Intradialytic use of sodium nitrite

Abstract

To provide a pharmaceutical dialysate for use in methods for maintaining physiological levels of nitrite ions in a subject undergoing hemodialysis.SOLUTION: The invention provides a sodium nitrite-containing nitrite ion-spiked dialysate. A method for maintaining physiological levels of nitrite ions comprises intradialytically contacting a subject's blood with a dialyzer membrane that is also in contact with a nitrite ion-spiked dialysate. The nitrite ion-spiked dialysate has a pH greater than about 7.0. The nitrite ion-spiked dialysate is for use in combination with one or more of copper, fluoride ions, iodine, iron, manganese, magnesium, phosphorus, selenium, thiosulfate ions, and zinc.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] (cross reference) This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 468,857, filed March 8, 2017. No. 60 / 699,999, filed on Dec. 1, 2003, the contents of which are incorporated herein by reference in their entirety.

[0002] (Field) Provided herein are methods for reducing the production of nitrite ions in subjects undergoing hemodialysis. Also provided herein is a method for maintaining a physiological level. and a method for administering aspirin-acceptable sodium nitrite to a subject undergoing hemodialysis. . [Background technology]

[0003] (background) Patients with chronic kidney disease (CKD) suffer from a deterioration of renal function, which is caused by a decrease in the excretion of metabolic waste products. The accumulation of metabolic waste products can become life-threatening within days. Patients with little or no function remaining are considered to have "end-stage renal disease." Therefore, such patients require an alternative means of eliminating waste products in order to survive. The process of excreting waste involves the transfer of waste products from the blood to the external fluid where they are subsequently discarded. It is a means of excretion (Am. J. Kidney Dis. 2002, 39(Suppl. 1), S1-266).

[0004] Dialysis is defined as the transfer of solutes and water between two liquids separated by a semi-permeable "dialysis membrane." In hemodialysis, blood flows through one side of a dialysis membrane and is mixed with a water-based solution called dialysate. The solution flows through the other side. The dialysis membrane contains pores that allow the solute to pass through. The concentration of a solute present in one liquid is such that, due to osmotic forces, the solute leaves the higher concentration liquid and becomes permeable. The membrane is forced through the pores into the less concentrated liquid, resulting in equilibration.

[0005] Dialysis membranes are designed with various pore sizes to determine which solutes can pass through during hemodialysis. During hemodialysis, the excessive amount of small molecule solutes that can diffuse through the dialysis membrane Removing it from the blood can be harmful.

[0006] Blood contains nitrite ions (NO2 - Contains low molecular weight solutes such as nitrite. Nitrite has a molecular weight of 46 daltons. Nitrite is the nitrite ion that regulates the physiological function of nitric oxide in humans. The scientific source is confirmed (Gladwin, PCT / US2004 / 021985, filed 2 (July 9, 2004). The concentration of nitrite in the blood of a healthy individual is approximately 300 nanomolar. .

[0007] The Association for the Advancement of Medical Instrumentation The American Association of Medical Informatics (AAMI) has established quality specification limits for the nitrate content in water used for dialysis (1 (2 mg per liter, or 2 ppm) (#ANSI / AAMI / ISO 13959:2009). AAMI also stipulates that the nitrate ion content in water should be measured using the "cadmium reduction method" In this method, the sample is passed through a column containing granular copper-cadmium, which releases nitrate ions. This is followed by the reduction of nitrite to a dark azo color which can be measured using a spectrophotometer. Diazotization with sulfanilamide to give N-(1-naphthyl)-ethylenediamine Nitrite is determined by coupling with hydrochloride (U.S. Environmental Protection Agency's National Environmental Methods Index. www.nemi.gov / methods / method_summary / 51 (Available online at 21). This test method does not distinguish between nitrate and nitrite. Instead, the test is actually a measurement of both nitrate and nitrite. Therefore, the test method specified by AAMI does not distinguish between nitrate and nitrite ions. Therefore, the AAMI nitrate quality specification is based on the nitrate and Therefore, the AAMI nitrate quality specification actually limits the amount of nitrite. This is the limit for the sum of nitrate and nitrite ions in water used for dialysis.

[0008] Myocardial infarction has been associated with decreased blood nitrite levels (Kehmeier et al., 2004). (Free Radic. Biol. Med. 2008, 44, 1945-1950). In myocardial ischemia, nitrite ions Nitrite is reduced to nitric oxide, which is a vasodilator. The reduction of nitric oxide to nitric oxide protects cardiac function by increasing blood flow to ischemic tissue. As long as nitrite ions remain available in the blood, the beneficial effects will be apparent. Nitrite depletion may prevent tissue ischemia from progressing to infarction when vasodilation cannot be maintained. may be a contributing factor in progression (Landmesser et al., Curr. Opin. Cardiol. 2005, 20, 547-551).

[0009] Cardiovascular disease accounts for more than half of all deaths in patients requiring chronic hemodialysis (G (N. Eng. J. Med. 2004, 351, 1296-1305). The risk of sudden death events increased 1.7-fold in patients with dialysis. increased both during and after treatment (Bleyer et al., Kidney Int. 2006, 12, 226 8-2273).

[0010] At the same time, plasma concentrations of nitrite ions decreased by more than 60% during the first hour of hemodialysis and by 4 hours. The subsequent time of the hemodialysis session remains significantly reduced (Bryan et al., Free Radic. Biol. Med. 2013, 58, 46-51).

[0011] Sodium nitrite can be administered into the blood by intravenous injection; however, However, it may not be effective in maintaining physiological levels in dialysis patients. This is because sodium nitrite is rapidly removed during hemodialysis. An effective method for maintaining physiological levels of nitrite in the blood of patients undergoing dialysis There is also no satisfactory method for administering sodium nitrite to patients during hemodialysis. do not have. Summary of the Invention

[0012] (overview) The present disclosure provides a method for maintaining physiological levels of nitrite in subjects undergoing hemodialysis. The present disclosure also provides a method for maintaining myocardial Infarction, sudden cardiac death, stroke, cardiovascular disease, hypertension, pulmonary hypertension, and / or renal The present disclosure also provides a method for preventing hypertension in a subject undergoing hemodialysis. The present invention provides a method for administering sodium nitrite in a patient.

[0013] In certain embodiments, provided herein are methods for treating hemodialysis in subjects undergoing hemodialysis. 2. A method for maintaining physiological levels of nitrite in a subject, comprising: During dialysis, the nitrite ion-spiked dialysate is contacted with the dialysis membrane. When the unspiked dialysate flows from the dialyzer to the dialysis membrane, sodium nitrite is released. An aqueous solution containing thorium is added to the unspiked dialysate and the spiked dialysate is The dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the nitrite is The method, wherein the ON spiked dialysate has a pH greater than about 7.0.

[0014] Also provided herein, in certain embodiments, is a method for treating a subject undergoing hemodialysis. 1. A method for maintaining physiological levels of nitrite in an elephant, comprising administering to said subject The method comprises contacting the blood with a dialysate spiked with nitrite ions during dialysis, When the undiluted dialysate flows from the dialysis machine to the dialysis membrane, it is mixed with sodium nitrite-containing water. A solution is added to the unspiked dialysate, and the unspiked dialysate is mixed with water. nitrite ion-spiked mixture of a concentrated acid solution and a concentrated bicarbonate solution. wherein the dialysate has a pH greater than about 7.0.

[0015] Also provided herein, in certain embodiments, is a method for administering to a subject undergoing dialysis. A method for preventing myocardial infarction in a subject, comprising sparing the blood of the subject with nitrite ions. contacting the spike with a dialysis membrane that is also in contact with the dialysis fluid during dialysis; When the undiluted dialysate flows from the dialyzer to the dialysis membrane, the aqueous solution containing sodium nitrite The solution is added to the unspiked dialysate, and the unspiked dialysate is mixed with water, A mixture of a concentrated acid solution and a concentrated bicarbonate solution spiked with the nitrite ion. The dialysate has a pH greater than about 7.0.

[0016] Also provided herein, in certain embodiments, is a method for administering to a subject undergoing dialysis. A method for preventing sudden cardiac death in a subject, comprising: during dialysis, contacting the dialysis membrane with a dialysis membrane that is also in contact with the dialysis fluid spiked with When unspiked dialysate flows from the dialyzer to the dialysis membrane, it contains sodium nitrite. An aqueous solution containing nitrite ion spies on a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution. The method, wherein the dialysate has a pH greater than about 7.0.

[0017] Also provided herein, in certain embodiments, is a method for administering to a subject undergoing dialysis. A method for preventing stroke in a subject, comprising spiking the blood of the subject with nitrite ions. contacting the spiked dialysis membrane with a dialysis membrane that is also in contact with the spiked dialysis fluid during dialysis; When the untreated dialysate flows from the dialysis machine to the dialysis membrane, an aqueous solution containing sodium nitrite is added to the unspiked dialysate, and the unspiked dialysate is mixed with water, acid, and a mixture of a concentrated solution of nitrite and a concentrated solution of bicarbonate, spiked with the nitrite ion. The method wherein the dialysate has a pH greater than about 7.0.

[0018] Also provided herein, in certain embodiments, is a method for administering to a subject undergoing dialysis. In patients with angina pectoris, cerebral vasospasm, claudication, critical limb ischemia, peripheral vascular disease, and sickle cell crises, 1. A method for preventing cardiovascular disease characterized by tissue ischemia, including ischemia, comprising administering to a subject During dialysis, the solution is brought into contact with a dialysis membrane that is also in contact with dialysate spiked with nitrite ions. and wherein the unspiked dialysate is mixed with the dialysis membrane as it flows from the dialyzer to the dialysis membrane. An aqueous solution containing sodium nitrate is added to the unspiked dialysate, and the spiked dialysate is The untreated dialysate comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and The method, wherein the nitrate spiked dialysate has a pH greater than about 7.0.

[0019] Also provided herein, in certain embodiments, is a method for administering to a subject undergoing dialysis. A method for preventing hypertension, pulmonary hypertension, and renal hypertension, comprising administering to said subject a During dialysis, elephant blood is in contact with a dialysis membrane that is also in contact with dialysate spiked with nitrite ions. contacting the unspiked dialysate with the dialysis membrane when the unspiked dialysate flows from the dialysis machine to the dialysis membrane. Then, an aqueous solution containing sodium nitrite is added to the unspiked dialysate, and the spa The uninjected dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and wherein the nitrite ion spiked dialysate has a pH greater than about 7.0.

[0020] Also provided herein, in certain embodiments, is a method for administering to a subject undergoing dialysis. A method for administering sodium nitrite, comprising sparing the subject's blood with nitrite ions. contacting the spike with a dialysis membrane that is also in contact with the dialysis fluid during dialysis; When the undiluted dialysate flows from the dialyzer to the dialysis membrane, the aqueous solution containing sodium nitrite The solution is added to the unspiked dialysate, and the unspiked dialysate is mixed with water, A mixture of a concentrated acid solution and a concentrated bicarbonate solution spiked with the nitrite ion. The dialysate has a pH greater than about 7.0. [Brief explanation of the drawings]

[0021] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figure 1 is a schematic diagram of elements of the flow paths for dialysate, patient blood, and aqueous solution containing sodium nitrite: (10) dialyzer; (20) acid concentrate solution; (30) bicarbonate concentrate solution; (40) aqueous solution containing sodium nitrite; (50) aqueous solution containing sodium nitrite flow; (60) dialysate tubing; (70) valves; (80) dialyzer; (90) dialysis membrane; (100) detection point "before" dialysis membrane; (110) detection point "after" dialysis membrane; (120) detection point "V"; (130) detection point "A"; and (140) spent dialysate. DETAILED DESCRIPTION OF THE INVENTION

[0022] (Detailed explanation) The following detailed description is not to be taken in a limiting sense, but merely as a guide to the present invention. This is provided for the purpose of illustrating an embodiment.

[0023] To facilitate understanding of the disclosure set forth herein, several terms are defined below. do.

