Intradialytic use of sodium thiosulfate

Abstract

To provide: a pharmaceutical dialysate for maintaining physiological levels of thiosulfate ions in a subject undergoing hemodialysis; and a method of producing the pharmaceutical dialysis solution.SOLUTION: A thiosulfate ion-spiked pharmaceutical dialysate comprises sodium thiosulfate, water, an acid concentrate solution, and a bicarbonate concentrate solution, wherein the thiosulfate ion-spiked pharmaceutical dialysate has a pH greater than about 7.0, wherein a concentration of thiosulfate ions in the thiosulfate ion-spiked pharmaceutical dialysate is 100 micromolar or less, and wherein the thiosulfate ion-spiked pharmaceutical dialysate is used to be administered to the subject together with one or more of copper, fluoride ions, iodine, iron, manganese, magnesium, nitrite ions, phosphorus, selenium, and zinc.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] (Cross-reference) This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 468,871, filed on Mar. 8, 2017, the content of which is incorporated herein by reference in its entirety. What is provided herein is a method for maintaining physiological levels of thiosulfate ions in a subject undergoing hemodialysis. Also provided herein is a method for administering sodium thiosulfate, which is pharmaceutically acceptable, to a subject undergoing hemodialysis.

[0002] What is provided herein is a method for maintaining physiological levels of thiosulfate ions in a subject undergoing hemodialysis. Also provided herein is a method for administering sodium thiosulfate, which is pharmaceutically acceptable, to a subject undergoing hemodialysis. What is provided herein is a method for maintaining physiological levels of thiosulfate ions in a subject undergoing hemodialysis. Also provided herein is a method for administering sodium thiosulfate, which is pharmaceutically acceptable, to a subject undergoing hemodialysis. What is provided herein is a method for maintaining physiological levels of thiosulfate ions in a subject undergoing hemodialysis. Also provided herein is a method for administering sodium thiosulfate, which is pharmaceutically acceptable, to a subject undergoing hemodialysis. is.

Background Art

[0003] (Background) Patients with chronic kidney disease (CKD) suffer from deterioration of renal function, which results in a reduction in the excretion of metabolic waste products. The accumulation of metabolic waste products may also become life-threatening within a few days. Patients with little or no remaining renal function are considered to have "end-stage renal disease". Therefore, such patients need alternative means of excreting waste products in order to survive. Dialysis is a means of excreting waste products that involves the transfer of waste products from the blood to an external fluid that will later be discarded (Am. J. Kidney Dis. 2002, 39 (Suppl. 1), S1-266). Patients with chronic kidney disease (CKD) suffer from deterioration of renal function, which results in a reduction in the excretion of metabolic waste products. The accumulation of metabolic waste products may also become life-threatening within a few days. Patients with little or no remaining renal function are considered to have "end-stage renal disease". Therefore, such patients need alternative means of excreting waste products in order to survive. Dialysis is a means of excreting waste products that involves the transfer of waste products from the blood to an external fluid that will later be discarded (Am. J. Kidney Dis. 2002, 39 (Suppl. 1), S1-266). Patients with chronic kidney disease (CKD) suffer from deterioration of renal function, which results in a reduction in the excretion of metabolic waste products. The accumulation of metabolic waste products may also become life-threatening within a few days. Patients with little or no remaining renal function are considered to have "end-stage renal disease". Therefore, such patients need alternative means of excreting waste products in order to survive. Dialysis is a means of excreting waste products that involves the transfer of waste products from the blood to an external fluid that will later be discarded (Am. J. Kidney Dis. 2002, 39 (Suppl. 1), S1-266). Patients with chronic kidney disease (CKD) suffer from deterioration of renal function, which results in a reduction in the excretion of metabolic waste products. The accumulation of metabolic waste products may also become life-threatening within a few days. Patients with little or no remaining renal function are considered to have "end-stage renal disease". Therefore, such patients need alternative means of excreting waste products in order to survive. Dialysis is a means of excreting waste products that involves the transfer of waste products from the blood to an external fluid that will later be discarded (Am. J. Kidney Dis. 2002, 39 (Suppl. 1), S1-266). Patients with chronic kidney disease (CKD) suffer from deterioration of renal function, which results in a reduction in the excretion of metabolic waste products. The accumulation of metabolic waste products may also become life-threatening within a few days. Patients with little or no remaining renal function are considered to have "end-stage renal disease". Therefore, such patients need alternative means of excreting waste products in order to survive. Dialysis is a means of excreting waste products that involves the transfer of waste products from the blood to an external fluid that will later be discarded (Am. J. Kidney Dis. 2002, 39 (Suppl. 1), S1-266). Patients with chronic kidney disease (CKD) suffer from deterioration of renal function, which results in a reduction in the excretion of metabolic waste products. The accumulation of metabolic waste products may also become life-threatening within a few days. Patients with little or no remaining renal function are considered to have "end-stage renal disease". Therefore, such patients need alternative means of excreting waste products in order to survive. Dialysis is a means of excreting waste products that involves the transfer of waste products from the blood to an external fluid that will later be discarded (Am. J. Kidney Dis. 2002, 39 (Suppl. 1), S1-266).

[0004] Dialysis is defined as the movement of solutes and water between two liquids separated by a semipermeable "dialysis membrane". In hemodialysis, blood flows on one side of the dialysis membrane and a water-based solution called dialysate flows on the opposite side. The dialysis membrane contains pores through which solutes can pass. These two Dialysis is defined as the movement of solutes and water between two liquids separated by a semipermeable "dialysis membrane". In hemodialysis, blood flows on one side of the dialysis membrane and a water-based solution called dialysate flows on the opposite side. The dialysis membrane contains pores through which solutes can pass. These two Dialysis is defined as the movement of solutes and water between two liquids separated by a semipermeable "dialysis membrane". In hemodialysis, blood flows on one side of the dialysis membrane and a water-based solution called dialysate flows on the opposite side. The dialysis membrane contains pores through which solutes can pass. These two The concentration of a solute present in two liquids is equalized due to the osmotic force that forces the solute out of the high-concentration liquid and through the pores of the dialysis membrane into the low-concentration liquid.

[0005] Dialysis membranes are designed with various pore sizes to limit the solutes that can pass through during hemodialysis. An excessive amount of small-molecule solutes that can diffuse through the dialysis membrane during hemodialysis may be harmful to remove from the blood.

[0006] Blood contains low-molecular-weight solutes such as thiosulfate ions (S 2 O 3 2- ). Thiosulfate anions have a molecular weight of approximately 112.13 daltons. In the body, thiosulfate ions convert a small amount of cyanide ions into harmless products. Thiosulfate ions may also be metabolized to sulfate ions (SO 4 2- ). (References: Gunnison et al., Environ. Res. 1981, 24, 432 - 443; Skarzynski et al., Nature 1959, 184, 994 - 995).

[0007] The Association for the Advancement of Medical Instrumentation (AAMI) has established quality specification limits for the sulfate ion content in water used for dialysis (maximum 100 mg per liter, i.e., 100 ppm) (#ANSI / AAMI / ISO 13959:2009). Also, AAMI has specified that the sulfate ion content in water should be measured using the "turbidimetric method." In this method, sulfate ions form barium sulfate crystals of uniform size with acetic acid. It is precipitated in the medium using barium chloride. The absorbance of the barium sulfate suspension is measured by a photometer and the sulfate anion concentration is determined by comparison of the reading with a standard curve (available online at American Public Health Association, https: / / law.resource.org / pub / us / cfr / ibr / 002 / apha.meth od.4500-so42.1992.pdf). In this test method, sulfate ions and thiosulfate ions are not distinguished. Instead, the test method actually measures both sulfate ions and thiosulfate ions. Therefore, the AAMI quality specification for sulfate ions is actually the limit of the sum of sulfate ions and thiosulfate ions in the water used for dialysis.

[0008] Coronary artery bypass patients have reduced plasma thiosulfate ion levels (Ivankovich et al., Anesthesiology 1983, 58, 11-17). Coronary artery bypass surgery is often recommended for patients with cardiovascular diseases characterized by significant narrowing and blockage of the heart arteries caused by atherosclerotic disease. Atherosclerotic disease is a chronic inflammatory condition that begins with the formation of calcified plaques inside the walls of large and medium-sized arteries. Calcium mineralization of the lumen within atherosclerotic arteries promotes plaque formation and makes it firm, causing narrowing of the blood vessels (Kalampogias et al., Med. Chem. 2016, 12, 103-113). Atherosclerotic plaques can cause significant narrowing in one or more coronary arteries. When blood flow within the coronary artery is completely blocked by an atherosclerotic plaque, a myocardial infarction occurs.

[0009] Cardiovascular diseases account for more than half of all deaths in patients requiring chronic hemodialysis (G o et al., N. Eng. J. Med. 2004, 351, 1296 - 1305).

[0010] During the 12 - hour period starting from dialysis treatment, the risk of sudden - death events increased by 1.7 - fold Sudden - death events increased both during and after the dialysis procedure itself (Bleyer et al. , Kidney Int. 2006, 12, 2268 - 2273).

[0011] At the same time, the plasma concentration of thiosulfate ions decreased by more than 60% in the first hour of hemodialysis and remained significantly decreased during the subsequent hours of the 4 - hour hemodialysis session (Freise et al., F ree Radic. Biol. Med. 2013, 58, 46 - 51).

[0012] Sodium thiosulfate can be administered into the blood by intravenous injection; however, it would not be effective in maintaining physiological levels in dialysis patients. This is because sodium thiosulfate is rapidly removed during hemodialysis. At present, there is no effective method to maintain the physiological level of thiosulfate ions in the blood of patients undergoing hemodialysis. Also, there is no satisfactory method to administer sodium thiosulfate to patients during hemodialysis.

Summary of the Invention

[0013] (Summary) The present disclosure provides a method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis. Also, the present disclosure provides a method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis. Also, the present disclosure provides a method for To provide a method for preventing atherosclerosis, myocardial infarction, sudden cardiac death, stroke, cardiovascular diseases, hypertension, pulmonary hypertension, and / or renal hypertension. Further, the present disclosure provides a method for administering sodium thiosulfate in a subject undergoing hemodialysis.

[0014] In one embodiment, what is provided herein is a method for maintaining a physiological level of thiosulfate ions in a subject undergoing hemodialysis, the method comprising contacting the subject's blood with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid comprising a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0.

[0015] Also, in one embodiment, what is provided herein is a method for maintaining a physiological level of thiosulfate ions in a subject undergoing hemodialysis, the method comprising contacting the subject's blood with a dialysis fluid spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid comprising a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0.

[0016] Also, in certain embodiments, what is provided herein is for a subject undergoing dialysis a method for preventing atherosclerosis in which the blood of the subject is contacted during dialysis with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions, including adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid containing a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0, said method. Also, in certain embodiments, what is provided herein is for a subject undergoing dialysis a method for preventing myocardial infarction in which the blood of the subject is contacted during dialysis with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions, including adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid containing a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0, said method. Also, in certain embodiments, what is provided herein is for a subject undergoing dialysis

[0017] a method for preventing sudden cardiac death in which the blood of the subject is contacted during dialysis with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions, including adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid containing a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0, said method. ions, including adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid containing a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0, said method. ions, including adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid containing a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0, said method. ions, including adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid containing a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0, said method. ions, including adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid containing a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0, said method. ions, including adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid containing a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0, said method.

[0018] Also, in certain embodiments, what is provided herein is for a subject undergoing dialysis a method for preventing sudden cardiac death in which the blood of the subject is contacted during dialysis with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions, including adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid containing a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0, said method. ions, including adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid containing a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0, said method. An aqueous solution containing is added to the non-spiked dialysate, and the non-spiked dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ion has a pH greater than about 7.0, said method.

[0019] Also, in certain embodiments, provided herein is a method for preventing stroke in a subject undergoing dialysis, comprising contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein when the non-spiked dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate, the non-spiked dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ion has a pH greater than about 7.0, said method. is contacted during dialysis, and the non-spiked dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate, the non-spiked dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ion has a pH greater than about 7.0, said method. contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ion has a pH greater than about 7.0, said method.

[0020] Also, in certain embodiments, provided herein is a method for preventing cardiovascular diseases characterized by tissue ischemia including angina pectoris, cerebral vasospasm, claudication, severe ischemic limb, peripheral vascular disease, and sickle cell crisis in a subject undergoing dialysis, comprising contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein when the non-spiked dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate, the non-spiked dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ion has a pH greater than about 7.0, said method. is contacted during dialysis, and the non-spiked dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate, the non-spiked dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ion has a pH greater than about 7.0, said method. contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ion has a pH greater than about 7.0, said method.

[0021] Also, in certain embodiments, provided herein is a method for preventing hypertension, pulmonary hypertension, and renal hypertension in a subject undergoing dialysis, the method comprising contacting the subject's blood with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysis fluid when the unspiked dialysis fluid flows from a dialysis device to the dialysis membrane, the unspiked dialysis fluid comprising a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0.

[0022] Also, in certain embodiments, provided herein is a method for administering sodium thiosulfate to a subject undergoing dialysis, the method comprising contacting the subject's blood with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysis fluid when the unspiked dialysis fluid flows from a dialysis device to the dialysis membrane, the unspiked dialysis fluid comprising a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions having a pH greater than about 7.0. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Brief Description of the Drawings

Figure 1

DETAILED DESCRIPTION OF THE INVENTION

[0024] (Detailed description) The following detailed description is not to be taken in a limiting sense, but is made for the sole purpose of describing the embodiments provided herein and is not to be construed as limiting the scope of the invention.

[0025] To facilitate understanding of the disclosure described herein, several terms are defined below for clarity.

[0026] Generally, the nomenclature used herein, as well as the laboratory methods of inorganic chemistry, analytical chemistry , organic chemistry, pharmaceutical chemistry, and pharmacology described herein, are well known and commonly employed in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Where there are multiple definitions for a term used herein, the definition in this section shall prevail unless otherwise stated. The term "subject" refers to an animal including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. "Subject" shall be construed accordingly.

