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 from U.S. Provisional Patent Application No. 62 / 468,857, filed March 8, 2017. No. 6,313,635, 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 of 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 reduced excretion of metabolic waste products. The accumulation of metabolic waste products can become life threatening within a few days. Patients with little or no function remaining are considered to have "end-stage renal disease." Therefore, such patients need 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. (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 the dialysate. The solution flows through the other side. The dialysis membrane contains pores through which solutes can pass. 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 a permeant As the membrane is forced through the pores into the less concentrated liquid, it equilibrates.

[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 - It contains low molecular weight solutes such as nitrite. Nitrite has a molecular weight of 46 daltons. Nitrite is the physiologic regulator 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 healthy individuals is approximately 300 nanomolar. .

[0007] The Association for the Advancement of Medical Instrumentation The American Association of Integrative Medicine (AAMI) has established quality specification limits for the nitrate content in water used for dialysis (1 (#ANSI / AAMI / ISO 13959:2009) and AAMI also states that 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 the nitrite ion to a dark azo color which is measured using a spectrophotometer. Diazotization with sulfanilamide to give N-(1-naphthyl)-ethylenediamine diamine The nitrite ion is determined by coupling with the hydrochloride salt (U.S. Environmental Protection Agency Agency's National Environmental Methods Index. www.nemi.gov / methods / method_summary / 51 (Available online at: 21.) This test 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 for nitrate and The AAMI nitrate specification is therefore, in effect, 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., 2003). (Free Radic. Biol. Med. 2008, 44, 1945-1950). In myocardial ischemia, nitrite ions Nitric oxide is reduced to nitrite, which is a vasodilator. The reduction of nitric oxide to nitric oxide protects cardiac function by increasing blood flow to ischemic tissues. As long as nitrite ions remain available in the blood, the beneficial effects are apparent. Nitrite depletion may prevent tissue ischemia from progressing to infarction when vasodilation cannot be maintained. This 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 (E. O. et al., N. Eng. J. Med. 2004, 351, 1296-1305). The risk of sudden death events was increased by 1.7-fold in It 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 hemodialysis sessions remains significantly decreased (Bryan et al., 2013). Radic. Biol. Med. 2013, 58, 46-51).

[0011] Sodium nitrite can be administered into the blood by intravenous injection; however, However, it would 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 is a method for treating hemodialysis in a subject undergoing hemodialysis. 2. A method for maintaining physiological levels of nitrite in a subject, comprising: During dialysis, the nitrite ion is placed in contact with a dialysis membrane that is also in contact with a dialysate spiked with nitrite ions. 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 dialysis fluid and the spiked dialysis fluid is The dialysate contains a mixture of water, a concentrated acid solution, and a concentrated bicarbonate 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 includes contacting the blood with a dialysis solution spiked with nitrite ions during dialysis, When undiluted dialysate flows from the dialysis machine to the dialysis membrane, it is mixed with sodium nitrite-containing aqueous solution. A solution is added to the unspiked dialysate, and the unspiked dialysate is mixed with water. , an acid concentrated solution, and a bicarbonate concentrated solution, spiked with the nitrite ion. 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 untreated dialysate flows from the dialysis machine to the dialysis membrane, aqueous solutions containing sodium nitrite The unspiked dialysate is added 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 comprising: contacting the dialysis membrane with a dialysis solution spiked with dialysis fluid during dialysis; When unspiked dialysate flows from the dialysis machine to the dialysis membrane, it contains sodium nitrite. An aqueous solution containing the dialysis solution is added to the unspiked dialysis solution, and the unspiked dialysis solution is The mixture includes a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, and is spiked with the nitrite ion. 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 solution with a dialysis membrane that is also in contact with the spiked dialysis solution 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 dialysis solution, and the unspiked dialysis solution is mixed with water, acid, 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, A method for preventing cardiovascular disease characterized by tissue ischemia, including ischemia, comprising administering to the subject The solution is contacted during dialysis with a dialysis membrane that is also in contact with a dialysate spiked with nitrite ions. and, when the unspiked dialysate flows from the dialysis device to the dialysis membrane, An aqueous solution containing sodium nitrate is added to the unspiked dialysis fluid, and the spiked dialysis fluid is The untreated dialysis fluid comprises a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, 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 The elephant's blood was placed in contact with a dialysis membrane during dialysis, which was also in contact with a dialysate spiked with nitrite ions. When the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, Then, an aqueous solution containing sodium nitrite is added to the unspiked dialysis fluid, and the spa The uninjected dialysis fluid 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 untreated dialysate flows from the dialysis machine to the dialysis membrane, aqueous solutions containing sodium nitrite The unspiked dialysate is added 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 description of the drawings]

[0021] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figure 1 is a schematic diagram of elements of the flow path of the dialysate, the patient's blood, and the aqueous solution containing sodium nitrite: (10) dialysis machine; (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) sensing point "before" dialysis membrane; (110) sensing point "after" dialysis membrane; (120) sensing point "V"; (130) sensing point "A"; (140) spent dialysate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] (Detailed Description) The following detailed description should not be taken in a limiting sense, but merely as a guide provided herein. 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 understood 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. In the event that 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), cows, sheep, goats, horses, dogs, mice, "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 or a disease or a symptom thereof that can be treated, prevented, or ameliorated by 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 disorder (ESRD). Patients with some or no kidney function are undergoing dialysis to reduce blood pressure. In another embodiment, the steady-state plasma concentration of nitrite ions in a subject undergoing hemodialysis is and saliva concentration is 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 a 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 or treatment of a disorder, disease, or delaying and / or preventing the onset of the disease and / or its associated symptoms; Prevent a subject from acquiring a disorder, disease, or illness; or reduce a subject's risk of acquiring a disorder, disease, or illness It is meant to include a method of making the

[0028] Generally, conventional dialysis fluids, including those that have recently been patented, are either proprietary or not. It is defined as any formulation heretofore known, regardless of the type of formulation. Many of these are For example, U.S. Patent No. 6,436,969 discloses a US Patent No. 5,869,444 discloses compositions containing GE inhibitors, and US Patent No. Nos. 6,306,836 and 6,380,163 claim a solution containing a mixture of tides. discloses a peritoneal dialysis solution that utilizes amino acids to achieve osmotic balance.

[0029] The term "concentrated bicarbonate solution" means an aqueous solution containing bicarbonate or a mixture of bicarbonate and ANSI / AAM I / Meets or exceeds current hemodialysis water quality standards as outlined in ISO#13959:2009 Purified water is a mixture of water and the Minntech Ren 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, sells 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. Sodium bicarbonate concentrate and 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, Additional monitors include fluid pressure and air bubble monitoring. Currently, dialysis machines use concentrated acid solutions, bicarbonate, An automated distribution system that mixes salt concentrate 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 dialysis solution or as an acid 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 tubing" refers to the tubing that connects the dialysis machine and the dialyzer.

