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 Marek • 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. Nitrite is reduced to nitric oxide in vivo, and the nitric oxide produced is an effective vasodilator. These effects occur at doses that do not produce clinically significant methemoglobinemia. These discoveries enable methods to prevent and treat conditions associated with the cardiovascular system, such as high blood pressure, pulmonary hypertension, cerebral vasospasm, and tissue ischemia-reperfusion injury. Methods also provide to increase blood flow to tissues, especially those in regions of low oxygen tension.

The problem being solved arises from previous understanding that nitrite was considered an inert metabolic end product of nitric oxide oxidation and lacked intrinsic vasodilator activity at physiological levels. Prior reports indicated that high concentrations of nitrite (greater than 100 μM) were required to vasodilate in vitro, and that infusion of nitrite at concentrations up to 200 μM in humans lacked vasodilatory effects. Furthermore, high doses of nitrite, such as those used to treat cyanide poisoning, formed clinically significant methemoglobinemia, precluding their use for other treatments. Thus, physiological levels of nitrite were not thought to serve as bioavailable nitric oxide or to regulate blood pressure.

The invention overcomes these limitations by demonstrating that nitrite, administered as pharmaceutically acceptable salts (such as sodium nitrite), is converted to nitric oxide in vivo via a reaction with deoxyhemoglobin, producing vasodilation at much lower concentrations than previously known, even as low as 0.9 μM. This nitrite reduction to nitric oxide is coupled to hemoglobin oxygen desaturation and tissue hypoxia, providing a mechanism for hypoxic vasodilation. Administration of nitrite salts reduces blood pressure and increases blood flow without inducing clinically significant methemoglobinemia. The invention further encompasses methods of treating malconditions associated with cardiovascular dysfunction, including ischemia-reperfusion injury, pulmonary hypertension, cerebral vasospasm, hemolytic conditions, and neonatal pulmonary hypertension, through administration of nitrite salts by various routes including injection and inhalation.

Claims Coverage

The patent contains independent claims covering methods of treating cerebral artery vasospasm using non-acidified sodium nitrite administration, focusing on dosage, administration routes, and combination therapies. Two independent claims are identified.

The claims collectively cover methods of treating cerebral artery vasospasm by administering non-acidified sodium nitrite at specific circulating concentrations and by various injection routes, optionally combined with other agents, providing a controlled and effective vasodilatory therapy.

Stated Advantages

Documented Applications