[0027] The term "subject" refers to an animal including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. "Subject" And the term "patient" is used herein to refer to a mammalian subject, e.g., a human subject. In one embodiment, the subject is diagnosed with a disease as provided herein. In another embodiment, the subject has or is at risk for a disease, disorder, or condition. having or being at risk for a disease, disorder, or illness, or symptoms thereof can be treated, prevented, or ameliorated by administration of sodium thiosulfate. In another embodiment, the subject is a patient with end stage renal disease (ESRD) undergoing regular hemodialysis. In another embodiment, the subject is a patient having waste products reduced from the blood to safe levels. Patients with some or no renal function undergoing dialysis to maintain normal functioning of the kidneys. In an embodiment, the steady state plasma concentration of thiosulfate ion in a subject undergoing hemodialysis is In another embodiment, the subject is , have plasma levels of thiosulfate ions below normal physiological levels.

[0028] 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.

[0029] 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

[0030] Generally, conventional dialysates are defined as any formulation known heretofore, including those that have recently received patents and regardless of whether they are proprietary. Many of these are specially formulated to meet certain types of requirements. For example, U.S. Patent No. 6,436,969 discloses a composition containing an AGE inhibitor, U.S. Patent No. 5,869,444 claims a solution containing a mixture of osmotically effective peptides, and U.S. Patent Nos. 6,306,836 and 6,380,163 disclose peritoneal dialysis solutions that utilize amino acids to achieve osmotic balance. The term "bicarbonate concentrate solution" refers to an aqueous solution containing bicarbonate or a mixture with water (hereinafter referred to as "purified water") that meets or exceeds the current hemodialysis water quality standards described in ANSI / AAMI / ISO #13959:2009. Minntech Renal Systems of Minneapolis, Minnesota supplies Centrisol® bicarbonate concentrate powder MB-330. Each package of Centrisol® 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 dialysate bicarbonate concentrate solution. The term "acid concentrate solution" refers to an aqueous solution containing acid or a mixture of acid and purified water. Representative examples of acids include, but are not limited to, hydrochloric acid, acetic acid, citric acid, and peracetic acid. Minntech Renal Systems of Minneapolis, Minnesota supplies Centrisol® acid concentrate GE inhibitor-containing composition, and U.S. Patent No. 5,869,444 claims a solution containing a mixture of osmotically effective peptides, and U.S. Patent Nos. 6,306,836 and 6,380,163 disclose peritoneal dialysis solutions that utilize amino acids to achieve osmotic balance. The term "bicarbonate concentrate solution" refers to an aqueous solution containing bicarbonate or a mixture with water (hereinafter referred to as "purified water") that meets or exceeds the current hemodialysis water quality standards described in ANSI / AAMI / ISO #13959:2009. Minntech Renal Systems of Minneapolis, Minnesota supplies Centrisol® bicarbonate concentrate powder MB-330. Each package of Centrisol® 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 dialysate bicarbonate concentrate solution. The term "acid concentrate solution" refers to an aqueous solution containing acid or a mixture of acid and purified water. Representative examples of acids include, but are not limited to, hydrochloric acid, acetic acid, citric acid, and peracetic acid. Minntech Renal Systems of Minneapolis, Minnesota supplies Centrisol® acid concentrate

[0031] The term "bicarbonate concentrate solution" refers to an aqueous solution containing bicarbonate or a mixture with water (hereinafter referred to as "purified water") that meets or exceeds the current hemodialysis water quality standards described in ANSI / AAMI / ISO #13959:2009. Minntech Renal Systems of Minneapolis, Minnesota supplies Centrisol® bicarbonate concentrate powder MB-330. Each package of Centrisol® 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 dialysate bicarbonate concentrate solution. The term "acid concentrate solution" refers to an aqueous solution containing acid or a mixture of acid and purified water. Representative examples of acids include, but are not limited to, hydrochloric acid, acetic acid, citric acid, and peracetic acid. Minntech Renal Systems of Minneapolis, Minnesota supplies Centrisol® bicarbonate concentrate powder MB-330. Each package of Centrisol® 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 dialysate bicarbonate concentrate solution. Each package of Centrisol® 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 dialysate bicarbonate concentrate solution.

[0032] The term "acid concentrate solution" refers to an aqueous solution containing acid or a mixture of acid and purified water. Representative examples of acids include, but are not limited to, hydrochloric acid, acetic acid, citric acid, and peracetic acid. Minntech Renal Systems of Minneapolis, Minnesota supplies Centrisol® acid concentrate ​Supplying the concentrate 45X SB-111. Each package of Centrisol® acid concentrate powder 45X contains acetic acid ions, bicarbonate ions, calcium, chloride ions, glucose, magnesium, and potassium ions. One volume part of the acid concentrate is mixed with 1.72 volume parts of a properly mixed MB-330 series sodium bicarbonate concentrate and 42.28 volume parts of purified water to prepare 45 volume parts of dialysis solution. It should be prepared.

[0033] The term "dialysis machine" refers to a machine equipped with an extracorporeal circuit and a dialysate circuit. The extracorporeal circuit further includes tubing, a blood pump, a heparin pump, a kidney, and monitors for blood flow, blood pressure, and air bubbles. The dialysate circuit further includes dialysate tubing, a dialysate pump, and monitors for dialysate flow, dialysate pressure, and air bubbles. Currently, dialysis machines utilize an automated proportioning system that mixes an acid concentrate solution, a bicarbonate salt concentrate solution, and purified water in specific ratios to produce dialysate. The dialysate concentrate solutions (acid and bicarbonate) are usually supplied by the manufacturer either as premixed powders (as bicarbonate powders) to be added to purified water in large storage tanks or as ready-to-use solutions (as acid concentrates). The dialysate concentrate solutions are pumped into chambers of the dialysis machine where they are mixed with purified water to produce dialysate.

[0034] The term "dialysate tubing" refers to the tubing connecting the dialysis machine and the dialyzer.

[0035] The term "dialyzer" refers to cellulose acetate, cupraphane, polyacry including, but not limited to, acetonitrile, polymethyl methacrylate, or polysulfone, a synthetic or semi-synthetic semi-permeable membrane made of chemical materials (hereinafter referred to as "dialysis membrane") An artificial kidney comprising intended to include. A constant blood flow on one side of the membrane and a dialysate on the other side enable the removal of waste products from the blood. Hemodialysis can be performed using an artificial kidney during which diffusion is the main mechanism for solute removal. On the other hand, hemofiltration (also called hemodiafiltration and diafiltration) removes solutes based on ultrafiltration and convective transport rather than diffusion, to the opposite side of a high-porosity semi-permeable membrane with a high porosity semi-permeable membrane The term "unspiked dialysate" refers to the dialysis solution that is mixed by a dialysis device, pumped into the dialysate tubing, and flows to the dialysis membrane before an aqueous solution containing sodium thiosulfate is added to the dialysate tubing through a valve

[0036] The term "unspiked dialysate" refers to the dialysis solution that is mixed by a dialysis device, pumped into the dialysate tubing, and flows to the dialysis membrane before an aqueous solution containing sodium thiosulfate is added to the dialysate tubing through a valve The term "unspiked dialysate" refers to the dialysis solution that is mixed by a dialysis device, pumped into the dialysate tubing, and flows to the dialysis membrane before an aqueous solution containing sodium thiosulfate is added to the dialysate tubing through a valve and flows to the dialysis membrane

[0037] The term "dialysate spiked with thiosulfate ions" refers to the dialysis solution in the dialysate tubing after an aqueous solution containing sodium thiosulfate has been added to the dialysate tubing through a valve The term "dialysate spiked with thiosulfate ions" refers to the dialysis solution in the dialysate tubing after an aqueous solution containing sodium thiosulfate has been added to the dialysate tubing through a valve

[0038] The term "therapeutically effective amount" is intended to include an amount of a compound that, when administered, is sufficient to prevent the occurrence of one or more of the symptoms of a disorder, disease, or illness being treated, or to alleviate it to some extent The term "therapeutically effective amount" is also intended to include an amount of a compound that is sufficient to induce a biological or medical response in a cell, tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or clinician. In one embodiment, the therapeutically effective amount is an amount sufficient to maintain the blood level of thiosulfate ions in a subject at approximately physiological levels at approximately physiological levels at approximately physiological levels is present

[0039] The terms "about" or "approximately" mean an acceptable error for a particular value determined by one of ordinary skill in the art, which is, in part, determined by how the value is measured or determined. In certain embodiments, the terms "about" or "approximately" mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms "about" or "approximately" mean within 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. In certain embodiments, the value preceded by the terms "about" or "approximately" is considered to be exact.

[0040] The term "normal physiological level" of thiosulfate ion means the level of thiosulfate ion found in a healthy adult subject. In one embodiment, the normal physiological level of thiosulfate ion in a subject is 1-10 micromolar concentration.

[0041] In certain embodiments, the methods provided herein include the use of a purified form of sodium thiosulfate, such as sodium thiosulfate pentahydrate (Na a 2 S 2 O 3 ·5H 2 O). In one embodiment, what is provided herein is pharmaceutical grade sodium thiosulfate. In another embodiment, what is provided herein is a form of sodium thiosulfate that meets or exceeds one, two or all of the FDA standards for use in pharmaceuticals. In another embodiment, what is provided herein is a form of sodium thiosulfate that meets or exceeds one, two or all of the United States Federal Regulations ​​​​​​​​​Sodium thiosulfate produced in accordance with the Good Manufacturing Practice (GMP) detailed in 21 CFR 211 in the form. In one embodiment, pharmaceutically acceptable sodium thiosulfate is the entire body incorporated herein by reference, the U.S. Patent Publication No. filed on July 7, 2010 2011 / 0008467.

[0042] In one embodiment, the sodium thiosulfate is solid.

[0043] In one embodiment, the appearance of the sodium thiosulfate is colorless crystals.

[0044] In one embodiment, the appearance of a 10% solution containing the sodium thiosulfate is transparent and colorless.

[0045] In one embodiment, the sodium thiosulfate is odorless.

[0046] In one embodiment, the presence of sodium thiosulfate in the 10% solution provided herein is confirmed by the release of a yellow color after the addition of a few drops of iodine TS .

[0047] In one embodiment, the presence of sodium in the sodium thiosulfate provided herein is confirmed by Method 191 of the United States Pharmacopeia XXXII (2009), which is incorporated herein by reference in its entirety .

[0048] In one embodiment, the presence of thiosulfate ions in the sodium thiosulfate provided herein is confirmed by Method 191 of the United States Pharmacopeia XXXII (2009).

[0049] In one embodiment, the sodium thiosulfate pentahydrate provided herein is anhydrous bas Calculated on a basis, it contains about 99% by weight or more and / or about 100.5% by weight or less of sodium thiosulfate. In certain embodiments, the amount of anhydrous Sodium thiosulfate in the sodium thiosulfate pentahydrate provided herein is determined by the United States Pharmacopeia colorimetric assay (United States Pharmacopeia XXXII (2009)). Determined.

[0050] In one embodiment, the sodium thiosulfate pentahydrate provided herein contains, as measured by ion chromatography, about 98% by weight or more and about 102% by weight or less of sodium thiosulfate on an anhydrous basis. Of sodium thiosulfate. Containing.

[0051] In one embodiment, the sodium thiosulfate pentahydrate provided herein contains, calculated on an anhydrous basis, about 98% by weight or more and / or about 102% by weight or less of sodium thiosulfate. Containing. In certain embodiments, the amount of anhydrous Sodium thiosulfate in the sodium thiosulfate pentahydrate provided herein is determined by ion chromatography. In certain embodiments, The amount of anhydrous sodium thiosulfate in the sodium thiosulfate pentahydrate provided herein is determined by ion chromatography using electrochemical conductivity detection as described herein. Lithium is determined by ion chromatography using electrochemical conductivity detection as described herein. Determined.

[0052] In another embodiment, the sodium thiosulfate provided herein has a pH of about 6 to about 8 when measured at 25 °C in a 10% solution. In certain embodiments, the pH of the sodium provided herein is measured using a pH meter. In certain embodiments, the sodium provided herein Provided herein Measured using a pH meter. In certain embodiments, the sodium provided herein The pH of the sodium thiosulfate provided is determined by Method 791 of the United States Pharmacopeia XXXII (2009). .

[0053] In yet another embodiment, the sodium thiosulfate provided herein has a water content of about 32% to about 37% by weight. In certain embodiments, the water content in the sodium thio sulfate provided herein is determined by the Karl Fischer method. In certain embodiments the water content in the sodium thiosulfate provided herein is quantified by Method 921 of the United States Pharmacopeia XXXII (2009).

[0054] In yet another embodiment, the heavy metal content in the sodium thiosulfate provided herein is heavy metals of about 10 ppm or less. The heavy metal content in the sodium thiosulfate provided herein is determined by Method 231 of the United States Pharmacopeia XXXII (2009).

[0055] In yet another embodiment, the sodium thiosulfate provided herein contains carbonate ions of about 0.02% by weight or less. In yet another embodiment, the sodium thiosulfate provided herein contains carbonate ions of about 0.01% by weight or less. In certain embodiments the amount of carbonate ions in the sodium thiosulfate provided herein is determined by contacting a sodium thiosulfate sample with an acid such as phosphoric acid to convert the carbonate ions to carbon dioxide and determining the amount of the carbon dioxide using a non-dispersive infrared detector.

[0056] In yet another embodiment, the sodium thiosulfate provided herein contains insolubles of about 0.005% by weight or less. In certain embodiments, the thiosulfuric acid provided herein ​​​​​​​​The amount of insoluble matter in sodium thiosulfate is calculated by adding 10 grams of the sodium thiosulfate provided herein. The solubility was determined by dissolving in 100 mL of water, heating the solution to boiling for 1 hour, and The liquid is filtered, washed with hot water, dried, cooled in a desiccator and weighed.

[0057] In yet another embodiment, the sodium thiosulfate provided herein is about 200 wt. In some embodiments, the thiamine monohydrate provided herein contains less than or equal to ppm chloride ion. The chloride ion content in sodium oxalate is determined by Method 221 of the United States Pharmacopeia XXXII (2009). will be done.

