and to either a starch polymer or an acrylic polymer used singly. The hardness of the media is between 65-90 Shore D.

Abstract: The invention relates to sulfated glycosaminoglycanoid derivatives of the heparin and heparan sulfate type, of which N-sulfate, N-acetate, and hydroxy groups, are replaced by alkoxy, aryloxy, aralkoxy, or O-sulfate groups. The compounds have antithrombotic and smooth muscle cell proliferation inhibiting activities.

Abstract: The present invention generally relates to a processes for preparing low affinity, low molecular weight heparins (LA-LWM-heparins) which are endowed with pharmacological and therapeutic properties that are surprisingly advantageous. In one embodiment, the process comprises: (1) nitrous acid depolymerization of unfractionated heparin to yield low molecular weight heparin (LMWH); (2) oxidation of the resulting LMWH to open the ring structures the nonsulfated uronic acid moieties using, for example, sodium periodate; and (3) reduction of the oxidized LMWH to reduce the aldehydes (to alcohols) formed during the depolymerization and oxidation steps using, for example, sodium borohydride. The resulting LA-LMW-heparins are capable of inactivating thrombin bound to fibrin within a thrombus or clot, whereby the ability of clot-bound thrombin to catalytically promote further clot accretion is substantially diminished or eliminated.

Abstract: A method of treating a patient with a medical device having immobilized heparin on a blood-contacting surface in which the covalently attached heparinized surface is provided with an adsorbed protein which may be activated by the immobilized heparin to block the coagulation of fibrinogen. Antithrombin III is the preferred adsorbed protein. The adsorbed protein is maintained on the immobilized heparin surface until the medical device is placed into contact with the patient's blood. When in contact with the patient's blood, the adsorbed protein will prevent initial thrombin formation at the biomaterial-blood interface. The preadsorption of ATIII is accomplished under conditions advantageous to maximum heparin/ATIII binding. When the preadsorbed surface comes in contact with whole blood, the maximum advantage of prophlactic properties of ATIII/heparin are obtained.

Abstract: Heparin derivatives are disclosed which may be used to inhibit formation of metastases. The heparin derivatives of the invention are N-acylated with mono- or dicarboxylic acids, have a molecular weight from about 1,000 to about 30,000 Daltons, and have at least one unit of an open D- or L-iduronic acid.

Abstract: The present invention provides compositions and methods for inactivating thrombin bound to fibrin within a thrombus or clot, whereby the ability of clot-bound thrombin to catalytically promote further clot accretion is substantially diminished or eliminated. The compositions and methods of the present invention are particularly useful for preventing thrombosis in the circuit of cardiac bypass apparatus and in patients undergoing renal dialysis, and for treating patients suffering from or at risk of suffering from thrombus-related cardiovascular conditions, such as unstable angina, acute myocardial infarction (heart attack), cerebrovascular accidents (stroke), pulmonary embolism, deep vein thrombosis, arterial thrombosis, etc.

Abstract: A water insoluble, biocompatible composition that is formed by a method which combines, in an aqueous mixture, a polyanionic polysaccharide, a nucleophile, and an activating agent, under conditions sufficient to form the composition. Also, a water insoluble, biocompatible composition that is formed by a method which combines, in an aqueous mixture, a polyanionic polysaccharide, a modifying compound, a nucleophile and an activating agent under conditions sufficient to form the composition.

Abstract: The present invention provides compositions and methods for inactivating thrombin bound to fibrin within a thrombus or clot, whereby the ability of clot-bound thrombin to catalytically promote further clot accretion is substantially diminished or eliminated. The compositions and methods of the present invention are particularly useful for preventing thrombosis in the circuit of cardiac bypass apparatus and in patients undergoing renal dialysis, and for treating patients suffering from or at risk of suffering from thrombus-related cardiovascular conditions, such as unstable angina, acute myocardial infarction (heart attack), cerebrovascular accidents (stroke), pulmonary embolism, deep vein thrombosis, arterial thrombosis, etc.

Abstract: A bio-active coating composition is described which is the reaction product of two different reactions. The first reaction includes reacting a bio-compatible polymer backbone having .alpha.,.beta.-unsaturated carbonyl functionality with a hydrophilic spacer having at least one reactive functional group at its first and second ends. In this reaction, one of the reactive functional groups of the spacer reacts with a .beta.-carbon of the carbonyl functionality to bond the spacer to the polymer backbone. The second reaction includes reacting a bio-active agent with a remaining unreacted reactive functional group of the spacer in the presence of an optional catalyst to covalently bind the bio-active agent to the spacer.

Abstract: This invention relates to compounds prepared by linking glycosaminoglycan to phospholipid or lipid, which are expected to exert a pharmacological effect for inhibiting metastasis because of their excellent function to inhibit adhesion of cancer cells to blood vessel endothelial cells and extracellular matrix. This phospholipid- or lipid-linked glycosaminoglycan can be produced for example by: cleaving and oxidizing reducing terminal group of glycosaminoglycan, and allowing an aldehyde group or a lactone compound of the thus-formed derivative or a carboxyl group in the glycosaminoglycan chain to react with a primary amino group of a phospholipid; or linking a glycosaminoglycan derivative to a phospholipid or a lipid by allowing a primary amino group of the derivative to react with a carboxyl group of the phospholipid or lipid. This phospholipid- or lipid-linked glycosaminoglycan is useful as a metastasis inhibitor because it has no toxicity.

