Use of sodium thiosulfate during dialysis

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.

[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 of administering sodium thiosulfate, which is pharmaceutically acceptable, to a subject undergoing hemodialysis.

Background Art

[0003] (Background) Patients with chronic kidney disease (CKD) suffer from deterioration of kidney function, which results in a reduction in the excretion of metabolic waste products. The accumulation of metabolic waste products can sometimes threaten life within a few days. Patients with little or no remaining kidney function are considered to have "end-stage renal disease." Thus, such patients need an alternative means of excreting waste products 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 ​​​​​​​​​​​The concentration of a solute present in a liquid depends on its permeability; due to permeability, the solute can move out of the high-concentration liquid. It is forced to enter a low-concentration liquid through the pores of the precipitated film, thus reaching equilibrium.

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

[0006] Blood contains thiosulfate ions (S2O3 2- It contains low molecular weight solutes such as thiosulfate anion. It has a molecular weight of approximately 112.13 daltons. In the body, thiosulfate ions are present in small amounts of cyanide. It converts ions into harmless products. Thiosulfate ions are converted into sulfate ions (SO4). 2- ) is metabolized (This can also be the case. (References by Gunnison et al., Environ. Res. 1981, 24, 432-443; References by Skarzynski et al.) , Nature 1959, 184, 994-995).

[0007] The Association for the Advancement of Medical Instruments The dialysis organization (AAMI) established quality specification limits for sulfate ion content in water used for dialysis (1 (Maximum 100 mg per liter, i.e., 100 ppm) (#ANSI / AAMI / ISO 13959:2009). Also, AA MI stipulated 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, and acetic acid It is precipitated using barium chloride in a medium. The absorbance of the barium sulfate suspension is measured using a photometer. The sulfate anion concentration is measured and determined by comparing the reading with a standard curve. (American Public Health Association, https: / / law.resource.org / pub / us / cfr / ibr / 002 / apha.meth (Available online as od.4500-so42.1992.pdf). In this test method, sulfate ions and thiosulfate ions are used. The on and off are not distinguished. Instead, the test method actually detects sulfate ions and thiosulfate ions. This involves the measurement of both ions. Therefore, the quality specifications for sulfate ions in AAMI are actually used in dialysis. This is the limit on the sum of sulfate ions and thiosulfate ions that can be present in water.

[0008] Coronary artery bypass patients have reduced plasma thiosulfate ion levels (Ivankovich et al.) References, Anesthesiology 1983, 58, 11-17). Coronary artery bypass surgery is used for atherosclerosis. A cardiovascular disease characterized by severe narrowing and occlusion of the cardiac arteries caused by chemoembolism. It is often recommended for patients with atherosclerosis. Atherosclerosis is a condition in which the walls of large and medium-sized arteries... This is a chronic inflammatory state that begins with the formation of calcified plaque within the artery. Calcium mineralization of the lumen promotes and strengthens plaque formation, narrowing the blood vessels. It causes miniaturization (Kalampogias et al., Med. Chem. 2016, 12, 103-113). Atheroma Hardened plaque can cause significant narrowing in one or more coronary arteries. Myocardial infarction occurs when blood flow within the pulse is completely blocked by atherosclerotic plaque. To occur.

[0009] Cardiovascular disease accounts for more than half of all deaths among patients requiring chronic hemodialysis (G The literature of oら, 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 It increased both during the dialysis procedure itself and after treatment (Bleyer et al. The literature of, 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 in the subsequent hours of the 4-hour hemodialysis session (Freise et al. The literature of, 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. In addition, the present disclosure provides a method for in a subject undergoing hemodialysis, atherosclerosis, myocardial infarction, sudden cardiac death, stroke, cardiovascular disease, hypertension ​The present invention provides a method for preventing pulmonary hypertension and / or renal hypertension. This paper proposes a method for administering sodium thiosulfate to patients undergoing hemodialysis. To provide.

[0014] In one embodiment, the invention provided herein is for subjects undergoing hemodialysis. A method for maintaining physiological levels of thiosulfate ions in the blood of the subject. This is brought into contact with the dialysis membrane, which is also in contact with the dialysate spiked with thiosulfate ions, during dialysis. This includes the process where, when the unspiked dialysate flows from the dialyzer to the dialysate membrane, thio An aqueous solution containing sodium sulfate is added to the non-spiked dialysate, and the spikes The dialysate that has not been treated contains a mixture of water, an acid concentrate, and a bicarbonate concentrate, and the The method is characterized in that the dialysate spiked with sulfuric acid ions has a pH greater than approximately 7.0.

[0015] Furthermore, in one embodiment, the one provided herein is a patient undergoing hemodialysis. A method for maintaining physiological levels of thiosulfate ions in elephants, the subject This involves bringing the blood into contact with a dialysate spiked with thiosulfate ions during dialysis. When unpiked dialysate flows from the dialyzer to the dialysate membrane, sodium thiosulfate is used. The aqueous solution containing the solution is added to the non-spiked dialysate, and the non-spiked dialysate However, it contains a mixture of water, an acid concentrate, and a bicarbonate concentrate, and the thiosulfate ion is The method is characterized in that the piked dialysate has a pH greater than approximately 7.0.

[0016] Furthermore, in one embodiment, the invention provided herein is for a subject undergoing dialysis. In this, a method for preventing atherosclerosis, wherein the blood of the subject is thio The dialysis membrane, which is also in contact with the dialysate spiked with sulfate ions, is brought into contact with the dialysis membrane during dialysis. When the unspiked dialysate flows from the dialyzer to the dialysate membrane, sodium thiosulfate is included. An aqueous solution containing thorium is added to the non-spiked dialysate, and the spiked The dialysis fluid contains a mixture of water, an acid concentrate, and a bicarbonate concentrate, and the thiosulfate The method is characterized in that the dialysate spiked with ions has a pH greater than approximately 7.0.

[0017] Furthermore, in one embodiment, the invention provided herein is for a subject undergoing dialysis. In this method for preventing myocardial infarction, the blood of the subject is treated with thiosulfate ions. This includes bringing the dialysis membrane, which is also in contact with the piked dialysate, into contact with the spy during dialysis. When unfiltered dialysis fluid flows from the dialysis machine to the dialysis membrane, sodium thiosulfate is present. The aqueous solution is added to the non-spiked dialysate, and the non-spiked dialysate is The mixture comprises water, an acid concentrate, and a bicarbonate concentrate, and the thiosulfate ion is used to spy The method is characterized in that the dialysis fluid has a pH greater than approximately 7.0.

[0018] Furthermore, in one embodiment, the invention provided herein is for a subject undergoing dialysis. In this method for preventing sudden cardiac death, the blood of the subject is treated with thiosulfate io This includes bringing the dialysis membrane, which is also in contact with the dialysis fluid that has been spiked with a rayon, into contact with the dialysis membrane during dialysis, When unspiked dialysate flows from the dialyzer to the dialysate membrane, sodium thiosulfate An aqueous solution containing the above is added to the non-spiked dialysate, and the non-spiked dialysate is then removed. The liquid contains a mixture of water, an acid concentrate, and a bicarbonate concentrate, and the thiosulfate ion The method is characterized in that the spiked dialysate has a pH greater than approximately 7.0.

[0019] Furthermore, in one embodiment, the invention provided herein is for a subject undergoing dialysis. In this method for preventing stroke, the blood of the subject is spat with thiosulfate ions. The dialysis membrane, which is also in contact with the dialysis fluid that has been heated, is brought into contact with the spike during dialysis, and the spike When untreated dialysate flows from the dialyzer to the dialysate membrane, water containing sodium thiosulfate The solution is added to the non-spiked dialysate, and the non-spiked dialysate is water The mixture comprises an acid concentrate and a bicarbonate concentrate, and the thiosulfate ions spike The method is such that the resulting dialysate has a pH greater than approximately 7.0.

[0020] Furthermore, in one embodiment, the invention provided herein is for a subject undergoing dialysis. In this context, angina pectoris, cerebral vasospasm, claudication, severe limb ischemia, peripheral vascular disease, and sickle cell carcinoma A method for preventing cardiovascular disease characterized by tissue ischemia including blood, wherein the blood of the target is... The liquid comes into contact with the dialysis membrane, which is also in contact with the dialysate spiked with thiosulfate ions, during dialysis. This includes the process of allowing the unspiked dialysate to flow from the dialyzer to the dialysate membrane, An aqueous solution containing sodium thiosulfate is added to the unspiked dialysate, and the spike The unprocessed dialysate contains a mixture of water, acid concentrate, and bicarbonate concentrate, and The method is characterized in that the dialysate spiked with thiosulfate ions has a pH greater than approximately 7.0.

[0021] Furthermore, in one embodiment, the invention provided herein is for a subject undergoing dialysis. In this regard, a method for preventing hypertension, pulmonary hypertension, and renal hypertension, Elephant blood is in contact with a dialysis membrane that is also in contact with dialysis fluid spiked with thiosulfate ions during dialysis. This includes bringing the unspiked dialysate into contact with the dialysate, which flows from the dialyzer to the dialysate membrane. Sometimes, an aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate, The unspiked dialysate contains a mixture of water, acid concentrate, and bicarbonate concentrate. and the dialysate spiked with thiosulfate ions has a pH greater than approximately 7.0, by the method described above. be.

[0022] Furthermore, in one embodiment, the invention provided herein is for a subject undergoing dialysis. A method for administering sodium thiosulfate, wherein the blood of the subject is treated with thiosulfate ions. This includes bringing the dialysis membrane, which is also in contact with the dialysis fluid that has been spiked, into contact with the dialysis membrane during dialysis, and the When unpiked dialysate flows from the dialyzer to the dialysate membrane, sodium thiosulfate is used. The aqueous solution containing the solution is added to the non-spiked dialysate, and the non-spiked dialysate However, it contains a mixture of water, an acid concentrate, and a bicarbonate concentrate, and the thiosulfate ion is The method is characterized in that the piked dialysate has a pH greater than approximately 7.0. [Brief explanation of the drawing]

[0023] Brief explanation of the drawing [Figure 1]Figure 1 is a schematic diagram of the elements of the flow paths for dialysate, patient blood, and aqueous solution containing sodium thiosulfate. (10) Dialysis machine; (20) Acid concentrate solution; (30) Bicarbonate concentrate solution; (40) Aqueous solution containing sodium thiosulfate; (50) Flow of aqueous solution containing sodium thiosulfate; (60) Dialysis piping; (70) Valve; (80) Dialyzer; (90) Dialysis membrane; (100) Detection point "before" the dialysis membrane; (110) Detection point "after" the dialysis membrane; (120) Detection point "V"; (130) Detection point "A"; (140) Used dialysate. [Modes for carrying out the invention]

[0024] (Detailed explanation) The following detailed explanation should not be taken as limiting, but merely as provided herein. This is done for the purpose of explaining the embodiment.

[0025] To facilitate understanding of the disclosures contained herein, several terms are defined below. ru.

[0026] The nomenclature used herein, as well as the inorganic and analytical chemistry described herein, are generally used. Laboratory methods in organic chemistry, medicinal chemistry, and pharmacology are well known in the relevant technical fields. This is a commonly used method. Unless otherwise defined, all technical uses as used herein Words and scientific terms are generally understood as they would be commonly understood by those skilled in the art to which this disclosure pertains. They have the same meaning. If there are multiple definitions of a term used herein, they are not otherwise defined. Unless otherwise noted, the information in this section takes precedence.

[0027] The term "subject" refers to primates (e.g., humans), cattle, sheep, goats, horses, dogs, etc. This refers to animals including, but not limited to, cows, rabbits, rats, or mice. The term "patient" is used herein to refer to mammalian subjects such as human subjects, for example. They are used interchangeably. In one embodiment, the subject is the disease presented herein. Having a disease, disability, or illness, or being at risk thereof. In another embodiment, the subject is: Having a disease, disability, or illness, or being at risk of having such disease, disability, or illness, Alternatively, the symptoms may be treated, prevented, or improved by the administration of sodium thiosulfate. In another embodiment, the subjects are patients with end-stage renal disease (ESRD) who are undergoing regular hemodialysis. The subject is a patient. In another embodiment, the subject has waste products in his blood reduced to a safe level. These are patients who are undergoing dialysis because they have some or no kidney function left. In this embodiment, the steady-state plasma concentration of thiosulfate ions in subjects undergoing hemodialysis is As a result of hemodialysis lasting approximately 3 to 5 hours, the reduction is quite significant. In another embodiment, the subject is , the patient has plasma levels of thiosulfate ions that are below normal physiological levels.

[0028] The terms “to treat,” “to treat,” and “treatment” refer to a disorder, disease, or To alleviate or suppress one or more of the symptoms of a disease, or the disorder, illness, or disease associated with the disease. to do; or to reduce or eliminate the cause of the disorder, disease, or illness itself. It means to include.