[0033] The term "dialyzer" refers to any material made of cellulose acetate, cupraphane, polyacrylonitrile, Polyimide, polyvinyl chloride, polymethyl methacrylate, or polysulfone. An artificial kidney equipped with a synthetic or semi-synthetic semipermeable membrane made of chemical materials (hereinafter referred to as a "dialysis membrane") that is not A constant flow of blood on one side of the membrane and dialysate on the other side. The artificial kidney allows the removal of waste products from the blood. During hemofiltration (hemodiafiltration and Diafiltration (also called ultrafiltration and diafiltration) is a high-altitude filtration process based on ultrafiltration and convective transport rather than diffusion. The solute is transported to the other side of the semipermeable membrane with a large porosity.

[0034] The term "unspiked dialysate" refers to an aqueous solution containing sodium nitrite that is The dialyzer mixes the dialysate before adding it to the dialysate tubing 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 tubing after the solution has been added to the dialysate tubing through the valve.

[0036] The term "therapeutically effective amount" refers to an amount that, when administered, effectively reduces the symptoms of the disorder, disease, or condition being treated. A compound sufficient to prevent or reduce to some extent the occurrence of one or more of the symptoms. The term "therapeutically effective amount" is intended to include any amount that is within the scope of the present invention and may be used by researchers, veterinarians, A physician or clinician is seeking a cell, tissue, system, animal, or human biological or medical A therapeutically effective amount also refers to an 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 term "about" or "approximately" refers to a particular value as determined by one of ordinary skill in the art. It refers to the tolerable error, which depends in part on how the value is measured or determined. In some embodiments, the term "about" or "approximately" refers to a range of In some embodiments, "about" or "approximately" means within 4 standard deviations. The term "subtract" 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%. " values ​​are considered to be accurate.

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

[0039] (Sodium Nitrite) In certain embodiments, the methods provided herein involve the use of a monosodium salt of nitrite. In one embodiment, the method includes the use of a purified form of sodium nitrite (NaNO2), also known as sodium nitrite. Provided herein is a pharma- ceutically acceptable sodium nitrite. In another embodiment, provided herein is a method for treating nitrous acid syndrome, comprising administering to a subject a subject a nitrous acid-containing compound comprising administering to said subject a subject a nitrous acid-containing compound for use in medicine. Forms of sodium nitrite that meet one, more than one, or all of the FDA standards for sodium In one embodiment, the pharma- ceutically acceptable sodium nitrite is nitrite in its entirety. No. 2010 / 013664, filed Feb. 10, 2010, which is incorporated herein by reference. This is disclosed in US Pat. No. 5,972,333.

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

[0041] In one embodiment, pharma- ceutically acceptable sodium nitrite is prepared according to the United States Pharmacopeia XXXII (20 09) Method <191> A confirmatory test for sodium, as determined by

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

[0043] In one embodiment, the sodium nitrite provided herein is about 97% by weight or more and and / or about 101% by weight or less of sodium nitrite. The amount of sodium nitrite in the sodium nitrite provided in is determined by the United States Pharmacopoeia colorimetric assay ( In some embodiments, the methods provided herein are as determined by the United States Pharmacopeia 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 determined by coupling suppressed conductivity detection as described herein. The concentration is 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. 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 certain embodiments, the sodium nitrite provided herein has a loss on drying of 0.05% or less. Loss on drying of capsules 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 based on 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 1% sodium nitrite. The amount of sodium nitrate in the sodium acetate is preferably 0.1 to 0.25% by weight. It is determined by an ion chromatography method coupled with conductivity detection.

[0049] In yet another embodiment, the sodium nitrite provided herein is about 0.02 wt. In some embodiments, the nitrite composition provided herein contains no more than 1% sodium carbonate. The amount of sodium carbonate in sodium acid is determined by mixing the sample with acid to convert 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 or equal to 10% insoluble matter. The amount of insoluble matter in sodium is calculated by dissolving 10 grams of the sodium nitrite provided herein in 100 mL of sodium nitrite. in water, the solution was 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 nitrite composition provided herein contains no more than about 10% chloride ion. 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 ion. 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 up to about 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 spectrometry. 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 no more than 5% 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 used to determine the

[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 no more than about 10% 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 less. or less than about 100 ppm, less than about 500 ppm, less than about 1000 ppm, or less than 5000 ppm of ethanol In one embodiment, the content of organic volatile impurities is determined according to the United States Pharmacopeia XXXII (2009) method. This is determined by Law 467.

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

[0058] In yet another embodiment, the sodium nitrite provided herein is at about 2.5 ppm or less. 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 non-volatile organic carbon. Sodium nitrate 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 one embodiment, the composition contains about 5.6 ppm or less of total non-volatile organic carbon. The total non-volatile organic carbon in the sodium nitrite provided in the document is calculated by the method described herein. It is determined using

[0059] In yet another embodiment, the sodium nitrite provided herein has a concentration of 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 of the sodium nitrite provided herein is based on the United States Pharmacopeia XXXII (2009). It is determined by the method 261 of the above.

[0060] In yet another embodiment, the sodium nitrite provided herein is about 2 ppm or less. In yet another embodiment, the nitrite provided herein contains The sodium contains about 0.2 ppm or less of aluminum. The aluminum content in the sodium nitrite provided in the literature is determined using ICP-MS. In some embodiments, the aluminum content in the sodium nitrite provided herein is In some embodiments, the nitrite nanoparticles provided herein are 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 nitrite composition provided herein contains about 1 ppm or less of arsenic. The arsenic content in the sodium acetate 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 It is determined by method 211 of XXXII (2009).

[0062] In yet another embodiment, the sodium nitrite provided herein is at about 10 ppm (0. In one embodiment, the anti-caking agent is an aluminum alloy. In one embodiment, the compound provided herein is sodium naphthalene sulfonate. The amount of sodium alkyl-naphthalene sulfonate in the sodium nitrite used is determined according to the present specification. 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 wt. In some embodiments, the sodium nitrite provided herein contains no more than 50% selenium. 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 It is determined by method 291 of XXXII (2009).

[0064] In yet another embodiment, the microbial load in the sodium nitrite provided herein The total aerobic bacteria 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 cassava extract in the sodium nitrite provided herein is The total yeast and fungal count in the sodium nitrite provided herein is about 20 CFU / g or less. The number of bismuths 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 less than 1 g of endotoxin. The amount of is quantified by Method 85 of the United States Pharmacopeia XXXII (2009).