[0058] In yet another embodiment, the sodium thiosulfate provided herein has a concentration of about 0.002 In some embodiments, the sodium thiosulfate provided herein contains up to 10% by weight of iron. The iron content in the lithium is determined using inductively coupled plasma mass spectrometry (ICP-MS). In an embodiment, the iron content in the sodium thiosulfate provided herein is determined by inductively coupled plasma In some embodiments, the method is performed using inductively coupled plasma-optical emission spectroscopy (ICP-OES). The iron content of sodium thiosulfate used is determined by Method 241 of the United States Pharmacopeia XXXII (2009). can be.

[0059] In yet another embodiment, the sodium thiosulfate provided herein has a concentration of about 0.001 In some embodiments, the sodium thiosulfate provided herein contains no more than 10% lead by weight. The lead content in sodium is determined by Method 251 of the United States Pharmacopeia XXXII (2009).

[0060] In yet another embodiment, the sodium thiosulfate provided herein is about 0.01 wt % or less calcium. In certain embodiments, the calcium content in the sodium thiosulfate provided herein is determined using ICP-MS. In certain embodiments the calcium content in the sodium thiosulfate provided herein is determined using flame emission spectroscopy (FES).

[0061] In yet another embodiment, the sodium thiosulfate provided herein does not cause turbidity when an ammonium oxalate test solution prepared according to United States Pharmacopeia XXXII (2009) is added to an aqueous solution containing sodium thiosulfate e.g., 1 gram of sodium thiosulfate dissolved in 20 mL of water).

[0062] In yet another embodiment, the sodium thiosulfate provided herein contains about 0.005 wt% or less potassium. In certain embodiments, the potassium content in the sodium thiosulfate provided herein is determined using ICP-MS. In certain embodiments the potassium content in the sodium thiosulfate provided herein is determined using FES .

[0063] In yet another embodiment, the sodium thiosulfate provided herein contains about 0.05 wt % or less sulfite ions, or about 0.1 wt% or less sulfite ions. In certain embodiments the sulfite ion content in the sodium thiosulfate provided herein is determined using the method described in "Reagent Chemicals, American Chemical Society the entirety of which is incorporated herein by reference ​​​​​Determined by the method for the determination of sulfite ions in the 10th edition of "American Chemical Society, Reagent Chemicals". Determined.

[0064] In yet another embodiment, the sodium thiosulfate provided herein contains sulfate ions of about 0.05% or less, about 0.1% or less, about 0.25% or less, or about 0.5 wt% or less (as SO ). In certain embodiments, the sulfate ion content in the sodium thiosulfate provided herein is determined by the method for the determination of sulfate ions in the 10th edition of "American Chemical Society, Reagent Chemicals". 4 2- In certain embodiments, the sulfate ion content in the sodium thiosulfate provided herein is determined by the method for the determination of sulfate ions in the 10th edition of "American Chemical Society, Reagent Chemicals". icals). Determined by the method for the determination of sulfate ions in the 10th edition of "American Chemical Society, Reagent Chemicals".

[0065] In yet another embodiment, the sodium thiosulfate provided herein contains sulfide ions of about 0.001 wt% or less. In certain embodiments, the sulfide ion content in the sodium thiosulfate provided herein is determined by the addition of lead(II) nitrate using the method described herein. In certain embodiments, the sulfide ion content in the sodium thiosulfate provided herein is determined by the addition of lead(II) nitrate using the method described herein. Determined by the addition of lead(II) nitrate using the method described herein.

[0066] In yet another embodiment, the sodium thiosulfate provided herein contains nitrogen compounds of about 0.002 wt% or less (as N). In certain embodiments, the nitrogen compound content (as N) in the sodium thiosulfate provided herein is determined by the method for the determination of nitrogen compounds in the 10th edition of "American Chemical Society, Reagent Chemicals". In certain embodiments, the nitrogen compound content (as N) in the sodium thiosulfate provided herein is determined by the method for the determination of nitrogen compounds in the 10th edition of "American Chemical Society, Reagent Chemicals". icals). Determined by the method for the determination of nitrogen compounds in the 10th edition of "American Chemical Society, Reagent Chemicals".

[0067] In yet another embodiment, the sodium thiosulfate provided herein is about 10 ppm or less, about 100 ppm or less, about 500 ppm or less, about 1000 ppm or less, or 5000 ppm or less of total volatile organic carbon is contained. In certain embodiments, the sodium thiosulfate provided herein is that the disclosure of which is incorporated by reference in its entirety, contains less than the specific limits of the organic volatile impurities or certain solvents (e.g., ethanol) described in ICH Q3C(R3). In certain embodiments the content of organic volatile impurities is determined by the method 467 of the United States Pharmacopeia XXXII (2009).

[0068] In yet another embodiment, the sodium thiosulfate provided herein is about 60 ppb or less, about 2.5 ppm or less, about 8 ppm or less, about 10 ppm or less, about 20 ppm or less, about 25 ppm or less, or about 50 pp m or less of total NPOC is contained. In certain embodiments, the sodium thiosulfate provided herein contains about 12 ppm or less of total NPOC. In certain embodiments, the total NPOC in the sodium thiosulfate provided herein is determined using the method described herein. In certain embodiments, the total NPOC in the sodium thiosulfate provided herein is determined by: a) contacting the sodium thiosulfate with an aqueous solution containing a predetermined amount of inorganic acid to prepare a sample aqueous solution ; b) removing the precipitate from the sample aqueous solution; c) contacting the sample solution with a predetermined amount of oxidizing agent ; and d) converting the organic carbon in the sample solution to carbon dioxide under supercritical water oxidation (SCWO) conditions.

[0069] In yet another embodiment, the sodium thiosulfate provided herein is about 0.05 pp​ contains mercury below m. In certain embodiments, the mercury content in the sodium thiosulfate provided herein is determined using ICP-MS. In certain embodiments, the mercury content in the sodium thiosulfate provided herein is determined using ICP-OES. In certain embodiments, the mercury content in the sodium thiosulfate provided herein is determined by Method 261 of the United States Pharmacopeia XXXI I (2009).

[0070] In yet another embodiment, the sodium thiosulfate provided herein contains aluminum below about 2 ppm. In certain embodiments, the aluminum content in the sodium thiosulfate provided herein is determined using ICP-MS. In certain embodiments, the aluminum content in the sodium thiosulfate provided herein is determined using ICP-OES. In certain embodiments, the aluminum content in the sodium thiosulfate provided herein is determined by Method 206 of the United States Pharmacopeia XXXII (2009). In certain embodiments, the aluminum content in the sodium thiosulfate provided herein is determined by Method 206 of the United States Pharmacopeia XXXII (2009).

[0071] In yet another embodiment, the sodium thiosulfate provided herein contains arsenic below about 3 ppm. In certain embodiments, the arsenic content in the sodium thiosulfate provided herein is determined using ICP-MS. In certain embodiments, the arsenic content in the sodium thiosulfate provided herein is determined using ICP-OES. In certain embodiments, the arsenic content in the sodium thiosulfate provided herein is determined by Method 211 of the United States Pharmacopeia XXXII (20 09). is determined by Method 211 of the United States Pharmacopeia XXXII (2009).

[0072] In yet another embodiment, the sodium thiosulfate provided herein is about 0.003 % by weight or less of selenium. In certain embodiments, the selenium content in the sodium thiosulfate provided herein is determined using ICP-MS. In certain embodiments, the selenium content in the sodium thiosulfate provided herein is determined using ICP-OES. In certain embodiments, the selenium content in the sodium thiosulfate provided herein is determined by Method 291 of the United States Pharmacopeia XXXII (2009). In certain embodiments, the selenium content in the sodium thiosulfate provided herein is determined by Method 291 of the United States Pharmacopeia XXXII (2009).

[0073] In yet another embodiment, the total aerobic count of the microbial load in the sodium thiosulfate provided herein is about 100 colony forming units per gram (CFU / g) or less. The total aerobic count of the microbial load in the sodium thiosulfate provided herein is quantified by Method 61 of the United States Pharmacopeia XXXII (2009).

[0074] In yet another embodiment, the total yeast and mold count in the sodium thiosulfate provided herein is about 20 CFU / g or less. The total yeast and mold count in the sodium thiosulfate provided herein is quantified by Method 61 of the United States Pharmacopeia XXXII (2009).

[0075] In yet another embodiment, the sodium thiosulfate provided herein contains about 0.02 endotoxin units per milligram (EU / mg) or less, about 0.1 EU / mg or less, or about 0.25 EU / mg or less of bacterial endotoxin. The amount of bacterial endotoxin in the sodium thiosulfate provided herein is quantified by Method 85 of the United States Pharmacopeia XXXII (2009).

[0076] ​​​​​​​​​​In yet another embodiment, the sodium thiosulfate provided herein contains a residual solidification inhibitor of 0.01% or less.

[0077] In yet another embodiment, the sodium thiosulfate provided herein has the following : containing sodium thiosulfate of about 99% by weight or more and / or about 100.5% by weight or less on an anhydrous basis determined by the United States Pharmacopeia colorimetric assay; containing sodium thiosulfate of about 98% by weight or more and / or about 102% by weight or less on an anhydrous basis determined by the ion chromatography assay; having a pH of about 6 to about 8 when measured at 25°C in a 10% solution; having a water content of about 32% to about 37% by weight; having the appearance of colorless crystals; having a clear and colorless appearance as a 10% solution; having no odor; having a positive sodium confirmation test; having a positive thiosulfate ion confirmation test; not forming turbidity when mixed with ammonium oxalate TS; having a heavy metal content of about 10 ppm or less; containing carbonate ions of about 0.01% by weight or less; containing insoluble matter of about 0.005% by weight or less; containing chloride ions of about 200 ppm or less; containing sulfide ions of about 0.001% by weight or less; containing sulfite ions of about 0.05% or less or about 0.1% by weight or less; containing sulfate ions of about 0.05% or less, about 0.1% or less, about 0.25% or less, or about 0.5% by weight or less; containing iron of about 0.002% by weight or less; containing calcium at about 0.01% by weight or less; containing potassium at about 0.005% by weight or less; containing organic volatile impurities at about 10 ppm or less, about 100 ppm or less, about 500 ppm or less, about 1000 ppm or less, or 5000 ppm or less; having a total NPOC of about 60 ppb or less, about 2.5 ppm or less, about 8 ppm or less, about 10 ppm or less, about 20 ppm or less, about 25 ppm or less, or about 50 ppm or less; containing mercury at about 0.05 ppm or less; containing aluminum at about 2 ppm or less; containing arsenic at about 3 ppm or less; containing lead at 0.001% by weight or less; containing nitrogen compounds at about 0.002% by weight or less (as N); containing selenium at about 0.003% by weight or less; containing a residual solidification inhibitor at 0.01% or less; having a total aerobic bacteria count of microbial load of about 100 CFU / g or less; having a total yeast and mold count of about 20 CFU / g or less; and containing endotoxin of about 0.02 EU / mg or less, about 0.1 EU / mg or less, or about 0.25 EU / mg or less characterized by one or more of the above.

[0078] In yet another embodiment, the sodium thiosulfate provided herein is as follows : containing sodium thiosulfate at about 99% by weight or more and / or about 100.5% by weight or less on an anhydrous basis determined by the United States Pharmacopeia colorimetric assay; containing sodium thiosulfate at about 98% by weight or more and / or about 102% by weight or less on an anhydrous basis determined by the ion chromatography assay; ​Having a pH of about 6 to about 8 when measured at 25°C in a 10% solution; Having a water content of about 32% to about 37% by weight; Having the appearance of colorless crystals; Having a clear and colorless appearance as a 10% solution; Having no odor; The confirmatory test for sodium being positive; The confirmatory test for thiosulfate ions being positive; Not forming turbidity when mixed with ammonium oxalate TS; Having a heavy metal content of about 10 ppm or less; Containing carbonate ions of about 0.01% by weight or less; Containing insoluble matter of about 0.005% by weight or less; Containing chloride ions of about 200 ppm or less; Containing sulfide ions of about 0.001% by weight or less; Containing sulfite ions of about 0.05% or less or about 0.1% by weight or less; Containing sulfate ions of about 0.05% or less, about 0.1% or less, about 0.25% or less, or about 0.5% by weight or less; ; Containing iron of about 0.002% by weight or less; Containing calcium of about 0.01% by weight or less; Containing potassium of about 0.005% by weight or less; Containing organic volatile impurities of about 10 ppm or less, about 100 ppm or less, about 500 ppm or less, about 1000 ppm or less, or 5000 ppm or less; ; Having a total NPOC of 60 ppb or less, about 2.5 ppm or less, about 8 ppm or less, about 10 ppm or less, about 20 ppm or less, about 25 ppm or less, or about 50 ppm or less; ; Containing mercury of about 0.05 ppm or less; Containing aluminum of about 2 ppm or less; Containing arsenic of about 3 ppm or less; Containing lead in an amount of 0.001% by weight or less; Containing a nitrogen compound in an amount of about 0.002% by weight or less (as N); Containing selenium in an amount of about 0.003% by weight or less; Having a total aerobic bacteria count with a microbial load of about 100 CFU / g or less; Having a total yeast and mold count of about 20 CFU / g or less; and Containing endotoxin in an amount of about 0.02 EU / mg or less, about 0.1 EU / mg or less, or about 0.25 EU / mg or less Characterized by one or more of the above.

[0079] Sodium thiosulfate is described as "containing" a certain substance "below" a certain amount In some embodiments, the sodium thiosulfate does not contain a detectable amount of the substance None.

[0080] (Method for maintaining the physiological level of thiosulfate ions) Provided herein is a method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, comprising contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, and adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, wherein the unspiked dialysis fluid comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0, said method. Also provided herein is a method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, comprising contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, and adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, wherein the unspiked dialysis fluid comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0, said method. Also provided herein is a method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, comprising contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, and adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, wherein the unspiked dialysis fluid comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0, said method. Also provided herein is a method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, comprising contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, and adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, wherein the unspiked dialysis fluid comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0, said method. Also provided herein is a method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, comprising contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, and adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, wherein the unspiked dialysis fluid comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0, said method. Also provided herein is a method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, comprising contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, and adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, wherein the unspiked dialysis fluid comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0, said method. Also provided herein is a method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, comprising contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, and adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, wherein the unspiked dialysis fluid comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0, said method.