[0029] The terms "prevent," "preventing," and "prevention" are used to describe a disorder, disease, or To delay and / or prevent the onset of a disease and / or its associated symptoms; to treat a disease To prevent acquisition; or to reduce the risk of the subject acquiring a disability, disease, or illness. This means including methods to make it happen.

[0030] Generally, conventional dialysis fluids, including recently patented ones, are considered to be proprietary. It is defined as any known formulation, regardless of the specific. Many of these are specific It is specially formulated to meet the requirements of the type. For example, U.S. Patent No. 6,436,969 is A U.S. Patent No. 5,869,444 discloses a composition containing a GE inhibitor, and describes an osmotically effective PEP A solution containing a mixture of cydos is claimed, and U.S. Patents No. 6,306,836 and No. 6,380,163 are claimed. We disclose a peritoneal dialysis solution that utilizes amino acids to achieve osmotic balance.

[0031] The term "bicarbonate concentrate" refers to an aqueous solution containing bicarbonate, or bicarbonate and ANSI / AAM Meets or exceeds the current hemodialysis water quality standards described in I / ISO#13959:2009. This refers to a mixture with water (hereinafter referred to as "purified water"). Minntech Ren, Minneapolis, Minnesota al Systems supplies Centrisol® bicarbonate concentrate powder MB-330. Each packet of (Registered Trademark) Bicarbonate Concentrate Powder 45X MB-330 contains approximately 650 grams of sodium bicarbonate. It contains the contents of the bag, which are mixed with purified water to form approximately 8 liters of concentrated dialysis fluid bicarbonate solution. A liquid is produced.

[0032] The term "acid concentrate" refers to an aqueous solution containing an acid or a mixture of an acid and purified water. Typical examples include hydrochloric acid, acetic acid, citric acid, and peracetic acid, but are not limited to these. No. Minntech Renal Systems in Minneapolis, Minnesota, has developed Centrisol® acid concentrate. We supply the reduced product 45X SB-111. Each packet of Centrisol® acid concentrate powder 45X contains acetic acid. Ions, bicarbonate ions, calcium, chloride ions, glucose, magnesium, and potassium It contains um. 1 volume part of acid concentrate is mixed with 1.72 volumes of MB-330 series. Mix sodium bicarbonate concentrate with 42.28 parts by volume of purified water to make 45 parts by volume of dialysis solution. It should be prepared.

[0033] The term "dialysis machine" refers to a machine equipped with an external circuit and a dialysate circuit. This includes piping, blood pumps, heparin pumps, kidneys, and monitoring of blood flow, blood pressure, and bubbles. It also includes: the dialysate circuit, dialysate piping, dialysate pump, and dialysate flow, dialysis. The system also includes monitoring of fluid pressure and bubbles. Currently, dialysis machines use concentrated acid solution and bicarbonate. An automated mixing and supply system that produces dialysate by mixing concentrated salt solution and purified water in a specific ratio. An automated proportioning system is used. The concentrated dialysate solution (acid and bicarbonate) is used. Typically, it is used as a pre-mixed powder (as bicarbonate powder) added to purified water in large storage tanks. Either as a ready-to-use solution (as an acid concentrate), according to the manufacturer. It is supplied. The concentrated dialysate solution is pumped into the chamber of the dialyzer, where, These are mixed with purified water to create dialysate.

[0034] The term "dialysis fluid piping" refers to the piping that connects the dialysis machine and dialyzer.

[0035] The term "dialysis machine" refers to cellulose acetate, cupraphane, and polyacrylic acid. This includes, but is not limited to, nitrile, polymethyl methacrylate, or polysulfone. An artificial kidney equipped with a synthetic or semi-synthetic semipermeable membrane made of chemical materials (hereinafter referred to as "dialysis membrane") It is intended to include: a constant blood flow on one side of the membrane and dialysate on the other side. This allows for the removal of waste products from the blood. Hemodialysis can be performed using an artificial kidney. In that context, diffusion is the main mechanism of solute removal. On the other hand, hemofiltration (hemodialysis filtration and (also called dialysis) is based on ultrafiltration and convective transport rather than diffusion, The solute is removed to the opposite side of the semipermeable membrane with porosity.

[0036] The term "unspiked dialysate" refers to an aqueous solution containing sodium thiosulfate. Before being added to the dialysate piping through the valve, it is mixed by the dialysis machine and then introduced into the dialysate piping. This refers to the dialysis solution that is pumped and flows onto the dialysis membrane.

[0037] The term "dialysis fluid spiked with thiosulfate ions" includes sodium thiosulfate. This refers to the dialysate solution in the dialysate piping after the aqueous solution has been added to the dialysate piping through a valve.

[0038] The term "therapeutic dose" refers to the amount administered that, when administered, effectively treats the disorder, disease, or condition being treated. A compound sufficient to prevent the occurrence of one or more of the conditions, or to mitigate them to some extent. It is intended to include the amount of [amount]. Also, the term "therapeutic effective dose" is used by researchers, veterinarians, A physician or clinician is seeking biological or medical samples of cells, tissues, systems, animals, or humans. This also refers to the amount of compound sufficient to induce a reaction. In one embodiment, the therapeutically effective amount is the target A sufficient amount to maintain blood levels of thiosulfate ions at approximately physiological levels. be.

[0039] The terms "approximately" or "about" refer to a specific value determined by those skilled in the art. This means an acceptable margin of error, which in part depends on how the value is measured or determined. Therefore, it is determined. In one embodiment, the terms "about" or "approximately" are 1, 2, 3 It means within 4 standard deviations. In some embodiments, it means "about" or "approximately". The terms refer to 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% of a given value or range. This means within 1%, 0.5%, or 0.05%. In one embodiment, it means "about" or "approximately". Values ​​preceded by the term "" are likely to be accurate.

[0040] The term "normal physiological levels" of thiosulfate ions is used in healthy adults. This refers to the level of thiosulfate ions. In one embodiment, the thiosulfate ions in the subject The normal physiological level of this substance is a concentration of 1 to 10 micromoles.

[0041] In one embodiment, the method provided herein involves sodium thiosulfate pentahydrate (N This includes the use of purified forms of sodium thiosulfate, such as a2S2O3·5H2O. In one embodiment, In this specification, the substance provided is pharmaceutical-grade sodium thiosulfate. In this embodiment, the substance provided herein is sodium thiosulfate for pharmaceutical use. Sodium thiosulfate that meets or exceeds one, two or more, or all of the FDA standards for thorium It is in the form of a lium. In another embodiment, what is provided herein is a U.S. Federal Standard Sodium thiosulfate produced in accordance with the Good Manufacturing Practices (GMP) detailed in Regulations 21 CFR 211 This is the form. In one embodiment, sodium thiosulfate that is pharmaceutically acceptable is its entire The part incorporated herein by reference is U.S. Patent Publication No. 7, filed July 7, 2010. This information is disclosed in document number 2011 / 0008467.

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

[0043] In one embodiment, the sodium thiosulfate appears as a colorless crystal.

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

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

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

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

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

[0049] In one embodiment, the sodium thiosulfate pentahydrate provided herein is anhydrous b It contains approximately 99% or more by weight and / or approximately 100.5% or less by weight of sodium thiosulfate. In one embodiment, the sodium thiosulfate pentahydrate provided herein contains The amount of sodium aqueous thiosulfate was determined by a colorimetric assay according to the United States Pharmacopeia (United States Pharmacopeia XXXII (2009)). It will be decided.

[0050] In one embodiment, the sodium thiosulfate pentahydrate provided herein is ionized Measured by chromatography, the percentage is approximately 98% by weight or more and approximately 102% by weight or less on an anhydrous basis. It contains sodium thiosulfate.

[0051] In one embodiment, the sodium thiosulfate pentahydrate provided herein is anhydrous b Based on calculations, it contains approximately 98% or more by weight and / or approximately 102% or less by weight of sodium thiosulfate. In one embodiment, the anhydrous sodium thiosulfate pentahydrate provided herein is used. The amount of sodium thiosulfate is determined by ion chromatography. In one embodiment, the anhydrous sodium thiosulfate in the sodium thiosulfate pentahydrate provided herein The amount of lium is determined by ion detection using electrochemical conductivity detection as described herein. It is determined by romagraphy.

[0052] In another embodiment, sodium thiosulfate provided herein is used in a 10% solution at 25°C. When measured, it has a pH of about 6 to about 8. In one embodiment, provided herein The pH of the sodium is measured using a pH meter. In one embodiment, as described herein The pH of the sodium thiosulfate to be supplied is determined by Method 791 of the United States Pharmacopeia XXXII (2009). .

[0053] In yet another embodiment, the sodium thiosulfate provided herein is about 32%~ It has a water content of approximately 37% by weight. In one embodiment, sodium thiosulfate provided herein The water content in thorium is determined by the Karl Fischer method. In one embodiment, The water content in the sodium thiosulfate provided herein is as specified in the United States Pharmacopeia XXXII (2009). This is quantified by Method 921.

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

[0055] In yet another embodiment, the sodium thiosulfate provided herein is approximately 0.02 times It contains carbonate ions in an amount of % or less. In yet another embodiment, provided herein Sodium thiosulfate contains carbonate ions at a concentration of approximately 0.01% by weight or less. In one embodiment, The amount of carbonate ions in sodium thiosulfate provided herein is The sample is brought into contact with an acid such as phosphoric acid to convert carbonate ions into carbon dioxide, and non-dispersive red The amount of carbon dioxide is determined by using an external detector.

[0056] In yet another embodiment, the sodium thiosulfate provided herein is about 0.005 It contains insoluble matter of weight % or less. In one embodiment, the thiosulfate provided herein is available. The amount of insoluble substances in sodium is 10 grams of sodium thiosulfate provided herein. The solution is determined by dissolving it in 100 mL of water, and the solution is heated to a boil for 1 hour. The liquid is filtered, washed with warm water, dried, cooled in a desiccator, and weighed.

[0057] In yet another embodiment, the sodium thiosulfate provided herein is approximately 200 times It contains chloride ions in an amount of ppm or less. In one embodiment, the t The chloride ion content in sodium sulfite was determined by Method 221 of the United States Pharmacopeia XXXII (2009). It will be done.

[0058] In yet another embodiment, the sodium thiosulfate provided herein is about 0.002 Contains less than % by weight of iron. In one embodiment, the sodium thiosulfate provided herein The iron content in the lium is determined using inductively coupled plasma mass spectrometry (ICP-MS). In one embodiment, the iron content in the sodium thiosulfate provided herein is inductively coupled plasma It is determined using intermittent emission spectroscopy (ICP-OES). In one embodiment, provided herein The iron content in the sodium thiosulfate used was determined by Method 241 of the United States Pharmacopeia XXXII (2009). It can be done.

[0059] In yet another embodiment, the sodium thiosulfate provided herein is about 0.001 Contains less than % by weight of lead. In one embodiment, sodium thiosulfate provided herein The lead content in the lium is determined by Method 251 of the United States Pharmacopeia XXXII (2009).

[0060] In yet another embodiment, the sodium thiosulfate provided herein is approximately 0.01 times Contains calcium in an amount of % or less. In one embodiment, the thiosulfur provided herein The calcium content in sodium phosphate is determined using ICP-MS. In one embodiment The calcium content in sodium thiosulfate provided herein is determined by flame emission spectroscopy. It is determined using FES analysis.

[0061] In yet another embodiment, the sodium thiosulfate provided herein is a U.S. Pharmacopoeia Ammonium oxalate test solution prepared according to Method XXXII (2009) is mixed with sodium thiosulfate. Add to an aqueous solution containing (for example, 1 gram of sodium thiosulfate dissolved in 20 mL of water) When doing so, do not cause turbidity.

[0062] In yet another embodiment, the sodium thiosulfate provided herein is about 0.005 It contains potassium by weight or less. In one embodiment, the thiosulfur provided herein The potassium content in sodium phosphate is determined using ICP-MS. In one embodiment, The potassium content in sodium thiosulfate provided herein is determined using FES. .

[0063] In yet another embodiment, the sodium thiosulfate provided herein is approximately 0.05 times It contains sulfite ions of % or less by weight, or approximately 0.1% or less by weight. In this specification, the sulfite ion content in sodium thiosulfate provided herein is as quoted below. The entirety of the "American Chemical Society Reagent Chemicals" is incorporated herein. According to the method for determining sulfite ions in the 10th edition of the "Reagent Chemicals Society" (Reagent Chemicals Society), It is determined.

[0064] In yet another embodiment, the sodium thiosulfate provided herein is about 0.05% The following contain sulfate ions at approximately 0.1% or less, approximately 0.25% or less, or approximately 0.5% by weight or less (SO4 2- (as) In one embodiment, the sulfate in sodium thiosulfate provided herein The ion content is defined as "American Chemical Society, Reagent Chem It is determined by the method for determining sulfate ions in the 10th edition of "icals".

[0065] In yet another embodiment, the sodium thiosulfate provided herein is about 0.001 It contains sulfide ions of less than or equal to weight percent. In one embodiment, the following is provided herein: The sulfide ion content in sodium sulfuric acid is determined by the method described herein for lead nitrate (I It is determined by the addition of (I).