[0024] Generally, the nomenclature used herein, as well as the inorganic and analytical chemistry described herein, Laboratory methods of organic chemistry, medicinal chemistry, and pharmacology are well known and widely used in the art. Unless otherwise defined, all technical terms used herein are those commonly employed. Terms and scientific terms are generally those commonly understood by one of ordinary skill in the art to which this disclosure belongs. When there is a plurality of definitions for terms used herein, Unless otherwise stated, this section takes precedence.

[0025] The term "subject" refers to any animal, including primates (e.g., humans), cattle, sheep, goats, horses, dogs, mice, and the like. "Subject" refers to an animal, including, but not limited to, a dog, rabbit, rat, or mouse. and the term "patient" is used herein to refer to a mammalian subject, e.g., a human subject. In one embodiment, the subject is a In another embodiment, the individual has or is at risk for the disease, disorder, or condition indicated. The subject may have or be at risk for a disease, disorder, or condition, and may be at risk for the disease, disorder, or condition. or diseases, or symptoms thereof, can be treated, prevented, or ameliorated by the administration of sodium nitrite. In another embodiment, the subject is a patient with end-stage renal disease undergoing regular hemodialysis. In another embodiment, the subject is a patient with endocrine systemic renal failure (ESRD). Patients with some or no kidney function undergoing dialysis to reduce blood pressure. In another embodiment, the steady-state plasma concentration of nitrite in a subject undergoing hemodialysis is and saliva concentrations are significantly reduced as a result of about 3 to about 5 hours of hemodialysis. In the method, the subject has plasma levels of nitrite that are below normal physiological levels.

[0026] The terms "treat," "treating," and "treatment" refer to the treatment of a disorder, disease, or Alleviating or inhibiting the disease or one or more symptoms associated with the disorder, disease, or condition or to alleviate or eradicate the cause of the disorder, disease, or illness itself. It is meant to include.

[0027] The terms "prevent," "preventing," and "prevention" refer to the prevention of a disorder, disease, or delaying and / or preventing the onset of the disease and / or its associated symptoms; Prevent a subject from acquiring or reducing the subject's risk of acquiring a disorder, disease, or illness It is meant to include methods of making

[0028] Generally, conventional dialysis fluids, including those recently patented, are either proprietary or not. Many of these are defined as any formulation known to date, regardless of the specific For example, U.S. Patent No. 6,436,969 discloses a U.S. Patent No. 5,869,444 discloses compositions containing GE inhibitors, and U.S. Patent No. 5,869,444 discloses compositions containing osmotically effective peptides. U.S. Patents 6,306,836 and 6,380,163 claim solutions containing a mixture of methacrylates. discloses a peritoneal dialysis solution that utilizes amino acids to achieve osmotic balance.

[0029] The term "bicarbonate concentrated solution" refers to an aqueous solution containing bicarbonate or a mixture of bicarbonate and ANSI / AAM Meets or exceeds current hemodialysis water quality standards as set forth in ISO#13959:2009 Minneapolis, Minnesota. al Systems supplies Centrisol® bicarbonate concentrate powder MB-330. Each packet of ® Bicarbonate Concentrate Powder 45X MB-330 contains approximately 650 grams of sodium bicarbonate The contents of the bag are mixed with purified water to produce approximately 8 liters of concentrated dialysate bicarbonate solution. Liquid is produced.

[0030] The term "concentrated acid solution" refers to an aqueous solution containing an acid or a mixture of an acid and purified water. Representative examples include, but are not limited to, hydrochloric acid, acetic acid, citric acid, and peracetic acid. No. Minntech Renal Systems, Minneapolis, Minnesota, offers Centrisol® acid concentrate. Each packet of Centrisol® Acid Concentrate Powder 45X contains acetic acid. ions, bicarbonate ions, calcium, chloride ions, glucose, magnesium, and potassium Mix 1 part by volume of the acid concentrate with 1.72 parts by volume of properly mixed MB-330 series Mix with 42.28 parts by volume of purified water to make 45 parts by volume of dialysis solution. should be prepared.

[0031] The term "dialysis machine" refers to a machine that includes an extracorporeal circuit and a dialysate circuit. tubing, blood pumps, heparin pumps, kidneys, and blood flow, blood pressure, and air bubble monitors The dialysate circuit further includes the dialysate tubing, the dialysate pump, and the dialysate flow, The system also includes fluid pressure and bubble monitors. Currently, dialysis machines use concentrated acid solutions, bicarbonate An automated distribution system that mixes concentrated salt solution and purified water in specific ratios to produce dialysis fluid. The dialysate concentrate solution (acid and bicarbonate) is typically added to purified water in a large storage tank. as a premixed powder (as bicarbonate powder) or as a ready-to-use solution ( The dialysate concentrate solution is supplied by the manufacturer either as a dialysate concentrate or as a dialysate concentrate. The fluid is then pumped into the chamber of the analyzer where it is mixed with purified water to form the dialysate. is created.

[0032] The term "dialysate piping" refers to the piping connecting the dialysis machine and the dialyzer.

[0033] The term "dialyzer" refers to a material made of cellulose acetate, cupraphane, polyacrylate, including, but not limited to, methylisothiazolinone, polymethylmethacrylate, or polysulfone. artificial kidney equipped with a synthetic or semi-synthetic semipermeable membrane made of chemical materials (hereinafter referred to as "dialysis membrane") A constant flow of blood on one side of the membrane and dialysate on the other side. The artificial kidney allows for the removal of waste products from the blood. During this period, diffusion is the primary mechanism of solute removal. Diafiltration (also called ultrafiltration and diafiltration) is a high-pressure system based on ultrafiltration and convective transport rather than diffusion. The solute is transported to the other side of the semipermeable membrane with a porosity.

[0034] The term "unspiked dialysate" refers to the aqueous solution containing sodium nitrite that is The dialyzer mixes the dialysate solution before adding it to the dialysate piping through the dialysate pump. This refers to the dialysis solution that is pumped through a pump and flows into the dialysis membrane.

[0035] The term "nitrite spiked dialysate" refers to an aqueous solution containing sodium nitrite. Refers to the dialysis solution in the dialysate line after the solution has been added to the dialysate line through the valve.

[0036] The term "therapeutically effective amount" refers to an amount that, when administered, reduces the symptoms of the disorder, disease, or condition being treated. A compound sufficient to prevent or alleviate to some extent the occurrence of one or more of the symptoms The term "therapeutically effective amount" is also intended to encompass amounts that are within the capabilities of researchers, veterinarians, Cell, tissue, system, animal, or human biological or medical information sought by a physician or clinician A therapeutically effective amount also refers to the amount of a compound sufficient to elicit a response. The amount is sufficient to maintain blood levels of nitrite at approximately physiological levels. do.

[0037] The terms "about" or "approximately" refer to a particular value as determined by one of ordinary skill in the art. It refers to the allowable error, which depends in part on how the value is measured or determined. In some embodiments, the term "about" or "approximately" is used to refer to a range of values, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, In some embodiments, "about" or "approximately" means within 4 standard deviations. The term "variable" refers to 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 4% or 5% of a given value or range. In some embodiments, "about" or "approximately" means within 1%, 0.5%, or 0.05%. " is considered to be the correct value.

[0038] The term "normal physiological levels" of nitrite refers to the nitrite levels found in healthy adult subjects. In one embodiment, the normal level of nitrite in a subject is A reasonable physiological level is approximately 300 nanomolar.

[0039] (sodium nitrite) In certain embodiments, the methods provided herein involve administering nitrite as the monosodium salt. In one embodiment, this involves the use of a purified form of sodium nitrite (NaNO), also known as sodium nitrite. In accordance with the present invention, provided herein is pharmaceutically acceptable sodium nitrite. In another embodiment, provided herein is a method for treating nitrous acid syndrome (NSS) in a patient receiving nitrous acid therapy. Forms of sodium nitrite that meet one, more than one, or all of the FDA standards for sodium In one embodiment, the pharmaceutically acceptable sodium nitrite is nitrite in its entirety. U.S. Patent Publication No. 2010 / 0104994, filed February 10, 2010, which is incorporated herein by reference. This is disclosed in US Pat. No. 5,972,622.

[0040] In one embodiment, the pharmaceutically acceptable sodium nitrite is white to off-white. It is a solid.

[0041] In one embodiment, pharmaceutically acceptable sodium nitrite is prepared according to the United States Pharmacopoeia XXXII (20 Method 09) <191> A confirmatory test for sodium determined by is positive.

[0042] In one embodiment, pharmaceutically acceptable sodium nitrite is prepared according to the United States Pharmacopoeia XXXII (20 Method 09) <191> The confirmatory test for nitrite ion determined by is positive.

[0043] In one embodiment, the sodium nitrite provided herein is greater than or equal to about 97% by weight and and / or contains about 101% by weight or less sodium nitrite. The amount of sodium nitrite in the sodium nitrite provided in the United States Pharmacopoeia colorimetric assay ( In some embodiments, the methods provided herein are determined by the United States Pharmacopoeia XXXII (2009). The amount of sodium nitrite in the sodium nitrite solution was determined by ion chromatography. In some embodiments, the sodium nitrite in the sodium nitrite provided herein is The amount of thorium can be measured using a suppressed conductivity detector coupled with a suppressed conductivity detector as described herein. Determined by ion chromatography.

[0044] In another embodiment, the sodium nitrite provided herein is In some embodiments, the compositions provided herein have a pH of about 7 to about 9, as measured by a pH sensor. The pH of the sodium nitrite used is measured using a pH meter. The pH of the sodium nitrite provided is determined by Method 791 of the United States Pharmacopeia XXXII (2009). do.

[0045] In yet another embodiment, the sodium nitrite provided herein is about 0.25 wt. In some embodiments, the sodium nitrite compositions provided herein have a loss on drying of 0.1% or less. Loss on drying of the syrup is quantified by Method 731 of the United States Pharmacopeia XXXII (2009).

[0046] In yet another embodiment, the sodium nitrite provided herein is about 0.5 wt. In some embodiments, the sodium nitrite provided herein has a water content of 0.1% or less. The water content in the emulsion is determined by the Karl Fischer method. The water content of sodium nitrite provided in the specification is determined according to Method 921 of the United States Pharmacopeia XXXII (2009). It becomes more quantified.

[0047] In yet another embodiment, the heavy metal content in the sodium nitrite provided herein The heavy metal content in the sodium nitrite provided herein is about 10 ppm or less. The amount is determined by Method 231 of the United States Pharmacopeia XXXII (2009).

[0048] In yet another embodiment, the sodium nitrite provided herein is about 0.4 wt. In some embodiments, the nitrite solution provided herein contains no more than 5% sodium nitrite. The amount of sodium nitrate in the sodium nitrate is It is determined by ion chromatography coupled with conductivity detection.

[0049] In yet another embodiment, the sodium nitrite provided herein is about 0.02 wt. In some embodiments, the nitrite solution provided herein contains no more than 1% sodium carbonate. The amount of sodium carbonate in the sodium acid is determined by mixing the sample with the acid and converting carbonate ions to carbon dioxide. and venting the carbon dioxide to a non-dispersive infrared detector for measurement. can be.

[0050] In yet another embodiment, the sodium nitrite provided herein has a concentration of about 0.005 wt. In some embodiments, the sodium nitrite provided herein contains less than 100% insoluble matter. The amount of insoluble material in sodium is calculated by dissolving 10 grams of the sodium nitrite provided herein in 100 mL of water. in water, the solution is heated to boiling for 1 hour, and the solution , filtered, washed with hot water, dried, cooled in a desiccator and weighed.

[0051] In yet another embodiment, the sodium nitrite provided herein has a concentration of about 0.005 wt. In some embodiments, the nitrites provided herein contain less than or equal to 100% chloride ions. The chloride ion content in sodium chloride is determined by Method 221 of the United States Pharmacopeia XXXII (2009). do.

