The State University of New York

Other

University of Miami

Hospital for Joint Diseases

Kuraray Co., Ltd.

Thomas F McNamara

Lorne M Golub

Nungavaram S Ramamurthy

Robert A Greenwald

Nangavarum S Ramamurthy

Norman L Block

Sanford R Simon

Hsi-Ming Lee

Balakrishna L Lokeshwar

Marie G Selzer

Steven B Abramson

Peter Vadas

Jerry J Pollock

Ashok R Amin

Waldemar Pruzanski

Maria Emanuel Ryan

Howard Trachtman

Tetsuo Takigawa

Goro Kobayashi

Jonathan Maimon

Tsutomu Kawai

Michiya Shimamura

Hisashi Iwata

Fred Confessore

Kenneth Gorray

Bruce Schneider

Takashi Hamasaki

Nungavarum S Ramamurthy

N S Ramamurthy

The invention is a method of inhibiting a sarcoma, such as Kaposi's sarcoma, in a mammal. The method employs 6-demethyl-6-deoxy-4-de(dimethylamino)tetracycline (CMT-3.)

Method of inhibiting cancer growth

The invention is a method of inhibiting cancer growth, by inhibiting cellular proliferation, invasiveness, or metastasis, or by inducing cytotoxicity against cancer in mammals. The method employs 6-demethyl-6-deoxy-4-de(dimethylamino)tetracycline (CMT-3) and other functionally related chemically modified, preferably non-antibacterial, tetracycline compounds to inhibit cancer growth. The method is particularly effective to inhibit the establishment, growth, and metastasis of solid tumors, such as tumors derived from colon cancer cells, breast cancer cells, melanoma cells, prostatic carcinoma cells, or lung cancer cells.

A method for treating mammals suffering from conditions associated with excess phospholipase A.sub.2 activity and/or production comprising administering to the mammal an effective amount of a non-antimicrobial tetracycline sufficient to inhibit excess phospholipase A.sub.2 activity and/or production is disclosed. A pharmaceutical composition is also disclosed.

Inhibition of excessive phospholipase A.sub.2 activity and/or production

A method for treating diabetes in a mammal by moderately controlling blood glucose concentration in the mammal together with administering to the mammal an amount of a tetracycline compound effective to reduce complications associated with diabetic hyperglycemia. The method enables long term management of diabetes by avoiding the problems associated with tight control of blood glucose concentrations, i.e., hypoglycemia tolerance and seizures, while simultaneously avoiding the problems associated with conventional moderate control of blood glucose concentrations, i.e., pathological complications associated with hyperglycemia, such as nephropathy, retinopathy, etc. Blood glucose concentration can be controlled by moderate administration (e.g., fewer injections per day) of insulin or another glucose-modulating agent, while pathological complications characteristic of diabetic hyperglycemia are ameliorated through the activity of tetracycline compound, the latter preferably administered in an amount that is substantially non-antimicrobial.

Therapeutic method for management of diabetes mellitus

The invention is a method of inhibiting the production of nitric oxide (NO) in an in vivo, in vitro, or ex vivo biological system. The method employs a tetracycline compound to inhibit the production of NO and/or to inhibit the expression or activity of an inducible isoform of nitric oxide synthase (iNOS). Preferably, the tetracycline compound has inhibitory activity for metalloproteinases. Also it is preferred that the tetracycline compound is provided to the biological system in an amount which has little or no antibacterial activity in the system. Accordingly, preferred tetracycline compounds are tetracycline compounds which have be modified to reduce or eliminate their antimicrobial activity. The method can be used to treat medical conditions in mammals characterized by NO production mediated by iNOS, including, for example, inflammatory conditions.

Method for inhibiting expression of inducible nitric oxide synthase with

The invention is a method of inhibiting cancer growth, including cellular proliferation, invasiveness, or metastasis in mammals. The method employs 6-demethyl-6-deoxy-4-dedimethylaminotetracycline (CMT-3) and other functionally related chemically modified, preferably non-antibacterial, tetracycline compounds to inhibit cancer growth. The method is particularly effective to inhibit the establishment, growth, and metastasis of solid tumors, such as tumors derived from colon cancer cells, breast cancer cells, melanoma cells, prostatic carcinoma cells, or lung cancer cells.