[0066] In yet another embodiment, the sodium thiosulfate provided herein is about 0.002 Contains less than % by weight of a nitrogen compound (as N). In one embodiment, provided herein The nitrogen compound content (as N) in sodium thiosulfate is defined by the American Chemical Society as a reagent. Reagent Chemicals (American Chemical Society), 10th Edition: Nitrogen compounds It is determined by the method used for the decision.

[0067] In yet another embodiment, the sodium thiosulfate provided herein is approximately 10 ppm The following are total volatile organic carbons with concentrations of approximately 100 ppm or less, approximately 500 ppm or less, approximately 1000 ppm or less, or 5000 ppm or less. It contains an element. In one embodiment, the sodium thiosulfate provided herein is The disclosure of the organic volatile organic compounds described in ICH Q3C(R3) is incorporated by reference as a whole. Contains impurities or specific solvents (e.g., ethanol) below specific limits. In this case, the content of organic volatile impurities was determined by Method 467 of the United States Pharmacopeia XXXII (2009). It can be done.

[0068] In yet another embodiment, the sodium thiosulfate provided herein is approximately 60 ppb Below are approximately 2.5 ppm or less, approximately 8 ppm or less, approximately 10 ppm or less, approximately 20 ppm or less, approximately 25 ppm or less, or approximately 50 ppm. Contains total NPOCs of ppm or less. In one embodiment, sodium thiosulfate provided herein The lium contains a total NPOC of approximately 12 ppm or less. In one embodiment, as provided herein, The total NPOC in the sodium thiosulfate is determined using the method described herein. In one embodiment, the total NPOC in the sodium thiosulfate provided herein is a) the A sample aqueous solution is prepared by contacting sodium osulfate with an aqueous solution containing a predetermined amount of inorganic acid. a) to remove precipitate from the aqueous sample solution; c) to mix the sample solution with a predetermined amount of oxidizing agent d) bringing the organic carbon in the sample solution into contact with the carbon dioxide under supercritical hydroxide (SCWO) conditions. It is determined by converting to its prime form.

[0069] In yet another embodiment, the sodium thiosulfate provided herein is about 0.05 pp Contains mercury m or less. In one embodiment, sodium thiosulfate provided herein The mercury content in the um is determined using ICP-MS. In one embodiment, as described herein... The mercury content in the supplied sodium thiosulfate is determined using ICP-OES. In this specification, the mercury content in sodium thiosulfate provided herein is as defined in the United States Pharmacopeia XXXI It is determined by method 261 of I(2009).

[0070] In yet another embodiment, the sodium thiosulfate provided herein is approximately 2 ppm or The following contains aluminum. In one embodiment, the sodium thiosulfate provided herein The aluminum content in thorium is determined using ICP-MS. In one embodiment, The aluminum content in sodium thiosulfate provided herein is determined using ICP-OES. It is determined. In one embodiment, aluminum in sodium thiosulfate provided herein The nium content is determined by method 206 of the United States Pharmacopeia XXXII (2009).

[0071] In yet another embodiment, the sodium thiosulfate provided herein is approximately 3 ppm or The following contains arsenic. In one embodiment, sodium thiosulfate provided herein. The arsenic content is determined using ICP-MS. In one embodiment, as provided herein The arsenic content in the sodium thiosulfate is determined using ICP-OES. In one embodiment In this specification, the arsenic content in sodium thiosulfate is as specified in the United States Pharmacopeia XXXII (20 Determined by method 211 of 09).

[0072] In yet another embodiment, the sodium thiosulfate provided herein is about 0.003 Contains selenium by weight % or less. In one embodiment, the thiosulfate provided herein. The selenium content in sodium is determined using ICP-MS. In one embodiment, The selenium content in sodium thiosulfate provided in the detailed document is determined using ICP-OES. In one embodiment, the selenium content in sodium thiosulfate provided herein is rice It is determined by Method 291 of the National Pharmacopoeia XXXII (2009).

[0073] In yet another embodiment, microbial necrosis in sodium thiosulfate provided herein The total number of aerobic bacteria in the shipment is approximately 100 colony-forming units (CFU / g) or less per gram. The total aerobic bacterial count in sodium thiosulfate provided in the book is as specified in the United States Pharmacopeia XXXII ( It is quantified by method 61 of 2009.

[0074] In yet another embodiment, total yeast in sodium thiosulfate provided herein The mold count is approximately 20 CFU / g or less. Total yeast in sodium thiosulfate provided herein. • The number of molds is quantified according to Method 61 of the United States Pharmacopeia XXXII (2009).

[0075] In yet another embodiment, the sodium thiosulfate provided herein is 1 milligram Approximately 0.02 endotoxin units (EU / mg) or less per rum, approximately 0.1 EU / mg or less, or approximately 0.25 EU / mg or less. It contains the following bacterial endotoxins. The bacterial endotoxins in sodium thiosulfate provided herein The quantity is quantified according to Method 85 of the United States Pharmacopeia XXXII (2009).

[0076] In yet another embodiment, the sodium thiosulfate provided herein is 0.01% or less It contains the following residual solidification inhibitor.

[0077] In yet another embodiment, the sodium thiosulfate provided herein is as follows: and: Approximately 99% by weight on an anhydrous basis, determined by the United States Pharmacopeia colorimetric assay. It must contain sodium thiosulfate at a concentration of 100.5% by weight or less; As determined by ion chromatography assay, on an anhydrous basis, approximately 98% by weight or more and / or containing approximately 102% by weight or less of sodium thiosulfate; The pH should be approximately 6 to 8 when measured in a 10% solution at 25°C; Having a water content of approximately 32% to 37% by weight; Having the appearance of a colorless crystal; It shall have a transparent and colorless appearance as a 10% solution; It must not have an odor; A positive confirmatory test for sodium is required. The thiosulfate ion confirmatory test must be positive; It should not produce turbidity when mixed with ammonium oxalate TS; It must have a heavy metal content of approximately 10 ppm or less; It must contain carbonate ions at a concentration of approximately 0.01% by weight or less; It must contain approximately 0.005% by weight or less of insoluble matter; It must contain chloride ions at a concentration of approximately 200 ppm or less; It must contain sulfide ions at a concentration of approximately 0.001% by weight or less; It must contain approximately 0.05% or less of sulfite ions, or approximately 0.1% by weight or less; Contains sulfate ions in amounts of approximately 0.05% or less, approximately 0.1% or less, approximately 0.25% or less, or approximately 0.5% by weight or less. to do; It must contain iron at a weight of approximately 0.002% or less; It must contain calcium at a concentration of approximately 0.01% by weight or less; It must contain potassium at a concentration of approximately 0.005% by weight or less; Organic gases with concentrations of approximately 10 ppm or less, approximately 100 ppm or less, approximately 500 ppm or less, approximately 1000 ppm or less, or 5000 ppm or less. Contains catabolic impurities; 60 ppb or less, approximately 2.5 ppm or less, approximately 8 ppm or less, approximately 10 ppm or less, approximately 20 ppm or less, approximately 25 ppm or less, or Having a total NPOC of approximately 50 ppm or less; It must contain mercury at a concentration of approximately 0.05 ppm or less; It must contain aluminum at a concentration of approximately 2 ppm or less. It must contain arsenic at a concentration of approximately 3 ppm or less. Contains 0.001% by weight or less of lead; It must contain nitrogen compounds at a concentration of approximately 0.002% by weight or less (as N); It must contain selenium at a concentration of approximately 0.003% by weight or less; It must contain 0.01% or less of a residual anti-caking agent; Having a total aerobic bacterial count of approximately 100 CFU / g or less in microbial load; Having a total yeast / mold count of approximately 20 CFU / g or less; and It must contain bacterial endotoxins at a concentration of approximately 0.02 EU / mg or less, approximately 0.1 EU / mg or less, or approximately 0.25 EU / mg or less. It is characterized by one or more of the following.

[0078] In yet another embodiment, the sodium thiosulfate provided herein is as follows: and: Approximately 99% by weight on an anhydrous basis, determined by the United States Pharmacopeia colorimetric assay. It must contain sodium thiosulfate at a concentration of 100.5% by weight or less; As determined by ion chromatography assay, on an anhydrous basis, approximately 98% by weight or more and / or containing approximately 102% by weight or less of sodium thiosulfate; The pH should be approximately 6 to 8 when measured in a 10% solution at 25°C; Having a water content of approximately 32% to 37% by weight; Having the appearance of a colorless crystal; It shall have a transparent and colorless appearance as a 10% solution; It must not have an odor; A positive confirmatory test for sodium is required. The thiosulfate ion confirmatory test must be positive; It should not produce turbidity when mixed with ammonium oxalate TS; It must have a heavy metal content of approximately 10 ppm or less; It must contain carbonate ions at a concentration of approximately 0.01% by weight or less; It must contain approximately 0.005% by weight or less of insoluble matter; It must contain chloride ions at a concentration of approximately 200 ppm or less; It must contain sulfide ions at a concentration of approximately 0.001% by weight or less; It must contain approximately 0.05% or less of sulfite ions, or approximately 0.1% by weight or less; Contains sulfate ions in amounts of approximately 0.05% or less, approximately 0.1% or less, approximately 0.25% or less, or approximately 0.5% by weight or less. to do; It must contain iron at a weight of approximately 0.002% or less; It must contain calcium at a concentration of approximately 0.01% by weight or less; It must contain potassium at a concentration of approximately 0.005% by weight or less; Organic gases with concentrations of approximately 10 ppm or less, approximately 100 ppm or less, approximately 500 ppm or less, approximately 1000 ppm or less, or 5000 ppm or less. Contains catabolic impurities; 60 ppb or less, approximately 2.5 ppm or less, approximately 8 ppm or less, approximately 10 ppm or less, approximately 20 ppm or less, approximately 25 ppm or less, or Having a total NPOC of approximately 50 ppm or less; It must contain mercury at a concentration of approximately 0.05 ppm or less; It must contain aluminum at a concentration of approximately 2 ppm or less. It must contain arsenic at a concentration of approximately 3 ppm or less. Contains 0.001% by weight or less of lead; It must contain nitrogen compounds at a concentration of approximately 0.002% by weight or less (as N); It must contain selenium at a concentration of approximately 0.003% by weight or less; Having a total aerobic bacterial count of approximately 100 CFU / g or less in microbial load; Having a total yeast / mold count of approximately 20 CFU / g or less; and It must contain bacterial endotoxins at a concentration of approximately 0.02 EU / mg or less, approximately 0.1 EU / mg or less, or approximately 0.25 EU / mg or less. It is characterized by one or more of the following.

[0079] Sodium thiosulfate is described as "containing" a certain amount or less of a specific substance. In some embodiments, the sodium thiosulfate contains a detectable amount of the substance. do not have.

[0080] (Methods for maintaining physiological levels of thiosulfate ions) The information provided herein concerns the thiosulfate ion in subjects undergoing hemodialysis. A method for maintaining physiological levels, wherein the blood of the subject is treated with thiosulfate ions. This includes contacting the dialysis membrane, which is also in contact with the spiked dialysis fluid, during dialysis, When untreated dialysate flows from the dialyzer to the dialysate membrane, water containing sodium thiosulfate The solution is added to the non-spiked dialysate, and the non-spiked dialysate is water The mixture comprises an acid concentrate and a bicarbonate concentrate, and the thiosulfate ions spike The method is such that the resulting dialysate has a pH greater than approximately 7.0.

[0081] Furthermore, the substances provided herein are used in subjects undergoing hemodialysis, specifically for thiosulfate A method for maintaining the physiological level of ON, wherein the blood of the subject is subjected to thiosulfate io This includes contact between spiked dialysate and unspiked dialysate during dialysis. When the liquid flows from the dialysis machine to the dialysis membrane, the aqueous solution containing sodium thiosulfate is present in the spike It is added to the unspiked dialysate, and the unspiked dialysate is mixed with water, acid concentrate, and A dialysate containing a mixture of bicarbonate concentrates and spiked with thiosulfate ions, The method described above has a pH greater than approximately 7.0.

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

[0083] In one embodiment, the physiological level of the thiosulfate ion in the subject is approximately The concentration is 100 micromoles or less. In another embodiment, the thiosulfur in the subject The physiological level of acid ions is less than approximately 10 micromolars. Further embodiments In the above-mentioned object, the physiological level of the thiosulfate ion is approximately 500 nanometers. The molar concentration is approximately 10 micromolars. In yet another embodiment, in the subject, The physiological levels of the thiosulfate ions are approximately 1 micromolar concentration to approximately 5 micromolar concentration. It is a degree. In yet another embodiment, the physiology of the thiosulfate ion in the subject The typical level is approximately 3 micromolar concentration.