[0052] In yet another embodiment, the sodium nitrite provided herein is about 0.01 wt. In some embodiments, the sodium nitrite provided herein contains no more than 5% sulfate ions. The sulfate ion content in thorium is determined by Method 221 of the United States Pharmacopeia XXXII (2009).

[0053] In yet another embodiment, the sodium nitrite provided herein has a concentration of about 0.001 by weight. In some embodiments, the sodium nitrite provided herein contains less than or equal to 100% iron. The iron content in the gum is determined using inductively coupled plasma mass spectrometry (ICP-MS). The iron content in the sodium nitrite provided herein is determined by inductively coupled plasma emission spectroscopy (ICP Emission Spectroscopy). It is determined using spectroscopic analysis (ICP-OES). The iron content in sodium nitrite is determined by Method 241 of the United States Pharmacopeia XXXII (2009).

[0054] In yet another embodiment, the sodium nitrite provided herein is about 0.01 wt. In some embodiments, the sodium nitrite provided herein contains less than or equal to 10% calcium. The calcium content in the thorium is determined using ICP-MS. The calcium content in the sodium nitrite provided in the specification was determined by flame emission spectroscopy (FES). ) is determined using

[0055] In yet another embodiment, the sodium nitrite provided herein has a concentration of about 0.005 wt. In some embodiments, the sodium nitrite provided herein contains less than or equal to 100% potassium. The potassium content in the thorium is determined using ICP-MS. The potassium content in the sodium nitrite provided herein is determined using FES.

[0056] In yet another embodiment, the sodium nitrite provided herein is at about 10 ppm or more. Contains less than about 100 ppm, less than about 500 ppm, less than about 1000 ppm, or less than 5000 ppm of ethanol In some embodiments, the content of organic volatile impurities is determined according to the United States Pharmacopeia XXXII (2009) method. It is determined by Law 467.

[0057] In yet another embodiment, the sodium nitrite provided herein is at about 10 ppm or more. Contains less than about 100 ppm, less than about 500 ppm, less than about 1000 ppm, or less than 3000 ppm of methanol In some embodiments, the content of organic volatile impurities is determined according to the United States Pharmacopeia XXXII (2009) method. It is determined by Law 467.

[0058] In yet another embodiment, the sodium nitrite provided herein is at about 2.5 ppm or more. Below, about 6ppm or less, about 8ppm or less, about 10ppm or less, about 20ppm or less, about 25ppm or less, or about 50ppm or less In some embodiments, the nitrous acid salts provided herein contain less than 100% total nonvolatile organic carbon. Sodium carbonate has a total non-volatile organic carbon (NVO) content of approximately 10 ppm or less. C) or equivalent non-purgeable organic carbon (NPOC). In certain embodiments, the sodium nitrite provided herein has a total impurity content of about 7.9 ppm or less. In some embodiments, the sodium nitrite provided herein contains volatile organic carbon. In some embodiments, the emulsion contains about 5.6 ppm or less of total nonvolatile organic carbon. The total nonvolatile organic carbon in the sodium nitrite provided in the document is calculated by the method described herein. is determined using

[0059] In yet another embodiment, the sodium nitrite provided herein is at about 0.05 ppm In some embodiments, the sodium nitrite provided herein contains mercury. The mercury content in the composition provided herein is determined using ICP-MS. The mercury content in the sodium nitrite is determined using ICP-OES. The mercury content in the sodium nitrite provided herein is determined in accordance with the United States Pharmacopeia XXXII (2009). It is determined by the method 261 of the present invention.

[0060] In yet another embodiment, the sodium nitrite provided herein is about 2 ppm or less. In yet another embodiment, the nitrite salts provided herein contain aluminum. The sodium contains about 0.2 ppm or less of aluminum. The aluminum content in the sodium nitrite provided herein is determined using ICP-MS. In some embodiments, the aluminum content in the sodium nitrite provided herein is , as determined using ICP-OES. The aluminum content in thorium is determined by Method 206 of the United States Pharmacopeia XXXII (2009).

[0061] In yet another embodiment, the sodium nitrite provided herein is about 3 ppm or less. In yet another embodiment, the sodium nitrite provided herein contains arsenic. In certain embodiments, the nitrites provided herein contain about 1 ppm or less of arsenic. The arsenic content in the sodium carbonate is determined using ICP-MS. The arsenic content in the sodium nitrite provided herein is determined using ICP-OES. In an embodiment, the arsenic content in the sodium nitrite provided herein is determined according to the United States Pharmacopoeia Determined by method 211 of XXXII (2009).

[0062] In yet another embodiment, the sodium nitrite provided herein is about 10 ppm (0. In one embodiment, the anti-caking agent is an aluminum alloy. In some embodiments, the compound provided herein is sodium hydroxy-naphthalenesulfonate. The amount of sodium alkyl-naphthalene sulfonate in the sodium nitrite used is determined by the amount of sodium alkyl-naphthalene sulfonate used in the present invention. Quantification is performed using mass spectrometry and liquid chromatography methods as described in the literature.

[0063] In yet another embodiment, the sodium nitrite provided herein has a concentration of about 0.003 by weight. In some embodiments, the sodium nitrite provided herein contains selenium at or below 50% by weight. The selenium content in the sodium is determined using ICP-MS. The selenium content in the sodium nitrite provided herein is determined using ICP-OES. In embodiments, the selenium content of the sodium nitrite provided herein is determined according to the United States Pharmacopoeia Determined by method 291 of XXXII (2009).

[0064] In yet another embodiment, the microbial load in the sodium nitrite provided herein The total aerobic bacterial count in the sodium nitrite provided herein is about 100 CFU / g or less. The total aerobic count of the microbial load is quantified by method 61 of the United States Pharmacopeia XXXII (2009).

[0065] In yet another embodiment, the total yeast and corn in the sodium nitrite provided herein The total yeast and fungal counts in the sodium nitrite provided herein are about 20 CFU / g or less. The number of bilirubins is quantified by Method 61 of the United States Pharmacopeia XXXII (2009).

[0066] In yet another embodiment, the sodium nitrite provided herein has a concentration of about 0.25 EU / m The endotoxin in the sodium nitrite provided herein contains 0.1 g or less of the endotoxin. The amount is quantified by Method 85 of the United States Pharmacopeia XXXII (2009).

[0067] In yet another embodiment, the sodium nitrite provided herein is : about 97% by weight or more and / or about 101% by United States Pharmacopeia colorimetric assay (United States Pharmacopeia XXXII (2009)) containing no more than % by weight of sodium nitrite; A positive confirmatory test for sodium; A positive confirmatory test for nitrite ions; having a pH of about 7 to about 9 when measured in a 10% solution at 25°C; having a loss on drying of about 0.25% by weight or less; having a water content of about 0.5% by weight or less; having a heavy metal content of about 10 ppm or less; containing not more than about 0.4% by weight sodium nitrate; containing not more than about 0.02% by weight sodium carbonate; Contains not more than about 0.005% by weight of insoluble matter; containing not more than about 0.005% by weight chloride ions; containing less than about 0.01% by weight of sulfate ions; containing not more than about 0.001% by weight iron; containing not more than about 0.01% by weight of calcium; containing not more than about 0.005% by weight of potassium; Ethanol of about 0.1% by weight or less, or about 10 ppm or less, about 100 ppm or less, about 500 ppm or less, about 1000 ppm or less, or contain 5000 ppm or less of ethanol; Methanol of about 10 ppm or less, about 100 ppm or less, about 500 ppm or less, about 1000 ppm or less, or 3000 ppm or less containing alcohol; About 2.5ppm or less, about 5.6ppm or less, about 6ppm or less, about 7.9ppm or less, about 8ppm or less, about 10ppm or less, about 20 ppm or less, about 25 ppm or less, or about 50 ppm or less; and in one embodiment, about 10 ppm or less Having a total nonvolatile organic carbon or equivalent below; Contains approximately 0.05 ppm or less of mercury; Contains approximately 2 ppm or less of aluminum; Contains approximately 3 ppm or less of arsenic; Contains about 10 ppm or less of an anti-caking agent; Contains less than approximately 0.003% (ICP-OES or equivalent) selenium; have a total aerobic count of microbial load of approximately 100 CFU / g or less; Have a total yeast and mold count of approximately 20 CFU / g or less; Contains approximately 0.25 EU / mg or less of endotoxin; It is characterized by one or more of the following:

[0068] In one embodiment, provided herein is a method for treating a vascular disease comprising administering to a subject the method comprising administering to said subject the vascular disease; Sodium nitrite having one or more of the following:

[0069] (Methods for maintaining physiological levels of nitrite) Provided herein are methods for reducing the production of nitrite ions in subjects undergoing hemodialysis. 2. A method for maintaining physiological levels in a subject, comprising stimulating the blood of the subject with nitrite ions. the spiked dialysate is contacted with a dialysis membrane during dialysis, the dialysis membrane also being in contact with the spiked dialysate. When the undiluted dialysate flows from the dialysis machine to the dialysis membrane, an aqueous solution containing sodium nitrite The non-spiked dialysate is added to the non-spiked dialysate, and the non-spiked dialysate contains water, concentrated acid, and a mixture of a concentrated solution of nitrite and a bicarbonate solution, and a permeabilized solution spiked with nitrite ions. The aforementioned method, wherein the deposition solution has a pH greater than about 7.0.

[0070] Also provided herein are methods for preventing the release of nitrite ions in subjects undergoing hemodialysis. 20. A method for maintaining physiological levels of nitrite in a subject, comprising: irrigating the blood of the subject with nitrite ions. contacting the spiked dialysate with the dialysate during dialysis, When the aqueous solution containing sodium nitrite flows from the dialyzer to the dialysis membrane, The unspiked dialysate is added to the unspiked dialysate, which contains water, concentrated acid solution, and bicarbonate. The nitrite ion-spiked dialysate contains a mixture of concentrated solutions of nitrite and nitrite ions, and the nitrite ion-spiked dialysate has a pH greater than about 7.0. The method has a pH of

[0071] In one embodiment, the subject is a mammal. is a human.

[0072] In one embodiment, the physiological level of nitrite in the subject is about 1 mg / kg. In another embodiment, the physiological concentration of nitrite in the subject is below chromolar. The therapeutic level is from about 100 nanomolar to about 700 nanomolar. In the method, the physiological level of nitrite in the subject is between about 200 nanomolar and about 5 In yet another embodiment, the concentration of nitrite in the subject is 0.000 nanomolar. Physiological levels are from about 250 nanomolar to about 400 nanomolar. In such a case, the physiological level of nitrite in the subject is about 300 nanomolar. is.

[0073] In one embodiment, the concentration of nitrite ions in the nitrite-spiked dialysate is In another embodiment, the concentration of nitrite ions is about 1 micromolar or less. The concentration of nitrite ions in the spiked dialysate ranges from approximately 100 nanomolar to approximately 700 nanomolar. In yet another embodiment, the nitrite ion-spiked dialysate The concentration of nitrate ions is about 200 nanomolar to about 500 nanomolar. In this case, the concentration of nitrite ions in the dialysis solution spiked with nitrite ions is about 25 In yet another embodiment, the nitrite ion is present in a concentration of from 0 nanomolar to about 400 nanomolar. The concentration of nitrite in the ON spiked dialysate is approximately 300 nanomolar.

[0074] In one embodiment, the aqueous solution containing sodium nitrite is about 1 mg / L, about 2 mg / L, or about 3 mg / L, about 4 mg / L, about 5 mg / L, about 6 mg / L, about 7 mg / L, about 8 mg / L, about 9 mg / L, or about 10 mg / L or less Contains sodium nitrite.

[0075] In some embodiments, the water contains about 1 mg / L, about 2 mg / L, about 3 mg / L, about 4 mg / L, about 5 mg / L, Contains about 6 mg / L, about 7 mg / L, about 8 mg / L, about 9 mg / L, or about 10 mg / L or less of nitrite ions.