[0081] Also provided herein is a method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, comprising contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, and adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, wherein the unspiked dialysis fluid comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0, said method. Also provided herein is a method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, comprising contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, and adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, wherein the unspiked dialysis fluid comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0, said method. including contacting the dialysate spiked with ions during dialysis, and when the unspiked dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the unspiked dialysate, the unspiked dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with thiosulfate ions has a pH greater than about 7.0, said method. When the unspiked dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the unspiked dialysate and the unspiked dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with thiosulfate ions has a pH greater than about 7.0, said method.

[0082] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0083] In one embodiment, the physiological level of thiosulfate ions in the subject is about 100 micromolar concentration or less. In another embodiment, the physiological level of thiosulfate ions in the subject is about 10 micromolar concentration or less. In yet another embodiment the physiological level of thiosulfate ions in the subject is about 500 nano molar concentration to about 10 micromolar concentration. In yet another embodiment, the physiological level of thiosulfate ions in the subject is about 1 micromolar concentration to about 5 micromolar concentration . In yet another embodiment, the physiological level of thiosulfate ions in the subject is about 3 micromolar concentration. In one embodiment, the concentration of thiosulfate ions in the dialysate spiked with thiosulfate ions is 100 micromolar concentration or less. In another embodiment, the concentration of thiosulfate ions in the dialysate spiked with thiosulfate ions is about 10 micromolar concentration or less . In yet another embodiment, the physiological level of thiosulfate ions in the subject is about 3 micromolar concentration. In one embodiment, the concentration of thiosulfate ions in the dialysate spiked with thiosulfate ions is 100 micromolar concentration or less. In another embodiment, the concentration of thiosulfate ions in the dialysate spiked with thiosulfate ions is about 10 micromolar concentration or less

[0084] In one embodiment, the concentration of thiosulfate ions in the dialysate spiked with thiosulfate ions is 100 micromolar concentration or less. In another embodiment, the concentration of thiosulfate ions in the dialysate spiked with thiosulfate ions is about 10 micromolar concentration or less . In yet another embodiment, the concentration of thiosulfate ions in the dialysate spiked with thiosulfate ions is about 10 micromolar concentration or less Furthermore, in another embodiment, thio- in the dialysate spiked with the thiosulfate ion The concentration of the sulfate ion is from about 500 nanomolar to about 10 micromolar. In yet another embodiment, the concentration of the thiosulfate ion in the dialysate spiked with the thiosulfate ion is from about 1 micromolar to about 5 micromolar. In yet another embodiment, the concentration of the thiosulfate ion in the dialysate spiked with the thiosulfate ion is about 3 micromolar.

[0085] In one embodiment, the aqueous solution containing sodium thiosulfate is about 10 mg / L, about 50 mg / L, about 100 mg / L, about 150 mg / L, about 200 mg / L, about 250 mg / L, about 300 mg / L, about 350 mg / L, about 400 mg / L, about 450 mg / mL, or contains sodium thiosulfate at about 500 mg / L or less.

[0086] In one embodiment, the water contains thiosulfate ions at about 10 mg / L, about 50 mg / L, about 100 mg / L, about 150 mg / L, about 20 0 mg / L, about 250 mg / L, about 300 mg / L, about 350 mg / L, about 400 mg / L, about 450 mg / mL, or about 500 mg / L or less thereof.

[0087] In one embodiment, the aqueous solution containing sodium thiosulfate is added to the unspiked dialysate through a valve attached to the pipe at a position before the dialysis pipe is connected to the dialyzer. In another embodiment, the unspiked dialysate flows through the dialysis pipe at a rate of about 200 mL / min to about 1000 mL / min. In yet another embodiment, the unspiked dialysate mentioned above flows through the dialysis pipe at a rate of about 300 mL / min to about 900 mL / min It flows. In yet another embodiment, the unspiked dialysate flows through the dialysis tubing at a rate of about 400 mL / min to about 800 mL / min. In yet another embodiment, the unspiked dialysate flows through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min. In yet another embodiment, the unspiked dialysate flows through the dialysis tubing at a rate of about 600 mL / min.

[0088] In one embodiment, the aqueous solution containing sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 0 mL / h to about 750 mL / h, about 50 mL / h to about 650 mL / h, about 100 mL / h to about 550 mL / h, about 150 mL / h to about 450 mL / h, or about 200 mL / h to about 350 mL / h. In another embodiment, the aqueous solution containing sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 250 mL / h.

[0089] In yet another embodiment, the pH of the dialysate spiked with thiosulfate ions is about 7.0 to about 8.0. In yet another embodiment, the pH of the dialysate spiked with thiosulfate ions is about 7.1 to about 8.0. In yet another embodiment, the pH of the dialysate spiked with thiosulfate ions is about 7.3 to about 8.0. In yet another embodiment, the pH of the dialysate spiked with sodium thiosulfate is about 7.3 to about 7.5. In yet another embodiment, the pH of the dialysate spiked with sodium thiosulfate is about 7.4.

[0090] ​​​In yet another embodiment, the subject is a human with chronic renal failure. In another embodiment the subject is a human with acute renal failure.

[0091] 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.

[0092] In one embodiment, the method provided herein restores and / or maintains the plasma level of thiosulfate ion in a subject to normal physiological levels.

[0093] (Method of prevention) (1. Method of preventing atherosclerosis) In one embodiment, what is provided herein is a method for preventing atherosclerosis in a subject undergoing dialysis, the method comprising contacting the blood of the subject with a dialysis membrane in dialysis contact with a dialysis fluid spiked with thiosulfate ion, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid comprising a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ion having a pH greater than about 7.0, said method.

[0094] In one embodiment, what is further provided herein is a method for preventing atherosclerosis in a subject undergoing hemodialysis, the method comprising contacting the blood of the subject with a dialysis fluid spiked with thiosulfate ion during dialysis, spiking When the undiluted dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the undiluted dialysate, and the undiluted dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ions has a pH greater than about 7.0, the method being as described above. The aqueous solution is added to the undiluted dialysate, and the undiluted dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ions has a pH greater than about 7.0, the method being as described above.

[0095] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0096] In certain embodiments, the methods provided herein return and / or maintain the plasma level of thiosulfate ions in the subject to normal physiological levels. return and / or maintain the plasma level of thiosulfate ions in the subject to normal physiological levels.

[0097] (2. Method for Preventing Myocardial Infarction) In certain embodiments, provided herein is a method for preventing myocardial infarction in a subject undergoing dialysis, the method comprising contacting the subject's blood with a dialysis membrane in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein when the undiluted dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the undiluted dialysate, and the undiluted dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ions has a pH greater than about 7.0, the method being as described above. contacting the subject's blood with a dialysis membrane in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein when the undiluted dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the undiluted dialysate, and the undiluted dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ions has a pH greater than about 7.0, the method being as described above. contacting the subject's blood with a dialysis membrane in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein when the undiluted dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the undiluted dialysate, and the undiluted dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ions has a pH greater than about 7.0, the method being as described above. contacting the subject's blood with a dialysis membrane in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein when the undiluted dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the undiluted dialysate, and the undiluted dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ions has a pH greater than about 7.0, the method being as described above. contacting the subject's blood with a dialysis membrane in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein when the undiluted dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the undiluted dialysate, and the undiluted dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ions has a pH greater than about 7.0, the method being as described above. contacting the subject's blood with a dialysis membrane in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein when the undiluted dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the undiluted dialysate, and the undiluted dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ions has a pH greater than about 7.0, the method being as described above. contacting the subject's blood with a dialysis membrane in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein when the undiluted dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the undiluted dialysate, and the undiluted dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ions has a pH greater than about 7.0, the method being as described above.

[0098] In certain embodiments, further provided herein is a method for preventing myocardial infarction in a subject undergoing hemodialysis, the method comprising contacting the subject's blood with a dialysis membrane in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein when the undiluted dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the undiluted dialysate, and the undiluted dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ions has a pH greater than about 7.0, the method being as described above. contacting the subject's blood with a dialysis membrane in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein when the undiluted dialysate flows from the dialysis device to the dialysis membrane, an aqueous solution containing sodium thiosulfate is added to the undiluted dialysate, and the undiluted dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ions has a pH greater than about 7.0, the method being as described above. comprising contacting the dialysate spiked with ions with the subject during dialysis, the unspiked aqueous solution containing sodium thiosulfate is added to the unspiked dialysate when the unspiked dialysate flows from the dialysis device to the dialysis membrane, the unspiked dialysate comprising a mixture of water, an acid concentrate , and a bicarbonate concentrate, and the dialysate spiked with the thiosulfate ions having a pH greater than about 7.0, said method.

[0099] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0100] In certain embodiments, the methods provided herein return and / or maintain the plasma level of thiosulfate ions in the subject to normal physiological levels.

[0101] (3. Method for preventing sudden cardiac death) In certain embodiments, provided herein is a method for preventing sudden cardiac death in a subject undergoing dialysis, the method comprising contacting the subject's blood with a dialysis membrane that is also in contact with a dialysate spiked with thiosulfate ions during dialysis, an aqueous solution containing sodium thiosulfate being added to the unspiked dialysate when the unspiked dialysate flows from the dialysis device to the dialysis membrane, the unspiked dialysate comprising a mixture of water, an acid concentrate, and a bicarbonate concentrate, and the dialysate spiked with the thiosulfate ions having a pH greater than about 7.0, said method.

[0102] In certain embodiments, further provided herein is a method for performing hemodialysis on a subject A method for preventing sudden cardiac death in a subject, the method comprising contacting the subject's blood with a dialysate spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysate when the unspiked dialysate flows from a dialysis apparatus to a dialysis membrane, the unspiked dialysate comprising a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with thiosulfate ions having a pH greater than about 7.0. and the unspiked dialysate is contacted with the dialysis membrane during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysate when the unspiked dialysate flows from a dialysis apparatus to a dialysis membrane, the unspiked dialysate comprising a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with thiosulfate ions having a pH greater than about 7.0. is the method described above.

[0103] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0104] In certain embodiments, the methods provided herein return and / or maintain the plasma level of thiosulfate ions in the subject at normal physiological levels.

[0105] (4. Method for Preventing Stroke) In certain embodiments, provided herein is a method for preventing stroke in a subject undergoing dialysis, the method comprising contacting the subject's blood with a dialysis membrane while in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysate when the unspiked dialysate flows from a dialysis apparatus to a dialysis membrane, the unspiked dialysate comprising a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with thiosulfate ions having a pH greater than about 7.0. wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysate when the unspiked dialysate flows from a dialysis apparatus to a dialysis membrane, the unspiked dialysate comprising a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with thiosulfate ions having a pH greater than about 7.0.

[0106] In certain embodiments, further provided herein is a method for​ A method for preventing stroke in a subject, comprising contacting the subject's blood with a dialysis fluid spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysis fluid when the unspiked dialysis fluid flows from a dialysis device to a dialysis membrane, the unspiked dialysis fluid contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0.

[0107] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0108] In certain embodiments, the methods provided herein return and / or maintain the plasma level of thiosulfate ions in the subject to normal physiological levels.

[0109] (5. Method for preventing cardiovascular diseases) In certain embodiments, provided herein is a method for preventing cardiovascular diseases characterized by tissue ischemia including angina pectoris, cerebral vasospasm, claudication, severe ischemic limb, peripheral vascular disease, and sickle cell crisis in a subject undergoing dialysis, comprising contacting the subject's blood with a dialysis membrane that is also in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysis fluid when the unspiked dialysis fluid flows from a dialysis device to a dialysis membrane, the unspiked dialysis fluid contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0. ​​​​​​​​​​​​​​

[0110] In one embodiment, further provided herein is a method for preventing cardiovascular diseases characterized by tissue ischemia including angina pectoris, cerebral vasospasm, claudication, severe ischemic limbs, peripheral vascular diseases, and sickle cell crises in a subject undergoing dialysis, the method comprising contacting blood of the subject with a dialysate spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysate when the unspiked dialysate flows from a dialysis device to a dialysis membrane, the unspiked dialysate comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with thiosulfate ions has a pH greater than about 7.0.

[0111] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0112] In certain embodiments, the methods provided herein restore and / or maintain the plasma level of thiosulfate ions in the subject to normal physiological levels.

[0113] (6. Method for Preventing Hypertension, Pulmonary Hypertension, and Renal Hypertension) In one embodiment, provided herein is a method for preventing hypertension, pulmonary hypertension, and renal hypertension in a subject undergoing dialysis, the method comprising contacting blood of the subject with a dialysis membrane that is also in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysate when the unspiked dialysate flows from a dialysis device to a dialysis membrane, ​​​​​​ The unspiked dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ion has a pH greater than about 7.0, is the method.

[0114] In certain embodiments, further provided herein is a method for preventing hypertension, pulmonary hypertension, and renal hypertension in a subject undergoing dialysis, comprising contacting the subject's blood with a dialysate spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysate as the unspiked dialysate flows from a dialysis device to a dialysis membrane, and the unspiked dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ion has a pH greater than about 7.0, is the method. In certain embodiments, the pulmonary hypertension is neonatal pulmonary hypertension, primary pulmonary hypertension, or

[0115] secondary pulmonary hypertension. In one embodiment, the subject is a mammal. In another embodiment, the subject

[0116] is a human. In certain embodiments, the method provided herein restores and / or maintains the plasma level of thiosulfate ions in the subject to normal physiological levels.

[0117] In certain embodiments, the embodiments in paragraphs

[0118] -

[0127] apply to all methods provided herein. In certain embodiments, the embodiments in paragraphs

[0118] -

[0127] apply to all methods provided herein.

[0118] In certain embodiments, the embodiments in paragraphs

[0118] -

[0127] apply to all methods provided herein. In certain embodiments, the embodiments in paragraphs

[0118] -

[0127] apply to all methods provided herein.