[0084] In one embodiment, thiosulfate ions in dialysate spiked with thiosulfate ions The concentration is 100 micromoles or less. In another embodiment, the thiosulfate io The concentration of thiosulfate ions in the dialysis fluid spiked by the rayon is approximately 10 micromolars or less. In yet another embodiment, the thiosulfate ions in the dialysate spiked with thiosulfate ions. The concentration of sulfate ions is approximately 500 nanomoles to approximately 10 micromoles. In one embodiment, the concentration of thiosulfate ions in the dialysate spiked with thiosulfate ions This is a concentration of approximately 1 micromolar to approximately 5 micromolars. In yet another embodiment, The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 3 micro This is molar concentration.

[0085] In one embodiment, aqueous solutions containing sodium thiosulfate are approximately 10 mg / L, approximately 50 mg / L, and approximately 100mg / L, approx. 150mg / L, approx. 200mg / L, approx. 250mg / L, approx. 300mg / L, approx. 350mg / L, approx. 400mg / L, approx. 450 Contains mg / mL or approximately 500 mg / L or less of sodium thiosulfate.

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

[0087] In one embodiment, the dialysis fluid piping is attached to the piping at a position before it is connected to the dialyzer. Through the valve, the aqueous solution containing sodium thiosulfate is not spiked. It is added to the dialysate. In another embodiment, the unspiked dialysate is the The dialysis tubing flows at a rate of approximately 200 mL / min to approximately 1000 mL / min. In yet another embodiment, The dialysis fluid, which is not spiked, flows through the dialysis tubing at a rate of approximately 300 mL / min to approximately 900 mL / min. In yet another embodiment, the unspiked dialysate is used in the dialysate piping. It flows at a rate of approximately 400 mL / min to approximately 800 mL / min. In yet another embodiment, the spikes The dialysis fluid that has not been treated flows through the dialysis piping at a rate of approximately 500 mL / min to approximately 700 mL / min. In this embodiment, the unspiked dialysate flows through the dialysate tubing at a rate of approximately 600 mL / min. It flows at speed.

[0088] In one embodiment, the aqueous solution containing sodium thiosulfate is passed through the valve to the S In the unpiked dialysate, at a rate of approximately 0 mL / hour to approximately 750 mL / hour, and approximately 50 mL / hour to approximately 650 mL / hour Speed: Approximately 100 mL / hour to 550 mL / hour, approximately 150 mL / hour to 450 mL / hour, or approximately 200 mL / hour It is added at a rate of approximately 350 mL / hour. In another embodiment, the sodium thiosulfate is included The aqueous solution is added to the undromatizing dialysis fluid through the valve at a rate of approximately 250 mL / hour. To be added.

[0089] In yet another embodiment, the pH of the dialysate spiked with thiosulfate ions is approximately It is approximately 7.0 to 8.0. In yet another embodiment, spiked with the thiosulfate ions The pH of the dialysate is approximately 7.1 to 8.0. In yet another embodiment, the thiosulfate ion The pH of the dialysis fluid spiked with is approximately 7.3 to 8.0. In yet another embodiment, The pH of dialysate spiked with sodium thiosulfate is approximately 7.3 to 7.5. In this embodiment, the pH of the dialysate spiked with sodium thiosulfate is approximately 7.4. ru.

[0090] In yet another embodiment, the subject is a human with chronic renal failure. In this study, the subjects are humans with acute renal failure.

[0091] In yet another embodiment, the subject receives hemodialysis 1 to 10 times per week. In yet another embodiment, the subject receives hemodialysis 3 to 7 times per week.

[0092] In one embodiment, the method provided herein involves the plasma thiosulfate ions of interest. To restore and / or maintain the bell at a normal physiological level.

[0093] (Methods of prevention) (1. Methods to prevent atherosclerosis) In one embodiment, provided herein, in a subject undergoing dialysis a method for preventing atherosclerosis, wherein the blood of the subject is treated with thiosulfate This includes contacting the dialysis membrane, which is also in contact with the dialysis fluid that is spiked when ON, during dialysis. When unspiked dialysate flows from the dialyzer to the dialysate membrane, sodium thiosulfate An aqueous solution containing the above is added to the non-spiked dialysate, and the non-spiked dialysate is then removed. The liquid contains a mixture of water, an acid concentrate, and a bicarbonate concentrate, and the thiosulfate ion The method is characterized in that the spiked dialysate has a pH greater than approximately 7.0.

[0094] In one embodiment, further provided herein, a person undergoing hemodialysis A method for preventing atherosclerosis in a subject, wherein the blood of the subject The liquid is brought into contact with the dialysate spiked with thiosulfate ions during dialysation, When unfiltered dialysis fluid flows from the dialysis machine to the dialysis membrane, sodium thiosulfate is present. The aqueous solution is added to the non-spiked dialysate, and the non-spiked dialysate is The mixture comprises water, an acid concentrate, and a bicarbonate concentrate, and the thiosulfate ion is used to spy The method is characterized in that the dialysis fluid has a pH greater than approximately 7.0.

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

[0096] In one embodiment, the method provided herein involves the blood of the target thiosulfate ions. To restore and / or maintain plasma levels at normal physiological levels.

[0097] (2. Methods to prevent myocardial infarction) In one embodiment, provided herein, in a subject undergoing dialysis a method for preventing myocardial infarction, wherein the blood of the subject is spiked with thiosulfate ions This includes contacting the dialysis membrane, which is also in contact with the dialysis fluid, during dialysis, and being spiked. When the dialysis fluid, which is not present in the dialysis machine, flows from the dialysis machine to the dialysis membrane, an aqueous solution containing sodium thiosulfate... It is added to the non-spiked dialysate, and the non-spiked dialysate is water, acid concentrate A mixture comprising a condensate and a concentrated bicarbonate solution, and spiked with thiosulfate ions The method is characterized in that the dialysate has a pH greater than approximately 7.0.

[0098] In one embodiment, further provided herein, a person undergoing hemodialysis A method for preventing myocardial infarction in a subject, wherein the subject's blood is treated with thiosulfate This includes contact with ion-spiked dialysate during dialysis, and non-spiked dialysate. When the dialysate flows from the dialyzer to the dialysate membrane, an aqueous solution containing sodium thiosulfate flows through the spa It is added to non-spiked dialysate, and the non-spiked dialysate is mixed with water and an acid concentrate. Dialysis fluid comprising a mixture of a concentrated bicarbonate solution and spiked with thiosulfate ions. However, the method described above has a pH greater than approximately 7.0.

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

[0100] In one embodiment, the method provided herein involves the blood of the target thiosulfate ions. To restore and / or maintain plasma levels at normal physiological levels.

[0101] (3. Methods to prevent sudden cardiac death) In one embodiment, provided herein, in a subject undergoing dialysis a method for preventing sudden cardiac death, wherein the blood of the subject is treated with thiosulfate ions. This includes bringing the dialysis membrane, which is also in contact with the piked dialysate, into contact with the spy during dialysis. When unfiltered dialysis fluid flows from the dialysis machine to the dialysis membrane, sodium thiosulfate is present. The aqueous solution is added to the non-spiked dialysate, and the non-spiked dialysate is The mixture comprises water, an acid concentrate, and a bicarbonate concentrate, and the thiosulfate ion is used to spy The method is characterized in that the dialysis fluid has a pH greater than approximately 7.0.

[0102] In one embodiment, further provided herein, a person undergoing hemodialysis A method for preventing sudden cardiac death in a subject, wherein the subject's blood is ch This involves contacting the dialysate, which is spiked with sulfur ions, during dialysis, and the spiked When the dialysis fluid, which is not present in the dialysis machine, flows from the dialysis machine to the dialysis membrane, an aqueous solution containing sodium thiosulfate... It is added to the non-spiked dialysate, and the non-spiked dialysate is water, acid concentrate A mixture comprising a condensate and a concentrated bicarbonate solution, and spiked with thiosulfate ions The method is characterized in that the dialysate has a pH greater than approximately 7.0.

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

[0104] In one embodiment, the method provided herein involves the blood of the target thiosulfate ions. To restore and / or maintain plasma levels at normal physiological levels.

[0105] (4. Methods to prevent stroke) In one embodiment, provided herein, in a subject undergoing dialysis a method for preventing stroke, wherein the blood of the subject is spiked with thiosulfate ions This includes bringing the dialysis membrane, which is also in contact with the dialysis fluid, into contact with the spiked membrane during dialysis. When the dialysis fluid, which is not present in the dialysis machine, flows from the dialysis machine to the dialysis membrane, an aqueous solution containing sodium thiosulfate... It is added to the non-spiked dialysate, and the non-spiked dialysate is water, acid concentrate A mixture comprising a condensate and a concentrated bicarbonate solution, and spiked with thiosulfate ions The method is characterized in that the dialysate has a pH greater than approximately 7.0.

[0106] In one embodiment, further provided herein, a person undergoing hemodialysis A method for preventing stroke in a subject, wherein the subject's blood is treated with thiosulfate This includes contact with spiked dialysate during dialysis, and with unspiked dialysate. As the precipitate flows from the dialysis machine to the dialysis membrane, an aqueous solution containing sodium thiosulfate is applied to the spy. It is added to unspiked dialysate, and the unspiked dialysate is mixed with water, acid concentrate, and a mixture of bicarbonate concentrate solution, and the dialysate spiked with thiosulfate ions The method is characterized by having a pH greater than approximately 7.0.

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

[0108] In one embodiment, the method provided herein involves the blood of the target thiosulfate ions. To restore and / or maintain plasma levels at normal physiological levels.

[0109] (5. Methods to prevent cardiovascular disease) In one embodiment, provided herein, in a subject undergoing dialysis This includes angina pectoris, cerebral vasospasm, claudication, severe limb ischemia, peripheral vascular disease, and sickle cell crisis. A method for preventing cardiovascular diseases characterized by tissue ischemia, wherein the blood of the subject is The dialysis membrane, which is also in contact with the dialysate spiked with thiosulfate ions, is brought into contact with the dialysis membrane during dialysis. The dialysis fluid, which is not spiked, flows from the dialysis machine to the dialysis membrane, and includes thiosulfur An aqueous solution containing sodium acid is added to the non-spiked dialysate, and the spiked The dialysis fluid, which is not dialysis fluid, contains a mixture of water, an acid concentrate, and a bicarbonate concentrate, and the thio The method is characterized in that the dialysate spiked with sulfate ions has a pH greater than approximately 7.0.

[0110] In one embodiment, further provided herein, a person undergoing dialysis is The subjects included angina pectoris, cerebral vasospasm, claudication, severe limb ischemia, peripheral vascular disease, and sickle cell anemia. A method for preventing cardiovascular diseases characterized by tissue ischemia, including cardiovascular crisis, and the corresponding This involves contacting elephant blood with a dialysate spiked with thiosulfate ions during dialysis, When unspiked dialysate flows from the dialyzer to the dialysate membrane, sodium thiosulfate An aqueous solution containing the above is added to the non-spiked dialysate, and the non-spiked dialysate is then removed. The liquid contains a mixture of water, an acid concentrate, and a bicarbonate concentrate, and the thiosulfate ion The method is characterized in that the spiked dialysate has a pH greater than approximately 7.0.

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

[0112] In one embodiment, the method provided herein involves the blood of the target thiosulfate ions. To restore and / or maintain plasma levels at normal physiological levels.

[0113] (6. Methods for preventing hypertension, pulmonary hypertension, and renal hypertension) In one embodiment, provided herein, in a subject undergoing dialysis A method for preventing hypertension, pulmonary hypertension, and renal hypertension, wherein the blood of the subject The liquid comes into contact with the dialysis membrane, which is also in contact with the dialysate spiked with thiosulfate ions, during dialysis. This includes the process of allowing the unspiked dialysate to flow from the dialyzer to the dialysate membrane, An aqueous solution containing sodium thiosulfate is added to the unspiked dialysate, and the spike 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, said 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, said 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 a normal physiological level.

[0117] In certain embodiments, the embodiments in paragraphs

[0118] -

[0127] apply to all methods provided herein. In one embodiment, the physiological level of thiosulfate ions in the subject is about

[0118] In certain embodiments, the embodiments in paragraphs

[0118] -

[0127] apply to all methods provided herein. In one embodiment, the physiological level of thiosulfate ions in the subject is about

[0119] In one embodiment, the physiological level of thiosulfate ions in the subject is about The concentration is 100 micromoles or less. In another embodiment, the thiosulfur in the subject The physiological level of acid ions is less than approximately 10 micromolars. Further embodiments In the above-mentioned sample, the physiological level of thiosulfate ions is approximately 500 nanomoles. The concentration is approximately 10 micromolars. In yet another embodiment, the preceding The physiological levels of thiosulfate ions range from approximately 1 micromolar concentration to approximately 5 micromolar concentrations. This is the concentration. In yet another embodiment, the production of the thiosulfate ion in the subject. The scientific level is approximately 3 micromolar concentration.