[0076] In one embodiment, the dialysate piping is attached to the piping at a position before the piping is connected to the dialyzer. The sodium nitrite-containing aqueous solution is introduced into the unspiked permeable tube through a valve. In another embodiment, the non-spiked dialysate is added to the dialysis solution. In yet another embodiment, the mixture flows through the analytical pipe at a rate of about 200 mL / min to about 1000 mL / min. Unspiked dialysate flows through the dialysis tubing at a rate of about 300 mL / min to about 900 mL / min. In yet another embodiment, the unspiked dialysate passes through the dialysis tubing at about In yet another embodiment, the spiked The undiluted dialysis fluid flows through the dialysis piping at a rate of about 500 mL / min to about 700 mL / min. In one embodiment, the unspiked dialysate flows through the dialysis tubing at a rate of about 600 mL / min. It flows at a rate of 1000kJ / s.

[0077] In one embodiment, the aqueous solution containing sodium nitrite is introduced into the spa through the valve. Dialysis fluid that has not been pumped is infused at a rate of approximately 0 mL / hour to approximately 750 mL / hour or approximately 50 mL / hour to approximately 650 mL / hour. at a rate of about 100 ml / hour to about 550 ml / hour, or at a rate of about 150 ml / hour to about 450 ml / hour, In another embodiment, the sodium nitrite is added at a rate of about 200 mL / hour to about 350 mL / hour. The thorium-containing aqueous solution is introduced through the valve into the unspiked dialysate at a rate of about 250 mL / min. It is added at a rate of 1000 kcal.

[0078] In yet another embodiment, the pH of the nitrite spiked dialysate is about 7. In yet another embodiment, the nitrite ion spiked dialyzate has a pH of 0 to about 8.0. The pH of the solution is about 7.1 to about 8.0. The pH of the dialysate pumped is about 7.3 to about 8.0. The pH of the acid ion spiked dialysate is about 7.3 to about 7.5. In this case, the pH of the dialysate spiked with nitrite ions is about 7.4.

[0079] In yet another embodiment, the subject is a human with chronic renal failure. wherein the subject is a human with acute renal failure.

[0080] In yet another embodiment, the subject undergoes hemodialysis 1 to 10 times per week. In yet another embodiment, the subject undergoes hemodialysis 3 to 7 times per week.

[0081] In certain embodiments, the methods provided herein involve measuring plasma levels of nitrite in a subject. The objective of the present invention is to restore and / or maintain normal physiological levels of ATP.

[0082] (Preventive measures) (1. How to prevent myocardial infarction) In certain embodiments, provided herein are methods for treating dialysis in a subject undergoing dialysis. A method for preventing myocardial infarction, comprising spiking the subject's blood with nitrite ions. The method includes contacting the spiked dialysis membrane with a dialysis membrane that is also in contact with the spiked dialysis fluid during dialysis. When the undiluted dialysate flows from the dialyzer to the dialysis membrane, the aqueous solution containing sodium nitrite is absorbed into the membrane. The unspiked dialysate is added to the unspiked dialysate, and the unspiked dialysate is mixed with water, an acid concentrate solution, and and a dialysis solution spiked with nitrite ions, the dialysis solution comprising a mixture of a bicarbonate-enriched solution and a bicarbonate-enriched solution. has a pH greater than about 7.0.

[0083] In certain embodiments, further provided herein are methods for treating a patient undergoing hemodialysis. 2. A method for preventing myocardial infarction in a subject suffering from myocardial infarction, comprising: The method includes contacting the patient with a spiked dialysate during dialysis, and contacting the patient with an unspiked dialysate. When the precipitate flows from the dialyzer to the dialysis membrane, the aqueous solution containing sodium nitrite The unspiked dialysate is added to the unspiked dialysate, and the unspiked dialysate is mixed with water, concentrated acid solution, and and a bicarbonate concentrated solution, and the nitrite ion spiked dialysate is about The method has a pH greater than 7.0.

[0084] In one embodiment, the subject is a mammal. is a human.

[0085] In certain embodiments, the methods provided herein involve measuring plasma levels of nitrite in a subject. The objective of the present invention is to restore and / or maintain normal physiological levels of ATP.

[0086] (2. How to prevent sudden cardiac death) In certain embodiments, provided herein are methods for treating dialysis in a subject undergoing dialysis. A method for preventing sudden cardiac death comprising sparing the subject's blood with nitrite ions. contacting the spike with a dialysis membrane that is also in contact with the dialysis fluid during dialysis; When the undiluted dialysate flows from the dialyzer to the dialysis membrane, the aqueous solution containing sodium nitrite The solution is added to the unspiked dialysate, and the unspiked dialysate is mixed with water, A mixture of a concentrated acid solution and a concentrated bicarbonate solution spiked with the nitrite ion. The dialysate has a pH greater than about 7.0.

[0087] In certain embodiments, further provided herein are methods for treating a patient undergoing hemodialysis. 1. A method for preventing sudden cardiac death in a subject suffering from cardiac arrest, comprising: The method includes contacting the patient with nitrate-spiked dialysate during dialysis, When the undiluted dialysate flows from the dialyzer to the dialysis membrane, the aqueous solution containing sodium nitrite is absorbed into the membrane. The unspiked dialysate is added to the unspiked dialysate, and the unspiked dialysate is mixed with water, an acid concentrate solution, and and a dialysis solution spiked with nitrite ions, the dialysis solution comprising a mixture of a bicarbonate-enriched solution and a bicarbonate-enriched solution. has a pH greater than about 7.0.

[0088] In one embodiment, the subject is a mammal. is a human.

[0089] In certain embodiments, the methods provided herein involve measuring plasma levels of nitrite in a subject. The objective of the present invention is to restore and / or maintain normal physiological levels of ATP.

[0090] (3. How to prevent stroke) In certain embodiments, provided herein are methods for treating dialysis in a subject undergoing dialysis. A method for preventing stroke, comprising administering to the subject a dose of nitrite spiked blood. contacting the spiked membrane with a dialysis membrane that is also in contact with the dialysis fluid during dialysis; When the undiluted dialysate flows from the dialyzer to the dialysis membrane, the aqueous solution containing sodium nitrite is absorbed into the membrane. The unspiked dialysate is added to the unspiked dialysate, and the unspiked dialysate is mixed with water, an acid concentrate solution, and and a dialysis solution spiked with nitrite ions, the dialysis solution comprising a mixture of a bicarbonate-enriched solution and a bicarbonate-enriched solution. has a pH greater than about 7.0.

[0091] In certain embodiments, further provided herein are methods for treating a patient undergoing hemodialysis. 2. A method for preventing stroke in a subject suffering from stroke, comprising: treating the subject's blood with nitrite ions. and contacting the unspiked dialysate with the dialysate spiked with benzoyl peroxide during dialysis. As the fluid flows from the dialyzer to the dialysis membrane, the aqueous solution containing sodium nitrite is spiked. The unspiked dialysate is added to the unspiked dialysate, the unspiked dialysate being composed of water, concentrated acid solution, and The dialysate containing the mixture of bicarbonate concentrated solution and spiked with the nitrite ions is about 7. The method has a pH greater than 0.

[0092] In one embodiment, the subject is a mammal. is a human.

[0093] In certain embodiments, the methods provided herein involve measuring plasma levels of nitrite in a subject. The objective of the present invention is to restore and / or maintain normal physiological levels of ATP.

[0094] (4. How to prevent cardiovascular disease) In certain embodiments, provided herein are methods for treating dialysis in a subject undergoing dialysis. angina, cerebral vasospasm, claudication, critical limb ischemia, peripheral vascular disease, and sickle cell crisis. 1. A method for preventing cardiovascular disease characterized by tissue ischemia, including ischemia, comprising: Contact during dialysis with a dialysis membrane that is also in contact with dialysate spiked with nitrite ions When the unspiked dialysate flows from the dialyzer to the dialysis membrane, the nitrite is released. An aqueous solution containing thorium is added to the unspiked dialysate and the spiked dialysate is The dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the nitrite is The method, wherein the ON spiked dialysate has a pH greater than about 7.0.

[0095] In certain embodiments, further provided herein is a method for treating a patient receiving dialysis. Subjects with angina, cerebral vasospasm, claudication, critical limb ischemia, peripheral vascular disease, and sickle cell anemia 1. A method for preventing cardiovascular disease characterized by tissue ischemia, including crises, comprising administering to said patient a therapeutically effective amount of The method involves contacting elephant blood with a dialysate spiked with nitrite ions during dialysis, When unspiked dialysate flows from the dialyzer to the dialysis membrane, it contains sodium nitrite. An aqueous solution containing nitrite ion spies on a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution. The method, wherein the dialysate has a pH greater than about 7.0.

[0096] In one embodiment, the subject is a mammal. is a human.

[0097] In certain embodiments, the methods provided herein involve measuring plasma levels of nitrite in a subject. The objective of the present invention is to restore and / or maintain normal physiological levels of ATP.

[0098] 5. Methods for preventing hypertension, pulmonary hypertension, and renal hypertension In certain embodiments, provided herein are methods for treating dialysis in a subject undergoing dialysis. a method for preventing hypertension, pulmonary hypertension, and renal hypertension, comprising administering to said subject a dose of 200 mg of ribozyme or ... During dialysis, the solution is brought into contact with a dialysis membrane that is also in contact with dialysate spiked with nitrite ions. and wherein the unspiked dialysate is mixed with the dialysis membrane as it flows from the dialyzer to the dialysis membrane. An aqueous solution containing sodium nitrate is added to the unspiked dialysate, and the spiked dialysate is The untreated dialysate comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and The method, wherein the nitrate spiked dialysate has a pH greater than about 7.0.

[0099] In certain embodiments, further provided herein is a method for treating a patient receiving dialysis. 1. A method for preventing hypertension, pulmonary hypertension, and renal hypertension in a subject, comprising: contacting the subject's blood with a dialysate spiked with nitrite ions during dialysis. When the unspiked dialysate flows from the dialyzer to the dialysis membrane, sodium nitrite is released. An aqueous solution containing acetone is added to the unspiked dialysate, and the unspiked dialysate is The precipitate contains a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, and the precipitate is formed by the nitrite ion. The method, wherein the spiked dialysate has a pH greater than about 7.0.

[0100] In certain embodiments, the pulmonary hypertension is neonatal pulmonary hypertension, primary pulmonary hypertension, or is secondary pulmonary hypertension.

[0101] In one embodiment, the subject is a mammal. is a human.

[0102] In certain embodiments, the methods provided herein involve measuring plasma levels of nitrite in a subject. The objective of the present invention is to restore and / or maintain normal physiological levels of ATP.

[0103] In some embodiments, the embodiments of paragraphs

[0103] to

[0112] are provided herein. This rule applies to all methods used.

[0104] In one embodiment, the physiological level of nitrite in the subject is about 1 mg / kg. In another embodiment, the physiological concentration of nitrite in the subject is below chromolar. The therapeutic level is from about 100 nanomolar to about 700 nanomolar. In the method, the physiological level of nitrite in the subject is between about 200 nanomolar and about 5 In yet another embodiment, the concentration of nitrite in the subject is 0.000 nanomolar. Physiological levels are from about 250 nanomolar to about 400 nanomolar. In such a case, the physiological level of nitrite in the subject is about 300 nanomolar. is.

[0105] In one embodiment, the concentration of nitrite ions in the nitrite-spiked dialysate is In another embodiment, the concentration of nitrite ions is about 1 micromolar or less. The concentration of nitrite ions in the spiked dialysate ranges from approximately 100 nanomolar to approximately 700 nanomolar. In yet another embodiment, the nitrite ion-spiked dialysate The concentration of nitrate ions is about 200 nanomolar to about 500 nanomolar. In this case, the concentration of nitrite ions in the dialysis solution spiked with nitrite ions is about 25 In yet another embodiment, the nitrite ion is present in a concentration of from 0 nanomolar to about 400 nanomolar. The concentration of nitrite in the ON spiked dialysate is approximately 300 nanomolar.

