The United States of America As Represented by the Department of Health

The United States of America, As Represented by the Secretary, Department of Health and Human Services

University of California

Johns Hopkins University

Louisiana State University and Agricultural & Mechanical College

The University of Arizona

The University of North Carolina at Chapel Hill

Wake Forest University

David A Wink

Larry K Keefer

James B Mitchell

Katrina M Miranda

Murali C Krishna

Joseph A Hrabie

Joseph E Saavedra

Angelo Russo

Tambra M Dunams

James E Liebmann

David A Kass

Nazareno Paolocci

Jon M Fukuto

Martin Feelisch

Tatsuo Katori

Debashree Basudhar

Danae D Christodoulou

Janet N Younathan

S Bruce King

Murali Krishna Cherukuri

Thomas J Meyer

Joseph Saavedra

Royce W Murray

Tadeusz Malinski

Wilmarie Flores-Santana

Debra J Salmon

Daniela Andrei

Melani Sullivan

Daniel Neil Granger

Matthew B Grisham

Pasquale Pagliaro

Ingeborg Hanbauer

The present disclosure provides methods utilizing the diazeniumdiolate-based prodrugs for the treatment of cancer via various mechanisms and procedures. The disclosure also provides kits comprising the diazeniumdiolate-based prodrugs.

Compositions and methods of diazeniumdiolate-based prodrugs for treating cancer

Disclosed are nitroxide modified NSAID compounds of the formula (I) or a pharmaceutically acceptable salt or enantiomer thereof:  in which R, R, R, R, R, R, R, R, R, R, R, and n are defined herein and pharmaceutical compositions thereof. Further disclosed is a method of treating or preventing various disorders, such as inflammation, cancer, diabetes, a cardiovascular disorder, weight gain, polyps, and/or chronic pain, in a patient comprising administering an effective amount of a compound or pharmaceutically acceptable salt or enantiomer of formula (I). A method of imaging the compound or pharmaceutically acceptable salt or enantiomer of formula (I) in the body of the animal is also provided.

Nitroxide modified non-steroidal anti-inflammatory compounds and uses thereof in the treatment and prevention of diseases or disorders

Disclosed is a compound of the formula (I) or a pharmaceutically acceptable salt thereof: (I) in which R, R, R, and Rare defined herein and pharmaceutical compositions thereof. Further provided is a method of treating various disorders, such as a disorder selected from the group consisting of a cardiovascular disorder, cancer, chronic pain, alcohol dependence, and inflammation in a patient comprising administering an effective amount of a compound or pharmaceutically acceptable salt of formula (I). 

Nitroxyl (HNO) releasing compounds and uses thereof in treating diseases

Nitroxyl donating compounds are administered prior to the onset of ischemia for the prevention and/or reduction of ischemia/reperfusion injury in subjects at risk for ischemia. Nitroxyl donors also are administered to organs to be transplanted for the prevention and/or reduction of ischemia/reperfusion injury upon reperfusion in a recipient. Nitroxyl donors include any nitroxyl donating compound. In particular cases the nitroxyl donor is a nitroxyl-donating diazeniumdiolate, such as Angeli's salt or IPA/NO.

Method of treating ischemia/reperfusion injury with nitroxyl donors

Administration of an HNO/NOdonating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure. Moreover, administration of the HNO/NOdonating compound isopropylamine (IPA)/NO(Na(CH)CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NOdonating compound Angeli's salt. Additionally, in contrast to the effects observed with NOdonors, administration of an HNO/NOdonor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent. Further, HNO/NOexerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy.

Nitroxyl progenitors in the treatment of heart failure

Administration of an HNO/NOdonating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure Moreover, administration of the HNO/NOdonating compound isopropylamine (IPA)/NO (Na(CH)CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NOdonating compound Angeli's salt. Additionally, in contrast to the effects observed with NOdonors, administration of an HNO/NOdonor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent Further, HNO/NOexerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy

The present invention provides a method for sensitizing hypoxic cells in a tumor to radiation, wherein nitric oxide is delivered to target hypoxic cells through the administration of a nitric oxide-containing compound that spontaneously releases nitric oxide under physiological conditions without requiring the presence of oxygen. Also provided are methods of protecting noncancerous cells or tissues in a mammal from radiation, sensitizing cancerous cells in a mammal to chemotherapeutic agents, and protecting noncancerous cells or tissues in a mammal from chemotherapeutic agents, all by administration of the same compounds.

Use of nitric oxide releasing compounds to protect noncancerous cells

Nitric oxide-releasing compounds to sensitive cancerous cells to

Use of nitric oxide-releasing compounds as hypoxic cell radiation

The present invention provides a method for treating oxygen free radical induced tissue damage associated with ischemia reperfusion injury, wherein nitric oxide is delivered to target cells/tissues through the administration of a nitric oxide-containing compound that spontaneously releases nitric oxide under physiological conditions without requiring the presence of oxygen.

Nitric oxide releasing compounds as protective agents in ischemia

There are disclosed anti-hypertensive compositions and a method of lowering blood pressure in mammals. The active component in the anti-hypertensive compositions is a compound of the formula ##STR1## wherein R.sub.1 and R.sub.2 are independently selected from straight chain and branched chain C.sub.1 -C.sub.12 alkyl groups and benzyl, with the proviso that no branch occur on the alpha carbon atom of the alkyl group; or R.sub.1 and R.sub.2 together with the nitrogen atom they are bonded to form a heterocyclic ring; M.sup.+x is a pharmaceutically acceptable cation, wherein x is the valence of the cation.

Anti-hypertension compositions of secondary amine-nitric oxide adducts

Use of nitric oxide releasing compounds as hypoxic cell radiation

An electrode sensor which may be used to specifically and quantitatively measure nitric oxide is provided, as well as a method of preparing and using such an electrode sensor to measure nitric oxide concentration in solution. A nitric oxide (NO) microsensor based on catalytic oxidation of NO comprises a thermally-sharpened carbon fiber with a tip diameter of about 0.5-0.7 .mu.m coated with several layers of p-type semiconducting polymeric porphyrin and cationic exchanger deposited thereon. The microsensor, which can be operated in either the amperometric, voltammetric or coulometric mode utilizing a two or three electrode system, is characterized by a linear response up to about 300 .mu.M, a response time better than 10 msec and a detection limit of about 10 nM. The sensor of the present invention also discriminates against nitrite, the most problematic interferant in NO measurements. The amount of NO released from a single cell can thus be selectively measured in situ by a porphyrinic microsensor of the invention. A larger scale sensor utilizing porphyrin and cationic exchanger deposited on larger fibers or wires, platinum mesh or tin indium oxide layered on glass, can also be employed when measurement of NO concentration in chemical media, tissue or cell culture is desired.

Nitric oxide sensor

Mixed ligand metal complexes of nitric oxide-nucleophile adducts, useful as cardiovascular agents of the formula KA, wherein A is

Mixed ligand metal complexes of nitric oxide-nucleophile adducts useful

This invention concerns antihypertensive compositions and a method of lowering blood pressure in mammals. The active component of the compositions is a compound of the formula: ##STR1## wherein J is an organic or inorganic moiety, M.sup.+x is a pharmaceutically acceptable cation and the compound decomposes under physiological conditions to release nitric oxide (NO).

Antihypertensive compositions and use thereof

Growing community of inventors

Hagerstown, MD, United States of America

David A Wink