[0067] In yet another embodiment, the sodium nitrite provided herein has : About 97% by weight or more and / or about 101% by United States Pharmacopeia colorimetric assay (United States Pharmacopeia XXXII (2009)) % by weight or less of sodium nitrite; A positive confirmatory test for sodium; A positive confirmatory test for nitrite ion; 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 moisture 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 insoluble matter; containing not more than about 0.005% by weight chloride ions; Contains about 0.01% by weight or less of sulfate ions; Contains not more than about 0.001% by weight iron; Contains not more than about 0.01% by weight calcium; containing not more than about 0.005% by weight potassium; About 0.1% by weight or less of ethanol, or about 10 ppm or less, about 100 ppm or less, about 500 ppm or less, about 1000 ppm or less ppm or less, or contain 5000 ppm or less of ethanol; About 10 ppm or less, about 100 ppm or less, about 500 ppm or less, about 1000 ppm or less, or about 3000 ppm or less of methanoic acid Contains alcohol; Approx. 2.5ppm or less, approx. 5.6ppm or less, approx. 6ppm or less, approx. 7.9ppm or less, approx. 8ppm or less, approx. 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 about 0.003% (ICP-OES or equivalent) selenium; have a total aerobic count with a microbial load of approximately 100 CFU / g or less; Have a total yeast and mold count of approximately 20 CFU / g or less; Contains less than about 0.25 EU / mg of endotoxin; It is characterized by one or more of the following:

[0068] In one embodiment, provided herein is a method for treating a subject having the characteristics mentioned herein. Sodium nitrite having one or more of the following:

[0069] (Method of maintaining physiological levels of nitrite) Provided herein are methods for reducing the production of nitrite ions in subjects undergoing hemodialysis. 20. A method for maintaining physiological levels in a subject, comprising spiking the blood of said subject with nitrite ions. contacting the spiked dialysis fluid with a dialysis membrane that is also in contact with the spiked dialysis fluid during dialysis; When the undiluted dialysate flows from the dialysis machine to the dialysis membrane, the aqueous solution containing sodium nitrite The unspiked dialysis solution is added with water, concentrated acid, and A permeabilization solution containing a mixture of a concentrated solution of nitrite and a concentrated bicarbonate solution and spiked with the nitrite ion. The process wherein the deposition solution has a pH greater than about 7.0.

[0070] Also provided herein are methods for preventing and treating hemodialysis using nitrite ions. 20. A method for maintaining physiological levels of nitrite in a subject, comprising: contacting the spiked dialysate with the dialysis fluid during dialysis, When the aqueous solution containing sodium nitrite flows from the dialysis device to the dialysis membrane, the aqueous solution is spiked into the dialysis membrane. The unspiked dialysate is added to the unspiked dialysate, the unspiked dialysate being composed of water, concentrated acid solution, and bicarbonate. The dialysis solution containing the mixture of concentrated solutions of nitrite and nitrite ions has a nitrite concentration of more 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 mil. In another embodiment, the physiological concentration of nitrite in the subject is below chromolar concentration. The therapeutic level is from about 100 nanomolar to about 700 nanomolar. In the method, the physiological level of nitrite ion in the subject is about 200 nanomolar to about 5 In yet another embodiment, the concentration of nitrite in the subject is 0.100 nmol. 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. It is.

[0073] In one embodiment, the concentration of nitrite ions in the dialysis solution spiked with nitrite ions is In another embodiment, the concentration of the nitrite ion is about 1 micromolar or less. The concentration of nitrite ions in the spiked dialysis fluid is about 100 nanomolar to about 700 nanomolar. In yet another embodiment, the nitrite ion-spiked dialysis solution is The concentration of nitrate ions is about 200 nanomolar to about 500 nanomolar. In the above manner, the concentration of nitrite ions in the dialysis solution spiked with nitrite ions is about 25 In yet another embodiment, the nitrite is in a concentration of about 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, 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 aqueous solution containing sodium nitrite 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 dialysis fluid 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 undissolved 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 30 degrees.

[0077] In one embodiment, the aqueous solution containing sodium nitrite is introduced into the spa through the valve. The dialysis fluid that has not been pumped is infused at a rate of about 0 mL / hour to about 750 mL / hour or about 50 mL / hour to about 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. is added at a rate of

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

[0079] In yet another embodiment, the subject is a human with chronic renal failure. In the present invention, 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 include measuring plasma levels of nitrite in a subject. The objective of the present invention is to restore and / or maintain normal physiological levels of

[0082] (Preventive measures) (1. How to prevent myocardial infarction) In certain embodiments, provided herein is a method 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 untreated dialysate flows from the dialysis device to the dialysis membrane, the aqueous solution containing sodium nitrite is absorbed into the membrane. The unspiked dialysis fluid is added with water, concentrated acid solution, and a mixture of a bicarbonate concentrated solution and a dialysis solution spiked with said nitrite ions. has a pH greater than about 7.0.

[0083] In certain embodiments, further provided herein is a method 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 dialysis fluid with a dialysis solution spiked with dialysis fluid, the dialysis fluid being spiked with dialysis fluid, and the dialysis fluid being spiked with dialysis fluid. When the precipitate flows from the dialyzer to the dialysis membrane, the aqueous solution containing sodium nitrite is mixed with the spike. 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 process 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 include measuring plasma levels of nitrite in a subject. The objective of the present invention is to restore and / or maintain normal physiological levels of

[0086] (2. How to Prevent Sudden Cardiac Death) In certain embodiments, provided herein is a method for treating dialysis in a subject undergoing dialysis. A method for preventing sudden cardiac death comprising sparing the blood of a subject with nitrite ions. contacting the spike with a dialysis membrane that is also in contact with the dialysis fluid during dialysis; When untreated dialysate flows from the dialysis machine to the dialysis membrane, aqueous solutions containing sodium nitrite The unspiked dialysate is added 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 is a method for treating a patient undergoing hemodialysis. 2. A method for preventing sudden cardiac death in a subject suffering from cardiovascular disease comprising: The method includes contacting the patient with a dialysis fluid spiked with nitrate ions during dialysis, When the untreated dialysate flows from the dialysis device to the dialysis membrane, the aqueous solution containing sodium nitrite is absorbed into the membrane. The unspiked dialysis fluid is added with water, concentrated acid solution, and a mixture of a bicarbonate concentrated solution and a dialysis solution spiked with said nitrite ions. 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 include measuring plasma levels of nitrite in a subject. The objective of the present invention is to restore and / or maintain normal physiological levels of

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

[0091] In certain embodiments, further provided herein is a method for treating a patient undergoing hemodialysis. 2. A method for preventing stroke in a subject suffering from stroke comprising administering to said subject's blood a nitrite ion. contacting the dialysis fluid with a dialysis fluid spiked with nicotine during dialysis; As the fluid flows from the dialyzer to the dialysis membrane, the aqueous solution containing sodium nitrite is spiked into the dialysis membrane. The unspiked dialysate is added to the unspiked dialysate, the unspiked dialysate being composed of water, concentrated acid solution, and The dialysate containing a mixture of concentrated bicarbonate solutions 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 include measuring plasma levels of nitrite in a subject. The objective of the present invention is to restore and / or maintain normal physiological levels of