Abstract: Disclosed are fibroblast growth factor (FGF) binding and FGF receptor activation, and a method of identifying small molecular weight compounds that interact with FGF to modulate its activity such as, e.g., activators and inhibitors. Illustrative small oligosaccharides, namely di- and tri-saccharides, are shown to be effective modulators of FGF binding and FGF receptor activation.

Abstract: A method and a pharmaceutical composition for non-topical wound, scar and keloid treatment is described which contains cross-linked glycosaminoglycans and conventional pharmaceutical auxiliary and/or carrier substances. The pharmaceutical composition is preferably administered intralesionally e.g. by injection in the form of a gel containing water. The cross-linked glycosaminoglycans are also suitable for use as cosmetics and skin care products.

Abstract: The invention relates to new mixtures of sulfated oligosaccharides having the general structure of heparin constitutive oligosaccharides, having an average molecular mass of 6.+-.0.6 kD, a polydispersiveness close to 1 and the capacity of inhibiting the production of thrombin. The invention also relates to their preparation and to pharmaceutical compositions containing them.

Abstract: The present invention relates to pharmaceutical compositions containing heparin or heparin fragments or their derivatives in combination with one or more glycerol esters of at least one fatty acid as single absorption enhancer. The compositions are useful for oral administration, for administration through mucous membranes or for transdermal administration. The compositions will when necessary contain further physiologically acceptable additives, such as diluents and/or carriers, suitable for the adaptation to oral, buccal, rectal, sublingual, nasal, subcutaneous or transdermal administration. The composition according to the invention provide excellent absorption and bioavailability without employing additional enhancers or promoters.

Abstract: A method and medicament for the inhibition of neutrophil elastase and cathepsin G in mammals comprising administering a treatment effective amount of 2-O-desulfated heparin to a mammal in need thereof. The medicament preferably is administered by aerosolization or by intravenous (IV) injection. Preferably, the 2-O-desulfated heparin medicament includes a physiologically acceptable carrier which may be selected from the group consisting of physiologically buffered saline, normal saline, and distilled water. Additionally provided is a method of synthesizing 2-O-desulfated heparin.

Abstract: The invention relates to new mixtures of sulfated oligosaccharides having the general structure of heparin constitutive oligosaccharides, having an average molecular mass of 6.+-.0.6 kD, a polydispersiveness close to 1 and the capacity of inhibiting the production of thrombin. The invention also relates to their preparation and to pharmaceutical compositions containing them.

Abstract: The accuracy of a diagnostic test for determining the coagulability of blood is improved by reducing the interference by heparin. At least one metal salt, preferably a copper or zinc salt, is added to the diagnostic test to avoid or considerably reduce the undesirable influence of heparin on the test.

Abstract: Methods of making and using, as prophylactics or therapeutics for preventing or treating certain diseases including cancer, O-desulfated heparin compositions, preferably 2-O, 3-O desulfated heparin compositions, wherein the methods permit regulating the degree of 2-O, 3-O desulfation to produce compositions that are variably desulfated upto about and 75% desulfated at the 2-O and 3-O positions, respectively.

Abstract: A novel polysaccharide derivative, a drug carrier comprising a novel polysaccharide derivative, and a drug complex are disclosed. The polysaccharide derivative according to the present invention comprises a polysaccharide having a carboxyl group in which a peptide chain is introduced at a part or all of the carboxyl groups of the polysaccharide. The peptide chain comprises 1-8 amino acids which may be the same or different. A part or all of the amino groups in the peptide chain which are not involved in the linkages with the carboxyl groups of the polysaccharide or the carboxyl groups in the peptide chain may form an acid amide linkage or an ester linkage with a carboxyl group, an amino group or a hydroxyl group of a third compound such as drugs. The polysaccharide derivative has a property of accumulating in a high amount at a tumor, and thus can deliver efficiently a drug which has a side-effect or a limited sustainment of the drug efficacy to the tumor.

Abstract: The present invention relates to methods for the prevention and/or treatment of pathological processes involving the induction of TNF-.alpha. secretion comprising a pharmaceutically acceptable carrier and a low molecular Weight heparin (LMWH). In the pharmaceutical compositions of the present invention, the LMWH present in a low effective dose and is administered at intervals of about 5-8 days. Furthermore, the LMWH is capable of inhibiting in vitro TNF-.alpha. secretion by resting T cells and/or macrophages in response to T cell-specific antigens, mitogens, macrophage activators, disrupted extracellular matrix (dECM), laminin, fibronectin, and the like.

Abstract: An improved method of making a medical device having immobilized heparin on a blood-contacting surface in which heparin is admixed with sufficient periodate to react with not more than two sugar units per heparin molecule in a buffer solution having a pH in the range of about 4.5-8. This mixture is reacted for at least 3 hours while protected from light and is then applied to the immobilized amine groups. This is an improvement over the prior art methods which included using an excess of periodate and then stopping the reaction at a desired point by the addition of glycerol since the conversion of only a few of the natural functional groups to aldehydes better preserves the antithrombotic bioeffectiveness of the heparin molecules bound to the surface. The invention also avoids the prior art steps of drying and reconstituting the heparin by providing a reacted mixture of heparin and periodate that can be stored as a stable liquid and applied directly to the aminated surface several days later.

Abstract: Oligosaccharides obtainable from heparin including heparinic constituents of molecular weights ranging from 2000 to 50,000. Said fractions have a Yin-Wessler titer and a USP titer in a ratio of at least 30. They consist of chains constituted by no more than 8 saccharidic moities. They possess a strong antithrombotic activity and are then useful as antithrombotic drugs.