Treatment of specific cardiovascular conditions with nitrite
Inventors
Gladwin, Mark T. • Schechter, Alan N. • Hunter, Christian J. • Power, Gordon G. • Kim-Shapiro, Daniel B. • Cannon, III, Richard O.
Assignees
Wake Forest University • Loma Linda University • US Department of Health and Human Services
Publication Number
US-9387224-B2
Publication Date
2016-07-12
Expiration Date
2024-07-09
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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
The invention provides methods for treating, preventing, or ameliorating specific cardiovascular conditions by administering pharmaceutically-acceptable nitrite salts, such as sodium nitrite, to a subject. It was unexpectedly discovered that nitrite can act as an effective vasodilator in vivo at concentrations much lower than previously believed necessary and can be administered in a non-acidified form. This administration results in a reduction of blood pressure and an increase in blood flow to tissues, particularly in regions of low oxygen tension.
Nitrite was historically believed to be an inert end product of nitric oxide metabolism and not effective in blood pressure regulation or as a vasodilator at physiological levels. Existing studies concluded that nitrite required extremely high concentrations to have any vasodilatory effect, and when administered at such levels (e.g., for cyanide poisoning), it resulted in unacceptable side effects like clinically significant methemoglobinemia. This prevented its use for broader cardiovascular indications.
The present disclosure reveals that nitrite is reduced to nitric oxide in vivo, producing vasodilatory effects at safe doses that do not generate clinically significant levels of methemoglobin. These findings enable the regulation of blood pressure and improvement of blood flow through the administration of nitrite salts, offering new methods to treat conditions such as ischemia-reperfusion injury, pulmonary hypertension (including neonatal pulmonary hypertension), and cerebral artery vasospasm. The invention also describes various routes of administration, including inhalation, which are effective for the intended treatments.
Claims Coverage
There are three independent claims covering three main inventive features.
Treatment of pulmonary hypertension with inhaled non-acidified sodium nitrite
A method for treating pulmonary hypertension in a subject by decreasing pulmonary arterial blood pressure or increasing vasodilation through administering by inhalation a therapeutically effective amount of pharmaceutically acceptable non-acidified sodium nitrite. This administration decreases pulmonary artery blood pressure or increases vasodilation, thereby treating pulmonary hypertension. The sodium nitrite is non-acidified and may be nebulized or administered intermittently, and the method specifies that minimal methemoglobin elevation occurs and systemic hypotension is not produced.
Treatment of pulmonary hypertension with inhaled non-acidified sodium nitrite
A method for treating pulmonary hypertension in a subject by administering by inhalation a therapeutically effective amount of non-acidified sodium nitrite. The sodium nitrite is administered to the subject by inhalation, without requiring acidification, to treat pulmonary hypertension.
Administration of non-acidified sodium nitrite for pulmonary hypertension to achieve defined blood concentrations
A method for treating pulmonary hypertension comprising administering by inhalation a therapeutically effective amount of pharmaceutically acceptable non-acidified sodium nitrite so that the sodium nitrite is administered to a circulating concentration of 0.6 to 240 μM, thereby treating pulmonary hypertension. The sodium nitrite can be nebulized, administered intermittently, and may be combined with at least one additional agent.
The independent claims define methods for treating pulmonary hypertension using non-acidified sodium nitrite administered by inhalation, including methods achieving specified circulating concentrations and encompassing features such as nebulization, intermittent dosing, minimal methemoglobin elevation, and no systemic hypotension.
Stated Advantages
Nitrite administration effectively reduces blood pressure and increases blood flow at doses that do not produce clinically significant methemoglobinemia.
The method allows vasodilation and regulation of the cardiovascular system with non-acidified nitrite salts, eliminating the need for acidification.
Nitrite treatment provides a novel, safe, and inexpensive therapy for cardiovascular and ischemic conditions, and can be administered easily, including by inhalation.
Beneficial effects occur at low, therapeutically effective doses, minimizing risk of toxicity or adverse side effects.
Sustained pulmonary vasodilation is achieved compared to inhaled nitric oxide, without systemic hypotension or significant elevation of methemoglobin.
Documented Applications
Treatment, prevention, or amelioration of pulmonary hypertension, including neonatal, primary, and secondary pulmonary hypertension.
Treatment, prevention, or amelioration of ischemia-reperfusion injury, including hepatic, cardiac, and brain ischemia-reperfusion injury.
Treatment, prevention, or amelioration of cerebral artery vasospasm.
Increasing blood flow to tissues, especially in regions of low oxygen tension.
Treatment of vascular complications associated with elevated blood pressure or hemolytic conditions.
Use in preventing delayed cerebral vasospasm after subarachnoid hemorrhage.
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