[0119] In one embodiment, the physiological level of the thiosulfate ion in the subject is about 100 micromolar or less. In another embodiment, the physiological level of the thiosulfate ion in the subject is about 10 micromolar or less. In yet another embodiment the physiological level of the thiosulfate ion in the subject is about 500 nanomolar concentration to about 10 micromolar concentration. In yet another embodiment, the physiological level of the thiosulfate ion in the subject is approximately about 1 micromolar concentration to about 5 micromolar concentration. In yet another embodiment, the physiological level of the thiosulfate ion in the subject is about 3 micromolar concentration.

[0120] In one embodiment, the concentration of thiosulfate ion in the dialysis fluid spiked with the thiosulfate ion is about 100 micromolar or less. In another embodiment, the concentration of thiosulfate ion in the dialysis fluid spiked with the thiosulfate ion is about 10 micromolar or less. In yet another embodiment, the concentration of thiosulfate ion in the dialysis fluid spiked with the thiosulfate ion is about 500 nanomolar concentration to about 10 micromolar concentration. In yet another embodiment, the concentration of thiosulfate ion in the dialysis fluid spiked with the thiosulfate ion is about 1 micromolar concentration to about 5 micromolar concentration. In yet another embodiment the concentration of thiosulfate ion in the dialysis fluid spiked with the thiosulfate ion is about 3 micromolar concentration.

[0121] In certain embodiments, the aqueous solution containing sodium thiosulfate is about 10 mg / L, about 50 mg / L ​, about 100 mg / L, about 150 mg / L, about 200 mg / L, about 250 mg / L, about 300 mg / L, about 350 mg / L, about 400 mg / L, contains sodium thiosulfate at about 450 mg / mL or less than about 500 mg / L.

[0122] In one embodiment, the water contains approximately about 10 mg / L, about 50 mg / L, about 100 mg / L, about 150 mg / L, about 200 mg / L, about 250 mg / L, about 300 mg / L, about 350 mg / L, about 400 mg / L, about 450 mg / mL, or about 500 mg / L or less of thiosulfate ions.

[0123] In one embodiment, an aqueous solution containing the sodium thiosulfate is added to the unspiked dialysate through a valve attached to the pipe at a position before the dialysis fluid pipe is connected to the dialyzer. In another embodiment, the unspiked dialysate flows through the dialysis pipe at a rate of about 200 mL / min to about 1000 mL / min. In yet another embodiment, the unspiked dialysate flows through the dialysis pipe at a rate of about 300 mL / min to about 900 mL / min. In yet another embodiment, the unspiked dialysate flows through the dialysis pipe at a rate of about 400 mL / min to about 800 mL / min. In yet another embodiment, the unspiked dialysate flows through the dialysis pipe at a rate of about 500 mL / min to about 700 mL / min. In yet another embodiment, the unspiked dialysate flows through the dialysis pipe at a rate of about 600 mL / min. In yet another embodiment, the unspiked dialysate flows through the dialysis pipe at a rate of about 500 mL / min to about 700 mL / min. In yet another embodiment, the unspiked dialysate flows through the dialysis pipe at a rate of about 600 mL / min. rate.

[0124] In one embodiment, the aqueous solution containing the sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 0 mL / h to about 750 mL / h, about 50 mL / h to about 650 mL / h, at a rate of about 100 mL / h to about 550 mL / h, at a rate of about 150 mL / h to about 450 mL / h, or at a rate of about 200 mL / h ~ about 350 mL / h. In another embodiment, the aqueous solution containing the sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 250 mL / h is added.

[0125] In yet another embodiment, the pH of the dialysate spiked with the thiosulfate ions is about 7.0 to about 8.0. In yet another embodiment, the pH of the dialysate spiked with the thiosulfate ions is about 7.1 to about 8.0. In yet another embodiment, the pH of the dialysate spiked with the thiosulfate ions is about 7.3 to about 8.0. In yet another embodiment, the pH of the dialysate spiked with the thiosulfate ions is about 7.3 to about 7.5. In yet another embodiment, the pH of the dialysate spiked with the thiosulfate ions is about 7.4

[0126] In yet another embodiment, the subject is a human with chronic renal failure. In another embodiment, the subject is a human with acute renal failure.

[0127] 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.

[0128] In one embodiment, the dialysate spiked with the thiosulfate ions is about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4% reflected in the sulfate ion, sulfide ion, and sulfite ion content measured in the sample taken from the detection point "before" (100) or the detection point "after" (110). ​ undergo decomposition of thiosulfate ions of less than about 5%, about 3%, about 2%, about 1%, about 0.5%, or about 0.1% .

[0129] (Method of administration) In certain embodiments, provided herein is a method for administering sodium thiosulfate to a subject undergoing dialysis, the method comprising contacting the subject's blood with a dialysis membrane during dialysis that is also in contact with a dialysis fluid spiked with thiosulfate ions, and adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from a dialysis device to the dialysis membrane, wherein the unspiked dialysis fluid comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0. In certain embodiments, further provided herein is a method for administering sodium thiosulfate, the method comprising contacting the blood of a subject undergoing hemodialysis with a dialysis fluid spiked with thiosulfate ions during dialysis, adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from a dialysis device to the dialysis membrane, wherein the unspiked dialysis fluid comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0.

[0130] In certain embodiments, further provided herein is a method for administering sodium thiosulfate to a subject undergoing hemodialysis, the method comprising contacting the subject's blood with a dialysis fluid spiked with thiosulfate ions during dialysis, adding an aqueous solution containing sodium thiosulfate to the unspiked dialysis fluid when the unspiked dialysis fluid flows from a dialysis device to the dialysis membrane, wherein the unspiked dialysis fluid comprises a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0.

[0131] In one embodiment, the dialysis fluid spiked with thiosulfate ions is measured for sulfate ions, sulfide ions, in a sample taken from detection point "before" (100) or detection point "after" (110) ​​​​​​​​​​​and undergoes decomposition of thiosulfate ions that is reflected in the sulfite ion content and is less than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4 %, about 3%, about 2%, about 1%, about 0.5%, or about 0.1%. .

[0132] (Combination therapy) In certain embodiments, the sodium thiosulfate provided herein is combined with or used in combination with another therapeutic agent useful for the treatment and / or prevention of the diseases and disorders presented herein.

[0133] As used herein, the term "in combination" includes the use of two or more therapies (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "in combination" does not limit the order in which the therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject having a disease or disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein) may be administered before (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 weeks, about 6 weeks, about 8 weeks, or about 12 weeks before), at the same time as, or after the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject (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 weeks, about 6 weeks, about 8 weeks, or about 12 weeks after). A three-drug combination therapy is also contemplated herein.

[0134] ​​​​​​​​​ As used herein, the term "synergistic" includes combinations of sodium thiosulfate provided herein with another therapy (e.g., a prophylactic or therapeutic agent) that has been or is currently used to treat, prevent, or manage a disease or disorder, and that is more effective than the additive effect of the therapy. The synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) enables the use of a lower dosage of one or more of the therapies and / or the less frequent administration of the therapy in a subject having the disorder. The ability to utilize a lower dosage of a therapy (e.g., a prophylactic or therapeutic agent) and / or to administer the therapy less frequently reduces the toxicity associated with the administration of the therapy to the subject without reducing the efficacy of the therapy in the prevention or treatment of the disorder. Additionally, the synergistic effect may result in improved efficacy of the agent in the prevention or treatment of the disorder. Finally, the synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of any of the therapies alone. The sodium thiosulfate provided herein can be administered in combination with or alternately with another therapeutic agent. In combination therapy, the effective dosages of two or more agents are administered together, while in alternate or sequential therapy, the effective dosages of each agent are administered continuously or sequentially. The dosage to be administered is determined by the absorption rate, inactivation rate, and excretion rate of the drug, as well as other factors known to those of skill in the art. It should be noted that the dosage value also varies depending on the severity of the disease to be alleviated. For any particular subject

[0135] ​​​​​​​​​​​​​​​​However, specific dosing regimens and schedules should be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition. This should be further understood.

[0136] The sodium thiosulfate provided herein is an endothelin converting enzyme (ECE) inhibitor, for example phosphoramidon; a thromboxane receptor antagonist, for example ifetroban; a potassium channel opener; a thrombin inhibitor, for example hirudin; a growth factor inhibitor, for example a modulator of PDGF activity; a platelet activating factor (PAF) antagonist; an antiplatelet agent, for example a GPIIb / IIIa blocker (for example abciximab, eptifibatide, and tirofiban), a P2Y(AC) antagonist (for example clopidogrel, ticlopidine, and CS-747), and aspirin; an anticoagulant, for example warfarin; a low molecular weight heparin, for example enoxaparin; a factor VIIa inhibitor and a factor Xa inhibitor; a renin inhibitor; a neutral endopeptidase (NEP) inhibitor; a vasopeptidase inhibitor (NEP-ACE dual inhibitor), for example omapatrilat and gemopatrilat; an HMG CoA reductase inhibitor, for example pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (alias: itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (alias: rosuvastatin, atavas¬ tatin, or bisvastatin); a squalene synthetase inhibitor; a fibrate; a bile acid sequestrant for example cholestyramine; niacin; an antiatherosclerotic agent, for example an ACAT inhibitor; an MTP inhibitor Agent; calcium channel blocker, e.g., amlodipine besylate; potassium channel a ctivator; alpha - adrenergic agent; beta - adrenergic agent, e.g., car vedilol and metoprolol; anti - arrhythmic agent; diuretic, e.g., chlorothiazide, hydroch lorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, meth yclothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid, ticrynafen, chlortalidone, furosemide, muzolimine, bumetanide, triamterene, amiloride, and spironolactone; thrombolytic agent, e.g., tissue - type plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase ase, prourokinase, and anisoylated plasminogen streptokinase activator - ter complex (APSAC); anti - diabetic agent, e.g., biguanide (e.g., metformin), gluc osidase inhibitor (e.g., acarbose), insulin, meglitinide (e.g., repaglinide), sulfonylurea (e.g., glimepiride, glipyride, and glypidide), thio zolidinedione (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR - gamma agonist; mineralocorticoid receptor antagonist, e.g., spironolactone and eplerenone; growth hormone - releasing factor; aP2 inhibitor; phos phodiesterase inhibitor, e.g., PDE III inhibitor (e.g., cilostazol) and PDE V inhibitor (e.g., sildenafil, tadalafil, and vardenafil); protein tyrosine kinase inhibitor; anti - inflammatory agent; anti - proliferative agent, e.g., methotrexate, FK506 (tacrolimus) ) Mycophenolate mofetil; chemotherapeutic agent; immunosuppressive agent; anti-cancer agent and cytotoxic agent (for example, alkylating agents such as nitrogen mustard, alkyl sulfonate, nitrosourea, ethyleneimine, and triazene); antimetabolites, for example, folic acid antagonists, purine analogs, and pyrimidine analogs; antibiotics, for example, anthracyclines, bleomycin, mitomycin, dactinomycin, and plicamycin; enzymes, for example, L- asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, for example, glucocorticoids (for example, cortisone), estrogen / anti-estrogen agents, andro- gen / anti-androgen agents, progestins, and luteinizing hormone releasing hormone antagonists, and octreotide acetate; microtubule-disruptor agents, for example, ecteinascidin; microtubule stabilizers, for example, pacitaxel, docetaxel, and epothilone A-F; plant-derived products, for example, vinca alkaloids, epipodophyllotoxin, and taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and cyclosporine; steroids, for example, prednisone and dexamethasone; cytotoxic drugs, for example, azathioprine and cyclophosphamide; TNF-alpha inhibitors, for example, tenidap; anti-TNF antibodies or soluble TNF receptors, for example, etanercept, rapamycin, and leflunimide; cyclooxygenase-2 (COX-2) inhibitors, for example, celecoxib and rofecoxib; and various other agents, for example, sodium nitrite, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold, and other various agents, for example, sodium nitrite, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold, Compounds, low molecular weight drugs, low molecular weight vitamins, and platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin, among others, can be administered in combination with another class of compounds.

[0137] The sodium thiosulfate provided herein can be administered in combination with other solutes that are naturally present in human blood, including copper, fluoride ions, iodine, iron, manganese, magnesium, nitrite ions, phosphorus, selenium, and zinc.

[0138] The present disclosure will be better understood by the following non-limiting examples.

Examples

[0139] (Example) As used herein, the symbols and terminology used in these experiments, processes, schemes, and examples are consistent with those used in modern chemical literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry, even though no specific abbreviations are specifically defined. Specifically, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimolar concentration); μM (micromolar concentration); nM (nanomolar concentration); mmol (millimoles); eq. (equivalent); hr or hrs (hours); min (minutes).

[0140] For all of the following experiments and the following examples, standard workups and The purification method can be used. Unless otherwise indicated, all temperatures are in °C (Celsius). It is represented. Unless otherwise specified, all reactions are carried out at room temperature. The methods exemplified in the following examples are intended to illustrate applicable chemistry using specific examples and do not represent the scope of the present invention.

[0141] (Stability experiment) The results of the following stability experiments (Examples 1 to 4) illustrate the instability of thiosulfate ions in an aqueous solution when an acid is added, and also the instability of thiosulfate ions when mixed with a solution containing an acid concentrated solution and a bicarbonate concentrated solution in the preparation of a dialysis fluid for dialysis.

[0142] The concentration of thiosulfate ions in the sample was assayed by ion chromatography. An electrochemical conductivity detector and a Dionex IonPac AS12A analytical column were attached to the ion chromatography apparatus. The sodium thiosulfate content in the tested sample was calculated relative to an external standard of sodium thiosulfate. The United States Pharmacopeia sodium thiosulfate reference standard (item number 1615107) was used as the test standard (United States Pharmacopeia. Rockville, Maryland).

[0143] (Example 1) The chemical safety data sheet of sodium thiosulfate indicates that the chemical decomposes when it comes into contact with an acid (chemical safety data sheet accessed online at http: / / www.thiosulfate.info / downloads / sodiumthiosulfate_msds.pdf).