[0106] In one embodiment, the aqueous solution containing sodium nitrite is about 1 mg / L, about 2 mg / L, or about 3 mg / L, about 4 mg / L, about 5 mg / L, about 6 mg / L, about 7 mg / L, about 8 mg / L, about 9 mg / L, or about 10 mg / L or less Contains nitrite ions.

[0107] In some embodiments, the water contains about 1 mg / L, about 2 mg / L, about 3 mg / L, about 4 mg / L, about 5 mg / L, Contains about 6 mg / L, about 7 mg / L, about 8 mg / L, about 9 mg / L, or about 10 mg / L or less of nitrite ions.

[0108] In one embodiment, the dialysate piping is attached to the piping at a position before the piping is connected to the dialyzer. The sodium nitrite-containing aqueous solution is introduced into the unspiked permeable tube through a valve. In another embodiment, the non-spiked dialysate is added to the dialysis solution. In yet another embodiment, the mixture flows through the analytical pipe at a rate of about 200 mL / min to about 1000 mL / min. Unspiked dialysate flows through the dialysis tubing at a rate of about 300 mL / min to about 900 mL / min. In yet another embodiment, the unspiked dialysate passes through the dialysis tubing at about In yet another embodiment, the spiked The undiluted dialysis fluid flows through the dialysis piping at a rate of about 500 mL / min to about 700 mL / min. In one embodiment, the unspiked dialysate flows through the dialysis tubing at a rate of about 600 mL / min. It flows at a rate of 1000kJ / s.

[0109] In one embodiment, the aqueous solution containing sodium nitrite is introduced into the spa through the valve. Dialysis fluid that has not been pumped is infused at a rate of approximately 0 mL / hour to approximately 750 mL / hour or approximately 50 mL / hour to approximately 650 mL / hour. at a rate of about 100 ml / hour to about 550 ml / hour, or at a rate of about 150 ml / hour to about 450 ml / hour, Alternatively, the sodium nitrite is added at a rate of about 200 ml / hour to about 350 ml / hour. The thorium-containing aqueous solution is introduced through the valve into the unspiked dialysate at a rate of about 250 ml / min. It is added at a rate of 1000 kcal.

[0110] In yet another embodiment, the pH of the nitrite spiked dialysate is about 7. In yet another embodiment, the nitrite ion spiked dialyzate has a pH of 0 to about 8.0. The pH of the solution is about 7.1 to about 8.0. The pH of the dialysate pumped is about 7.3 to about 8.0. The pH of the acid ion spiked dialysate is about 7.3 to about 7.5. In this case, the pH of the dialysate spiked with nitrite ions is about 7.4.

[0111] In yet another embodiment, the subject is a human with chronic renal failure. wherein the subject is a human with acute renal failure.

[0112] In yet another embodiment, the subject undergoes hemodialysis 1 to 10 times per week. In yet another embodiment, the subject undergoes hemodialysis 3 to 7 times per week.

[0113] In one embodiment, the nitrite spiked dialysate is spiked "before" (100 ) or the nitrate ion content measured in the sample taken "after" the detection point (110), Approximately 10%, approximately 9%, approximately 8%, approximately 7%, approximately 6%, approximately 5%, approximately 4%, approximately 3%, approximately 2%, approximately 1%, approximately 0.4%, or undergoes decomposition of less than about 0.1% nitrite ions.

[0114] (Method of administration) In certain embodiments, provided herein are methods for administering nitrite to a subject undergoing dialysis. A method for administering sodium comprising: spiking the subject's blood with nitrite ions; contacting the spiked dialysis solution with a dialysis membrane that is also in contact with the spiked dialysis solution during dialysis; When the undiluted dialysate flows from the dialysis machine to the dialysis membrane, the aqueous solution containing sodium nitrite It is added to unspiked dialysate, and the unspiked dialysate contains water, acid concentrate, a dialysis solution containing a mixture of a solution and a bicarbonate-enriched solution and spiked with the nitrite ions; The method, wherein the solution has a pH greater than about 7.0.

[0115] Further provided herein, in certain embodiments, is sodium nitrite. 2. A method for administering to a subject undergoing hemodialysis, the method comprising: contacting the dialysate with ion-spiked dialysate during dialysis, and When the dialysate flows from the dialyzer to the dialysis membrane, the aqueous solution containing sodium nitrite The unspiked dialysate is added to the unspiked dialysate, which contains water, concentrated acid solution, and a bicarbonate concentrated solution, and the nitrite ion spiked dialysate comprises: The method has a pH greater than about 7.0.

[0116] In one embodiment, the nitrite spiked dialysate is spiked "before" (100 ) or the nitrate ion content measured in the sample taken "after" the detection point (110), Approximately 10%, approximately 9%, approximately 8%, approximately 7%, approximately 6%, approximately 5%, approximately 4%, approximately 3%, approximately 2%, approximately 1%, approximately 0.4%, or undergoes decomposition of less than about 0.1% nitrite ions.

[0117] (combination therapy) In some embodiments, the sodium nitrite provided herein is in combination with other therapeutic agents useful in the treatment and / or prevention of the indicated diseases and disorders; Or it may be used in combination with it.

[0118] As used herein, the term "in combination" refers to two or more therapies (e.g., one However, the use of "in combination" includes the use of any of the above prophylactic and / or therapeutic agents. The use of the term refers to the administration of a therapy (e.g., a prophylactic and / or therapeutic agent) to a subject with a disease or disorder. The order in which the first therapy (e.g., a prophylactic agent such as a compound provided herein) is administered is not limited. or therapeutic agent) is administered (e.g., prior to administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. , about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, Approximately 24 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 weeks, about 6 weeks, about 8 weeks, or about 12 weeks before), or at the same time as, or after (e.g., , about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, Approximately 24 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 The triple therapy can also be administered after about 1 week, about 6 weeks, about 8 weeks, or about 12 weeks. Contemplated herein.

[0119] As used herein, the term "synergistic" refers to the use of sodium nitrite as provided herein. Thorium and other compounds that have been or are currently used to treat, prevent, or manage diseases or disorders In combination with another therapy (e.g., a prophylactic or therapeutic agent) being used, Combinations of therapies (e.g., combinations of prophylactic or therapeutic agents) The synergistic effect of the two therapeutic agents may allow for the use of lower dosages of one or more of the therapies in a subject with a disorder. This allows for the use of lower dosages of the therapy (e.g., The availability of a therapeutic agent (prophylactic or therapeutic agent) and / or the ability to administer the therapy less frequently is administering said therapy to a subject without reducing the efficacy of said therapy in preventing or treating a disorder In addition, a synergistic effect may be achieved that reduces the toxicity associated with the administration of the compound. Finally, combination therapies (e.g., preventive or The synergistic effects of combinations of therapeutic agents (or combinations of therapeutic agents) can reduce the harmful or life-threatening effects associated with the use of either therapy alone. Undesirable side effects may be avoided or reduced.

[0120] The sodium nitrite provided herein may be administered in combination with or without another therapeutic agent. In combination therapy, effective dosages of two or more drugs are administered together. In alternating or sequential step therapy, an effective dosage of each agent is administered sequentially or sequentially. The dosage given will depend on the absorption, inactivation, and excretion rates of the drug, as well as The dosage amount will depend on the type of disease to be alleviated and other factors known to those skilled in the art. It should be noted that the results will vary depending on the severity of the condition. However, the specific dosing regimen and schedule will depend on the individual needs and the manner in which the composition is administered. should be adjusted over time according to the professional judgment of the person supervising the administration of the composition; should be further understood.

[0121] The sodium nitrite provided herein is an endothelin-converting enzyme (ECE) inhibitor, e.g. thromboxane receptor antagonists, e.g., ifetroban; sodium channel openers; thrombin inhibitors, e.g., hirudin; growth factor inhibitors, e.g., Modulators of PDGF activity; platelet-activating factor (PAF) antagonists; antiplatelet agents, e.g. , GPIIb / IIIa blockers (e.g., abciximab, eptifibatide, and tirofiba) P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine, and CS-747), and and aspirin; anticoagulants, e.g., warfarin; low molecular weight heparins, e.g., enoxaban; Phosphorus; Factor VIIa and Xa inhibitors; Renin inhibitors; Neutral endopeptidase (NEP) inhibitors; vasopeptidase inhibitors (NEP-ACE dual inhibitors), such as omapatrilat and gemostat Patrilat; HMG CoA reductase inhibitors, e.g., pravastatin, lovastatin, atorva Statins, simvastatin, NK-104 (also known as itavastatin, nisvastatin) ), or nisbastatin), and ZD-4522 (also known as rosuvastatin, atavastatin) squalene synthetase inhibitors; fibrates; bile acid sequestrants, Questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP inhibitors calcium channel blockers, e.g., amlodipine besylate; potassium channel activators alpha-adrenergic agonists; beta-adrenergic agonists, e.g., carbethamin Diuretics, such as chlorothiazide, hydrochloride, thiaz ... Lothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methyl Chlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid , ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide , triamterene, amiloride, and spironolactone; thrombolytic agents, such as tissue-type Plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase , prourokinase, and anisoylated plasminogen streptokinase activator antidiabetic agents, such as biguanides (e.g., metformin), glucosides; enzyme inhibitors (e.g., acarbose), insulin, meglitinides (e.g., Repagli sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozole Thiozolidinedione (e.g., troglitazone, rosiglitazone, and thiozolidinedione) glitazones), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, e.g. For example, spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phospholipase A inhibitors; Diesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors agents (e.g., sildenafil, tadalafil, and vardenafil); protein tyrosine Kinase inhibitors; anti-inflammatory drugs; anti-proliferative drugs, e.g., methotrexate, FK506 (tacrolimus) , mycophenolate mofetil; chemotherapeutic agents; immunosuppressants; anticancer and cytotoxic agents (e.g. , nitrogen mustard, alkyl sulfonate, nitrosourea, ethyleneimine alkylating agents such as benzodiazepines, benzodiazepines, and triazenes; antimetabolites, e.g., folate antagonists, promethazines, Phosphorus analogues, and pyrimidine analogues; antibiotics, e.g., anthracyclines, bleomycins, isin, mitomycin, dactinomycin, and plicamycin; enzymes, e.g., L-amycin paraginase; farnesyl-protein transferase inhibitors; hormones, e.g. glucocorticoids (e.g., cortisone), estrogens / antiestrogens, and androgens / antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists octreotide, and octreotide acetate; microtubule-disruptor agents, such as Ecteinascidins; microtubule stabilizers, such as pacitaxel, docetaxel, and epothilone AF; plant-derived products, such as vinca alkaloids, epipodophyllotoxins and topoisomerase inhibitors; prenyl-protein transferases enzyme inhibitors; and cyclosporine; steroids, such as prednisone and dexamethasone cytotoxic drugs, such as azathioprine and cyclophosphamide; TNF-alpha inhibitors anti-TNF antibodies or soluble TNF receptors, e.g., etanercept, laminin, cyclooxygenase-2 (COX-2) inhibitors; For example, celecoxib and rofecoxib; and various other agents, for example, thiosulfur sodium benzoate, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, low molecular weight drugs, low molecular weight vitamins, and platinum coordination complexes, e.g., cisplatin, Another class of compounds includes, but is not limited to, satraplatin, and carboplatin. The compound may be administered in combination with other compounds.

[0122] The sodium nitrite provided herein is a nitrite that is soluble in copper, fluoride ions, iodine, iron, manganese, and other metals. Naturally occurring minerals in human blood, including iron, magnesium, phosphorus, selenium, thiosulfate ions, and zinc It may be administered in combination with other solutes present in the

[0123] The present disclosure will be better understood from the following non-limiting examples. [Example]

[0124] (Example) As used herein, in these experiments, processes, schemes, and examples The symbols and terms used are those of the modern Scientific literature, such as the Journal of the American Chemical Society or the Journal of Consistent with those used in Biological Chemistry. Specifically, the following limitations apply: Although not required, the following abbreviations may be used in the examples and throughout the specification: : g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimole concentration) μM (micromolar concentration); nM (nanomolar concentration); mmol (millimolar); eq. (equivalent); hr or hrs (hours) interval);min(minutes).