[0094] (4. How to prevent cardiovascular disease) In certain embodiments, provided herein is a method for treating dialysis in a subject undergoing dialysis. angina, cerebral vasospasm, claudication, critical limb ischemia, peripheral vascular disease, and sickle cell crisis. 2. A method for preventing cardiovascular disease characterized by tissue 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 unspiked dialysate is saturated with sodium nitrite. An aqueous solution containing thorium is added to the unspiked dialysis fluid and the spiked dialysis fluid is The dialysate contains a mixture of water, a concentrated acid solution, and a concentrated bicarbonate 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. In subjects, angina pectoris, cerebral vasospasm, claudication, critical limb ischemia, peripheral vascular disease, and sickle cell anemia A method for preventing cardiovascular disease characterized by tissue ischemia, including crises, comprising administering to said subject The method comprises contacting the elephant's blood with a dialysate spiked with nitrite ions during dialysis, When unspiked dialysate flows from the dialysis machine to the dialysis membrane, it contains sodium nitrite. An aqueous solution containing the dialysis solution is added to the unspiked dialysis solution, and the unspiked dialysis solution is The mixture includes a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, and is spiked with the nitrite ion. 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 include measuring plasma levels of nitrite in a subject. The objective of the present invention is to restore and / or maintain normal physiological levels of

[0098] (5. Methods for preventing hypertension, pulmonary hypertension, and renal hypertension) In certain embodiments, provided herein is a method for treating dialysis in a subject undergoing dialysis. A method for preventing hypertension, pulmonary hypertension, and renal hypertension comprising administering to the subject a The solution is contacted during dialysis with a dialysis membrane that is also in contact with a dialysate spiked with nitrite ions. and, when the unspiked dialysate flows from the dialysis device to the dialysis membrane, An aqueous solution containing sodium nitrate is added to the unspiked dialysis fluid, and the spiked dialysis fluid is The untreated dialysis fluid comprises a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, 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 dialysis solution spiked with nitrite ions during dialysis. When unspiked dialysate flows from the dialyzer to the dialysis membrane, sodium nitrite is released. An aqueous solution containing glycerol is added to the unspiked dialysis solution, and the unspiked dialysis solution is The precipitation solution comprises a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, and the nitrite ion is The method, wherein the spiked dialysate has a pH greater than about 7.0.

[0100] In one embodiment, the pulmonary hypertension is selected from the group consisting of neonatal pulmonary hypertension, primary pulmonary hypertension, and is secondary pulmonary hypertension.

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

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

[0103] In some embodiments, the embodiments of paragraphs

[0103] to

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

[0104] In one embodiment, the physiological level of nitrite in the subject is about 1 mil. In another embodiment, the physiological concentration of nitrite in the subject is below chromolar concentration. The therapeutic level is from about 100 nanomolar to about 700 nanomolar. In the method, the physiological level of nitrite ion in the subject is about 200 nanomolar to about 5 In yet another embodiment, the concentration of nitrite in the subject is 0.100 nmol. 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. It is.

[0105] In one embodiment, the concentration of nitrite ions in the dialysis solution spiked with nitrite ions is In another embodiment, the concentration of the nitrite ion is about 1 micromolar or less. The concentration of nitrite ions in the spiked dialysis fluid is about 100 nanomolar to about 700 nanomolar. In yet another embodiment, the nitrite ion-spiked dialysis solution is The concentration of nitrate ions is about 200 nanomolar to about 500 nanomolar. In the above manner, the concentration of nitrite ions in the dialysis solution spiked with nitrite ions is about 25 In yet another embodiment, the nitrite is in a concentration of about 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, 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 ion.

[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 aqueous solution containing sodium nitrite 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 dialysis fluid 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 undissolved 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 30 degrees.

[0109] In one embodiment, the aqueous solution containing sodium nitrite is introduced into the spa through the valve. The dialysis fluid that has not been pumped is infused at a rate of about 0 mL / hour to about 750 mL / hour or about 50 mL / hour to about 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. is added at a rate of

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

[0111] In yet another embodiment, the subject is a human with chronic renal failure. In the present invention, 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 with nitrite ions "before" the detection point (100 ) or after the detection point (110), reflected in the nitrate ion content measured in the sample taken, About 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.4%, or undergoes decomposition of less than about 0.1% nitrite ions.

[0114] (Method of Administration) In some embodiments, provided herein is a method for administering nitrite to a subject undergoing dialysis. A method for administering sodium to a subject 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 untreated dialysate flows from the dialysis machine to the dialysis membrane, the aqueous solution containing sodium nitrite is absorbed into the dialysis membrane. It is added to unspiked dialysis fluid, and the unspiked dialysis fluid contains water, acid concentrate, A dialysis solution containing a mixture of a concentrated bicarbonate solution and spiked with the nitrite ion. The method, wherein the liquid has a pH greater than about 7.0.

[0115] Further provided herein in certain embodiments is sodium nitrite. to a subject undergoing hemodialysis, the subject's blood being diluted with nitrite contacting the dialysate with ion-spiked dialysate during dialysis; When the dialysate flows from the dialysis machine to the dialysis membrane, the aqueous solution containing sodium nitrite enters the spirometer. The unspiked dialysate is added to the unspiked dialysate, which contains water, concentrated acid solution, and a bicarbonate concentrated solution, said dialysis solution spiked with nitrite ions comprising: The process has a pH greater than about 7.0.

