Abstract: The present invention provides assays to identify compounds that affect microglial cell activation, and specifically assays to identify compounds that affect secretion of cytokines from these microglial cells by modulating PGE2-mediated activity. The assays of the invention include assays for testing microglial cell activation by contacting microglia with compounds that modulate &bgr;-amyloid PGE2-mediated activation, which can be identified by cellular activity such as secretion of cytokines, e.g., TNF-&agr; and IL-1&agr;. The effect of the candidate compound can be determined by comparing the effect with a control culture which is not contacted with the compound, or by comparing the effect with a standardized profile.

Abstract: Indoles, benzimidazoles and benztriazoles which are substituted at the 5 or 6 position with a substituent comprising an aromatic moiety linked through a piperazine ring to said indole, benzimidazole or benztriazole are useful in treating cardiac conditions associated with heart failure and in treating conditions characterized by proinflammation.

Abstract: The cDNA sequence encoding porcine brain natriuretic peptide and related genes encoding canine and human peptides with natriuretic activity are disclosed. The gene is shown to make accessible the DNAs encoding analogous natriuretic peptides in other vertebrate species. The genes encoding these NPs can be used to effect modifications of the sequence to produce alternate forms of the NPs and to provide practical amounts of these proteins. The NPs of the invention can also be synthesized chemically.

Abstract: The present invention provides cell-free &ggr;-secretase activity. The method of the invention utilizes a membrane source of APP/&ggr;-secretase mixture in the assay to determine factors that may enhance or decrease enzymatic activity affecting &bgr;-amyloid peptide production. The cell membranes used in the assay may be from cells expressing an endogenous APP or, preferably, cells expressing a recombinant APP. The APP may be full-length or a fragment capable of being proteolytically cleaved by &ggr;-secretase. In addition, the APP expressed in the cells may have one or more mutation, such as a point mutation, small deletion, etc.

Abstract: The invention is directed to methods for treating conditions mediated by by P38&agr; kinase using compounds of the formula wherein Ar1 and Ph are limited to specific embodiments or wherein the compound of formula (3) is a compound set forth in FIGS. 1A-1T.

Abstract: There are disclosed methods for the treatment of non-insulin dependent diabetes mellitus in a mammal comprising the prolonged administration of GLP-1 (7-37), and related peptides. Also disclosed are compositions to prolong the administration of the peptides.

Abstract: The invention is directed to a method of enhancing the biological activity of vascular endothelial growth factors (VEGF). The invention further concerns certain VEGF variants having enhanced biological activity, methods and means for preparing these variants, and pharmaceutical compositions comprising them. In a further aspect, the invention concerns methods of treatment using, and articles of manufacture containing such VEGF variants.

Abstract: The invention is directed to methods to inhibit TGF-&bgr; and/or p38-&agr; kinase using compounds of the formula or the pharmaceutically acceptable salts thereof wherein R3 is a noninterfering substituent; each Z is CR2 or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N; each R2 is independently a noninterfering substituent; L is a linker; n is 0 or 1; and Ar′ is the residue of a cyclic aliphatic, cyclic heteroaliphatic, aromatic or heteroaromatic moiety optionally substituted with 1-3 noninterfering substituents.

Abstract: The substitution of the L-Pro at the 7-position of the peptide hormone bradykinin or other substituted analogs of bradykinin with an isoquinoline derivative which converts bradykinin agonists into bradykinin antagonists. The invention further includes the novel 7-position modified bradykinin antagonists which increase enzyme resistance, antagonist potency, and/or specificity of the new bradykinin antagonists. The analogs produced are useful in treating conditions and diseases of a mammal and human in which an excess of bradykinin or related kinins are produced or injected as by insect bites.

Abstract: Compounds of the formula: wherein the dotted line represents an optional bond; and the pharmaceutically acceptable salts thereof, wherein X1 is an alkyl bridge optionally containing an O, S, or N heteroatom that forms an aliphatic 5-7 membered ring and is optionally substituted by one or more of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, or NROCR where R is H or alkyl (1-6C), or by one or more CN or═O, or by one or more aliphatic or aromatic 5- or 6-membered rings optionally containing 1-2 heteroatoms; R1 is  wherein X2 is CO or an isostere thereof; m is 0 or 1; Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y taken together may form an alkylene (2-3C) bridge; n is 0-4; Z1 is CH or N; X3 is CH or CHR where R is H or alkyl (1-6C), or an isostere thereof; and Ar, R2 and R3 are as defined in the specification. These compounds are selective inhibitors of p38&agr; kinase.

Abstract: The present invention provides a method of assaying for and arresting, preventing and/or reversing the impairment of central and peripheral nervous system function comprising reducing &bgr;-amyloid plaque burden by the administration of compounds that reduce apoE expression. The compounds used in the method of the invention may be: 1) inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase; 2) inhibitors of cholesterol biosynthesis; 3) inhibitors of protein isoprenylation, specifically geranylgeranylation; and/or 4) inhibitors of NF-&kgr;B activation or function. Assays for compounds with inhibit apoE expression from microglial cells are also disclosed.

