University of Utah Research Foundation

The Charlotte-mecklenburg Hospital Authority

Duke University

Cavalier Pharmaceuticals

Glycomira Therapeutics, Inc.

Carolinas Healthcare System

Paringenix, Inc.

Charlotte Hospital Authority

Charlotte-mecklenburg Hospital Authoirty

Energyhub, Inc.

Thomas P Kennedy

Glenn D Prestwich

Andrew J Ghio

Jianxing Zhang

Narayanam Rao

Claude A Piantadosi

Xiaoyu Xu

Won Yong Lee

Bart Lipkens

Seth Frader-Thompson

Louis Masi

Brian Dutra

Daniel Riegel

Justin Savage

Jeanine M Walenga

Siam Oottamasathein

Claude A Piantadcsi

Abigail Pulsipher

Walter M Presz

Stanley Kowalski

Mark Whitney

Chaoyi Guo

Ari Mercado

Arthur Martin

Jason Dionne

Stephan Von Muehlen

Justin Rodney Savage

Xiayou Xu

Described herein are methods for reducing or maintaining the size of a tumor in a subject, where the method involves exposing the tumor to ionizing radiation and administering to the subject a modified hyaluronan or a pharmaceutically acceptable salt or ester. The use of the modified hyaluronan enhances or potentiates the effect of ionizing radiation used in cancer treatment. Additionally, the methods described herein prevent or reduces tumor regrowth in the subject after exposing the tumor to ionizing radiation and administration of the modified hyaluronan to the subject.

Methods for potentiating cancer treatment using ionizing radiation

Described herein are methods for preventing a serious health consequence and/or tissue damage in a subject after the subject has been exposed to ionizing radiation and/or chemotherapy. The methods involve administering to the subject a sulfated polysaccharide or the pharmaceutically acceptable salt or ester thereof after the subject has been exposed to ionizing radiation and/or chemotherapy. The methods described herein are most beneficial to cancer patients who suffer from mucositis after exposure to ionizing radiation.

Methods for preventing a serious health consequence and/or tissue damage after exposure to ionizing radiation and/or chemotherapy

Described herein is the use of partially and fully sulfated hyaluronan or the pharmaceutically acceptable salt or ester thereof for therapeutic and cosmetic applications as well as the treatment of a number of systemic, dermatological, periodontal, ophthalmic, and urological inflammatory diseases.

Applications of partially and fully sulfated hyaluronan

Described herein are methods for treating inflammation in a subject comprising administering to the subject an effective amount of a modified hyaluronan or a pharmaceutically acceptable salt or ester thereof, wherein said hyaluronan or its pharmaceutically acceptable salt or ester comprises at least one sulfate group and the primary C-6 hydroxyl proton of at least one N-acetyl-glucosamine residue is substituted with a C-Cunsubstituted alkyl group or fluoroalkyl group.

Use of alkylated semi-synthetic glycosaminoglycosan ethers for the treatment of inflammation

Described herein are methods for treating a dental disorder in a subject comprising administering to the subject an effective amount of a modified hyaluronan or a pharmaceutically acceptable salt or ester thereof, wherein said hyaluronan or its pharmaceutically acceptable salt or ester comprises at least one sulfate group and the primary C-6 hydroxyl proton of at least one N-acetyl-glucosamine residue is substituted with a C-Cunsubstituted alkyl group or fluoroalkyl group.

Use of alkylated semi-synthetic glycosaminoglycosan ethers for the treatment of dental disorders

Described herein is the synthesis of alkylated and semi-synthetic glycosaminoglycosan ethers, referred to herein as 'SAGEs.' The synthesis of sulfated alkylated SAGEs is also described. The compounds described herein are useful in a number of applications including wound healing, drug delivery, and the treatment of a number of inflammatory diseases and skin disorders.

Alkylated semi synthetic glycosaminoglycosan ethers, and methods for making and using thereof

Described herein are alkylated and semi-synthetic glycosaminoglycosan ethers, referred to herein as 'SAGEs.' The synthesis of sulfated and alkylated SAGEs is also described. The compounds described herein are useful in a number of applications including use for ocular or ophthalmic treatment.

