University of Pittsburgh

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

Wake Forest University

The Uab Research Foundation (the University of Alabama at Birmingham)

Loma Linda University

Louisiana State University and Agricultural & Mechanical College

Aires Pharmaceuticals, Inc.

Mark Thomas Gladwin

Jesus Tejero Bravo

Daniel B Kim-Shapiro

Rakesh P Patel

Alan N Schechter

Richard O Cannon, Iii

Christian J Hunter

Gordon G Power

David J Lefer

Edward H Oldfield

Ryszard Marek Pluta

Jason Joseph Rose

Edwin Parsley

Qinzi Xu

Hunter Clay Champion

S Bruce King

Michael Jurczak

Courtney E Sparacino-Watkins

Mauro Tiso

Daniel A Sweeney

Jeffrey Kerby

Richard O Cannon

Ryszard Pluta

Richard Iii Cannon

Described herein is a new antidote for the rapid elimination of carbon monoxide from hemoglobin, including brain, heart, and red cell hemoglobin. The disclosed therapy involves the use of modified human globins, particularly neuroglobins modified at residue 64 and cytoglobins modified at residue 81, which bind carbon monoxide with extremely high affinity. The monomeric mutant globins are infused into blood, where they rapidly and irreversibly sequester carbon monoxide, and thus limit toxic effects of carbon monoxide on cellular respiration and oxygen transport and utilization.

Compositions and methods for the treatment of carboxyhemoglobinemia

In vitro and in vivo methods of removing carbon monoxide from hemoglobin in blood or animal tissue are described. Methods of treating carboxyhemoglobinemia (carbon monoxide poisoning) in a subject are also described. The methods include administering natural or artificial oxygen carriers that are in their reduced form. Methods of producing a reduced oxygen carrier are further described. Methods of treating cyanide poisoning or hydrogen sulfide poisoning with oxygen carriers are also described.

Reduced oxygen carriers and their use for the treatment of carboxyhemoglobinemia

Disclosed herein are methods for treating acute or chronic heart failure using inorganic nitrite, such as sodium nitrite. The method includes administering to a subject in need of treatment a therapeutically effective amount of inorganic nitrite. The nitrite may be administered by inhalation and may be nebulized. The nitrite may be administered at an emitted dose or in an escalated titrated dose. The nitrite may be a liquid formulation or a dry powder formulation.

Inorganic nitrite to improve cardiopulmonary hemodynamics

It is disclosed herein that microperoxidases are capable of binding carbon monoxide (CO) with high affinity and displacing CO from hemoglobin, thereby acting as CO scavengers. The present disclosure provides methods of treating carboxyhemoglobinemia (or CO poisoning) in a subject by administering a therapeutically amount of an isolated or recombinant microperoxidase. Methods of removing CO from hemoglobin in blood or tissue by administering a therapeutically amount of an isolated or recombinant microperoxidase are also described. Methods of determining the effectiveness of a microperoxidase for removing CO from hemoglobin are further described.

Use of microperoxidases for the treatment of carboxyhemoglobinemia

A method of treating hyperglycemia, diabetes, metabolic syndrome, insulin resistance (insulin insensitivity), impaired glucose tolerance, high glucose levels, pulmonary hypertension, and/or a condition arising from any of the foregoing in a patient is provided. The method comprises knocking down mARC2 or mARC1 expression in the patient, or otherwise decreasing mARC2 and mARC1 activity in the patient.

Method of treating insulin resistance

It has been surprisingly discovered that administration of nitrite to subjects causes a reduction in blood pressure and an increase in blood flow to tissues. The effect is particularly beneficial, for example, to tissues in regions of low oxygen tension. This discovery provides useful treatments to regulate a subject's blood pressure and blood flow, for example, by the administration of nitrite salts. Provided herein are methods of administering a pharmaceutically-acceptable nitrite salt to a subject, for treating, preventing or ameliorating a condition selected from: (a) ischemia-reperfusion injury (e.g., hepatic or cardiac or brain ischemia-reperfusion injury); (b) pulmonary hypertension (e.g., neonatal pulmonary hypertension); or (c) cerebral artery vasospasm.

Use of nitrite salts for the treatment of cardiovascular conditions

Treatment of specific cardiovascular conditions with nitrite

Described herein is the finding that a mutant form of human neuroglobin (H64L) with a stable five-coordinate geometry reduces nitrite to nitric oxide approximately 2000-times faster than the wild type neuroglobin. Five-coordinate neuroglobin is also capable of binding and releasing oxygen. Based on these findings, the use of five-coordinate neuroglobin as a blood substitute is described herein. Particularly provided is a method of replacing blood and/or increasing oxygen delivery to tissues in a subject by administering to the subject a therapeutically effective amount of neuroglobin with a stable five-coordinate geometry. In some cases, five-coordinate neuroglobin is administered in combination with another therapeutic agent or composition, such as a second blood replacement product (for example, a hemoglobin-based oxygen carrier), a blood product (such as red blood cells, serum or plasma) or whole blood.

Five-coordinate neuroglobin and use thereof as a blood substitute

Provided herein are methods of treating hemolysis by administering an active compound in an amount sufficient to treat said hemolysis. It has been found that nitroxyl donors or similar compounds preferentially react with cell-free OxyHb, as compared to OxyHb encapsulated in a red blood cell, and reacts with MetHb to form iron-nitrosyl Hb or nitrite bound MetHb. It has also been found that such compounds reduce cell-free Hb and hemolysis. Active compounds are also contemplated for use in combination therapies, for example, in combination with the administration of red blood cells and/or an agent that promotes hematopoiesis, or in combination with the administration of a nitric oxide donor.

Methods of treatment for hemolysis

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Pittsburgh, PA, United States of America

Mark Thomas Gladwin