[0144] Example 1 measures the stability of sodium thiosulfate in an aqueous solution when an acid is added. ​​​​​​​​​​It was carried out to do so. A 60 mg sample of sodium thiosulfate was transferred into a 50 mL volumetric flask. 2 mL of 0.1 N hydrochloric acid was added to the flask. The flask was capped and heated at 80 °C for about 24 hours. After that, the flask was cooled to ambient temperature. 2 mL of 0.1 N sodium hydroxide was added to neutralize the acid, and deionized water was added to make the volume 50 mL. The percentage of thiosulfate ion decomposition in this sample was 28.6%. The information published about the reaction between the acid and thiosulfate ion (https: / / www.quora.com / Why-does-sodium-thiosulphate-react-with-hydrochloric-acid, available online) was consistent with this result, and it was confirmed that sodium thiosulfate decomposes when exposed to acid.

[0145] (Example 2) Example 2 was carried out to measure the stability of sodium thiosulfate in the dialysate bicarbonate concentrate solution. At room temperature, 12500 mg of sodium thiosulfate (a 250 mg / mL solution in 50 mL) was added to 7700 mL of the dialysate bicarbonate concentrate solution. The thiosulfate ion concentration in the dialysate bicarbonate concentrate solution was analyzed by ion chromatography: 1) before the addition of sodium thiosulfate; 2) 5 minutes after the addition of sodium thiosulfate; and 3) 2 hours after the addition of sodium thiosulfate. Since the concentration of sodium thiosulfate did not decrease over time and the concentrations of the decomposition products sulfate ion, sulfite ion, and sulfide ion did not increase over time, the results shown in Table 1 and Table 2 indicate that thiosulfate ion is stable when added to the dialysate bicarbonate concentrate solution. (Table 1: Sodium thiosulfate concentration in the dialysate bicarbonate concentrate)

Table 1

[0146] Example 3 Example 3 shows the effect of sodium thiosulfate from Example 2 when mixed with a concentrated acid solution in a dialysis machine. The stability of thiosulfate in mixtures of concentrated sodium and dialysate bicarbonate solutions was further determined. The dialysis machine was used to dialyze the bicarbonate concentrate solution (thiosulfuric acid solution from Example 2). The dialysis equipment was used in an actual clinical setting to test the dialysis solution (containing sodium phosphate), concentrated acid solution, and purified water. The dialysate is mixed by mixing 1 part of the concentrated acid solution, 1.72 parts of the concentrated bicarbonate solution, The dialysis equipment used in this experiment was Freseni The device was a 2008K hemodialysis machine (Fresenius Medical Care, Waltham, MA). Priming was performed in bypass mode (dialysis fluid rate and ultrafiltration rate set to zero) using saline. After priming, the hemodialysis machine was set to the following settings: blood flow rate 300 mL / min, peritoneum Operated in "treatment mode" with an analyte flow rate of 600 mL / min, an ultrafiltration rate of 0 mL / min, and an ultrafiltration time of 25 minutes. Samples of the mixed dialysate were taken as they left the dialysis machine and analyzed by ion chromatography. The analysis was carried out by.

[0147] The results shown in Table 3 indicate that thiosulfate ions in the concentrated bicarbonate solution of the dialysis fluid act as an acidifier in the dialysis machine. This indicates that the decomposition was almost complete during the process of mixing with the concentrated solution. (Table 3: Concentration of thiosulfate ions in the dialysate after mixing in the hemodialysis device)

Table 3

[0148] (Example 4) Example 4 was conducted to measure the stability of thiosulfate ions when sodium thiosulfate was added to the dialysate after the dialysate was prepared in a Fresenius 2008K hemodialysis device (Fresenius Medical Care, Waltham , MA). The dialysate bicarbonate concentrate solution was prepared by adding one package (650 g) of Centrisol( registered trademark) MB-330 series sodium bicarbonate concentrated powder to 7.7 liters of purified water. The bicarbonate concentrate solution and the acid concentrate solution were mixed by the hemodialysis device at a dilution ratio of 1 part acid concentrate solution, 1.7

[0149] parts bicarbonate concentrate solution, and 42.38 parts purified water. The device was primed in bypass mode (setting the dialysate flow rate and ultrafiltration rate to zero) using physiological saline water. After priming, the hemodialysis device was operated in "treatment mode" using the following settings: blood flow rate 300 mL / min, dialysate flow rate 600 mL / min, ultrafiltration rate 0 mL / min. An aqueous solution of sodium thiosulfate was prepared by dissolving 25 mg of sodium thiosulfate in 1 liter of purified water. Since the obtained sodium thiosulfate solution had a thiosulfate anion concentration of about 17.72 mg / L, this sodium thiosulfate solution met the quality specifications of AAMI for sulfate ions

[0150] (and thiosulfate ions). The sodium thiosulfate solution was added to the Al ​​​​The aris (registered trademark) IV infusion pump (Model 8100, CareFusion, San Diego, CA) was used to directly inject through a valve (Fr esensius Dialysate Sample Valve: Part number 650993) into the dialysate tubing between the hemodialysis device and the dialyzer The valve was placed approximately 8 inches (about 20.3 cm) upstream of the dialyzer (prefilter) in the dialysate tubing. Two sampling ports were placed 4 inches (10.2 cm) upstream (pre-dialyzer sampling port) and 10 inches (25.4 cm) downstream (post-dialyzer sampling port) from the dialyzer to collect samples of dialysate for nitrate ion assay by ion chromatography 。 。

[0151] The infusion pump injected a sodium thiosulfate solution into the tubing at a rate of 250 mL / h (4.16 mL / min) through the valve 。

[0152] Normal saline flowed from the arterial line into the dialyzer at a rate of 300 mL / min and exited the dialyzer through the venous line Samples of normal saline were collected from the venous side of the dialyzer

[0153] The results shown in Table 4 indicate that when the sodium thiosulfate solution mixed with the dialysate in the dialysate tubing is injected into the tubing at the position between the hemodialysis device and the dialysis membrane, thiosulfate ions are stable 。 。 (Table 4: Thiosulfate ion concentrations in the dialysate before and after the sodium thiosulfate solution is added to the dialysate in the dialysate tubing before the dialysate contacts the dialysis membrane) 。

Table 4

[0154] The results shown in Table 4 indicate that if thiosulfate ions are added to the dialysis fluid that is not spiked from the hemodialysis device at the position between the hemodialysis device and the dialysis membrane, the thiosulfate ions can either proceed along or pass through the dialyzer. The above examples are provided to give those skilled in the art a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to those skilled in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference as if each such publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein. The present application provides an invention in the following aspects.

