Abstract: Novel antibacterial agents that act as multibinding agents are disclosed. The compounds of the invention comprise from 2-10 ligands covalently connected, each of said ligands being capable of binding to a transglycosylase enzyme substrate thereby modulating the biological processes/functions thereof.

Abstract: A method for identifying a Factor V gene mutation resulting in activated protein C resistance comprising detecting in a nucleic acid sample isolated from a human the presence of a genetic mutation characterized as a change from a guanine nucleotide to an adenine nucleotide at nucleotide position 205 in exon 10 of the Factor V gene that is associated with replacement of arginine 506 by glutamine, thereby identifying said mutation.

Abstract: Disclosed are compounds which inhibit or modulate the activity of protein kinases and pharmaceutical compositions containing such compounds. The disclosed compound contain two or more ligand moicties covalently linked together by one or more linking groups. Such compounds are useful for treating diseases or medical disorders mediated by protein kinases.

Abstract: The present invention has determined that exogenously added glycosylceramide (GlcCer) and other neutral glycolipids such as the homologous Glc-containing globotriaosylceramide (Gb3Cer), dose-dependently prolonged clotting times of normal plasma in the presence but not absence of APC:protein S, indicating GlcCer or Gb3Cer can enhance protein C pathway anticoagulant activity. In studies using purified proteins, inactivation of factor Va by APC:protein S was enhanced by GlcCer alone and by GlcCer, globotriaosylceramide, lactosylceramide, and galactosylceramide in multicomponent vesicles containing phosphatidylserine and phosphatidylcholine. Thus, the present invention provides neutral glycolipids such as GlcCer and Gb3Cer, as anticoagulant cofactors that contribute to the antithrombotic activity of the protein C pathway. The present invention has also determined that a deficiency of plasma GlcCer is a risk factor for thrombosis.

Abstract: The compounds of this invention comprise 2-10 ligands covalently connected, each of the ligands being capable of binding to a ligand binding site in a Na+ channel, thereby modulating the biological activities thereof.

Abstract: This invention relates to novel multibinding compounds (agents) that are H1 histamine receptor antagonists and pharmaceutical compositions comprising such compounds. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of allergic diseases such as rhinitis, urticaria, asthma, and anaphylaxis, and the like.

Abstract: The compounds of this invention comprise 2-10 ligands covalently connected, each of the ligands being capable of binding to a ligand binding site in a Na+ channel, thereby modulating the biological activities thereof.

Abstract: Disclosed are multibinding compounds which inhibit cyclooxygenase-2 (COX-2), an enzyme which catalyzes the first committed step in the biosynthesis of prostaglandins. The multibinding compounds of this invention containing from 2 to 10 ligands covalently attached to one or more linkers. Each ligand is a moiety capable of binding to COX-2. The multibinding compounds of this invention are useful in the treatment inflammation, pain, fever and the like.

Abstract: Disclosed are multibinding compounds which are &bgr;2 adrenergic receptor agonists and are useful in the treatment and prevention of respiratory diseases such as asthma, bronchitis. They are also useful in the treatment of nervous system injury and premature labor.

Abstract: Disclosed are multibinding compounds which are antibiotics effective against bacterial infections, in particular, Gram-negative bacterial infections. The multibinding compounds of this invention containing from 2 to 10 ligands covalently attached to one or more linkers. Each ligand is a polymyxin, circulin or octapeptin antibiotic or other suitable compound which binds to the LPS present in bacteria, in particular, Gram-negative bacteria. The multibinding compounds of this invention are useful for the prophylaxis and treatment of various bacterial infections caused by bacteria.

Abstract: The present invention is directed to multibinding compounds which are &bgr;2 adrenergic receptor agonists and are therefore useful in the treatment and prevention of respiratory diseases such asthma, bronchitis, and the like. They are also useful in the treatment of nervous system injury and premature labor.