[0120] In one embodiment, thiosulfate ions in dialysate spiked with thiosulfate ions The concentration is approximately 100 micromoles or less. In another embodiment, the thiosulfate is The concentration of thiosulfate ions in the dialysate spiked during the ON phase is approximately 10 micromolars or less. In yet another embodiment, the dialysate spiked with thiosulfate ions The concentration of sulfate ions is approximately 500 nanomoles to approximately 10 micromoles. In this embodiment, the concentration of thiosulfate ions in the dialysate spiked with thiosulfate ions The concentration ranges from approximately 1 micromolar to approximately 5 micromolars. In yet another embodiment, The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 3 microns. This is the molal concentration.

[0121] In one embodiment, the aqueous solution containing sodium thiosulfate was approximately 10 mg / L, approximately 50 mg / L , about 100mg / L, about 150mg / L, about 200mg / L, about 250mg / L, about 300mg / L, about 350mg / L, about 400mg / L, It contains approximately 450 mg / mL or less of sodium thiosulfate, or approximately 500 mg / L or less.

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

[0123] In one embodiment, the dialysis fluid piping is attached to the piping at a position before it is connected to the dialyzer. Through the valve, the aqueous solution containing sodium thiosulfate is not spiked. It is added to the dialysate. In another embodiment, the unspiked dialysate is the The dialysis tubing flows at a rate of approximately 200 mL / min to approximately 1000 mL / min. In yet another embodiment, The dialysis fluid, which is not spiked, flows through the dialysis tubing at a rate of approximately 300 mL / min to approximately 900 mL / min. In yet another embodiment, the unspiked dialysate is used in the dialysate piping. It flows at a rate of approximately 400 mL / min to approximately 800 mL / min. In yet another embodiment, the spikes The dialysis fluid that has not been treated flows through the dialysis piping at a rate of approximately 500 mL / min to approximately 700 mL / min. In this embodiment, the unspiked dialysate flows through the dialysate tubing at a rate of approximately 600 mL / min. It flows at speed.

[0124] In one embodiment, the aqueous solution containing sodium thiosulfate is passed through the valve to the S In the unpiked dialysate, at a rate of approximately 0 mL / hour to approximately 750 mL / hour, and approximately 50 mL / hour to approximately 650 mL / hour at a rate of about 100 mL / h to about 550 mL / h, a rate of about 150 mL / h to about 450 mL / h, or 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.

[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 a sample taken from detection point "before" (1 00) or detection point "after" (110). ​​​​​​It undergoes decomposition of thiosulfate ions at a rate of %, approximately 3%, approximately 2%, approximately 1%, approximately 0.5%, or less than approximately 0.1%. .

[0129] (Method of administration) In one embodiment, provided herein, thio is applied to a subject undergoing dialysis. A method for administering sodium sulfate, wherein the blood of the subject is spat with thiosulfate ions. The dialysis membrane, which is also in contact with the dialysis fluid that has been heated, is brought into contact with the spike during dialysis, and the spike When untreated dialysis fluid flows from the dialysis machine to the dialysis membrane, water containing sodium thiosulfate The solution is added to the non-spiked dialysate, and the non-spiked dialysate is water The solution comprises a mixture of an acid concentrate and a bicarbonate concentrate, which is spiked with thiosulfate ions. The method is characterized in that the dialysis fluid has a pH greater than approximately 7.0.

[0130] In one embodiment, further provided herein, sodium thiosulfate A method for administering thio to a subject undergoing hemodialysis, wherein the subject's blood is administered to the subject. This includes contact with a dialysate spiked with sulfate ions during dialysis, and the spiked When the dialysis fluid flows from the dialysis machine to the dialysis membrane, an aqueous solution containing sodium thiosulfate is present. It is added to non-spiked dialysate, and the non-spiked dialysate contains water and concentrated acid. A solution comprising a mixture of a solution and a concentrated bicarbonate solution, and a tetraphosphate spiked with thiosulfate ions. The method is characterized in that the precipitate has a pH greater than approximately 7.0.

[0131] In one embodiment, the dialysate spiked with thiosulfate ions is detected "before" (1 Sulfate ions, sulfide ions, etc., measured in the sample taken from 00) or "after" the detection point (110) And reflected in the sulfite ion content, approximately 10%, 9%, 8%, 7%, 6%, 5%, and 4%. It undergoes decomposition of thiosulfate ions at a rate of %, approximately 3%, approximately 2%, approximately 1%, approximately 0.5%, or less than approximately 0.1%. .

[0132] (Combination therapy) In one embodiment, sodium thiosulfate provided herein is used in this specification. In combination with other therapeutic agents useful for the treatment and / or prevention of the diseases and illnesses presented. Alternatively, it may be used in combination with it.

[0133] As used herein, the term “in combination” means two or more therapies (for example, one type This includes the use of the above-mentioned preventive and / or therapeutic agents. However, the use of "in combination" The use of the term implies that a therapy (e.g., a preventive and / or therapeutic agent) is administered to a person with a disease or disability. The order in which they are administered is not limited. The first therapy (e.g., prevention of compounds provided herein) (or therapeutic agents) should be administered before the second therapy (e.g., prophylactic or therapeutic agents) is administered to the subject (e.g., Approximately 5 minutes, approximately 15 minutes, approximately 30 minutes, approximately 45 minutes, approximately 1 hour, approximately 2 hours, approximately 4 hours, approximately 6 hours, approximately 12 hours, Approximately 24 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 (A week, about 6 weeks, about 8 weeks, or about 12 weeks prior), or at the same time, or afterward (for example) Approximately 5 minutes, approximately 15 minutes, approximately 30 minutes, approximately 45 minutes, approximately 1 hour, approximately 2 hours, approximately 4 hours, approximately 6 hours, approximately 12 hours, Approximately 24 hours, approximately 48 hours, approximately 72 hours, approximately 96 hours, approximately 1 week, approximately 2 weeks, approximately 3 weeks, approximately 4 weeks, approximately 5 It can be administered after weeks, approximately 6 weeks, approximately 8 weeks, or approximately 12 weeks. Triple combination therapy is also available. This is assumed in this specification.

[0134] As used herein, the term “synergistic” refers to the thiosulfate provided herein. Sodium and substances that have been used, or are currently used, to treat, prevent, or manage diseases or disorders. A combination with another therapy currently in use (e.g., a preventive or therapeutic agent), and the aspect of said therapy This includes combinations of therapies (e.g., combinations of preventive or therapeutic agents) that are more effective than the additive effect. The synergistic effect of (se) is that one or more of the therapies can reduce the dosage of the medication given to the affected subject. Allows for the use and / or less frequent administration of the therapy. Therapy with a lower dosage (e.g.) If so, the availability of preventive or therapeutic agents and / or the ability to perform such therapy at a lower frequency. This does not reduce the efficacy of the therapy in preventing or treating the disorder, and does not reduce the efficacy of the therapy in treating the subject. To reduce toxicity associated with the implementation of the law. In addition, synergistic effects will be beneficial in the prevention or treatment of the drug. It can also lead to improved efficacy of the drug. Finally, combinations of therapies (for example, prevention) The synergistic effect of either therapy or a combination of therapeutic drugs may cause adverse effects associated with the use of any therapy alone. Alternatively, undesirable side effects may be avoided or reduced.

[0135] The sodium thiosulfate provided herein may be used in combination with or without other therapeutic agents. They can be administered alternately. In combination therapy, the effective dosage of two or more drugs is administered together. Although administered, in alternating or sequential therapy, the effective dosage of each drug is administered sequentially or sequentially. It is administered. The amount of medication given is determined by the rate of absorption, inactivation, and excretion of the drug, and Furthermore, it depends on other factors known to those skilled in the art. The value of the dosage depends on the disease to be alleviated. It should be noted that this also varies depending on the severity of the disease. In contrast, a specific medication plan and schedule is required for each individual need and for administering the composition. The composition should be adjusted over time according to the professional judgment of the person supervising its administration. This needs to be understood more deeply.

[0136] The sodium thiosulfate provided herein is an endothelin-converting enzyme (ECE) inhibitor, e.g. For example, phosphoramidon; thromboxane receptor antagonists, such as ifetroban; Potassium channel openers; thrombin inhibitors, e.g., hirudin; growth factor inhibitors, e.g. , PDGF activity modulator; platelet-activating factor (PAF) antagonist; antiplatelet agent, for example For example, GPIIb / IIIa blockers (e.g., absiximab, eptifibatide, and tyrofi) (BAN), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine, and CS-747), and aspirin; anticoagulants, e.g., warfarin; low molecular weight heparin, e.g., enoxa Parin; Factor VIIa inhibitors and Factor Xa inhibitors; Renin inhibitors; Neutral endopeptidase (NE) P) Inhibitors; vasopeptidase inhibitors (NEP-ACE dual inhibitors), e.g., omapatril and ge Mopatrilato; HMG CoA reductase inhibitors, e.g., pravastatin, lovastatin, ator Vastatin, Simvastatin, NK-104 (also known as Itavastatin, Nisvastatin) (in), or nisbastatin, and ZD-4522 (also known as rosuvastatin, atabas) Tatin or bisastatin; squalene synthetase inhibitors; fibrates; bile acid scavengers For example, Questran; niacin; anti-atherosclerotic agents, for example, ACAT inhibitors; MTP inhibitors. Agents; calcium channel blockers, e.g., amlodipine besylate; potassium channel blockers Activators; alpha-adrenergic agonists; beta-adrenergic agonists, for example, Cal Vegilol and metoprolol; antiarrhythmic agents; diuretics, e.g., chlorothiazide, hydrochloride Lolothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, meth Luchlorothiazide, trichloromethiazide, polythiazide, benzothiazide, ethacrine Acid, ticlinafen, chlorthalidone, furosenide, muzolimin, bumetan Triamterene, amiloride, and spironolactone; thrombolytic agents, e.g., tissue Type plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase Ze, prourokinase, and anisoylated plasminogen streptokinase activate APSACs (antidiabetic agents), such as biguanides (e.g., metformin), and glutaramines. Cosidase inhibitors (e.g., acarbose), insulin, meglitinide (e.g., Repag) Linide, sulfonylurea (e.g., glimepiride, glybrid, and glipizide), thio thiozolidinedione (e.g., troglitazone, rosiglitazone, and pi) Oglitazone, and PPAR-gamma agonists; mineralocorticoid receptor antagonists, For example, spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphates Hodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors. Harmful agents (e.g., sildenafil, tadalafil, and vardenafil); protein tyrosine Gluta kinase inhibitors; anti-inflammatory drugs; antiproliferative drugs, e.g., methotrexate, FK506 (tacrolimus ), mycophenolate mofetil; chemotherapeutic agents; immunosuppressants; anticancer agents and cytotoxic agents (for example) Nitrogen mustard, alkyl sulfonate, nitrosourea, ethyleneimi Alkylating agents such as triazenes; antimetabolites, for example, folic acid antagonists, Purine analogs and pyrimidine analogs; antibiotics, e.g., anthracyclines, bleod Mycin, mitomycin, dactinomycin, and plicamycin; enzymes, e.g., L- Asparaginase; farnesyl-protein transferase inhibitors; hormones, e.g. For example, glucocorticoids (e.g., cortisone), estrogen / anti-estrogen agents, Androgens / antiandrogens, progestins, and progesterone-releasing hormone antagonists Nist and octreotide acetate; microtubule-disruptor agents, for example Ectinacidin; microtubule stabilizers, e.g., pacitaxel, docetaxel , and Epothiron AF; plant-derived products, e.g., vinca alkaloids, epipodophyllot Xin and taxane; and topoisomerase inhibitors; prenyl protein transfer Lase inhibitors; and cyclosporine; steroids, such as prednisone and dexamethasone. N; cytotoxic drugs, e.g., azathioprine and cyclophosphamide; TNF-alpha inhibitors Harmful agents, e.g., Tenidap; anti-TNF antibodies or soluble TNF receptors, e.g., etanercept. Rapamycin and leflunimide; cyclooxygenase-2 (COX-2) inhibitors For example, celecoxib and rofecoxib; and various other drugs, for example, nitrite. Sodium hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold Compounds, low molecular weight drugs, low molecular weight vitamins, and platinum-coordinate complexes, such as cisplatin, This includes, but is not limited to, satraplatin and carboplatin, another class of chemicals. It can be administered in combination with other compounds.

[0137] The sodium thiosulfate provided herein contains copper, fluoride ions, iodine, iron, and man. Cancer, magnesium, nitrite ions, phosphorus, selenium, and zinc, naturally occurring in human blood It can be administered in combination with other solutes present in the system.

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

[0139] (Examples) When used herein, these experiments, processes, schemes, and examples The symbols and idioms used, regardless of whether specific abbreviations are specifically defined, are modernized. Academic literature, for example, the Journal of the American Chemical Society or the Journal of B This is consistent with what is used in iological chemistry. Specifically, it is limiting. However, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); μL (microliters); mM (millimole 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 examples, a standard workup known to those skilled in the art was used. Purification methods can be used. Unless otherwise specified, all temperatures are in °C (Celsius). This is expressed. Unless otherwise specified, all reactions are carried out at room temperature. The following examples illustrate this. The method is intended to illustrate applicable chemistry using specific examples, and is within the scope of the present invention. It does not represent that.