[0155] (Aspect 1) A method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, the method comprising contacting the blood of the subject with a dialysis membrane that is in contact with dialysis fluid spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the non-spiked dialysis fluid when the non-spiked dialysis fluid flows from the hemodialysis device to the dialysis membrane, the non-spiked dialysis fluid contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0. The method according to Aspect 1, wherein the physiological level of the thiosulfate ions in the subject is below about 10 micromolar concentration. All publications, patents, and patent applications cited herein are hereby incorporated by reference as if each such publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein. The present application provides an invention in the following aspects. (Aspect 1) A method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, the method comprising contacting the blood of the subject with a dialysis membrane that is in contact with dialysis fluid spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the non-spiked dialysis fluid when the non-spiked dialysis fluid flows from the hemodialysis device to the dialysis membrane, the non-spiked dialysis fluid contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0. The method according to Aspect 1, wherein the physiological level of the thiosulfate ions in the subject is below about 10 micromolar concentration. (Aspect 1) A method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, the method comprising contacting the blood of the subject with a dialysis membrane that is in contact with dialysis fluid spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the non-spiked dialysis fluid when the non-spiked dialysis fluid flows from the hemodialysis device to the dialysis membrane, the non-spiked dialysis fluid contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0. (Aspect 2) The method according to Aspect 1, wherein the physiological level of the thiosulfate ions in the subject is below about 10 micromolar concentration. (Aspect 1) A method for maintaining the physiological level of thiosulfate ions in a subject undergoing hemodialysis, the method comprising contacting the blood of the subject with a dialysis membrane that is in contact with dialysis fluid spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the non-spiked dialysis fluid when the non-spiked dialysis fluid flows from the hemodialysis device to the dialysis membrane, the non-spiked dialysis fluid contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0. (Aspect 2) The method according to Aspect 1, wherein the physiological level of the thiosulfate ions in the subject is below about 10 micromolar concentration. (Aspect 2) The method according to Aspect 1, wherein the physiological level of the thiosulfate ions in the subject is below about 10 micromolar concentration. The method according to Aspect 1, wherein the physiological level of the thiosulfate ions in the subject is below about 10 micromolar concentration. (Aspect 3) The physiological level of the thiosulfate ion in the subject is from about 500 nanomolar concentration to about 5 micromolar concentration, the method according to Aspect 1. (Aspect 4) The physiological level of the thiosulfate ion in the subject is about 3 micromolar concentration in, the method according to Aspect 1. (Aspect 5) The concentration of the thiosulfate ion in the dialysis fluid spiked with the thiosulfate ion is about 10 micro molar concentration or less, the method according to Aspect 1. (Aspect 6) The concentration of the thiosulfate ion in the dialysis fluid spiked with the thiosulfate ion is from about 500 nano molar concentration to about 5 micromolar concentration, the method according to Aspect 1. (Aspect 7) The concentration of the thiosulfate ion in the dialysis fluid spiked with the thiosulfate ion is about 3 micro molar concentration, the method according to Aspect 1. (Aspect 8) The aqueous solution containing the sodium thiosulfate contains sodium thiosulfate of about 300 mg / L or less , the method according to Aspect 1. (Aspect 9) The water contains thiosulfate ions of about 200 mg / L or less, the method according to Aspect 1. (Aspect 10) Through a valve attached to the pipe at a position before the dialysis fluid pipe is connected to the dialyzer, the aqueous solution containing the sodium thiosulfate is added to the unspiked dialysis fluid, the method according to Aspect 1. (Aspect 11) The unspiked dialysis fluid flows through the dialysis pipe at a rate of about 500 mL / min to about 700 mL / min , the method according to Aspect 10. (Aspect 12) The aspect in which the non-spiked dialysate flows through the dialysis tubing at a rate of about 600 mL / min The method according to 10. (Aspect 13) The method according to aspect 10, wherein the aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate through the valve at a rate of about 100 mL / h to about 550 mL / h. (Aspect 14) The method according to aspect 10, wherein the aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate through the valve at a rate of about 250 mL per hour. (Aspect 15) The method according to aspect 1, wherein the pH of the dialysate spiked with thiosulfate ions is about 7.3 to about 7.5. (Aspect 16) The method according to aspect 1, wherein the pH of the dialysate spiked with thiosulfate ions is about 7.4. (Aspect 17) The method according to aspect 1, wherein the subject is a human with chronic renal failure. (Aspect 18) The method according to aspect 1, wherein the subject is a human with acute renal failure. (Aspect 19) The method according to aspect 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 contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysate spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate when the non-spiked dialysate flows from the dialysis apparatus to the dialysis membrane, the non-spiked dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with thiosulfate ions has a pH greater than about 7.0. (Aspect 21) The physiological level of the thiosulfate ion in the subject is at or below about 10 micromolar concentration, the method according to Aspect 20. (Aspect 22) The physiological level of the thiosulfate ion in the subject is from about 500 nanomolar concentration to about 5 micromolar concentration, the method according to Aspect 20. (Aspect 23) The physiological level of the thiosulfate ion in the subject is about 3 micromolar concentration, the method according to Aspect 20. (Aspect 24) The concentration of the thiosulfate ion in the dialysate spiked with the thiosulfate ion is at or below about 10 micromolar concentration, the method according to Aspect 20. (Aspect 25) The concentration of the thiosulfate ion in the dialysate spiked with the thiosulfate ion is from about 500 nanomolar concentration to about 5 micromolar concentration, the method according to Aspect 20. (Aspect 26) The concentration of the thiosulfate ion in the dialysate spiked with the thiosulfate ion is about 3 micromolar concentration, the method according to Aspect 20. (Aspect 27) The aqueous solution containing the sodium thiosulfate contains sodium thiosulfate at or below about 300 mg / L, the method according to Aspect 20. (Aspect 28) The water contains thiosulfate ion at or below about 200 mg / L, the method according to Aspect 20. (Aspect 29) Before the dialysis fluid tubing is connected to the dialyzer, through a valve attached to the tubing at that position, the aqueous solution containing the sodium thiosulfate is added to the unspiked dialysis fluid, the method according to Aspect 20. (Aspect 30) ​​​​​​​​​The unspiked dialysate flows through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min The method according to embodiment 29. (Embodiment 31) The unspiked dialysate flows through the dialysis tubing at a rate of about 600 mL per minute The method according to embodiment 29. (Embodiment 32) An aqueous solution containing the sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 100 mL / hour to about 550 mL / hour The method according to embodiment 29. (Embodiment 33) An aqueous solution containing the sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 250 mL per hour The method according to embodiment 29. (Embodiment 34) The pH of the dialysate spiked with the thiosulfate ions is about 7.3 to about 7.5, the method according to embodiment 20 The method. (Embodiment 35) The pH of the dialysate spiked with the thiosulfate ions is about 7.4, the method according to embodiment 20 . (Embodiment 36) The subject is a human with chronic renal failure, the method according to embodiment 20. (Embodiment 37) The subject is a human with acute renal failure, the method according to embodiment 20. (Embodiment 38) The subject undergoes dialysis 3 to 7 times per week, the method according to embodiment 20. (Embodiment 39) A method for preventing sudden cardiac death in a subject undergoing dialysis, comprising contacting the blood of the subject with a dialysis membrane that is also in contact with a dialysate spiked with thiosulfate ions during dialysis wherein the unspiked dialysate flows from the dialysis device to the dialysis membrane The method. At times, an aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate, and the non-spiked dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution and the dialysate spiked with the thiosulfate ion has a pH greater than about 7.0, said method. (Aspect 40) The physiological level of the thiosulfate ion in the subject is below about 10 micromolar concentration, the method according to aspect 39. (Aspect 41) The physiological level of the thiosulfate ion in the subject is from about 500 nanomolar concentration to about 5 micromolar concentration, the method according to aspect 39. (Aspect 42) The physiological level of the thiosulfate ion in the subject is about 3 micromolar concentration therein, the method according to aspect 39. (Aspect 43) The concentration of the thiosulfate ion in the dialysate spiked with the thiosulfate ion is about 10 micro molar concentration or less, the method according to aspect 39. (Aspect 44) The concentration of the thiosulfate ion in the dialysate spiked with the thiosulfate ion is from about 500 nano molar concentration to about 5 micromolar concentration, the method according to aspect 39. (Aspect 45) The concentration of the thiosulfate ion in the dialysate spiked with the thiosulfate ion is about 3 micro molar concentration, the method according to aspect 39. (Aspect 46) The aqueous solution containing sodium thiosulfate contains sodium thiosulfate at about 300 mg / L or less , the method according to aspect 39. (Aspect 47) The water contains thiosulfate ion at about 200 mg / L or less, the method according to aspect 39. (Aspect 48) Before the dialysis fluid tubing is connected to the dialyzer, through a valve attached to the tubing, the aqueous solution containing the sodium thiosulfate described above is added to the unspiked dialysis fluid, The method according to embodiment 39. (Embodiment 49) The method according to embodiment 48, wherein the unspiked dialysis fluid flows through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min. The method according to embodiment 48. (Embodiment 50) The method according to embodiment 48, wherein the unspiked dialysis fluid flows through the dialysis tubing at a rate of about 600 mL per minute. The method according to embodiment 48. (Embodiment 51) The method according to embodiment 48, wherein the aqueous solution containing the sodium thiosulfate is added to the unspiked dialysis fluid through the valve at a rate of about 100 mL / hour to about 550 mL / hour. The method according to embodiment 48. (Embodiment 52) The method according to embodiment 48, wherein the aqueous solution containing the sodium thiosulfate is added to the unspiked dialysis fluid through the valve at a rate of about 250 mL per hour. The method according to embodiment 48. (Embodiment 53) The method according to embodiment 39, wherein the pH of the dialysis fluid spiked with the thiosulfate ion is about 7.3 to about 7.5. The method. (Embodiment 54) The method according to embodiment 39, wherein the pH of the dialysis fluid spiked with the thiosulfate ion is about 7.4. . (Embodiment 55) The method according to embodiment 39, wherein the subject is a human with chronic renal failure. (Embodiment 56) The method according to embodiment 39, wherein the subject is a human with acute renal failure. (Embodiment 57) The method according to embodiment 39, wherein the subject undergoes dialysis 3 to 7 times per week. (Embodiment 58) A method for preventing stroke in a subject undergoing dialysis, comprising the blood of the subject contacting during dialysis with a dialysis membrane that is also in contact with a dialysate spiked with thiosulfate ions including, when the unspiked dialysate flows from the dialysis device to the dialysis membrane, adding an aqueous solution containing sodium thiosulfate to the unspiked dialysate, the unspiked dialysate including a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with thiosulfate ions having a pH greater than about 7.0, said method (Aspect 59) wherein the physiological level of the thiosulfate ions in the subject is below about 10 micromolar concentration, the method according to aspect 58 (Aspect 60) wherein the physiological level of the thiosulfate ions in the subject is from about 500 nanomolar concentration to about 5 micromolar concentration, the method according to aspect 58 (Aspect 61) wherein the physiological level of the thiosulfate ions in the subject is about 3 micromolar concentration, the method according to aspect 58 (Aspect 62) wherein the concentration of thiosulfate ions in the dialysate spiked with thiosulfate ions is below about 10 micromolar concentration, the method according to aspect 58 (Aspect 63) wherein the concentration of thiosulfate ions in the dialysate spiked with thiosulfate ions is from about 500 nanomolar concentration to about 5 micromolar concentration, the method according to aspect 58 (Aspect 64) wherein the concentration of thiosulfate ions in the dialysate spiked with thiosulfate ions is about 3 micromolar concentration, the method according to aspect 58 (Aspect 65) wherein the aqueous solution containing sodium thiosulfate contains sodium thiosulfate at about 300 mg / L or less, the method according to aspect 58 ​​​​​​​​​​(Aspect 66) The method according to aspect 58, wherein the water contains thiosulfate ions of about 200 mg / L or less. (Aspect 67) Before the dialysate tubing is connected to the dialyzer, an aqueous solution containing the sodium thiosulfate described above is added to the unspiked dialysate through a valve attached to the tubing. The method according to aspect 58. (Aspect 68) The method according to aspect 67, wherein the unspiked dialysate flows through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min. (Aspect 69) The method according to aspect 67, wherein the unspiked dialysate flows through the dialysis tubing at a rate of about 600 mL per minute. (Aspect 70) The method according to aspect 67, wherein the aqueous solution containing sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 100 mL / hour to about 550 mL / hour. (Aspect 71) The method according to aspect 67, wherein the aqueous solution containing sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 250 mL per hour. (Aspect 72) The method according to aspect 58, wherein the pH of the dialysate spiked with thiosulfate ions is about 7.3 to about 7.5. (Aspect 73) The method according to aspect 58, wherein the pH of the dialysate spiked with thiosulfate ions is about 7.4. (Aspect 74) The method according to aspect 58, wherein the subject is a human with chronic renal failure. (Aspect 75) The method according to aspect 58, wherein the subject is a human with acute renal failure. (Aspect 76) The method according to aspect 58, wherein the subject undergoes dialysis 3 to 7 times per week. (Aspect 77) In a subject undergoing dialysis, for preventing a cardiovascular disease characterized by tissue ischemia including angina pectoris, cerebral vasospasm, claudication, severe ischemic limbs, peripheral vascular disease, and sickle cell crisis, a method comprising contacting the blood of the subject with a dialysis membrane during dialysis that is also in contact with a dialysis fluid spiked with thiosulfate ions, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysis fluid when the unspiked dialysis fluid flows from a dialysis device to the dialysis membrane, the unspiked dialysis fluid contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0. The method as described above. (Aspect 78) The method according to aspect 77, wherein the physiological level of the thiosulfate ions in the subject is below about 10 micromolar concentration. (Aspect 79) The method according to aspect 77, wherein the physiological level of the thiosulfate ions in the subject is from about 500 nanomolar concentration to about 5 micromolar concentration. (Aspect 80) The method according to aspect 77, wherein the physiological level of the thiosulfate ions in the subject is about 3 micromolar concentration. (Aspect 81) The method according to aspect 77, wherein the concentration of thiosulfate ions in the dialysis fluid spiked with thiosulfate ions is below about 10 micromolar concentration. (Aspect 82) The method according to aspect 77, wherein the concentration of thiosulfate ions in the dialysis fluid spiked with thiosulfate ions is from about 500 nanomolar concentration to about 5 micromolar concentration. (Aspect 83) The concentration of thiosulfate ion in the dialysate spiked with the thiosulfate ion is about 3 micro mol / L, the method according to embodiment 77. (Embodiment 84) The aqueous solution containing the sodium thiosulfate contains sodium thiosulfate of about 300 mg / L or less , the method according to embodiment 77. (Embodiment 85) The water contains thiosulfate ions of about 200 mg / L or less, the method according to embodiment 77. (Embodiment 86) Before the dialysate tubing is connected to the dialyzer, through a valve attached to the tubing, the aqueous solution containing the sodium thiosulfate is added to the unspiked dialysate, the method according to embodiment 77. (Embodiment 87) The unspiked dialysate flows through the dialysis tubing at a rate of about 500 mL / min to about 700 mL / min , the method according to embodiment 86. (Embodiment 88) The unspiked dialysate flows through the dialysis tubing at a rate of about 600 mL per minute , the method according to embodiment 86. (Embodiment 89) The aqueous solution containing the sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 100 mL / h to about 550 mL / h, the method according to embodiment 86. (Embodiment 90) The aqueous solution containing the sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 250 mL per hour, the method according to embodiment 86. (Embodiment 91) The pH of the dialysate spiked with the thiosulfate ion is about 7.3 to about 7.5, the method according to embodiment 77 described. (Embodiment 92) The pH of the dialysate spiked with the thiosulfate ion is about 7.4, the method according to embodiment 77 。 (Aspect 93) The method according to aspect 77, wherein the subject is a human with chronic renal failure. (Aspect 94) The method according to aspect 77, wherein the subject is a human with acute renal failure. (Aspect 95) The method according to aspect 77, wherein the subject undergoes dialysis 3 to 7 times per week. (Aspect 96) A method for preventing hypertension, pulmonary hypertension, and renal hypertension in a subject undergoing dialysis, comprising contacting the blood of the subject with a dialysis membrane that is in contact with a dialysis fluid spiked with thiosulfate ions during dialysis, wherein an aqueous solution containing sodium thiosulfate is added to the unspiked dialysis fluid when the unspiked dialysis fluid flows from the dialysis device to the dialysis membrane, the unspiked dialysis fluid contains a mixture of water, an acid concentrate solution, and a bicarbonate salt concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0. during dialysis, and the unspiked dialysis fluid contains a mixture of water, an acid concentrate solution, and a bicarbonate salt concentrate solution, and the dialysis fluid spiked with thiosulfate ions has a pH greater than about 7.0. The method according to aspect 96, wherein the physiological level of thiosulfate ions in the subject is below about 10 micromolar concentration. The method according to aspect 96, wherein the physiological level of thiosulfate ions in the subject is about 500 nanomolar concentration to about 5 micromolar concentration. The method according to aspect 96, wherein the physiological level of thiosulfate ions in the subject is about 3 micromolar concentration. The method according to aspect 96, wherein the concentration of thiosulfate ions in the dialysis fluid spiked with thiosulfate ions is below about 10 micromolar concentration. The method according to aspect 96, wherein the concentration of thiosulfate ions in the dialysis fluid spiked with thiosulfate ions is below about 10 micromolar concentration. (Aspect 97) The method according to aspect 96, wherein the physiological level of thiosulfate ions in the subject is below about 10 micromolar concentration. The method according to aspect 96, wherein the physiological level of thiosulfate ions in the subject is about 500 nanomolar concentration to about 5 micromolar concentration. (Aspect 98) The method according to aspect 96, wherein the physiological level of thiosulfate ions in the subject is about 3 micromolar concentration. The method according to aspect 96, wherein the physiological level of thiosulfate ions in the subject is about 3 micromolar concentration. (Aspect 99) The method according to aspect 96, wherein the physiological level of thiosulfate ions in the subject is about 3 micromolar concentration. The method according to aspect 96, wherein the physiological level of thiosulfate ions in the subject is about 3 micromolar concentration. (Aspect 100) The method according to aspect 96, wherein the concentration of thiosulfate ions in the dialysis fluid spiked with thiosulfate ions is below about 10 micromolar concentration. The method according to aspect 96, wherein the concentration of thiosulfate ions in the dialysis fluid spiked with thiosulfate ions is below about 10 micromolar concentration. (Aspect 101) The concentration of thiosulfate ions in the dialysate spiked with the thiosulfate ions is about 500 nano mol / L to about 5 micromol / L, the method according to embodiment 96. (Embodiment 102) The concentration of thiosulfate ions in the dialysate spiked with the thiosulfate ions is about 3 micro mol / L, the method according to embodiment 96. (Embodiment 103) The aqueous solution containing the sodium thiosulfate contains sodium thiosulfate of about 300 mg / L or less , the method according to embodiment 96. (Embodiment 104) The water contains thiosulfate ions of about 200 mg / L or less, the method according to embodiment 96. (Embodiment 105) Through a valve attached to the pipe at a position before the dialysis fluid pipe is connected to the dialyzer, the aqueous solution containing the sodium thiosulfate is added to the unspiked dialysate, the method according to embodiment 96. (Embodiment 106) The unspiked dialysate flows through the dialysis pipe at a rate of about 500 mL / min to about 700 mL / min , the method according to embodiment 105. (Embodiment 107) The unspiked dialysate flows through the dialysis pipe at a rate of about 600 mL per minute , the method according to embodiment 105. (Embodiment 108) The aqueous solution containing the sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 100 mL / h to about 550 mL / h , the method according to embodiment 105. (Embodiment 109) The aqueous solution containing the sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 250 mL per hour , the method according to embodiment 105. (Embodiment 110) The method according to embodiment 96, wherein the pH of the dialysate spiked with the thiosulfate ion is from about 7.3 to about 7.5. Method. (Embodiment 111) The method according to embodiment 96, wherein the pH of the dialysate spiked with the thiosulfate ion is about 7.4. . (Embodiment 112) The method according to embodiment 96, wherein the subject is a human with chronic renal failure. (Embodiment 113) The method according to embodiment 96, wherein the subject is a human with acute renal failure. (Embodiment 114) The method according to embodiment 96, wherein the subject undergoes dialysis 3 to 7 times per week. (Embodiment 115) A method for preventing atherosclerosis in a subject undergoing dialysis, wherein the blood of the subject is contacted with a dialysis membrane that is also in contact with a dialysate spiked with thiosulfate ions during dialysis, and an aqueous solution containing sodium thiosulfate is added to the unspiked dialysate when the unspiked dialysate flows from the dialysis device to the dialysis membrane, and the unspiked dialysate contains a mixture of water, an acid concentrate solution, and a bicarbonate concentrate solution, and the dialysate spiked with the thiosulfate ion has a pH greater than about 7.0. The method described above. Method. (Embodiment 116) The method according to embodiment 115, wherein the physiological level of the thiosulfate ion in the subject is at or below about 10 micromolar concentration. Method. (Embodiment 117) The method according to embodiment 115, wherein the physiological level of the thiosulfate ion in the subject is from about 500 nanomolar concentration to about 5 micromolar concentration. (Embodiment 118) The method according to embodiment 115, wherein the physiological level of the thiosulfate ion in the subject is about 3 micromolar concentration. The method according to aspect 115. (Aspect 119) The concentration of thiosulfate ion in the dialysate spiked with the thiosulfate ion is about 10 micro mol / L or less. The method according to aspect 115. (Aspect 120) The concentration of thiosulfate ion in the dialysate spiked with the thiosulfate ion is about 500 nano mol / L to about 5 micromol / L. The method according to aspect 115. (Aspect 121) The concentration of thiosulfate ion in the dialysate spiked with the thiosulfate ion is about 3 micro mol / L. The method according to aspect 115. (Aspect 122) The aqueous solution containing sodium thiosulfate contains sodium thiosulfate of about 300 mg / L or less . The method according to aspect 115. (Aspect 123) The water contains thiosulfate ion of about 200 mg / L or less. The method according to aspect 115. (Aspect 124) Before the dialysate pipe is connected to the dialyzer, through a valve attached to the pipe, the aqueous solution containing the above sodium thiosulfate is added to the unspiked dialysate. The method according to aspect 115. (Aspect 125) The unspiked dialysate flows through the dialysis pipe at a rate of about 500 mL / min to about 700 mL / min . The method according to aspect 124. (Aspect 126) The unspiked dialysate flows through the dialysis pipe at a rate of about 600 mL per minute . The method according to aspect 124. (Aspect 127) The aqueous solution containing sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 100 mL / h to about 550 mL / h. The method according to aspect 124. ​ (Aspect 128) The aqueous solution containing the sodium thiosulfate is added to the unspiked dialysate through the valve at a rate of about 250 mL per hour, according to the method described in Aspect 124. (Aspect 129) The pH of the dialysate spiked with the thiosulfate ions is about 7.3 to about 7.5, according to the method described in Aspect 115. (Aspect 130) The pH of the dialysate spiked with the thiosulfate ions is about 7.4, according to the method described in Aspect 115. (Aspect 131) The subject is a human with chronic renal failure, according to the method described in Aspect 115. (Aspect 132) The subject is a human with acute renal failure, according to the method described in Aspect 115. (Aspect 133) The subject undergoes dialysis 3 to 7 times per week, according to the method described in Aspect 115.​​​