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

[0117] (Combination therapy) In certain embodiments, the sodium nitrite provided herein is Combined 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 the use of 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. 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 not limited. or therapeutic agent) prior to administration (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, About 24 hours, about 48 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 about 12 weeks, about 6 weeks, about 8 weeks, or about 12 weeks before, or at the same time, or subsequently (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, About 24 hours, about 48 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 The triple therapy can also be administered after about 12 weeks, 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 compounds that have been or are currently used to treat, prevent, or manage a disease or disorder In combination with another therapy (e.g., a prophylactic or therapeutic agent) being used, the additive effect of that therapy is Combinations of therapies (e.g., combinations of prophylactic or therapeutic agents) The synergistic effect of the two therapeutic agents may allow the use of lower dosages of one or more of the therapies in a subject with a disorder. and / or less frequent administration of the therapy. 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 Finally, combinations of therapies (e.g., prophylaxis or The synergistic effects of combinations of therapeutic agents (or combinations of therapeutic agents) can reduce the harmful or In this way, unwanted side effects can 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 drug is administered either sequentially or sequentially. The dosage given will depend on the absorption, inactivation, and excretion rates of the drug, as well as The dosage value depends on the disease to be alleviated, the dosage amount, 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; thrombin inhibitors, such as hirudin; growth factor inhibitors, such as 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 gemocalin. Patrilat; HMG CoA reductase inhibitors, e.g., pravastatin, lovastatin, atorvastatin 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, For example, Questran; Niacin; Anti-atherosclerotic agents, for example, ACAT inhibitors; MTP inhibitors Calcium channel blockers, e.g., amlodipine besylate; Potassium channel activators activators; alpha-adrenergic agonists; beta-adrenergic agonists, e.g., carbetoclamide; Diarrhea drugs such as chlorothiazide, hydrochloride, 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; sidase inhibitors (e.g., acarbose), insulin, meglitinides (e.g., repaglitin nide), 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; phospho 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, proline antagonists, Phosphorus analogues, and pyrimidine analogues; antibiotics, such as anthracyclines, bleomycins, isin, mitomycin, dactinomycin, and plicamycin; enzymes, such as L-amycin, paraginase; farnesyl-protein transferase inhibitors; hormonal agents, e.g. For example, 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, e.g., pacitaxel, docetaxel, and epothilone AF; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and topoisomerase inhibitors; prenyl-protein transferases and cyclosporine; steroids, such as prednisone and dexamethasone. ;Cytotoxic drugs, e.g., 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, thiosulfates. sodium acetamide, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, low molecular weight drugs, low molecular weight vitamins, and platinum coordination complexes such as cisplatin, Another class of chemotherapeutic agents includes, but is not limited to, satraplatin, and carboplatin. The compound can be administered in combination with other compounds.

[0122] The sodium nitrite provided herein is capable of absorbing copper, fluoride ions, iodine, iron, manganese, and other ions. Naturally occurring minerals in human blood, including magnesium, phosphorus, selenium, thiosulfate, and zinc The compound may be administered in combination with other solutes present in the formulation.

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

[0124] (Example) As used herein, in these experiments, processes, schemes, and examples The symbols and terminology used are consistent with those of the present day, regardless of whether a particular abbreviation is specifically defined. Scientific literature, such as the Journal of the American Chemical Society or the Journal of The term is consistent with that used in Biological Chemistry. Although not required, the following abbreviations may be used in the examples and throughout the specification: : g (grams); mg (milligrams); mL (milliliters); μL (microliters); mM (millimolar concentration) ); μM (micromolar); nM (nanomolar); 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 testing procedures known to those skilled in the art. Purification methods are available. All temperatures are in degrees Celsius unless otherwise indicated. Unless otherwise noted, all reactions are carried out at room temperature. The methods described are intended to illustrate the applicable chemistry with specific examples and are not intended to be within the scope of the present invention. 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 ion, and in the preparation of dialysis fluid, concentrated acid solutions and concentrated bicarbonate solutions This illustrates the instability of the nitrite ion when mixed with a solution containing

[0127] The concentration of nitrite ions in the samples was assayed by ion chromatography. The chromatography equipment is equipped with an electric conductivity detector, a self-regenerating suppressor system, and an eluent generator. The nitrite ion concentration in the sample was measured using a 100% nitrite concentration analyzer and a Dionex IonPacAS19 analytical column. The concentration was measured and calculated against an external sodium nitrite standard. Sodium Nitrite, USP The 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. have shown that this 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 gas (NO, NO2, N2O3, and N2O4) was measured using a -46 type nitrogen oxide (NOx) electrode and a pH meter. With constant stirring, the mV readings at the NOx electrodes 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 (detection of 1 ppm NOx). When the pH of the sodium nitrite solution was decreased from 6.7 to 4.9, the nitrogen oxides were 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. It 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 concentrated solution was calculated as follows: 1) Addition of 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 concentration in dialysis bicarbonate concentrate) [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 dialysis machine produces a dialysate bicarbonate concentrate solution (sodium nitrite from Example 2 added). The dialysate was mixed with the dialysis equipment in an actual clinical setting. 1 part of the concentrated acid solution, 1.72 parts of the concentrated bicarbonate solution, and 42.38 parts of purified water, as described above. The dialysis machine used in this experiment was a Fresenius 2008K hemodialysis machine (Fr The device was then bypassed with saline. Priming was performed in the saturation mode (dialysis fluid rate and ultrafiltration rate were set to zero). After that, the hemodialysis machine was operated with 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 "therapy mode" with a flow 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 the nitrite ion in the concentrated bicarbonate solution of the dialysis fluid increases the acid concentration in the dialysis device. This indicates that the polymer was completely decomposed during mixing with the condensation solution. (Table 2: Nitrite ion concentration in the dialysis fluid 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 study was carried out to determine the stability of the nitrite ion when it is mixed with 1 part concentrated acid solution, 1.72 Using a dilution ratio of 42.38 parts purified water, 38.22 mL of bicarbonate concentrate solution was prepared. solution and 22.22 mL of the acid concentrate solution to 938.56 mL of purified water. One liter of dialysis solution was prepared using 1 mL of 3 mg / mL DMSO. 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. Sodium nitrite 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 concentration in premixed dialysis fluid in the laboratory [Table 3]

[0135] Example 5 Example 5 shows a dialysis solution prepared using a Fresenius 2008K hemodialysis machine (Fresenius Medical Care, Waltham The nitrite concentration is reduced when sodium nitrite is added to the dialysis solution after preparation in a dialysis tank (MA). The dialysate bicarbonate concentrate was prepared using Centrisol (registered trademark) as a dialysis drug. 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 is operated to mix 1 part of the bicarbonate concentrate solution and 1.7 parts of the acid concentrate solution. A dilution ratio of 2 parts bicarbonate concentrated solution and 42.38 parts purified water was mixed. Prime with water in bypass mode (dialysis fluid 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. The resulting sodium nitrite solution contained approximately 2 mg / L of anion nitrite. Since the sodium nitrite solution had a high nitrate concentration, the nitrate ions (and nitrite) of AAMI were The sodium nitrite solution met the quality specifications for sodium nitrite (NaCl) infusion. A fluid pump (Model 8100, CareFusion, San Diego, CA) was used to pump the blood through a valve (Fresensius Dialysate The dialysate piping between the hemodialysis machine and the dialyzer through the Sample Valve (part number 650993) The valve was placed approximately 8 inches (20.3 cm) below the dialyzer (prefilter) in the dialysate tubing. The two sample ports were placed 4 inches (10.2 cm) upstream from the dialyzer (pre-dialyzer sample port). The ion chromatograph was placed at the sample collection port (after the dialysis machine) and 10 inches (25.4 cm) downstream (after the dialysis machine). Dialysate samples were taken for nitrate assay by chromatographic analysis.

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

[0139] Saline flows from the arterial line through the dialyzer at a rate of 300 mL / min and through the venous line. Saline samples were 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. This 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 dialysis fluid 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 the untreated dialysate, the nitrite ions will This indicates that you can either move through or move along it.