[0141] (Stability experiment) The following stability experiments (Examples 1-4) show the results of thiosulfate in aqueous solution when acid is added. Ion instability, and in the preparation of dialysate for dialysis, acid concentrates and bicarbonate concentrates This illustrates the instability of thiosulfate ions when mixed with solutions containing liquids.

[0142] The concentration of thiosulfate ions in the sample was assayed using ion chromatography. The chromatography apparatus includes an electrochemical conductivity detector and a Dionex IonPacAS12A analytical chromatograph. The ram was attached. The sodium thiosulfate content in the tested sample was measured outside the sodium thiosulfate. Calculations were performed against the United States Pharmacopeia Sodium Thiosulfate Reference Standard (Item No. 16151). 07) was used as the test standard (United States Pharmacopeia, Rockville, Maryland).

[0143] (Example 1) The chemical safety data sheet for sodium thiosulfate states that when this chemical comes into contact with an acid... This indicates that it decomposes (http: / / www.thiosulfate.info / downloads / sodiumthiosulfate). (Chemical substance safety data sheet accessed online as _msds.pdf).

[0144] Example 1 measures the stability of sodium thiosulfate in aqueous solution when an acid is added. This was done to transfer a 60 mg sample of sodium thiosulfate into a 50 mL volumetric flask. 2 mL of 0.1 N hydrochloric acid was added to the flask. The flask was covered and heated at 80°C for approximately 24 hours. Then, the flask was cooled to ambient temperature. 2 mL of 0.1 N sodium hydroxide was added. The acid was neutralized, and deionized water was added to make a volume of 50 mL. The thiosulfate ion decomposition in this sample The percentage was 28.6%. Published information on the reaction between acids and thiosulfate ions (h at ttps: / / www.quora.com / Why-does-sodium-thiosulphate-react-with-hydrochloric-acid (Available online) Consistent with this result, this finding indicates that sodium thiosulfate, when exposed to acid... It was then confirmed that it could be disassembled.

[0145] (Example 2) Example 2 was used to measure the stability of sodium thiosulfate in a concentrated bicarbonate solution of dialysate. The procedure was carried out at room temperature. 12,500 mg of sodium thiosulfate (50 mL of 250 mg / mL solution) was added to 7,700 mL of water. It was added to the concentrated bicarbonate solution of the dialysate. The thiosulfate ion concentration of the concentrated bicarbonate solution of the dialysate was 1) Before the addition of sodium thiosulfate; 2) 5 minutes after the addition of sodium thiosulfate; and 3) thiosulfate Analysis was performed by ion chromatography 2 hours after the addition of sodium. The concentration of thorium does not decrease over time, and the decomposition products, sulfate ions, sulfite ions, and Because the sulfide ion concentration did not increase over time, the results shown in Tables 1 and 2 are for dialysis. This demonstrates that thiosulfate ions are stable when added to a concentrated liquid bicarbonate solution. (Table 1: Sodium thiosulfate concentration in dialysate bicarbonate concentrate) [Table 1] (Table 2: Sulfate ions, sulfide ions, and in dialysate bicarbonate concentrate + sodium thiosulfate) (Sulfite ion concentration) [Table 2]

[0146] (Example 3) Example 3 shows the sodium thiosulfate from Example 2 when mixed with an acid concentrate solution in a dialysis machine. Further measurement of the stability of thiosulfate ions in a mixture of lium and dialysate bicarbonate concentrate solution. This was done for the purpose of using a dialysis machine to concentrate the dialysate bicarbonate solution (thiosulfur from Example 2). (Sodium acid added), concentrated acid solution, and purified water are used in the dialysis machine in actual clinical practice. Similar to how the dialysate is mixed, 1 part of the concentrated acid solution and 1.72 parts of the concentrated bicarbonate solution are mixed together. The solution was mixed with 42.38 parts purified water. The dialysis apparatus used in this experiment was Freseni The machine was a US 2008K hemodialysis machine (Fresenius Medical Care, Waltham, MA). Using saline solution, in bypass mode (dialysis fluid velocity and ultrafiltration velocity set to zero) Priming was performed. After priming, the hemodialysis machine was set to the following settings: blood flow rate 300 mL / min, dialysis. Operated in "Therapy Mode" with a precipitate flow rate of 600 mL / min, ultrafiltration rate of 0 mL / min, and ultrafiltration time of 25 minutes. A sample of the dialysate mixed when it left the dialysis machine was taken and ion chromatography was performed. —This was analyzed by [the specified method].

[0147] The results shown in Table 3 indicate that thiosulfate ions in the concentrated bicarbonate solution of dialysate are present in the acid inside the dialyzer. This indicates that the substance was almost completely decomposed during the mixing process with the concentrated solution. (Table 3: Thiosulfate ion concentration in dialysate after mixing in a hemodialysis machine) [Table 3]

[0148] (Example 4) Example 4 is a case where the dialysis fluid is used in a Fresenius 2008K hemodialysis machine (Fresenius Medical Care, Waltham When sodium thiosulfate is added to the dialysate after it has been prepared in MA, This was done to measure the stability of acid ions. Dialysis fluid bicarbonate concentrate was used, Centrisol ( One packet (650g) of MB-330 series sodium bicarbonate concentrate powder (registered trademark) is used to purify 7.7 liters of water. It was prepared by adding it to water.

[0149] The hemodialysis apparatus used to obtain a concentrated bicarbonate solution and a concentrated acid solution, with 1 part of the concentrated acid solution and 1.7 A mixture of 2 parts concentrated bicarbonate solution and 42.38 parts purified water was prepared. The apparatus was then used to test physiological salt Priming is performed using water in bypass mode (dialysis fluid velocity and ultrafiltration velocity are set to zero). After priming, the hemodialysis machine was set to the following settings: blood flow rate 300 mL / min, dialysate. The system was operated in "therapeutic mode" with a flow rate of 600 mL / min and an ultrafiltration rate of 0 mL / min.

[0150] By dissolving 25 mg of sodium thiosulfate in 1 liter of purified water, An aqueous solution of sodium thiosulfate was prepared. The resulting sodium thiosulfate solution contained approximately 17.72 mg / L Since it had a thiosulfate anion concentration, this sodium thiosulfate solution was AAMI's sulfate anion The sodium thiosulfate solution met the quality specifications for ions (and thiosulfate ions). Using an aris(registered trademark) IV infusion pump (Model 8100, CareFusion, San Diego, CA), the valve (Fr Esensius Dialysate Sample Valve (Part Number 650993) is used in hemodialysis machines and dialyzers. It was injected directly into the dialysate piping between the two. The valve is located in the dialysate piping of the dialyzer (prefilter). It was positioned approximately 8 inches (about 20.3 cm) upstream from the dialyzer. Two sample collection ports were positioned 4 inches (10.2 cm) upstream from the dialyzer. It is positioned 10 inches (25.4 cm) upstream (sampling port before dialyzer) and 10 inches (25.4 cm) downstream (sampling port after dialyzer). Then, a sample of the dialysate was collected for a nitrate ion assay using ion chromatography. .

[0151] The infusion pump delivers sodium thiosulfate solution through a valve at a rate of 250 mL / hour (4.16 mL / min). It was injected into the pipe.

[0152] Physiological saline flows from the arterial line into the dialyzer at a rate of 300 mL / min, and through the venous line. Then I left the dialyzer. A sample of physiological saline solution was taken from the venous side of the dialyzer.

[0153] The results shown in Table 4 indicate that the sodium thiosulfate solution mixed with the dialysate in the dialysate tubing, When injected into the piping at a position between the liquid dialysis machine and the dialysis membrane, thiosulfate ions are stable. To indicate that. (Table 4: Sodium thiosulfate solution in the dialysate tubing before the dialysate comes into contact with the dialysate membrane) (Thiosulfate ion concentration in the dialysate before and after addition to the solution) [Table 4] *Average result from two samples

[0154] The results shown in Table 4 indicate that spikes from the hemodialysis machine occur at a position between the hemodialysis machine and the dialysis membrane. If thiosulfate ions are added to dialysate that has not been treated, then the thiosulfate ions will be in the dialyzer. This indicates that you can either proceed along it or pass through it.