Claims

1. To maintain physiological levels of thiosulfate in subjects undergoing hemodialysis Sodium thiosulfate, water, concentrated acid solution, and concentrated bicarbonate solution for use in a method for 1. A medical dialysis solution spiked with thiosulfate ions comprising a solution comprising: The method also includes contacting the subject's blood with a medicated dialysate spiked with thiosulfate ions. contacting the dialysis membrane with a dialysis membrane containing the dialysis solution during dialysis; the thiosulfate spiked medicinal dialysate has a pH greater than about 7.0; and The concentration of thiosulfate ions in the pharmaceutical dialysis solution spiked with thiosulfate ions is 100 μg / mL. sub-100 molar concentration, and The thiosulfate ion spiked medicinal dialysate is then administered to the subject to deliver copper, fluoride, iodide, and other ions. One or more of uranyl, iron, manganese, magnesium, nitrite, phosphorus, selenium, and zinc It is used to be administered in conjunction with A medicinal dialysis solution spiked with said thiosulfate ions.

2. For use in a method for preventing myocardial infarction in a subject undergoing dialysis Thiosulfate ion containing sodium thiosulfate, water, concentrated acid solution, and concentrated bicarbonate solution. A spiked medicinal dialysis solution comprising: The method also includes contacting the subject's blood with a medicated dialysate spiked with thiosulfate ions. contacting the dialysis membrane with a dialysis membrane containing the dialysis solution during dialysis; the thiosulfate spiked medicinal dialysate has a pH greater than about 7.0; and The concentration of thiosulfate ions in the pharmaceutical dialysis solution spiked with thiosulfate ions is 100 μg / mL. sub-100 molar concentration, and The thiosulfate ion spiked medicinal dialysate is then administered to the subject to deliver copper, fluoride, iodide, and other ions. One or more of uranyl, iron, manganese, magnesium, nitrite, phosphorus, selenium, and zinc It is used to be administered in conjunction with A medicinal dialysis solution spiked with said thiosulfate ions.

3. Use in a method for preventing sudden cardiac death in a subject undergoing dialysis. Thiosulfate ion exchanger containing sodium thiosulfate, water, concentrated acid solution, and concentrated bicarbonate solution for the 2. A medicated dialysis solution spiked with nicotinamide, comprising: The method also includes contacting the subject's blood with a medicated dialysate spiked with thiosulfate ions. contacting the dialysis membrane with a dialysis membrane containing the dialysis solution during dialysis; the thiosulfate spiked medicinal dialysate has a pH greater than about 7.0; and The concentration of thiosulfate ions in the pharmaceutical dialysis solution spiked with thiosulfate ions is 100 μg / mL. sub-100 molar concentration, and The thiosulfate ion spiked medicinal dialysate is then administered to the subject to deliver copper, fluoride, iodide, and other ions. One or more of uranyl, iron, manganese, magnesium, nitrite, phosphorus, selenium, and zinc It is used to be administered in conjunction with A medicinal dialysis solution spiked with said thiosulfate ions.

4. 2. A method for preventing stroke in a subject undergoing dialysis. A spatula containing sodium thiosulfate, water, concentrated acid solutions, and concentrated bicarbonate solutions. A medicinal dialysis solution comprising: The method also includes contacting the subject's blood with a medicated dialysate spiked with thiosulfate ions. contacting the dialysis membrane with a dialysis membrane containing the dialysis solution during dialysis; the thiosulfate spiked medicinal dialysate has a pH greater than about 7.0; and The concentration of thiosulfate ions in the pharmaceutical dialysis solution spiked with thiosulfate ions is 100 μg / mL. sub-100 molar concentration, and The thiosulfate ion spiked medicinal dialysate is then administered to the subject to deliver copper, fluoride, iodide, and other ions. One or more of uranyl, iron, manganese, magnesium, nitrite, phosphorus, selenium, and zinc It is used to be administered in conjunction with A medicinal dialysis solution spiked with said thiosulfate ions.

5. Angina pectoris, cerebral vasospasm, claudication, critical limb ischemia, and peripheral vascular disease in subjects undergoing dialysis and for preventing cardiovascular disease characterized by tissue ischemia, including sickle cell crisis. Sodium thiosulfate, water, concentrated acid solution, and concentrated bicarbonate solution for use in the method A pharmaceutical dialysis solution spiked with thiosulfate ions comprising: The method also includes contacting the subject's blood with a medicated dialysate spiked with thiosulfate ions. contacting the dialysis membrane with a dialysis membrane containing the dialysis solution during dialysis; the thiosulfate spiked medicinal dialysate has a pH greater than about 7.0; and The concentration of thiosulfate ions in the pharmaceutical dialysis solution spiked with thiosulfate ions is 100 μg / mL. sub-micromolar, and The thiosulfate ion spiked medicinal dialysate is then administered to the subject to deliver copper, fluoride, iodide, and other ions. One or more of uranyl, iron, manganese, magnesium, nitrite, phosphorus, selenium, and zinc It is used to be administered in conjunction with A medicinal dialysis solution spiked with said thiosulfate ions.

6. Preventing hypertension, pulmonary hypertension, and renal hypertension in subjects undergoing dialysis Sodium thiosulfate, water, concentrated acid solution, and concentrated bicarbonate for use in a method for 1. A medical dialysis solution spiked with thiosulfate ions comprising a dialysis solution, comprising: The method also includes contacting the subject's blood with a medicated dialysate spiked with thiosulfate ions. contacting the dialysis membrane with a dialysis membrane containing the dialysis solution during dialysis; the thiosulfate spiked medicinal dialysate has a pH greater than about 7.0; and The concentration of thiosulfate ions in the pharmaceutical dialysis solution spiked with thiosulfate ions is 100 μg / mL. sub-micromolar, and The thiosulfate ion spiked medicinal dialysate is then administered to the subject to deliver copper, fluoride, iodide, and other ions. One or more of uranyl, iron, manganese, magnesium, nitrite, phosphorus, selenium, and zinc It is used to be administered in conjunction with A medicinal dialysis solution spiked with said thiosulfate ions.

7. In a method for preventing atherosclerosis in a subject undergoing dialysis Thiosulfate, including sodium thiosulfate, water, concentrated acid solutions, and concentrated bicarbonate solutions for use in 1. A medicinal dialysate spiked with sulfate ions, comprising: The method also includes contacting the subject's blood with a medicated dialysate spiked with thiosulfate ions. contacting the dialysis membrane with a dialysis membrane containing the dialysis solution during dialysis; the thiosulfate spiked medicinal dialysate has a pH greater than about 7.0; and The concentration of thiosulfate ions in the pharmaceutical dialysis solution spiked with thiosulfate ions is 100 μg / mL. sub-micromolar, and The thiosulfate ion spiked medicinal dialysate is then administered to the subject to deliver copper, fluoride, iodide, and other ions. One or more of uranyl, iron, manganese, magnesium, nitrite, phosphorus, selenium, and zinc It is used to be administered in conjunction with A medicinal dialysis solution spiked with said thiosulfate ions.

8. The physiological level of the thiosulfate ion in the subject is greater than or equal to about 10 micromolar. The pharmaceutical dialysis solution spiked with thiosulfate ions according to any one of claims 1 to 7, wherein 。

9. The physiological level of thiosulfate ion in the subject is between about 500 nanomolar and about 5 The thiosulfate ion spiked solution according to any one of claims 1 to 7, which is in micromolar concentration. A medicinal dialysis solution.

10. The physiological level of thiosulfate ion in the subject is about 3 micromolar. The pharmaceutical dialysis solution spiked with thiosulfate ions according to any one of claims 1 to 7.

11. The concentration of thiosulfate ions in the pharmaceutical dialysis solution spiked with thiosulfate ions is about 10 times higher than that of the pharmaceutical dialysis solution spiked with thiosulfate ions. Spiked with thiosulfate ions according to any one of claims 1 to 10, which is submicromolar. A medicinal dialysis solution.

12. The concentration of thiosulfate ions in the thiosulfate-spiked medicinal dialysis solution is about 500 The thiosulfate of any one of claims 1 to 10, which is in a nanomolar to about 5 micromolar concentration. Medicinal dialysate spiked with ions.

13. The concentration of thiosulfate ions in the medicinal dialysis solution spiked with thiosulfate ions is about 3 mg / mL.

11. The method of claim 1, further comprising: Medicated dialysis fluid.

14. The pH of the thiosulfate spiked medical dialysate is about 7.3 to about 7.

5. A pharmaceutical dialysis solution spiked with thiosulfate ions according to any one of claims 1 to 13.

15. The method of any one of claims 1 to 13, wherein the pH of the thiosulfate spiked medicinal dialysate is about 7.

4. A pharmaceutical dialysis solution spiked with thiosulfate ions according to any one of claims 1 to 4.

16. The thiosulfate ionomer according to any one of claims 1 to 15, wherein the subject is a human suffering from chronic renal failure. Medicated dialysate spiked with nicotine.

17. The thiosulfate ionomer according to any one of claims 1 to 15, wherein the subject is a human suffering from acute renal failure. Medicated dialysate spiked with nicotine.

18. The thiourea compound according to any one of claims 1 to 17, wherein the subject undergoes dialysis 3 to 7 times per week. Medicated dialysate spiked with sulfate ions.

19. A dialysis fluid pipe connecting a dialysis device and a dialyzer having a dialysis membrane according to any one of claims 1 to 7. A method for preparing a pharmaceutical dialysis solution spiked with thiosulfate ions according to any one of claims 1 to 4, ： Pumping unspiked dialysate from the dialysis machine into the dialysate tubing; flowing into the membrane; and As the unspiked dialysate flows from the dialyzer to the dialysis membrane, sodium thiosulfate is released. The thorium-containing aqueous solution is added to the dialysis solution pipe at a position before the connection part of the dialysis solution pipe with the dialyzer. adding to the unspiked dialysis fluid through a valve attached to the tubing. 、 The unspiked dialysate is a mixture of water, an acid-concentrated solution, and a bicarbonate-concentrated solution. The method comprising:

20. The aqueous solution containing sodium thiosulfate contains about 300 mg / L or less of sodium thiosulfate.

20. The method of claim 19.

21. 20. The method of claim 19, wherein the water contains about 200 mg / L or less of thiosulfate ions.

22. The unspiked dialysate flows through the dialysate tubing at a rate of about 500 mL / min to about 700 mL / min. The method of any one of claims 19 to 21, wherein the flow is

23. The unspiked dialysate flows through the dialysate tubing at a rate of about 600 mL / min. The method according to any one of claims 19 to 21.

24. The aqueous solution containing sodium thiosulfate is then allowed to flow through the valve into the unspiked permeate. The method according to any one of claims 19 to 21, wherein the precipitation solution is added at a rate of about 100 mL / hour to about 550 mL / hour. method.

25. The aqueous solution containing sodium thiosulfate is then allowed to flow through the valve into the unspiked permeate. The method of any one of claims 19 to 21, wherein the precipitation solution is added at a rate of about 250 mL / hour.

26. The thiosulfate spiked medicinal dialysate is administered to the subject along with copper. The method according to any one of claims 19 to 25, wherein the method is used to

27. The thiosulfate ion spiked medicinal dialysate is delivered to the subject together with fluoride ions. The method according to any one of claims 19 to 25, wherein the method is administered to both.

28. The thiosulfate spiked medicinal dialysate is administered to the subject along with iodine. The method according to any one of claims 19 to 25, wherein the method is used as follows:

29. The thiosulfate spiked medicinal dialysate is administered to the subject along with iron. The method according to any one of claims 19 to 25, wherein the method is used to

30. The thiosulfate spiked medicinal dialysate is administered to the subject along with manganese. The method according to any one of claims 19 to 25, wherein the method is administered as described above.

31. The thiosulfate ion spiked medicinal dialysate is administered to the subject along with magnesium. The method according to any one of claims 19 to 25, wherein the method is administered to

32. The thiosulfate spiked medicinal dialysate is delivered to the subject along with nitrite. The method according to any one of claims 19 to 25, wherein the method is administered to

33. The thiosulfate spiked medicinal dialysate is administered to the subject along with phosphorus. The method according to any one of claims 19 to 25, wherein the method is used to

34. The thiosulfate spiked medicinal dialysate is administered to the subject along with selenium. The method according to any one of claims 19 to 25, wherein the method is used as follows:

35. The thiosulfate spiked medicinal dialysate is administered to the subject along with zinc. The method according to any one of claims 19 to 25, wherein the method is used to

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