Alkylated semi-synthetic glycosaminoglycosan ethers, and methods of making and using thereof

There is provided a method for inhibiting ATF/CREB and cancer cell growth using disulfiram, administered in combination with heavy metals. It was found that disulfiram disrupts transcription factor DNA binding by forming mixed disulfides with thiols within the DNA-binding region, and that this process is facilitated by metal ions. Disulfiram administered to melanoma cells in combination with copper (II) or zinc(II) decreased expression of cyclin A, reduced proliferation in vitro, and inhibited growth of melanoma cells. The combination of oral zinc gluconate and disulfiram at currently approved doses for alcoholism stabilized tumor growth in two of three patients with Stage IV metastatic melanoma, with 12 and 17 month survivals, respectively, to date, and produced a &#x3e;50% reduction in hepatic metastases in one individual.

Method of inhibiting ATF/CREB and cancer cell growth and pharmaceutical compositions for same

A method and medicament for treating and preventing platelet activation or thrombosis in the presence of heparin-and platelet factor 4-complex reactive antibodies using a 2-O desulfated heparin with an average degree of sulfation of 0.6 sulfate groups per monosaccharide or greater and an average molecular weight or 2.4 kD or greater. The medicament preferably is administered intravenously, by aerosolization or orally. 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.

Method and medicament for sulfated polysaccharide treatment of heparin-induced thrombocytopenia (HIT) syndrome

Malignant melanoma cells spontaneously generate reactive oxygen species (ROS) that promote constitutive activation of the transcription factor nuclear factor-kB (NF-kB). Although antioxidants and inhibitors of NAD(P)H oxidases significantly reduce constitutive NF-kB activation and suppress cell proliferation, the nature of the enzyme responsible for ROS production in melanoma cells has not been determined. To address this issue, we now have characterized the source of ROS production in melanoma cells. ROS are generated by isolated, cytosol-free melanoma plasma membranes, with inhibition by NAD(P)H oxidase inhibitors. The p22, gp91and p67components of the human phagocyte NAD(P)H oxidase, and the 91homolog NOXwere demon-strated in melanomas by RT-PCR and sequencing, and protein product for both p22and gp91were detected in cell membranes by immunoassay. Normal human epidermal melanocytes expressed only p22and NOX. Melanoma proliferation was reduced by NAD(P)H oxidase inhibitors and by transfection of antisense but not sense oligonucleotides for p22and NOX. Also, the flavoprotein inhibitor diphenylene iodonium inhibited constitutive DNA binding of nuclear protein to the NF-kB and cyclic-AMP response element consensus oligonucleotides, without affecting DNA binding activity to AP-1 or OCT-.

Regulation of NAD(P)H oxidase growth and transcription in melanoma cells

Dithiocarbamate, particularly tetraethylthiuram disulfide, and thiocarbamate anions strongly inhibit the growth of cancer cells of a variety of cell types. Such inhibitory effect is enhanced by heavy metal ions such as copper ions, cytokines and ceruloplasmin. A method is presented for using tetraethylthiuram disulfide to reduce tumor growth, and to potentiate the effect of other anticancer agents.

Method of treating cancer using dithiocarbamate derivatives

Dithiocarbamate, particularly tetraethylthiuram disulfide strongly inhibits the growth of cancer cells of a variety of cell types. Such inhibitory effect is enhanced by heavy metal ions such as copper ions, cytokines and ceruloplasmin. A method is presented for using tetraethylthiuram disulfide to reduce tumor growth, and to potentiate the effect of other anticancer agents.

Method of treating cancer using tetraethyl thiuram disulfide

Heparin reduces ischemia-reperfusion injury to myocardium. This effect has been attributed complement inhibition, but heparin also has other activities that might diminish ischemia-reperfusion. To further probe these mechanisms, we compared heparin and an O-desulfated nonanticoagulant heparin with greatly reduced anti-complement activity. Given at the time of coronary artery reperfusion in a canine model of myocardial infarction, both heparin and O-desulfated heparin equally reduced neutrophil adherence to ischemic-reperfused coronary artery endothelium, influx of neutrophils into ischemic-reperfused myocardium, myocardial necrosis and release of creatine kinase into plasma. Heparin and O-desulfated heparin also prevented dysfunction of endothelial-dependent coronary relaxation following ischemic injury. In addition, heparin and O-desulfated heparin inhibited translocation of the transcription factor NF-&kgr;B from cytoplasm to the nucleus in human endothelial cells and decreased NF-&kgr;B DNA binding in human endothelium and ischemic-reperfused rat myocardium. Thus, heparin and nonanticoagulant heparin decrease ischemia-reperfusion injury by disrupting multiple levels of the inflammatory cascade, including the novel observation that heparins inhibit activation of the pro-inflammatory transcription factor NF-&kgr;B.

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Charlotte, NC, United States of America

Thomas P Kennedy