[0155] The above examples illustrate how to manufacture and use the claimed embodiments. Provided to give those skilled in the art a full disclosure and explanation, as disclosed herein. It is not intended to limit the scope of the patent. Modifications that are obvious to those skilled in the art may result in the following patent application It is intended to be within the scope of the request. All publications, patents, etc. cited herein And patent applications are as if each of such publications, patents, or patent applications is clearly Furthermore, individually, as indicated by the citation, that they are incorporated herein by reference. This specification is incorporated herein. This application provides the invention in the following embodiments. (Aspect 1) In patients undergoing hemodialysis, maintaining physiological levels of thiosulfate ions A method which involves bringing the blood of the subject into contact with a dialysate spiked with thiosulfate ions. The dialysis membrane is in contact with the dialysis device, and the non-spiked dialysate is in contact with the dialysis device during dialysis. When the aqueous solution containing sodium thiosulfate flows from the dialysis membrane, it does not spike. The dialysis fluid is added to the dialysis fluid, and the dialysis fluid that has not been spiked is water, acid concentrate, and bicarbonate concentrate. A dialysate containing a mixture of condensed solutions and spiked with thiosulfate ions has a pH greater than approximately 7.0 The method comprising the above. (Aspect 2) The physiological level of thiosulfate ions in the subject is approximately 10 micromolars or less. The method described in Embodiment 1, which is shown below. (Aspect 3) The physiological level of thiosulfate ions in the subject is approximately 500 nanomolar concentration to approximately 5 The method according to embodiment 1, wherein the concentration is micromolar. (Aspect 4) The physiological level of thiosulfate ions in the subject is approximately 3 micromolars. A method according to one aspect 1. (Appendix 5) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 10 microns. The method according to Embodiment 1, wherein the concentration is less than or equal to the romole concentration. (Aspect 6) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 500 nanometers. The method according to embodiment 1, wherein the molar concentration is approximately 5 micromolars. (Aspect 7) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 3 microns. The method according to Embodiment 1, which is the romole concentration. (Pattern 8) The aqueous solution containing sodium thiosulfate contains approximately 300 mg / L or less of sodium thiosulfate. The method described in Embodiment 1. (Aspect 9) The method according to embodiment 1, wherein the water contains thiosulfate ions at a concentration of approximately 200 mg / L or less. (Aspect 10) Before the dialysate piping is connected to the dialyzer, through a valve attached to the piping, An aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate. The method described in Embodiment 1. (Aspect 11) The undrilled dialysate flows through the dialysing tubing at a rate of approximately 500 mL / min to approximately 700 mL / min. The method described in embodiment 10, which involves flowing. (Aspect 12) The non-spiked dialysate flows through the dialysate piping at a rate of approximately 600 mL / min. Method described in 10. (Aspect 13) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 10, wherein the solution is added to the precipitation at a rate of approximately 100 mL / hour to approximately 550 mL / hour. (Aspect 14) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 10, wherein the solution is added to the precipitate at a rate of approximately 250 mL per hour. (Aspect 15) The pH of the dialysate spiked with thiosulfate ions is approximately 7.3 to approximately 7.5, as described in Embodiment 1. The method. (Aspect 16) The method according to embodiment 1, wherein the pH of the dialysate spiked with thiosulfate ions is approximately 7.4. (Aspect 17) The method according to embodiment 1, wherein the subject is a human with chronic renal failure. (Aspect 18) The method according to embodiment 1, wherein the subject is a human with acute renal failure. (Aspect 19) The method according to embodiment 1, wherein the subject receives dialysis 3 to 7 times per week. (Aspect 20) A method for preventing myocardial infarction in a person undergoing dialysis, wherein the blood of the person is used. The liquid comes into contact with the dialysis membrane, which is also in contact with the dialysate spiked with thiosulfate ions, during dialysis. This includes the process of allowing the unspiked dialysate to flow from the dialyzer to the dialysate membrane, An aqueous solution containing sodium thiosulfate is added to the unspiked dialysate, and the spike The unprocessed dialysate contains a mixture of water, acid concentrate, and bicarbonate concentrate, and The method wherein the dialysate spiked with thiosulfate ions has a pH greater than approximately 7.0. (Aspect 21) The physiological level of thiosulfate ions in the subject is approximately 10 micromolars or less. The method described in Embodiment 20, which is shown below. (Aspect 22) The physiological level of thiosulfate ions in the subject is approximately 500 nanomolar concentration to approximately 5 The method according to embodiment 20, wherein the concentration is micromolar. (Aspect 23) The physiological level of thiosulfate ions in the subject is approximately 3 micromolars. A method described in one aspect 20. (Aspect 24) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 10 microns. The method according to embodiment 20, wherein the concentration is less than or equal to the romole concentration. (Aspect 25) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 500 nanometers. The method according to embodiment 20, wherein the molar concentration is approximately 5 micromolars. (Aspect 26) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 3 microns. The method described in Embodiment 20, which is the romole concentration. (Aspect 27) The aqueous solution containing sodium thiosulfate contains approximately 300 mg / L or less of sodium thiosulfate. The method described in embodiment 20. (Aspect 28) The method according to embodiment 20, wherein the water contains thiosulfate ions at a concentration of approximately 200 mg / L or less. (Aspect 29) Before the dialysate piping is connected to the dialyzer, through a valve attached to the piping, An aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate. The method described in aspect 20. (Aspect 30) The undrilled dialysate flows through the dialysing tubing at a rate of approximately 500 mL / min to approximately 700 mL / min. The method described in aspect 29, which involves flowing. (Aspect 31) The undrilled dialysate flows through the dialysate tubing at a rate of approximately 600 mL per minute. The method described in aspect 29. (Aspect 32) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 29, wherein the solution is added to the precipitation at a rate of approximately 100 mL / hour to approximately 550 mL / hour. (Aspect 33) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 29, wherein the solution is added to the precipitation at a rate of approximately 250 mL per hour. (Aspect 34) The pH of the dialysate spiked with thiosulfate ions is approximately 7.3 to approximately 7.5, as described in Embodiment 20. The method. (Aspect 35) The method according to embodiment 20, wherein the pH of the dialysate spiked with thiosulfate ions is approximately 7.4. . (Aspect 36) The method according to embodiment 20, wherein the subject is a human with chronic renal failure. (Aspect 37) The method according to embodiment 20, wherein the subject is a human with acute renal failure. (Aspect 38) The method according to embodiment 20, wherein the subject receives dialysis 3 to 7 times per week. (Aspect 39) A method for preventing sudden cardiac death in a person undergoing dialysis, the same Elephant blood is in contact with a dialysis membrane that is also in contact with dialysis fluid spiked with thiosulfate ions during dialysis. This includes bringing the unspiked dialysate into contact with the dialysate, which flows from the dialyzer to the dialysate membrane. Sometimes, an aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate, The unspiked dialysate contains a mixture of water, acid concentrate, and bicarbonate concentrate. The method wherein the dialysate spiked with thiosulfate ions has a pH greater than approximately 7.0. (Approach 40) The physiological level of thiosulfate ions in the subject is approximately 10 micromolars or less. The method described in aspect 39, below. (Aspect 41) The physiological level of thiosulfate ions in the subject is approximately 500 nanomolar concentration to approximately 5 The method according to embodiment 39, wherein the concentration is micromolar. (Aspect 42) The physiological level of thiosulfate ions in the subject is approximately 3 micromolars. A method described in one aspect 39. (Aspect 43) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 10 microns. The method according to embodiment 39, wherein the concentration is less than or equal to the romole concentration. (Aspect 44) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 500 nanometers. The method according to aspect 39, wherein the molar concentration is approximately 5 micromolars. (Aspect 45) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 3 microns. The method described in Embodiment 39, which is the romole concentration. (Aspect 46) The aqueous solution containing sodium thiosulfate contains approximately 300 mg / L or less of sodium thiosulfate. The method described in aspect 39. (Aspect 47) The method according to embodiment 39, wherein the water contains thiosulfate ions at a concentration of approximately 200 mg / L or less. (Aspect 48) Before the dialysate piping is connected to the dialyzer, through a valve attached to the piping, An aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate. The method described in aspect 39. (Aspect 49) The undrilled dialysate flows through the dialysing tubing at a rate of approximately 500 mL / min to approximately 700 mL / min. The method described in aspect 48, which involves flowing. (Appearance 50) The undrilled dialysate flows through the dialysate tubing at a rate of approximately 600 mL per minute. The method described in aspect 48. (Aspect 51) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 48, wherein the solution is added to the precipitation at a rate of approximately 100 mL / hour to approximately 550 mL / hour. (Appearance 52) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 48, wherein the solution is added to the precipitation at a rate of approximately 250 mL per hour. (Aspect 53) The pH of the dialysate spiked with thiosulfate ions is approximately 7.3 to approximately 7.5, as described in Embodiment 39. The method. (Aspect 54) The method according to embodiment 39, wherein the pH of the dialysate spiked with thiosulfate ions is approximately 7.4. . (Aspect 55) The method according to embodiment 39, wherein the subject is a human with chronic renal failure. (Aspect 56) The method according to embodiment 39, wherein the subject is a human with acute renal failure. (Aspect 57) The method according to embodiment 39, wherein the subject receives dialysis 3 to 7 times per week. (Pattern 58) A method for preventing stroke in a person undergoing dialysis, wherein the blood of the person is used. This is brought into contact with the dialysis membrane, which is also in contact with the dialysate spiked with thiosulfate ions, during dialysis. This includes the process of when the unspiked dialysate flows from the dialyzer to the dialysate membrane, An aqueous solution containing sodium osulfate is added to the non-spiked dialysate, and the spike The dialysate that has not been treated contains a mixture of water, an acid concentrate, and a bicarbonate concentrate, and The method wherein the dialysate spiked with thiosulfate ions has a pH greater than approximately 7.0. (Aspect 59) The physiological level of thiosulfate ions in the subject is approximately 10 micromolars or less. The method described in aspect 58, below. (Appendix 60) The physiological level of thiosulfate ions in the subject is approximately 500 nanomolar concentration to approximately 5 The method according to embodiment 58, wherein the concentration is micromolar. (Aspect 61) The physiological level of thiosulfate ions in the subject is approximately 3 micromolars. A method described in one aspect 58. (Aspect 62) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 10 microns. The method according to embodiment 58, wherein the concentration is less than or equal to the romole concentration. (Aspect 63) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 500 nanometers. The method according to aspect 58, wherein the molar concentration is approximately 5 micromolars. (Personal aspect 64) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 3 microns. The method described in Embodiment 58, which is the romole concentration. (Patent 65) The aqueous solution containing sodium thiosulfate contains approximately 300 mg / L or less of sodium thiosulfate. The method described in aspect 58. (Aspect 66) The method according to embodiment 58, wherein the water contains thiosulfate ions at a concentration of approximately 200 mg / L or less. (Patent 67) Before the dialysate piping is connected to the dialyzer, through a valve attached to the piping, An aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate. The method described in aspect 58. (Pattern 68) The undrilled dialysate flows through the dialysing tubing at a rate of approximately 500 mL / min to approximately 700 mL / min. The method described in aspect 67, which involves flowing. (Patent 69) The undrilled dialysate flows through the dialysate tubing at a rate of approximately 600 mL per minute. The method described in aspect 67. (Aspect 70) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 67, wherein the solution is added to the precipitation at a rate of approximately 100 mL / hour to approximately 550 mL / hour. (Aspect 71) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 67, wherein the solution is added to the precipitate at a rate of approximately 250 mL per hour. (Aspect 72) The pH of the dialysate spiked with thiosulfate ions is approximately 7.3 to approximately 7.5, as described in Embodiment 58. The method. (Aspect 73) The method according to embodiment 58, wherein the pH of the dialysate spiked with thiosulfate ions is approximately 7.4. . (Aspect 74) The method according to embodiment 58, wherein the subject is a human with chronic renal failure. (Aspect 75) The method according to embodiment 58, wherein the subject is a human with acute renal failure. (Aspect 76) The method according to embodiment 58, wherein the subject receives dialysis 3 to 7 times per week. (Aspect 77) In patients undergoing dialysis, angina pectoris, cerebral vasospasm, claudication, severe limb ischemia, and peripheral vascular disease are among the conditions that may be present. To prevent cardiovascular diseases characterized by disease and tissue ischemia, including sickle cell crisis. A method wherein the blood of the subject is also in contact with a dialysate spiked with thiosulfate ions. This includes bringing the dialysis membrane into contact with the dialysis fluid during dialysis, and the non-spiked dialysis fluid is in contact with the dialysis machine. When it flows to the dialysis membrane, the aqueous solution containing sodium thiosulfate is not spiked. The dialysis fluid, which is not spiked, is added to the precipitate, and the dialysis fluid is mixed with water, acid concentrate, and bicarbonate concentrate. A dialysis solution containing a mixture of solutions, spiked with thiosulfate ions, has a pH greater than approximately 7.0. The method described above. (Pattern 78) The physiological level of thiosulfate ions in the subject is approximately 10 micromolars or less. The method described in aspect 77, below. (Aspect 79) The physiological level of thiosulfate ions in the subject is approximately 500 nanomolar concentration to approximately 5 The method according to embodiment 77, wherein the concentration is micromolar. (Appendix 80) The physiological level of thiosulfate ions in the subject is approximately 3 micromolars. A method according to one aspect 77. (Aspect 81) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 10 microns. The method according to embodiment 77, wherein the concentration is less than or equal to the romole concentration. (Aspect 82) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 500 nanometers. The method according to aspect 77, wherein the molar concentration is approximately 5 micromolars. (Aspect 83) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 3 microns. The method according to embodiment 77, which is the romole concentration. (Pattern 84) The aqueous solution containing sodium thiosulfate contains approximately 300 mg / L or less of sodium thiosulfate. The method described in aspect 77. (Pattern 85) The method according to embodiment 77, wherein the water contains thiosulfate ions at a concentration of approximately 200 mg / L or less. (Pattern 86) Before the dialysate piping is connected to the dialyzer, through a valve attached to the piping, An aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate. The method described in aspect 77. (Aspect 87) The undrilled dialysate flows through the dialysing tubing at a rate of approximately 500 mL / min to approximately 700 mL / min. The method described in aspect 86, which involves flowing. (Pattern 88) The undrilled dialysate flows through the dialysate tubing at a rate of approximately 600 mL per minute. The method described in aspect 86. (Pattern 89) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 86, wherein the solution is added to the precipitation at a rate of approximately 100 mL / hour to approximately 550 mL / hour. (Aspect 90) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 86, wherein the solution is added to the precipitation at a rate of approximately 250 mL per hour. (Aspect 91) The pH of the dialysate spiked with thiosulfate ions is approximately 7.3 to approximately 7.5, as described in Embodiment 77. The method. (Patent 92) The method according to embodiment 77, wherein the pH of the dialysate spiked with thiosulfate ions is approximately 7.4. . (Aspect 93) The method according to embodiment 77, wherein the subject is a human with chronic renal failure. (Aspect 94) The method according to embodiment 77, wherein the subject is a human with acute renal failure. (Aspect 95) The method according to embodiment 77, wherein the subject receives dialysis 3 to 7 times per week. (Personal aspect 96) To prevent hypertension, pulmonary hypertension, and renal hypertension in patients undergoing dialysis. A method for which the blood of the subject is also brought into contact with the dialysate spiked with thiosulfate ions. This includes bringing the dialysis membrane into contact with the dialysis fluid during dialysis, and the non-spiked dialysis fluid being used for dialysis. As the aqueous solution containing sodium thiosulfate flows from the device to the dialysis membrane, it is spiked. It is added to the dialysate that is not spiked, and the dialysate is water, acid concentrate, and bicarbonate. A dialysate containing a mixture of concentrated salt solutions and spiked with thiosulfate ions is approximately 7.0 The method having a pH of [value]. (Patent 97) The physiological level of thiosulfate ions in the subject is approximately 10 micromolars or less. The method described in aspect 96, below. (Pattern 98) The physiological level of thiosulfate ions in the subject is approximately 500 nanomolar concentration to approximately 5 The method according to embodiment 96, wherein the concentration is micromolar. (Pattern 99) The physiological level of thiosulfate ions in the subject is approximately 3 micromolars. A method described in one aspect 96. (Aspect 100) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 10 microns. The method according to embodiment 96, wherein the concentration is less than or equal to the romole concentration. (Aspect 101) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 500 nanometers. The method according to aspect 96, wherein the molar concentration is approximately 5 micromolars. (Aspect 102) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 3 microns. The method described in Embodiment 96, which is the romole concentration. (Aspect 103) The aqueous solution containing sodium thiosulfate contains approximately 300 mg / L or less of sodium thiosulfate. The method described in aspect 96. (Aspect 104) The method according to embodiment 96, wherein the water contains thiosulfate ions at a concentration of approximately 200 mg / L or less. (Aspect 105) Before the dialysate piping is connected to the dialyzer, through a valve attached to the piping, An aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate. The method described in aspect 96. (Aspect 106) The undrilled dialysate flows through the dialysing tubing at a rate of approximately 500 mL / min to approximately 700 mL / min. The method described in aspect 105, which involves flowing. (Aspect 107) The undrilled dialysate flows through the dialysate tubing at a rate of approximately 600 mL per minute. The method described in aspect 105. (Aspect 108) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 105, wherein the solution is added to the precipitation at a rate of approximately 100 mL / hour to approximately 550 mL / hour. (Aspect 109) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 105, wherein the solution is added to the precipitate at a rate of approximately 250 mL per hour. (Aspect 110) The pH of the dialysate spiked with thiosulfate ions is approximately 7.3 to approximately 7.5, as described in Embodiment 96. The method. (Aspect 111) The method according to embodiment 96, wherein the pH of the dialysate spiked with thiosulfate ions is approximately 7.4. . (Aspect 112) The method according to embodiment 96, wherein the subject is a human with chronic renal failure. (Aspect 113) The method according to embodiment 96, wherein the subject is a human with acute renal failure. (Aspect 114) The method according to embodiment 96, wherein the subject receives dialysis 3 to 7 times per week. (Aspect 115) In patients undergoing dialysis, this was a method for preventing atherosclerosis. The blood in question is then placed in contact with the dialysis membrane, which is also in contact with the dialysis fluid spiked with thiosulfate ions. Including contact during dialysis, the unspiked dialysate is transferred from the dialysis machine to the dialysis membrane. As the dialysis fluid flows, an aqueous solution containing sodium thiosulfate is added to the dialysis fluid that has not been spiked. The unspiked dialysate is a mixture of water, acid concentrate, and bicarbonate concentrate. A dialysis solution containing a substance and spiked with thiosulfate ions has a pH greater than approximately 7.0. How to write. (Aspect 116) The physiological level of thiosulfate ions in the subject is approximately 10 micromolars or less. The method described in aspect 115, below. (Aspect 117) The physiological level of thiosulfate ions in the subject is approximately 500 nanomolar concentration to approximately 5 The method according to embodiment 115, wherein the concentration is micromolar. (Aspect 118) The physiological level of thiosulfate ions in the subject is approximately 3 micromolars. A method described in one aspect 115. (Aspect 119) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 10 microns. The method according to embodiment 115, wherein the concentration is less than or equal to the romole concentration. (Aspect 120) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 500 nanometers. The method according to aspect 115, wherein the molar concentration is approximately 5 micromolars. (Aspect 121) The concentration of thiosulfate ions in the dialysate spiked with the aforementioned thiosulfate ions is approximately 3 microns. The method described in Embodiment 115, which is the romole concentration. (Aspect 122) The aqueous solution containing sodium thiosulfate contains approximately 300 mg / L or less of sodium thiosulfate. The method described in aspect 115. (Aspect 123) The method according to embodiment 115, wherein the water contains thiosulfate ions at a concentration of approximately 200 mg / L or less. (Aspect 124) Before the dialysate piping is connected to the dialyzer, through a valve attached to the piping, An aqueous solution containing sodium thiosulfate is added to the non-spiked dialysate. The method described in aspect 115. (Aspect 125) The undrilled dialysate flows through the dialysing tubing at a rate of approximately 500 mL / min to approximately 700 mL / min. The method described in aspect 124, which involves flowing. (Aspect 126) The undrilled dialysate flows through the dialysate tubing at a rate of approximately 600 mL per minute. The method described in Embodiment 124. (Aspect 127) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 124, wherein the solution is added to the precipitation at a rate of approximately 100 mL / hour to approximately 550 mL / hour. (Aspect 128) The aqueous solution containing sodium thiosulfate passes through the valve, the non-spiked perforated The method according to embodiment 124, wherein the solution is added to the precipitation at a rate of approximately 250 mL per hour. (Aspect 129) The pH of the dialysate spiked with thiosulfate ions is approximately 7.3 to approximately 7.5, as described in Embodiment 115. Method of loading. (Aspect 130) The method according to embodiment 115, wherein the pH of the dialysate spiked with thiosulfate ions is approximately 7.4. . (Aspect 131) The method according to embodiment 115, wherein the subject is a human with chronic renal failure. (Aspect 132) The method according to embodiment 115, wherein the subject is a human with acute renal failure. (Aspect 133) The method according to embodiment 115, wherein the subject receives dialysis 3 to 7 times per week.