[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 disclosure and description to one of ordinary skill in the art, and is not intended to be limiting unless otherwise specified. The present invention is not intended to limit the scope of the present invention. Modifications obvious to one of ordinary skill in the art may be included within the scope of the following claims. All publications, patents, and related documents 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 in its entirety. Each of the above-referenced articles is incorporated herein by reference, as if each was individually and individually indicated to be incorporated by reference. and is hereby incorporated 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, further comprising contacting the subject's blood with a dialysate spiked with nitrite ions. and contacting the unspiked dialysate with a dialysis membrane during dialysis, When flowing through the dialysis membrane, the aqueous solution containing sodium nitrite is mixed with the unspiked dialysis fluid. , the unspiked dialysate being a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution. and the nitrite ion spiked dialysate has a pH greater than about 7.0. , the method. (Aspect 2) the physiological level of nitrite in the subject is 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 the nitrite in the subject is about 300 nanomolar. 2. The method of embodiment 1. (Aspect 5) The concentration of nitrite ions in the dialysis solution spiked with nitrite ions is about 1 micromolar. The method of embodiment 1, wherein the concentration of the (Aspect 6) The concentration of nitrite in the nitrite-spiked dialysate is about 200 nanomolar. The method of embodiment 1, wherein the concentration is 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) 1. 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 dialysis fluid piping is connected to the dialyzer via a valve attached to the piping at a position before the piping is connected to the dialyzer. 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 pumped 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) The unspiked dialysate flows through the dialysis tubing at a rate of about 600 mL / min. The method described in 10. (Aspect 13) The aqueous solution containing sodium nitrite is passed through the valve to the unspiked dialysis solution. The method of embodiment 10, wherein the aqueous solution is added to the liquid at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 14) The aqueous solution containing sodium nitrite is passed through the valve to the unspiked dialysis solution. The method of embodiment 10, wherein the solution is added at a rate of about 250 mL per hour. (Aspect 15) 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) A method for preventing myocardial infarction in a subject undergoing dialysis, comprising administering to said subject blood The solution is contacted during dialysis with a dialysis membrane that is also in contact with a dialysate spiked with nitrite ions. and, when the unspiked dialysate flows from the dialysis device to the dialysis membrane, An aqueous solution containing sodium nitrate is added to the unspiked dialysis fluid, and the spiked dialysis fluid is The untreated dialysis fluid comprises a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, The method, wherein the dialysate spiked with nitrate ions has a pH greater than about 7.0. (Aspect 21) the physiological level of nitrite in the subject is 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 the nitrite in the subject is about 300 nanomolar. 21. The method of embodiment 20. (Aspect 24) The concentration of nitrite ions in the dialysis solution spiked with nitrite ions is about 1 micromolar. 21. The method of embodiment 20, wherein the concentration of the (Aspect 25) The concentration of nitrite in the nitrite-spiked dialysate is about 200 nanomolar. The method of embodiment 20, wherein the concentration is about 500 nanomolar. (Aspect 26) The concentration of nitrite in the nitrite-spiked dialysate is about 300 nanomolar. 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 dialysis fluid piping is connected to the dialyzer via a valve attached to the piping at a position before the piping is connected to the dialyzer. The aqueous solution containing sodium nitrite is added to the unspiked dialysis solution. The method described in Example 20. (Aspect 30) The unspiked dialysis fluid is pumped 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 about 600 mL per minute. 30. The method of embodiment 29. (Aspect 32) The aqueous solution containing sodium nitrite is passed through the valve to the unspiked dialysis solution. The method of embodiment 29, wherein the aqueous solution is added to the liquid at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 33) The aqueous solution containing sodium nitrite is passed through the valve to the unspiked dialysis solution. 30. The method of embodiment 29, wherein the solution is added to the solution at a rate of about 250 mL per hour. (Aspect 34) The method according to claim 20, wherein the pH of the dialysis solution 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) The method of embodiment 20, wherein the subject is a human with chronic renal failure. (Aspect 37) The method of embodiment 20, wherein the subject is a human with acute renal failure. (Aspect 38) 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 The elephant's blood was placed in contact with a dialysis membrane during dialysis, which was also in contact with a dialysate spiked with nitrite ions. When the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, Then, an aqueous solution containing sodium nitrite is added to the unspiked dialysis fluid, and the spa The uninjected dialysis fluid 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. (Aspect 40) the physiological level of nitrite in the subject is 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. The method of embodiment 39, wherein the concentration is nanomolar. (Aspect 42) The physiological level of the nitrite in the subject is about 300 nanomolar. 40. The method of embodiment 39. (Aspect 43) The concentration of nitrite ions in the dialysis solution spiked with nitrite ions is about 1 micromolar. The method of embodiment 39, wherein the concentration of the (Aspect 44) The concentration of nitrite in the nitrite-spiked dialysate is about 200 nanomolar. The method of embodiment 39, wherein the concentration is about 500 nanomolar. (Aspect 45) The concentration of nitrite in the nitrite-spiked dialysate is about 300 nanomolar. 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 (Aspect 47) 40. The method of embodiment 39, wherein the water contains about 2 mg / L or less of nitrite ions. (Aspect 48) The dialysis fluid piping is connected to the dialyzer via a valve attached to the piping at a position before the piping is connected to the dialyzer. 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 pumped through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min. The method of embodiment 48, wherein the (Aspect 50) The unspiked dialysate flows through the dialysis tubing at a rate of about 600 mL per minute. 49. The method of embodiment 48. (Aspect 51) The aqueous solution containing sodium nitrite is passed through the valve to the unspiked dialysis solution. The method of embodiment 48, wherein the aqueous solution is added to the liquid at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 52) The aqueous solution containing sodium nitrite is passed through the valve to the unspiked dialysis solution. The method of embodiment 48, wherein the solution is added at a rate of about 250 mL per hour. (Aspect 53) 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) The method of embodiment 39, wherein the subject is a human with chronic renal failure. (Aspect 56) 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 is contacted during dialysis with a dialysis membrane that is also in contact with a dialysate spiked with nitrite ions. and when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the nitrite is removed. An aqueous solution containing sodium chloride is added to the unspiked dialysis fluid, and the spiked dialysis fluid is The untreated dialysis fluid comprises a mixture of water, a concentrated acid solution, and a concentrated bicarbonate solution, and the nitrite is The method, wherein the dialysate spiked with acid ions has a pH greater than about 7.0. (Aspect 59) the physiological level of nitrite in the subject is 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. The method of embodiment 58, wherein the concentration is nanomolar. (Aspect 61) The physiological level of the nitrite in the subject is about 300 nanomolar. 59. The method of embodiment 58. (Aspect 62) The concentration of nitrite ions in the dialysis solution spiked with nitrite ions is about 1 micromolar. 59. The method of embodiment 58, wherein the concentration of (Aspect 63) The concentration of nitrite in the nitrite-spiked dialysate is about 200 nanomolar. The method of embodiment 58, wherein the concentration is about 500 nanomolar. (Aspect 64) The concentration of nitrite in the nitrite-spiked dialysate is about 300 nanomolar. 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 according to claim 8. (Aspect 66) 60. The method of embodiment 58, wherein the water contains about 2 mg / L or less of nitrite ions. (Aspect 67) The dialysis fluid piping is connected to the dialyzer via a valve attached to the piping at a position before the piping is connected to the dialyzer. 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 pumped 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 about 600 mL per minute. 68. The method of embodiment 67. (Aspect 70) The aqueous solution containing sodium nitrite is passed through the valve to the unspiked dialysis solution. The method of embodiment 67, wherein the solution is added to the liquid at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 71) The aqueous solution containing sodium nitrite is passed through the valve to the unspiked dialysis solution. 70. The method of embodiment 67, wherein the solution is added to the solution at a rate of about 250 mL per hour. (Aspect 72) 59. The method according to claim 58, wherein the pH of the dialysis solution spiked with nitrite ions is about 7.3 to about 7.5. method. (Aspect 73) 59. The method of embodiment 58, wherein the pH of the nitrite ion spiked dialysate is about 7.4. (Aspect 74) The method of embodiment 58, wherein the subject is a human with chronic renal failure. (Aspect 75) The method of embodiment 58, wherein the subject is a human with acute renal failure. (Aspect 76) 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 for preventing cardiovascular disease characterized by tissue ischemia, including sickle cell crisis. The method also comprises contacting the subject's blood with a dialysate spiked with nitrite ions. contacting the unspiked dialysate with a dialysis membrane during dialysis; When flowing through the dialysis membrane, the aqueous solution containing sodium nitrite is mixed with the unspiked dialysis fluid. , the unspiked dialysate being a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution. and the nitrite ion spiked dialysate has a pH greater than about 7.0. , the method. (Aspect 78) the physiological level of nitrite in the subject is 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. The method of embodiment 77, wherein the concentration is nanomolar. (Aspect 80) The physiological level of the nitrite in the subject is about 300 nanomolar. 78. The method of embodiment 77. (Aspect 81) The concentration of nitrite ions in the dialysis solution spiked with nitrite ions is about 1 micromolar. 78. The method of embodiment 77, wherein the concentration of (Aspect 82) The concentration of nitrite in the nitrite-spiked dialysate is about 200 nanomolar. The method of embodiment 77, wherein the concentration is about 500 nanomolar. (Aspect 83) The concentration of nitrite in the nitrite-spiked dialysate is about 300 nanomolar. The method of embodiment 77, wherein the concentration is (Aspect 84) Aspect 7, wherein the aqueous solution containing sodium nitrite contains 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 dialysis fluid piping is connected to the dialyzer via a valve attached to the piping at a position before the piping is connected to the dialyzer. 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 pumped 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 about 600 mL per minute. 87. The method of embodiment 86. (Aspect 89) The aqueous solution containing sodium nitrite is passed through the valve to the unspiked dialysis solution. The method of embodiment 86, wherein the aqueous solution is added to the liquid at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 90) The aqueous solution containing sodium nitrite is passed through the valve to the unspiked dialysis solution. The method of embodiment 86, wherein the solution is added to the solution at a rate of about 250 mL per hour. (Aspect 91) 78. The method according to claim 77, wherein the pH of the dialysate spiked with nitrite ions is about 7.3 to about 7.5. method. (Aspect 92) 78. The method of embodiment 77, wherein the pH of the nitrite ion spiked dialysate is about 7.4. (Aspect 93) The method of embodiment 77, wherein the subject is a human with chronic renal failure. (Aspect 94) The method of embodiment 77, wherein the subject is a human with acute renal failure. (Aspect 95) 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 during dialysis, the unspiked dialysate being 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 and nitrite ions has a pH greater than about 7.0. The method comprising: (Aspect 97) the physiological level of nitrite in the subject is 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 the nitrite in the subject is about 300 nanomolar. 97. The method of embodiment 96. (Aspect 100) The concentration of nitrite ions in the dialysis solution spiked with nitrite ions is about 1 micromolar. 97. The method of embodiment 96, wherein the concentration of the (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 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) 9. The aqueous solution comprising sodium nitrite comprises about 3 mg / L or less of sodium nitrite. 6. The method according to claim 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 dialysis fluid piping is connected to the dialyzer via a valve attached to the piping at a position before the piping is connected to the dialyzer. 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 pumped through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min. The method of embodiment 105, wherein the (Aspect 107) The unspiked dialysate flows through the dialysis tubing at a rate of about 600 mL per minute. The method of embodiment 105. (Aspect 108) The aqueous solution containing sodium nitrite is passed through the valve to the unspiked dialysis solution. The method of embodiment 105, wherein the aqueous solution is added to the liquid at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 109) The aqueous solution containing sodium nitrite is passed through the valve to the unspiked dialysis solution. The method of embodiment 105, wherein the solution is added to the solution at a rate of about 250 mL per hour. (Aspect 110) 97. The method according to claim 96, wherein the pH of the dialysis solution spiked with nitrite ions is about 7.3 to about 7.5. method. (Aspect 111) 97. The method of embodiment 96, wherein the pH of the nitrite ion 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) The method of embodiment 96, wherein the subject undergoes dialysis 3 to 7 times per week.