Abstract: The invention is directed to methods to treat conditions mediated by p38-&agr;kinase using compounds of the formula and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, wherein Z is N or CR1, R1 is a noninterfering substituent, each of X1 and X2 is a linker, Ar1 and Ar2 are identical or different, and represent optionally substituted C1-C20 hydrocarbyl residues wherein at least one of Ar1 and Ar2 is an optionally substituted aryl group, with the proviso that when X2 is CH2 or an isostere thereof, X1 is CO or an isostere thereof, and Ar2 is optionally substituted phenyl, Ar1 is other than an optionally substituted indolyl, benzimidazolyl or benzotriazolyl substituent, and wherein said optionally substituted phenyl is not an optionally substituted indolyl, benzimidazolyl, or benzotriazolyl, Y is a noninterfering substituent, wherein n is an integer from 0-4, and wherein m is an integer from 0-4 and 1 is an integer from 0-3.

Abstract: The invention concerns the use of ligands of peripheral-type benzodiazepine receptors (PTBR) in the diagnosis and treatment of diseases involving cyst formation and in particular polycystic kidney disease. The invention further concerns the treatment of hypertension accompanying polycystic kidney disease, and pharmaceutical compositions and articles of manufacture for the treatment or diagnosis of the target disease or condition.

Abstract: The present invention provides reagents and assays for the quantification of hBNP in biological fluid samples such as plasma or serum. Antibodies are provided which are monospecific to epitopes comprising the amino acid sequences 5-13, 1-10 and 15-25 of hBNP. These antibodies, and peptide fragments containing these sequences, can be employed in the assays of the invention, which may be carried out in a sandwich format or a competition format.

Abstract: The present invention concerns methods for the treatment of salt-sensitive hypertension. The methods generally involve administering a vascular endothelial growth factor (VEGF) in an amount effective to reduce the blood pressure of a patient suffering from salt-sensitive hypertension to a normal range.

Abstract: The invention concerns the use of agonists and antagonists of peripheral-type benzodiazcpine receptors (PTBR) in the diagnosis and treatment of cardiac hypertrophy and other circulatory conditions. The invention specifically concerns the use of PTBR antagonists in the prevention or treatment of decompensated cardiac hypertrophy and, eventually, heart failure. The invention also concerns the use of PTBR agonists in the management of conditions calling for increased blood flow or cardiac output, including injury or functional compromise of the heart, increased demand for physical exercise, or an acquired or inherited predisposition to cardiac contractile disfunction. Pharmaceutical compositions for the treatment of such conditions and screening methods to identify PTBR agonists and antagonists are also included.

Abstract: A compound of the formula: and the pharmaceutically acceptable salts thereof, wherein each of Z1 and Z2 is independently CR4 or N; where each R4 is independently H or is alkyl (1-6C) optionally including one or more heteroatoms selected from O, S and N and optionally substituted by one or more of halo, OR, SR, NR2, RCO, COOR, CONR2, OOCR, or NROCR where R is H or alkyl (1-6C), or by CN or ═O, or by an aliphatic or aromatic 5 or 6 membered ring optionally containing 1-2 N heteroatoms; or two R4 taken together form a bridge optionally containing a heteroatom; R1 is  wherein X1 is CO or an isostere thereof; m is 0 or 1; Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two 6 taken together may form an alkyene (2-3C) bridge; n is 0 or 2; Z3 is CH or N; X2 is CH, CH2 or an isostere thereof; and Ar consists of one or two phenyl moieties directly coupled to X2 optionally substituted by halo, nitro, alkyl (1-

Abstract: Compositions and methods are disclosed for the controlled release delivery of polypeptide growth factors. The compositions of the invention are hydrogels which comprise: a polypeptide growth factor having at least one region of positive charge; a physiologically acceptable water-miscible anionic polymer; a physiologically acceptable non-ionic polymeric viscosity controlling agent; and water.

Abstract: The invention pertains to isolated nucleic acid molecules containing sequences specified herein, to mutant CD36 genes and their encoded gene products, to methods of screening blood or a blood product by detecting a CD36 gene mutation, methods of administering blood or a blood product based on the presence or absence of a CD36 gene mutation, to methods of matching a biological sample donor with a recipient based on detection of a mutation in the CD36 gene, methods of determining the resistance of a patient to infection by a parasite by detecting a CD36 gene mutation, methods of diagnosing a disease associated with a defect in insulin action, glucose metabolism, fatty acid metabolism, and/or catecholamine action by detecting a mutation in the CD36 gene, and methods of disease treatment by altering the mutation(s).

Abstract: A method is described for producing a peptide having a pI above 8 or below 5 wherein the peptide is expressed as a fusion protein in which it is linked to a fusion partner through an acid cleavage site. The peptide is released from the fusion partner by acid cleavage in the absence of chaotrope. The fusion partner and its acid cleavage products, if any, have a net charge sufficiently different from that of the desired peptide to allow isolation of the peptide by ion-exchange chromatography.