[0125] All of the following experiments and examples were carried out using standard work-up and Purification methods are available. All temperatures are in °C (degrees Celsius) unless otherwise indicated. Unless otherwise noted, all reactions are carried out at room temperature. The methods described are intended to illustrate applicable chemistry with specific examples and are not intended to be within the scope of the present invention. It does not represent.

[0126] (Stability experiment) The results of the following stability experiments (Examples 1-4) show that nitrite in aqueous solution is stable when acid is added. Instability of the acid and bicarbonate concentrates in the preparation of dialysis fluids. This illustrates the instability of nitrite ions when mixed with solutions containing

[0127] The concentration of nitrite ions in the samples was assayed by ion chromatography. The chromatography equipment is equipped with a conductivity detector, a self-regenerating suppressor system, and an eluent generator. The sample was fitted with a bioreactor and a Dionex IonPacAS19 analytical column. The concentration was measured and calculated against an external sodium nitrite standard. A reference standard (item no. 1614454) served as the test standard (United States Pharmacopoeia, Rockville, Maryland ).

[0128] Example 1 The International Chemical Safety Card for sodium nitrite states that the chemical decomposes when in contact with acid. and produces toxic nitrogen oxide fumes (www.ilo.org / dyn / icsc / showca International Program accessed online at rd.display?p_card_id-1120 me on Chemical Safety).

[0129] Example 1 measures the stability of sodium nitrite in aqueous solution when acid is added. A 100 mL sample of 30 mg / mL sodium nitrite solution was added to the Orion 95 Nitrogen oxide gases (NO, NO2, N2O3, and N2O4) were measured using a -46 type nitrogen oxide (NOx) electrode and a pH meter. With constant stirring, the mV readings at the NOx electrode and the The pH readings on the pH electrode were measured after successive additions of 100 μL of either 0.02 N or 1 N hydrochloric acid. The initial pH of the sodium nitrite solution was 8.73. With the continued addition of hydrochloric acid, When the pH of the sodium nitrite solution dropped to 6.7, nitrogen oxides were detected (1 ppm NOx detection). When the pH of the sodium nitrite solution was decreased from 6.7 to 4.9, the nitrogen oxides The polar response increased from 8.0 mV to 99.5 mV. These results indicate that sodium nitrite It has been confirmed that it decomposes when exposed to acid, and that the degree of decomposition is generally inversely proportional to the pH. was done.

[0130] Example 2 Example 2 was used to determine the stability of sodium nitrite in concentrated dialysate bicarbonate solutions. At room temperature, 300 mg of sodium nitrite was added to 7,700 mL of concentrated dialysate bicarbonate solution. The nitrite ion concentration of the dialysate bicarbonate concentrate solution was adjusted by: 1) adding sodium nitrite. 1) before; 2) 5 min after addition of sodium nitrite; and 3) 2 h after addition of sodium nitrite. The results shown in Table 1 indicate that nitrite ions are stable. and does not degrade to produce nitrate ions when added to a concentrated bicarbonate solution of dialysis fluid. This indicates that Table 1: Nitrite ion concentrations in dialysate bicarbonate concentrates [Table 1]

[0131] Example 3 Example 3 shows the effect of sodium nitrite from Example 2 when mixed with an acid-concentrated solution in a dialysis machine. To further determine the stability of nitrite in mixtures of nitrite and concentrated dialysate bicarbonate solutions, This was done for this purpose.

[0132] The dialyzer generates a dialysate bicarbonate concentrate solution (sodium nitrite from Example 2) The dialysate was mixed with the dialysate prepared by the dialysis machine in an actual clinical setting. 1 part of the concentrated acid solution, 1.72 parts of the concentrated bicarbonate solution, and 42.38 parts purified water, as described above. The dialysis machine used in this experiment was a Fresenius 2008K hemodialysis machine (Fr The device was then placed in a bypass vein using saline. Priming was performed in the saturation mode (dialysis fluid rate and ultrafiltration rate were set to zero). After that, the hemodialysis machine was set to the following settings: blood flow rate 300 mL / min, dialysate flow rate 600 mL / min, ultrafiltration rate 100 mL / min, and dialysis fluid flow rate 100 mL / min. The dialysis machine was operated in "therapeutic mode" with a filter rate of 0 mL / min and an ultrafiltration time of 25 minutes. A sample of the mixed dialysate was taken and analyzed by ion chromatography.

[0133] The results shown in Table 2 indicate that nitrite ions in the concentrated bicarbonate solution of the dialysate contribute to the acid concentration in the dialysis device. This indicates that the polymer was completely decomposed during the process of mixing with the condensation solution. (Table 2: Nitrite ion concentration in the dialysate after mixing in the hemodialysis machine) [Table 2]

[0134] Example 4 Example 4 shows that sodium nitrite was added to the dialysate after it was prepared in the laboratory. This was done to determine the stability of nitrite ions when 1 part concentrated acid solution, 1.72 Using a dilution ratio of 42.38 parts bicarbonate concentrate solution and 42.38 parts purified water, 38.22 mL of bicarbonate concentrate solution and 22.22 mL of acid concentrate solution to 938.56 mL of purified water. One liter of dialysis solution was prepared using 1 mL of 3 mg / mL dialysis solution. The pH of the dialysis solution was 7.34 at 24.9°C. 1 mL of sodium nitrite solution was added to 1 L of premixed dialysis solution. After the addition of sodium nitrite, the pH of the dialysis solution was 7.32 at 24.4°C. A sample of the solution was analyzed for nitrite ion concentration. The results, shown in Table 3, show that nitrite ion It shows partial degradation after addition to the premixed dialysis solution. Table 3: Nitrite concentrations in laboratory premixed dialysates [Table 3]

[0135] Example 5 Example 5 shows the dialysate used in a Fresenius 2008K hemodialysis machine (Fresenius Medical Care, Waltham The nitrite-containing dialysate is prepared in a dialysis chamber (MA) and then sodium nitrite is added to the dialysate. The dialysate bicarbonate concentrate solution was prepared using Centrisol (registered trademark). Add one packet (650g) of MB-330 Series Sodium Bicarbonate Concentrate Powder to 7.7 liters of purified water. It was prepared by adding

[0136] The hemodialysis machine mixes the bicarbonate concentrate solution and the acid concentrate solution in a ratio of 1 part acid concentrate solution, 1.7 parts A dilution ratio of 2 parts bicarbonate concentrate solution and 42.38 parts purified water was mixed. Prime with water in bypass mode (dialysate rate and ultrafiltration rate set to zero) After priming, the hemodialysis machine was set to the following settings: blood flow rate 300 mL / min, dialysate It was operated in "therapeutic mode" using a flow rate of 600 mL / min and an ultrafiltration rate of 0 mL / min.

[0137] Sodium nitrite was prepared by dissolving 3 mg of sodium nitrite in 1 liter of purified water. An aqueous solution of sodium nitrite was prepared. The resulting sodium nitrite solution contained approximately 2 mg / L of anionic nitrite. Since the sodium nitrite solution had a high nitrate concentration, the nitrate ions (and nitrite) of AAMI The sodium nitrite solution met the quality specifications for sodium nitrite (ion). A fluid pump (Model 8100, CareFusion, San Diego, CA) was used to pump the fluid through a valve (Fresensius Dialysate Dialysis fluid piping between the hemodialysis machine and the dialyzer through the Sample Valve (Part Number 650993) The valve was inserted approximately 8 inches (20.3 mm) into the dialyzer (pre-filter) in the dialysate tubing. Two sample ports were placed 4 inches (10.2 cm) upstream from the dialyzer (pre-dialyzer sample port). The sample collection port was placed 10 inches (25.4 cm) downstream (post-dialysis sample collection port). Dialysate samples were taken for nitrate assay by lithography.

[0138] The infusion pump pumps sodium nitrite solution through the valve at a rate of 250 mL / hour (4.16 mL / min). was injected inside.

[0139] Normal saline solution flows from the arterial line through the dialyzer at a rate of 300 mL / min and is then pumped through the venous line. The saline solution exited the dialyzer. A sample of saline was taken from the venous side of the dialyzer.

[0140] The results shown in Table 4 indicate that the sodium nitrite solution mixed with the dialysate in the dialysate piping Nitrite ions are stable when injected into the piping at a location between the dialysis machine and the dialysis membrane. Indicates that. (Table 4: Sodium nitrite solution enters the dialysate in the dialysate tubing before it comes into contact with the dialysis membrane. Nitrite ion concentration in the dialysate before and after addition [Table 4] *Average result from two samples

[0141] The results shown in Table 4 were obtained by spiking the hemodialysis machine at a location between the hemodialysis machine and the dialysis membrane. If nitrite ions are added to untreated dialysate, the nitrite ions will This indicates that you can either move through or move forward.