Claims

1. To maintain physiological levels of nitrite in subjects undergoing hemodialysis ION-SPIKED MEDICINES CONTAINING SODIUM NITRITE FOR USE IN THE METHOD OF METHODS - Patent application a dialysis solution for said subject's blood, comprising: and contacting the nitrite ions with a dialysis membrane that is also in contact with the dialysis fluid during dialysis, and The medicinal dialysis solution spiked with nitrite ions has a pH greater than about 7.0 and The medicinal dialysis solution contains copper, fluoride ions, iodine, iron, manganese, magnesium, phosphorus, and selenium. , thiosulfate, and zinc.

2. A medicinal dialysis solution spiked with said nitrite ions.

2. For use in a method for preventing myocardial infarction in a subject undergoing hemodialysis. A medicinal dialysis solution spiked with nitrite ions, comprising sodium nitrite for the treatment of nitrite ions, but also contacting the subject's blood with a medicated dialysate spiked with the nitrite ions. contacting the nitrite ion spiked medicinal dialysate with a membrane during dialysis, and a pH of greater than about 7.0, and the nitrite-spiked medicinal dialysate is iron, manganese, magnesium, phosphorus, selenium, thiosulfate, and The nitrite ion is for use in combination with one or more of the following: Piked medicinal dialysis fluid.

