Use of nitrite salts for the treatment of cardiovascular conditions

Inventors

Gladwin, Mark T. • Schechter, Alan N. • Lefer, David J. • Patel, Rakesh P. • Hunter, Christian J. • Power, Gordon G. • Kim-Shapiro, Daniel B. • Pluta, Ryszard • Oldfield, Edward H. • Cannon, III, Richard O.

Assignees

Wake Forest University • UAB Research Foundation • Loma Linda University • Louisiana State University • US Department of Health and Human Services

Abstract

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.

Core Innovation

It has been surprisingly discovered that administration of pharmaceutically-acceptable salts of nitrite is useful in the regulation of the cardiovascular system. Specifically, nitrite is reduced to nitric oxide (NO) in vivo, and the resulting NO acts as an effective vasodilator, leading to a reduction in blood pressure and an increase in blood flow to tissues, even at doses that do not produce clinically significant methemoglobinemia. This is particularly impactful for tissues in regions of low oxygen tension and enables regulation of blood pressure and increased perfusion without toxic side effects.

Prior to this disclosure, it was believed, based on the state of the art, that physiological levels of nitrite do not act as vasodilators or as sources for NO delivery, and that high levels were necessary to see these effects—levels which also produced undesirable methemoglobinemia. Furthermore, nitrite was not applied therapeutically for cardiovascular conditions except in cases such as cyanide poisoning, where risk of methemoglobinemia was acceptable for short-term emergency use.

The invention provides methods for administering non-acidified, pharmaceutically acceptable nitrite salts for the treatment, prevention, or amelioration of cardiovascular conditions selected from ischemia-reperfusion injury (including hepatic, cardiac, or brain ischemia-reperfusion injury), pulmonary hypertension (including neonatal pulmonary hypertension), and cerebral artery vasospasm. Administration can occur intravenously or by inhalation (in nebulized form), with dosing regulated to achieve effective vasodilation while avoiding clinically significant formation of methemoglobin.

Claims Coverage

The patent claims disclose one main independent inventive feature relating to the treatment or amelioration of specific cardiovascular conditions using sodium nitrite.

The claims cover the use of non-acidified, pharmaceutically acceptable sodium nitrite to treat or ameliorate hepatic, cardiac, or brain ischemia-reperfusion injury, pulmonary hypertension (including neonatal), and cerebral artery vasospasm, via intravenous or inhaled administration, with defined blood concentration thresholds and compatibility for combination therapy.

Stated Advantages

Documented Applications