A method for improving the healing response of epithelialized tissue (e.g., skin, mucosae) to acute traumatic injury is disclosed. The method includes employing a tetracycline compound, having substantially no antibacterial activity, to improve the capacity of the epithelialized tissue to heal acute wounds. Specifically, the method involves increasing the rate of collagen accumulation of the healing epithelialized tissue above that associated with wound healing in the individual. The method decreases proteolytic activity in the epithelialized tissue by means of the tetracycline compound, most commonly decreasing collagenolytic activity and/or decreasing gelatinolytic activity. Collagenase and gelatinase activity have been shown to be decreased by the method of the invention. Preferably, the method is employed to improve the wound healing capacity of human or animal subjects in whom such capacity is impaired. Also, the non-antibiotic tetracycline is preferably administered topically at the site of the wound.

Promotion of wound healing by chemically-modified tetracyclines

A method is disclosed for inhibiting endogenous production of nitric oxide (NO) in an in vivo, in vitro, or ex vivo mammalian system. The method employs a tetracycline compound to inhibit production of NO and/or to inhibit the expression or activity of an inducible isoform of nitric oxide synthase (iNOS). Preferably, the tetracycline compound has inhibitory activity for metalloproteinases. Also it is preferred that the tetracycline compound is provided to the mammalian system in an amount which has little or no antibacterial activity in the system. Accordingly, preferred tetracycline compounds are tetracycline compounds which have be modified to reduce or eliminate their antimicrobial activity. The method can be used to treat medical conditions in mammals characterized by NO production mediated by iNOS, including, for example, inflammatory conditions.

Method of using tetracycline compounds for inhibition of endogenous

Methods of inhibiting root caries formation on mammalian tooth surfaces are disclosed. The methods include topically contacting the tooth root surfaces with an effective amount of a non-antibacterial tetracycline which is not systemically absorbed into the blood stream. In preferred embodiments, the tetracyclines are included in various oral hygiene products such as dentifrices, lozenges, chewing gums and the like to contact the tooth root surfaces.

Non-antibacterial tetracycline compositions of the prevention and

A pair of weighted handles for a jump rope is provided. Each weighted handle includes an attachment connected to the jump rope. The attachment is internally threaded and is connected to an externally threaded handweight. The handweight may be quickly attached to or detached from the attachment simply by screwing it to or unscrewing it from the attachment. A stopwatch is optionally provided on the exterior face of one attachment.

Weighted handle for a jump rope

A method for treating mammals suffering from excessive extracellular protein glycosylation which is associated with diabetes, scleroderma and progeria by administering to the mammal a tetracycline which effectively inhibits excessive protein glycosylation.

Tetracyclines including non-antimicrobial chemically-modified

A method for treating mammals suffering from conditions associated with excess phospholipase A.sub.2 activity and/or production comprising administering to the mammal an effective amount of a non-antimicrobial tetracycline sufficient to inhibit excess phospholipase A.sub.2 activity and/or production is disclosed.

A method for treating mammals suffering from rheumatoid arthritis and other tissue-destructive (chronic inflammatory or other) conditions associated with excess metalloproteinase activity comprising administering to the mammal an amount of a tetracycline that is effectively anti-metalloproteinase, but that is not effectively antimicrobial, and an amount of non-steroidal anti-inflammatory agent which, when combined with the effectively anti-metalloproteinase amount of tetracycline, results in a significant reduction of tissue destruction and/or bone loss.

Composition comprising indomethacin [non-steroidal anti-inflammatory

Composition comprising fluriprofen and effectively non-antibacterial

A method for treating mammals suffering from rheumatoid arthritis, other tissue-destructive conditions, and chronic inflammatory or other conditions associated with excess metalloproteinase activity comprising administering to the mammal an amount of a tetracycline that is effectively anti-metalloproteinase, but that is not effectively antimicrobial, and an amount of a non-steroidal anti-inflammatory agent which, when combined with the effectively anti-metalloproteinase amount of tetracycline, results in a significant reduction of tissue destruction and/or bone loss.

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Port Jefferson, NY, United States of America

Thomas F McNamara