[0142] The above examples are provided as complete instructions on how to make and use the claimed embodiments. This disclosure and description is provided to provide a complete understanding of the present invention and is not to be construed as limiting the present invention. The present invention is not intended to limit the scope of the present invention. Modifications obvious to those skilled in the art may be incorporated into the following patent claims. All publications, patents, and related art cited herein are intended to be within the scope of the claims. and patent applications are hereby incorporated by reference as if each such publication, patent, or patent application were expressly incorporated by reference. and individually indicated to be incorporated herein by reference. and is incorporated herein by reference. The present application provides the following aspects of the invention. (Aspect 1) To maintain physiological levels of nitrite in subjects undergoing hemodialysis The method of claim 1, wherein the subject's blood is also contacted with a dialysate spiked with nitrite ions. and contacting the unspiked dialysate with a dialysis membrane containing the dialysis fluid during dialysis, When flowing through the dialysis membrane, the aqueous solution containing sodium nitrite is mixed with the unspiked dialysate. and the unspiked dialysate is added to a solution of water, an acid concentrate, and a bicarbonate concentrate. and wherein the nitrite ion spiked dialysate has a pH greater than about 7.0. , the method. (Aspect 2) a physiological level of the nitrite ion in the subject of about 1 micromolar or less; 2. The method of embodiment 1, wherein (Aspect 3) The physiological level of the nitrite ion in the subject is between about 200 nanomolar and about 500 nanomolar. The method of embodiment 1, wherein the concentration is nanomolar. (Aspect 4) the physiological level of nitrite in the subject is about 300 nanomolar; 2. The method of embodiment 1. (Aspect 5) The concentration of nitrite ions in the nitrite-spiked dialysate is about 1 micromolar. The method of embodiment 1, wherein the concentration is equal to or less than 1000 mg / kg of the soluble polymer. (Aspect 6) The concentration of nitrite in the nitrite-spiked dialysate is about 200 nanomolar. The method of embodiment 1, wherein the concentration is from about 500 nanomolar. (Aspect 7) The concentration of nitrite in the nitrite-spiked dialysate is about 300 nanomolar. The method of embodiment 1, wherein the concentration is (Aspect 8) Aspect 1, wherein the aqueous solution containing sodium nitrite contains about 3 mg / L or less of sodium nitrite. The method described. (Aspect 9) 2. The method of embodiment 1, wherein the water contains about 2 mg / L or less of nitrite ions. (Aspect 10) The dialysate piping is connected to the dialyzer through a valve attached to the piping. The aqueous solution containing sodium nitrite is added to the unspiked dialysis solution. The method described in Example 1. (Aspect 11) The unspiked dialysis fluid is passed through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min. 11. The method of embodiment 10, wherein the (Aspect 12) an embodiment in which the unspiked dialysate flows through the dialysis tubing at a rate of about 600 mL / min. The method described in 10. (Aspect 13) The sodium nitrite-containing aqueous solution is then passed through the valve to the unspiked dialyzer. 11. The method of embodiment 10, wherein the solution is added to the solution at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 14) The sodium nitrite-containing aqueous solution is then passed through the valve to the unspiked dialyzer. 11. The method of embodiment 10, wherein the solution is added at a rate of about 250 mL per hour. (Aspect 15) The method according to aspect 1, wherein the pH of the dialysate spiked with nitrite ions is about 7.3 to about 7.5. method. (Aspect 16) 2. The method of embodiment 1, wherein the pH of the nitrite-spiked dialysate is about 7.4. (Aspect 17) The method of embodiment 1, wherein the subject is a human with chronic renal failure. (Aspect 18) The method of embodiment 1, wherein the subject is a human with acute renal failure. (Aspect 19) The method of embodiment 1, wherein the subject undergoes dialysis 3 to 7 times per week. (Aspect 20) 1. A method for preventing myocardial infarction in a subject undergoing dialysis, comprising administering to said subject blood During dialysis, the solution is brought into contact with a dialysis membrane that is also in contact with dialysate spiked with nitrite ions. and wherein the unspiked dialysate is mixed with the dialysis membrane as it flows from the dialyzer to the dialysis membrane. An aqueous solution containing sodium nitrate is added to the unspiked dialysate, and the spiked dialysate is The untreated dialysate comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and The method, wherein the nitrate spiked dialysate has a pH greater than about 7.0. (Aspect 21) a physiological level of the nitrite ion in the subject of about 1 micromolar or less; 21. The method of embodiment 20, wherein (Aspect 22) The physiological level of the nitrite ion in the subject is between about 200 nanomolar and about 500 nanomolar. 21. The method of embodiment 20, wherein the concentration is nanomolar. (Aspect 23) the physiological level of nitrite in the subject is about 300 nanomolar; 21. The method of embodiment 20. (Aspect 24) The concentration of nitrite ions in the nitrite-spiked dialysate is about 1 micromolar. 21. The method of embodiment 20, wherein the concentration of the HCl solution is equal to or less than 100 mg / mL. (Aspect 25) The concentration of nitrite in the nitrite-spiked dialysate is about 200 nanomolar. 21. The method of embodiment 20, wherein the concentration is from about 500 nanomolar. (Aspect 26) The concentration of nitrite in the nitrite-spiked dialysate is about 300 nanomolar. 21. The method of embodiment 20, wherein the concentration is (Aspect 27) Aspect 2, wherein the aqueous solution containing sodium nitrite contains about 3 mg / L or less of sodium nitrite. The method described in 0. (Aspect 28) 21. The method of embodiment 20, wherein the water contains about 2 mg / L or less of nitrite ions. (Aspect 29) The dialysate piping is connected to the dialyzer through a valve attached to the piping. The aqueous solution containing sodium nitrite is added to the unspiked dialysis solution. The method described in 20. (Aspect 30) The unspiked dialysis fluid is passed through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min. 30. The method of embodiment 29, wherein the (Aspect 31) The unspiked dialysate flows through the dialysis tubing at a rate of approximately 600 mL per minute. 30. The method of embodiment 29. (Aspect 32) The sodium nitrite-containing aqueous solution is then passed through the valve to the unspiked dialyzer. 30. The method of embodiment 29, wherein the solution is added to the solution at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 33) The sodium nitrite-containing aqueous solution is then passed through the valve to the unspiked dialyzer. 30. The method of embodiment 29, wherein the solution is added at a rate of about 250 mL per hour. (Aspect 34) 21. The method according to claim 20, wherein the pH of the dialysate spiked with nitrite ions is about 7.3 to about 7.5. method. (Aspect 35) 21. The method of embodiment 20, wherein the pH of the nitrite-spiked dialysate is about 7.4. (Aspect 36) 21. The method of embodiment 20, wherein the subject is a human with chronic renal failure. (Aspect 37) 21. The method of embodiment 20, wherein the subject is a human with acute renal failure. (Aspect 38) 21. The method of embodiment 20, wherein the subject undergoes dialysis 3 to 7 times per week. (Aspect 39) 1. A method for preventing sudden cardiac death in a subject undergoing dialysis, comprising administering to said subject During dialysis, elephant blood is in contact with a dialysis membrane that is also in contact with dialysate spiked with nitrite ions. contacting the unspiked dialysate with the dialysis membrane when the unspiked dialysate flows from the dialysis machine to the dialysis membrane. Then, an aqueous solution containing sodium nitrite is added to the unspiked dialysate, and the spa The uninjected dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, wherein the nitrite ion spiked dialysate has a pH greater than about 7.0. (Aspect 40) a physiological level of the nitrite ion in the subject of about 1 micromolar or less; 40. The method of embodiment 39, wherein (Aspect 41) The physiological level of the nitrite ion in the subject is between about 200 nanomolar and about 500 nanomolar. 40. The method of embodiment 39, wherein the concentration is nanomolar. (Aspect 42) the physiological level of nitrite in the subject is about 300 nanomolar; 40. The method of embodiment 39. (Aspect 43) The concentration of nitrite ions in the nitrite-spiked dialysate is about 1 micromolar. 40. The method of embodiment 39, wherein the concentration of the HCl solution is equal to or less than 1000 mg / mL. (Aspect 44) The concentration of nitrite in the nitrite-spiked dialysate is about 200 nanomolar. 40. The method of embodiment 39, wherein the concentration is from about 500 nanomolar. (Aspect 45) The concentration of nitrite in the nitrite-spiked dialysate is about 300 nanomolar. 40. The method of embodiment 39, wherein the concentration is (Aspect 46) Aspect 3, wherein the aqueous solution containing sodium nitrite contains about 3 mg / L or less of sodium nitrite. 9. The method described in 9. (Aspect 47) 40. The method of embodiment 39, wherein the water contains about 2 mg / L or less of nitrite ions. (Aspect 48) The dialysate piping is connected to the dialyzer through a valve attached to the piping. The aqueous solution containing sodium nitrite is added to the unspiked dialysis solution. The method described in 39. (Aspect 49) The unspiked dialysis fluid is passed through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min. 49. The method of embodiment 48, wherein the (Aspect 50) The unspiked dialysate flows through the dialysis tubing at a rate of approximately 600 mL per minute. 49. The method of embodiment 48. (Aspect 51) The sodium nitrite-containing aqueous solution is then passed through the valve to the unspiked dialyzer. 49. The method of embodiment 48, wherein the solution is added to the solution at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 52) The sodium nitrite-containing aqueous solution is then passed through the valve to the unspiked dialyzer. 49. The method of embodiment 48, wherein the solution is added at a rate of about 250 mL per hour. (Aspect 53) 40. The method of claim 39, wherein the pH of the dialysate spiked with nitrite ions is about 7.3 to about 7.5. method. (Aspect 54) 40. The method of embodiment 39, wherein the pH of the nitrite spiked dialysate is about 7.4. (Aspect 55) 40. The method of embodiment 39, wherein the subject is a human with chronic renal failure. (Aspect 56) 40. The method of embodiment 39, wherein the subject is a human with acute renal failure. (Aspect 57) The method of embodiment 39, wherein the subject undergoes dialysis 3 to 7 times per week. (Aspect 58) 1. A method for preventing stroke in a subject undergoing dialysis, comprising administering to said subject blood during dialysis, in contact with a dialysis membrane that is also in contact with a dialysate spiked with nitrite ions. and wherein the non-spiked dialysate is irradiated with nitrite when the non-spiked dialysate flows from the dialyzer to the dialysis membrane. An aqueous solution containing sodium chloride is added to the unspiked dialysate, and the spiked dialysate is The undiluted dialysate comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the nitrite The method, wherein the acid ion spiked dialysate has a pH greater than about 7.0. (Aspect 59) a physiological level of the nitrite ion in the subject of about 1 micromolar or less; 59. The method of embodiment 58, wherein (Aspect 60) The physiological level of the nitrite ion in the subject is between about 200 nanomolar and about 500 nanomolar. 60. The method of embodiment 58, wherein the concentration is nanomolar. (Aspect 61) the physiological level of nitrite in the subject is about 300 nanomolar; 59. The method of embodiment 58. (Aspect 62) The concentration of nitrite ions in the nitrite-spiked dialysate is about 1 micromolar. 59. The method of embodiment 58, wherein the concentration of the HCl solution is equal to or less than 100 mg / mL. (Aspect 63) The concentration of nitrite in the nitrite-spiked dialysate is about 200 nanomolar. 59. The method of embodiment 58, wherein the concentration is from about 500 nanomolar. (Aspect 64) The concentration of nitrite in the nitrite-spiked dialysate is about 300 nanomolar. 59. The method of embodiment 58, wherein the concentration is (Aspect 65) Aspect 5. The aqueous solution comprising sodium nitrite comprises about 3 mg / L or less of sodium nitrite. 8. The method described in (Aspect 66) 59. The method of embodiment 58, wherein the water contains about 2 mg / L or less of nitrite ions. (Aspect 67) The dialysate piping is connected to the dialyzer through a valve attached to the piping. The aqueous solution containing sodium nitrite is added to the unspiked dialysis solution. The method described in 58. (Aspect 68) The unspiked dialysis fluid is passed through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min. 70. The method of embodiment 67, wherein the (Aspect 69) The unspiked dialysate flows through the dialysis tubing at a rate of approximately 600 mL per minute. 68. The method of embodiment 67. (Aspect 70) The sodium nitrite-containing aqueous solution is then passed through the valve to the unspiked dialyzer. 68. The method of embodiment 67, wherein the solution is added to the solution at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 71) The sodium nitrite-containing aqueous solution is then passed through the valve to the unspiked dialyzer. 68. The method of embodiment 67, wherein the solution is added at a rate of about 250 mL per hour. (Aspect 72) 59. The method of claim 58, wherein the pH of the nitrite ion-spiked dialysate is about 7.3 to about 7.5. method. (Aspect 73) 59. The method of embodiment 58, wherein the pH of the nitrite spiked dialysate is about 7.4. (Aspect 74) 59. The method of embodiment 58, wherein the subject is a human with chronic renal failure. (Aspect 75) 59. The method of embodiment 58, wherein the subject is a human with acute renal failure. (Aspect 76) 59. The method of embodiment 58, wherein the subject undergoes dialysis 3 to 7 times per week. (Aspect 77) In subjects undergoing dialysis, the incidence of angina pectoris, cerebral vasospasm, claudication, critical limb ischemia, and peripheral vascular disease and cardiovascular diseases characterized by tissue ischemia, including sickle cell crisis. The method also includes contacting the subject's blood with a dialysate spiked with nitrite ions. and contacting the unspiked dialysate with a dialysis membrane during dialysis, wherein the unspiked dialysate is removed from the dialysis machine. When flowing through the dialysis membrane, the aqueous solution containing sodium nitrite is mixed with the unspiked dialysate. and the unspiked dialysate is added to a solution of water, an acid concentrate, and a bicarbonate concentrate. and wherein the nitrite ion spiked dialysate has a pH greater than about 7.0. , the method. (Aspect 78) a physiological level of the nitrite ion in the subject of about 1 micromolar or less; 78. The method of embodiment 77, wherein (Aspect 79) The physiological level of the nitrite ion in the subject is between about 200 nanomolar and about 500 nanomolar. 78. The method of embodiment 77, wherein the concentration is nanomolar. (Aspect 80) the physiological level of nitrite in the subject is about 300 nanomolar; 78. The method of embodiment 77. (Aspect 81) The concentration of nitrite ions in the nitrite-spiked dialysate is about 1 micromolar. 78. The method of embodiment 77, wherein the concentration of the HCl solution is equal to or less than 100 mg / mL. (Aspect 82) The concentration of nitrite in the nitrite-spiked dialysate is about 200 nanomolar. 78. The method of embodiment 77, wherein the concentration is from about 500 nanomolar. (Aspect 83) The concentration of nitrite in the nitrite-spiked dialysate is about 300 nanomolar. 78. The method of embodiment 77, wherein the concentration is (Aspect 84) Aspect 7. The aqueous solution comprising sodium nitrite comprises about 3 mg / L or less of sodium nitrite. 7. The method described in 7. (Aspect 85) 78. The method of embodiment 77, wherein the water contains about 2 mg / L or less of nitrite ions. (Aspect 86) The dialysate piping is connected to the dialyzer through a valve attached to the piping. The aqueous solution containing sodium nitrite is added to the unspiked dialysis solution. The method described in 77. (Aspect 87) The unspiked dialysis fluid is passed through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min. 87. The method of embodiment 86, wherein the (Aspect 88) The unspiked dialysate flows through the dialysis tubing at a rate of approximately 600 mL per minute. 87. The method of embodiment 86. (Aspect 89) The sodium nitrite-containing aqueous solution is then passed through the valve to the unspiked dialyzer. 87. The method of embodiment 86, wherein the solution is added to the solution at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 90) The sodium nitrite-containing aqueous solution is then passed through the valve to the unspiked dialyzer. 87. The method of embodiment 86, wherein the solution is added at a rate of about 250 mL per hour. (Aspect 91) 78. The method of claim 77, wherein the pH of the nitrite-spiked dialysate is about 7.3 to about 7.5. method. (Aspect 92) 78. The method of embodiment 77, wherein the pH of the nitrite-spiked dialysate is about 7.4. (Aspect 93) 78. The method of embodiment 77, wherein the subject is a human with chronic renal failure. (Aspect 94) 78. The method of embodiment 77, wherein the subject is a human with acute renal failure. (Aspect 95) 78. The method of embodiment 77, wherein the subject undergoes dialysis 3 to 7 times per week. (Aspect 96) Preventing hypertension, pulmonary hypertension, and renal hypertension in subjects undergoing dialysis The method also includes contacting the subject's blood with a dialysate spiked with nitrite ions. and contacting the unspiked dialysate with a dialysis membrane containing the unspiked dialysate during dialysis, When the aqueous solution containing sodium nitrite flows from the device to the dialysis membrane, The unspiked dialysate is added to the dialysate, and the unspiked dialysate contains water, a concentrated acid solution, and a concentrated bicarbonate solution. The dialysate containing the mixture of nitrite ions and the nitrite ion spiked dialysate has a pH greater than about 7.0. The method comprising: (Aspect 97) a physiological level of the nitrite ion in the subject of about 1 micromolar or less; 97. The method of embodiment 96, wherein (Aspect 98) The physiological level of the nitrite ion in the subject is between about 200 nanomolar and about 500 nanomolar. 97. The method of embodiment 96, wherein the concentration is nanomolar. (Aspect 99) the physiological level of nitrite in the subject is about 300 nanomolar; 97. The method of embodiment 96. (Aspect 100) The concentration of nitrite ions in the nitrite-spiked dialysate is about 1 micromolar. 97. The method of embodiment 96, wherein the concentration of the HCl solution is equal to or less than 100 mg / mL. (Aspect 101) The concentration of nitrite in the nitrite-spiked dialysate is about 200 nanomolar. 97. The method of embodiment 96, wherein the concentration is from about 500 nanomolar. (Aspect 102) The concentration of nitrite in the nitrite-spiked dialysate is about 300 nanomolar. 97. The method of embodiment 96, wherein the concentration is (Aspect 103) Aspect 9: The aqueous solution comprising sodium nitrite comprises about 3 mg / L or less of sodium nitrite. 6. The method described in 6. (Aspect 104) 97. The method of embodiment 96, wherein the water contains about 2 mg / L or less of nitrite ions. (Aspect 105) The dialysate piping is connected to the dialyzer through a valve attached to the piping. The aqueous solution containing sodium nitrite is added to the unspiked dialysis solution. The method described in 96. (Aspect 106) The unspiked dialysis fluid is passed through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min. 106. The method of embodiment 105, wherein the (Aspect 107) The unspiked dialysate flows through the dialysis tubing at a rate of approximately 600 mL per minute. 106. The method of embodiment 105. (Aspect 108) The sodium nitrite-containing aqueous solution is then passed through the valve to the unspiked dialyzer. 106. The method of embodiment 105, wherein the solution is added to the solution at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 109) The sodium nitrite-containing aqueous solution is then passed through the valve to the unspiked dialyzer. 106. The method of embodiment 105, wherein the solution is added at a rate of about 250 mL per hour. (Aspect 110) 97. The method of claim 96, wherein the pH of the nitrite-spiked dialysate is about 7.3 to about 7.5. method. (Aspect 111) 97. The method of embodiment 96, wherein the pH of the nitrite-spiked dialysate is about 7.4. (Aspect 112) 97. The method of embodiment 96, wherein the subject is a human with chronic renal failure. (Aspect 113) 97. The method of embodiment 96, wherein the subject is a human with acute renal failure. (Aspect 114) 97. The method of embodiment 96, wherein the subject undergoes dialysis 3 to 7 times per week.