3. Use in a method for preventing sudden cardiac death in a subject undergoing hemodialysis.

1. A nitrite ion spiked medical dialysis solution comprising sodium nitrite for use in a patient with dialysis, comprising: The method also includes contacting the subject's blood with a medicated dialysate spiked with the nitrite ions. and contacting said nitrite ion spiked pharmaceutical permeation membrane with said nitrite ion spiked pharmaceutical permeation membrane during dialysis. The dialysate has a pH greater than about 7.0, and the nitrite ion spiked medicinal dialysate contains copper, Fluoride ion, iodine, iron, manganese, magnesium, phosphorus, selenium, thiosulfate ion and zinc. Medicated dialysate spiked with nicotine.

4. For use in a method for preventing stroke in a subject undergoing hemodialysis nitrite ion spiked medicinal dialysis solution comprising sodium nitrite of a dialysis membrane in contact with the subject's blood, the dialysis solution also being spiked with the nitrite ions. and contacting the nitrite ion spiked medicinal dialysate during dialysis with The medicinal dialysate having a pH greater than about 7.0 and spiked with the nitrite ion is Ions, iodine, iron, manganese, magnesium, phosphorus, selenium, thiosulfate, and The nitrite ion is for use in combination with one or more of the following: The medicinal dialysis fluid was extracted.

5. Angina pectoris, cerebral vasospasm, claudication, critical limb ischemia, peripheral blood in subjects undergoing hemodialysis To prevent cardiovascular disease characterized by tissue ischemia, including vascular disease and sickle cell crisis. Nitrite-spiked pharmaceutical preparations, including sodium nitrite, for use in methods for a pharmaceutical dialysis solution, the method comprising: The method includes contacting the nitrite ion with a dialysis membrane that is also in contact with the dialysis solution during dialysis, and The spiked medicinal dialysis solution has a pH greater than about 7.0 and is spiked with the nitrite ion. The medical dialysis solution contains copper, fluoride ions, iodine, iron, manganese, magnesium, phosphorus, selenium, for use in combination with one or more of the following: thiosulfate, thiosulfate, and zinc. The medicinal dialysis solution spiked with nitrite ions.

6. Preventing hypertension, pulmonary hypertension, and renal hypertension in subjects undergoing hemodialysis 20060236330 20060235112 ... Method for preparing a nitrite spiked nitrite ion containing sodium nitrite and a dialysis solution spiked with nitrite ions, the method comprising: contacting said nitrite ions with a dialysis membrane which is also in contact with a medicinal dialysis solution during dialysis; The medicinal dialysate spiked with nitrite ions has a pH greater than about 7.0 and is The medical dialysis solution contains copper, fluoride ions, iodine, iron, manganese, magnesium, phosphorus, , selenium, thiosulfate, and zinc. The medicinal dialysis solution spiked with nitrite ions.

7. the physiological level of nitrite in the subject is about 1 micromolar or less; The pharmaceutical dialysis solution spiked with nitrite ions according to any one of claims 1 to 6, wherein

8. The physiological level of the nitrite ion in the subject is between about 200 nanomolar and about 500 nanomolar. The pharmaceutical composition according to any one of claims 1 to 6, which is spiked with nitrite ions at nanomolar concentrations. Medicated dialysis solution.

9. The physiological level of the nitrite in the subject is about 300 nanomolar. A pharmaceutical dialysis solution spiked with nitrite ions according to any one of claims 1 to 6.

10. The concentration of nitrite ions in the medicinal dialysis solution spiked with nitrite ions is about 1 microliter. The nitrite ion spiked solution according to any one of claims 1 to 9, which is sub-micromolar. Medicinal dialysis fluid.

11. The concentration of nitrite ions in the medicinal dialysis solution spiked with nitrite ions is about 200 nanometers. The nitrite ion according to any one of claims 1 to 9 is used in a concentration of from 100 to about 500 nanomolar. Piked medicinal dialysis fluid.

12. The concentration of nitrite ions in the medicinal dialysis solution spiked with nitrite ions is about 300 nanometers. The nitrite ion spiked pharmaceutical permeation agent according to any one of claims 1 to 9, which is in a molar concentration. Precipitation liquid.

13. 1. The method of claim 1, wherein the pH of the nitrite ion spiked medicinal dialysate is about 7.3 to about 7.

5.

13. A medicinal dialysis solution spiked with nitrite ions according to any one of claims 1 to 12.

14. The method according to any one of claims 1 to 12, wherein the pH of the medicinal dialysis solution spiked with nitrite ions is about 7.

4. A medicinal dialysis solution spiked with nitrite ions according to any one of claims 1 to 4.

15. The nitrite ion according to any one of claims 1 to 14, wherein the subject is a human suffering from chronic renal failure. Medicated dialysate spiked with

16. The nitrite ion according to any one of claims 1 to 14, wherein the subject is a human suffering from acute renal failure. Medicated dialysate spiked with

17. The nitrous acid solution according to any one of claims 1 to 16, wherein the subject undergoes dialysis 3 to 7 times per week. Medicinal dialysate spiked with acid ions.

18. The nitrite ion spiked medicinal dialysate is for use in combination with copper. The pharmaceutical dialysis solution spiked with nitrite ions according to any one of claims 1 to 17.

19. The nitrite ion spiked medicinal dialysate is used in combination with fluoride ion. The nitrite ion spiked composition according to any one of claims 1 to 17 is intended to Medicinal dialysis fluid.

20. The nitrite ion spiked medicinal dialysate is for use in combination with iodine. The pharmaceutical dialysis solution spiked with nitrite ions according to any one of claims 1 to 17, liquid.

21. The nitrite ion spiked medicinal dialysate is for use in combination with iron. The pharmaceutical dialysis solution spiked with nitrite ions according to any one of claims 1 to 17.

22. The nitrite spiked medicinal dialysate is for use in combination with manganese. The nitrite ion spiked pharmaceutical permeation composition according to any one of claims 1 to 17 is for use in a pharmaceutical composition for treating inflammatory bowel disease. Precipitation liquid.

23. The nitrite spiked medicinal dialysate is used in combination with magnesium. The pharmaceutical composition spiked with nitrite ions according to any one of claims 1 to 17, Medicated dialysis solution.

24. The nitrite ion spiked medicinal dialysis solution is for use in combination with phosphorus The pharmaceutical dialysis solution spiked with nitrite ions according to any one of claims 1 to 17. .

25. The nitrite ion spiked medicinal dialysate is for use in combination with selenium. The pharmaceutical dialysis solution spiked with nitrite ions according to any one of claims 1 to 17, liquid.

26. The nitrite ion spiked medicinal dialysis solution is used in combination with thiosulfate ion. The nitrite ion spiked composition according to any one of claims 1 to 17 is intended to Medicinal dialysis fluid.

27. The nitrite ion spiked medicinal dialysis solution is for use in combination with zinc. The pharmaceutical dialysis solution spiked with nitrite ions according to any one of claims 1 to 17. .

Images