Abstract: Disclosed are multibinding compounds which inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-COA reductase), the rate limiting enzyme in cholesterol biosynthesis. The multibinding compounds of this invention containing from 2 to 10 ligands covalently attached to one or more linkers. Each ligand is a moiety capable of binding to HMG-CoA reductase and the distance between ligands is at least 10 Å. The multibinding compounds of this invention are useful in the treatment and prevention of hypercholesterolemia, hyperlipidemia, atherosclerosis and the like.

Abstract: Disclosed are multibinding compounds which inhibit microsomal triglyceride transferase protein (MTP), a protein which mediates the transfer of lipids during the assembly of lipoproteins and related biomolecules. The multibinding compounds contain from 2 to 10 ligands covalently attached to one or more linkers. The multibinding compounds of this invention are useful for lowering serum lipid, cholesterol and/or triglyceride levels, and for preventing and treating disorders associated with hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholestrolemia, hypertriglyceridemia and the like, such atherosclerosis.

Abstract: The present invention provides methods for treating subjects having or at risk of having a neuropathological disorder or brain inflammatory diseases with and without vascular involvement, and systemic inflammatory vascular disease by administering a therapeutically effective amount of Activated Protein C (APC) to the subject. Brain disorders and brain inflammatory vascular diseases that can be treated by the invention method include all neurodegenerative diseases with different types of neuronal dysfunction, including stroke, Alzheimer's disease, Parkinson's disease, Huntington disease, neuroimmunological disorders such as multiple scelrosis and Gullian-Barre, encephalitis, meningitis, as well as other peripheral vascular diseases, such as diabetes, hypertension, artheriosclerosis. Also included are methods of treatment using APC in combination with a co-factor, such as Protein S.

Abstract: Disclosed are compounds which inhibit or modulate the activity of protein kinases and pharmaceutical compositions containing such compounds. The disclosed compound contain two or more ligand moieties covalently linked together by one or more linking groups. Such compounds are useful for treating diseases or medical disorders mediated by protein kinases.

Abstract: Disclosed are multibinding compounds which inhibit microsomal triglyceride transferase protein (MTP), a protein which mediates the transfer of lipids during the assembly of lipoproteins and related biomolecules. The multibinding compounds contain from 2 to 10 ligands covalently attached to one or more linkers. The multibinding compounds of this invention are useful for lowering serum lipid, cholesterol and/or triglyceride levels, and for preventing and treating disorders associated with hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholestrolemia, hypertriglyceridemia and the like, such atherosclerosis.

Abstract: Novel multibinding compounds are disclosed. The compounds of the invention comprise from 2-10 ligands covalently connected, each of said ligands being capable of binding to an nAChR receptor, thereby modulating the biologcial processes/functions thereof.

Abstract: The present invention provides an in vitro method useful for the diagnosis of a thrombotic disorder in a subject, having or at risk of having the disorder. Specifically, the disorder exemplified herein is associated with APC resistant Factor V and Va. The clotting time of a test sample is analyzed in the presence and absence of APC and compared with a standard reference sample in order to diagnose the subject.

Abstract: The present invention describes polypeptides and anti-peptide antibodies capable of inhibiting serine protease enzymatic activity. In particular, polypeptides and anti-peptide antibodies derived from the blood coagulation serine proteases Factor VIIa, Factor IXa, Factor Xa, Factor XIa, thrombin and plasma kallikrein are described that are capable of inhibiting coagulation. The polypeptide and antibody are useful in methods and systems for inhibiting serine proteases, and particularly for inhibiting blood coagulation processes mediated by serine proteases in vitro or in a human patient.

Abstract: The present invention provides an in vitro method useful for the diagnosis of a thrombotic disorder in a subject, having or at risk of having the disorder. Specifically, the disorder exemplified herein is associated with APC resistant Factor V and Va. The clotting time of a test sample is analyzed in the presence and absence of APC and compared with a standard reference sample in order to diagnose the subject.