Claims

1. 1. Use of sodium nitrite for the manufacture of a medicament for maintaining physiological levels of nitrite ions in a subject undergoing hemodialysis, wherein the sodium nitrite is prepared for contacting the subject's blood with a dialysis membrane that is also in contact with a dialysate spiked with nitrite ions during dialysis, wherein an aqueous solution containing sodium nitrite is added to the unspiked dialysate as it flows from the dialyzer to the dialysis membrane, wherein the unspiked dialysate comprises a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, and the nitrite-spiked dialysate has a pH greater than about 7.0, and wherein the medicament further comprises one or more low-molecular-weight drugs and / or low-molecular-weight vitamins, or is for use in combination with one or more low-molecular-weight drugs and / or low-molecular-weight vitamins.

2. 1. Use of sodium nitrite for the manufacture of a medicament for the prevention of myocardial infarction in a subject undergoing hemodialysis, wherein the sodium nitrite is prepared to contact the subject's blood with a dialysis membrane that is also in contact with a dialysate spiked with nitrite ions during dialysis, wherein an aqueous solution containing sodium nitrite is added to the unspiked dialysate as it flows from the dialyzer to the dialysis membrane, wherein the unspiked dialysate comprises a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, and the nitrite ion spiked dialysate has a pH greater than about 7.0, and wherein the medicament further comprises one or more low molecular weight drugs and / or low molecular weight vitamins, or is for use in combination with one or more low molecular weight drugs and / or low molecular weight vitamins.

3. 1. Use of sodium nitrite for the manufacture of a medicament for the prevention of sudden cardiac death in a subject undergoing hemodialysis, wherein the sodium nitrite is prepared to contact the subject's blood during dialysis with a dialysis membrane that is also in contact with a dialysate spiked with nitrite ions, wherein an aqueous solution containing sodium nitrite is added to the unspiked dialysate as it flows from a dialyzer to the dialysis membrane, wherein the unspiked dialysate comprises a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, and the nitrite ion spiked dialysate has a pH greater than about 7.0, and wherein the medicament further comprises one or more low molecular weight drugs and / or low molecular weight vitamins, or is for use in combination with one or more low molecular weight drugs and / or low molecular weight vitamins.

4. 1. Use of sodium nitrite for the manufacture of a medicament for the prevention of stroke in a subject undergoing hemodialysis, wherein the sodium nitrite is prepared for contacting the subject's blood during dialysis with a dialysis membrane that is also in contact with a dialysate spiked with nitrite ions, wherein an aqueous solution containing sodium nitrite is added to the unspiked dialysate as it flows from a dialyzer to the dialysis membrane, wherein the unspiked dialysate comprises a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, and the nitrite ion spiked dialysate has a pH greater than about 7.0, and wherein the medicament further comprises one or more low molecular weight drugs and / or low molecular weight vitamins, or is for use in combination with one or more low molecular weight drugs and / or low molecular weight vitamins.

5. 1. Use of sodium nitrite for the manufacture of a medicament for the prevention of cardiovascular diseases characterized by tissue ischemia, including angina pectoris, cerebral vasospasm, claudication, critical limb ischemia, peripheral vascular disease, and sickle cell crisis, in a subject undergoing hemodialysis, wherein the sodium nitrite is prepared for contacting the subject's blood with a dialysis membrane that is also in contact with a dialysate spiked with nitrite ions during dialysis, an aqueous solution containing sodium nitrite is added to the unspiked dialysate as it flows from the dialyzer to the dialysis membrane, the unspiked dialysate comprising a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, the nitrite ion spiked dialysate having a pH greater than about 7.0, and the medicament further comprises one or more low molecular weight drugs and / or low molecular weight vitamins, or is for use in combination with one or more low molecular weight drugs and / or low molecular weight vitamins.

6. 1. Use of sodium nitrite for the manufacture of a medicament for the prevention of hypertension in a subject undergoing hemodialysis, wherein the sodium nitrite is prepared for contacting the subject's blood with a dialysis membrane that is also in contact with a dialysate spiked with nitrite ions during dialysis, wherein an aqueous solution containing sodium nitrite is added to the unspiked dialysate as it flows from the dialyzer to the dialysis membrane, wherein the unspiked dialysate comprises a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, and the nitrite ion spiked dialysate has a pH greater than about 7.0, and wherein the medicament further comprises one or more low molecular weight drugs and / or low molecular weight vitamins, or is for use in combination with one or more low molecular weight drugs and / or low molecular weight vitamins.

7. The use according to any one of claims 1 to 6, wherein the physiological level of nitrite in the subject is about 1 micromolar or less.

8. The use according to any one of claims 1 to 6, wherein the physiological level of nitrite in the subject is between about 200 nanomolar and about 500 nanomolar.

9. The use according to any one of claims 1 to 6, wherein the physiological level of nitrite in the subject is about 300 nanomolar.

10. The use according to any one of claims 1 to 6, wherein the concentration of nitrite ions in the nitrite-spiked dialysate is about 1 micromolar or less.

11. The use according to any one of claims 1 to 6, wherein the concentration of nitrite in the nitrite-spiked dialysate is from about 200 nanomolar to about 500 nanomolar.

12. The use according to any one of claims 1 to 6, wherein the concentration of nitrite in the nitrite-spiked dialysate is about 300 nanomolar.

13. The use according to any one of claims 1 to 6, wherein the aqueous solution containing sodium nitrite contains about 3 mg / L or less of sodium nitrite.

14. The use according to any one of claims 1 to 6, wherein the water contains no more than about 2 mg / L of nitrite ions.

15. The use according to any one of claims 1 to 6, wherein the aqueous solution containing sodium nitrite is added to the unspiked dialysate through a valve attached to the dialysate tubing at a position before the dialysate tubing connects to the dialysis membrane.

16. 16. The use of claim 15, wherein the unspiked dialysate flows through the dialysate tubing at a rate of about 500 mL / min to about 700 mL / min.

17. 16. The use of claim 15, wherein the unspiked dialysate flows through the dialysate tubing at a rate of about 600 mL / min.

18. 16. The use of claim 15, wherein the aqueous solution containing sodium nitrite is added through the valve to the unspiked dialysate at a rate of about 100 mL / hour to about 550 mL / hour.

19. 16. The use of claim 15, wherein the aqueous solution containing sodium nitrite is added through the valve to the unspiked dialysis fluid at a rate of about 250 mL / hour.

20. The use according to any one of claims 1 to 6, wherein the pH of the nitrite ion spiked dialysate is from about 7.3 to about 7.

5.

21. The use according to any one of claims 1 to 6, wherein the pH of the dialysate spiked with nitrite ions is about 7.

4.

22. The use according to any one of claims 1 to 6, wherein the subject is a human with chronic renal failure.

23. The use according to any one of claims 1 to 6, wherein the subject is a human with acute renal failure.

24. The use according to any one of claims 1 to 6, wherein the subject undergoes dialysis 3 to 7 times per week.

25. 7. The use according to claim 6, wherein the subject is a human with pulmonary hypertension or renal hypertension.

26. 7. The use according to any one of claims 1 to 6, wherein the medicament further comprises one or more low molecular weight drugs or is for use in combination with one or more low molecular weight drugs.

27. 7. The use according to any one of claims 1 to 6, wherein the medicament further comprises or is for use in combination with one or more low molecular weight vitamins.

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