Claims

1. A thiosulfate-spiked medical dialysis fluid comprising sodium thiosulfate, water, acid concentrate, and bicarbonate concentrate, for use in a method for maintaining physiological levels of thiosulfate ions in subjects undergoing hemodialysis, The method includes bringing the blood of the subject into contact with a dialysis membrane that is also in contact with a medical dialysis fluid spiked with thiosulfate ions during dialysis, and The pharmaceutical dialysis fluid spiked with thiosulfate ions has a pH greater than approximately 7.0, and The concentration of thiosulfate ions in the medical dialysis fluid spiked with thiosulfate ions is 100 micromolars or less, and The thiosulfate ion-spiked pharmaceutical dialysis fluid is used to be administered to the subject together with one or more low molecular weight drugs and / or low molecular weight vitamins. The aforementioned thiosulfate ion-spiked pharmaceutical dialysis fluid.

2. A thiosulfate ion-spiked pharmaceutical dialysis solution containing sodium thiosulfate, water, acid concentrate, and bicarbonate concentrate, for use in a method for preventing myocardial infarction in patients undergoing dialysis, The method includes bringing the blood of the subject into contact with a dialysis membrane that is also in contact with a medical dialysis fluid spiked with thiosulfate ions during dialysis, and The pharmaceutical dialysis fluid spiked with thiosulfate ions has a pH greater than approximately 7.0, and The concentration of thiosulfate ions in the medical dialysis fluid spiked with thiosulfate ions is 100 micromolars or less, and The thiosulfate ion-spiked pharmaceutical dialysis fluid is used to be administered to the subject together with one or more low molecular weight drugs and / or low molecular weight vitamins. The aforementioned thiosulfate ion-spiked pharmaceutical dialysis fluid.

3. A thiosulfate ion-spiked pharmaceutical dialysis fluid, comprising sodium thiosulfate, water, acid concentrate, and bicarbonate concentrate, for use in a method to prevent sudden cardiac death in patients undergoing dialysis, The method includes bringing the blood of the subject into contact with a dialysis membrane that is also in contact with a medical dialysis fluid spiked with thiosulfate ions during dialysis, and The pharmaceutical dialysis fluid spiked with thiosulfate ions has a pH greater than approximately 7.0, and The concentration of thiosulfate ions in the medical dialysis fluid spiked with thiosulfate ions is 100 micromolars or less, and The thiosulfate ion-spiked pharmaceutical dialysis fluid is used to be administered to the subject together with one or more low molecular weight drugs and / or low molecular weight vitamins. The aforementioned thiosulfate ion-spiked pharmaceutical dialysis fluid.

4. A thiosulfate ion-spiked pharmaceutical dialysis fluid, comprising sodium thiosulfate, water, acid concentrate, and bicarbonate concentrate, for use in a method for preventing stroke in patients undergoing dialysis, The method includes bringing the blood of the subject into contact with a dialysis membrane that is also in contact with a medical dialysis fluid spiked with thiosulfate ions during dialysis, and The pharmaceutical dialysis fluid spiked with thiosulfate ions has a pH greater than approximately 7.0, and The concentration of thiosulfate ions in the medical dialysis fluid spiked with thiosulfate ions is 100 micromolars or less, and The thiosulfate ion-spiked pharmaceutical dialysis fluid is used to be administered to the subject together with one or more low molecular weight drugs and / or low molecular weight vitamins. The aforementioned thiosulfate ion-spiked pharmaceutical dialysis fluid.

5. A thiosulfate ion-spiked pharmaceutical dialysis fluid comprising sodium thiosulfate, water, acid concentrate, and bicarbonate concentrate, for use in methods for preventing cardiovascular diseases characterized by tissue ischemia, including angina pectoris, cerebral vasospasm, claudication, severe limb ischemia, peripheral vascular disease, and sickle cell crisis, in patients undergoing dialysis, The method includes bringing the blood of the subject into contact with a dialysis membrane that is also in contact with a medical dialysis fluid spiked with thiosulfate ions during dialysis, and The pharmaceutical dialysis fluid spiked with thiosulfate ions has a pH greater than approximately 7.0, and The concentration of thiosulfate ions in the medical dialysis fluid spiked with thiosulfate ions is 100 micromolars or less, and The thiosulfate ion-spiked pharmaceutical dialysis fluid is used to be administered to the subject together with one or more low molecular weight drugs and / or low molecular weight vitamins. The aforementioned thiosulfate ion-spiked pharmaceutical dialysis fluid.

6. A thiosulfate ion-spiked pharmaceutical dialysis fluid containing sodium thiosulfate, water, acid concentrate, and bicarbonate concentrate, for use in a method for preventing hypertension, pulmonary hypertension, and renal hypertension in patients undergoing dialysis, The method includes bringing the blood of the subject into contact with a dialysis membrane that is also in contact with a medical dialysis fluid spiked with thiosulfate ions during dialysis, and The pharmaceutical dialysis fluid spiked with thiosulfate ions has a pH greater than approximately 7.0, and The concentration of thiosulfate ions in the medical dialysis fluid spiked with thiosulfate ions is 100 micromolars or less, and The thiosulfate ion-spiked pharmaceutical dialysis fluid is used to be administered to the subject together with one or more low molecular weight drugs and / or low molecular weight vitamins. The aforementioned thiosulfate ion-spiked pharmaceutical dialysis fluid.

7. A thiosulfate ion-spiked pharmaceutical dialysis fluid, comprising sodium thiosulfate, water, acid concentrate, and bicarbonate concentrate, for use in a method for preventing atherosclerosis in patients undergoing dialysis, The method includes bringing the blood of the subject into contact with a dialysis membrane that is also in contact with a medical dialysis fluid spiked with thiosulfate ions during dialysis, and The pharmaceutical dialysis fluid spiked with thiosulfate ions has a pH greater than approximately 7.0, and The concentration of thiosulfate ions in the medical dialysis fluid spiked with thiosulfate ions is 100 micromolars or less, and The thiosulfate ion-spiked pharmaceutical dialysis fluid is used to be administered to the subject together with one or more low molecular weight drugs and / or low molecular weight vitamins. The aforementioned thiosulfate ion-spiked pharmaceutical dialysis fluid.

8. A thiosulfate-spiked pharmaceutical dialysis fluid according to any one of claims 1 to 7, wherein the physiological level of thiosulfate ions in the subject is approximately 10 micromolars or less.

9. A pharmaceutical dialysis solution spiked with thiosulfate ions according to any one of claims 1 to 7, wherein the physiological level of thiosulfate ions in the subject is approximately 500 nanomolar to approximately 5 micromolar.

10. A pharmaceutical dialysis solution spiked with thiosulfate ions according to any one of claims 1 to 7, wherein the physiological level of thiosulfate ions in the subject is approximately 3 micromolars.

11. The thiosulfate ion-spiked pharmaceutical dialysis fluid according to any one of claims 1 to 10, wherein the concentration of thiosulfate ions in the thiosulfate ion-spiked pharmaceutical dialysis fluid is about 10 micromolars or less.

12. The thiosulfate ion-spiked pharmaceutical dialysis fluid according to any one of claims 1 to 10, wherein the concentration of thiosulfate ions in the thiosulfate ion-spiked pharmaceutical dialysis fluid is approximately 500 nanomolar to approximately 5 micromolar.

13. The thiosulfate ion-spiked pharmaceutical dialysis fluid according to any one of claims 1 to 10, wherein the concentration of thiosulfate ions in the thiosulfate ion-spiked pharmaceutical dialysis fluid is approximately 3 micromolars.

14. The thiosulfate ion-spiked pharmaceutical dialysis fluid according to any one of claims 1 to 13, wherein the pH of the thiosulfate ion-spiked pharmaceutical dialysis fluid is approximately 7.3 to approximately 7.

5.

15. The thiosulfate ion-spiked pharmaceutical dialysis fluid according to any one of claims 1 to 13, wherein the pH of the thiosulfate ion-spiked pharmaceutical dialysis fluid is approximately 7.

4.

16. The aforementioned subject is a human with chronic renal failure, wherein the subject is a thiosulfate ion-spiked pharmaceutical dialysis fluid according to any one of claims 1 to 15.

17. The aforementioned subject is a human with acute renal failure, wherein the medical dialysis solution is spiked with thiosulfate ions according to any one of claims 1 to 15.

18. The subject undergoes dialysis 3 to 7 times per week, and the medical dialysis solution is spiked with thiosulfate ions according to any one of claims 1 to 17.

19. A method for preparing a thiosulfate ion-spiked pharmaceutical dialysis fluid in a dialysis fluid piping connecting a dialysis machine and a dialyzer having a dialysis membrane, according to any one of claims 1 to 7: Pumping unspiked dialysate from the dialyzer into the dialysate piping and flowing it through the dialysate membrane; and This includes adding an aqueous solution containing sodium thiosulfate to the unspiked dialysate through a valve attached to the dialysate piping at a position prior to the connection point between the dialysate piping and the dialyzer, as the unspiked dialysate flows from the dialyzer to the dialysate membrane, The method wherein the unspiked dialysate comprises a mixture of water, an acid concentrate, and a bicarbonate concentrate.

20. The method according to claim 19, wherein the aqueous solution containing sodium thiosulfate contains about 300 mg / L or less of sodium thiosulfate.

21. The method according to claim 19, wherein the water contains thiosulfate ions at a concentration of approximately 200 mg / L or less.

22. The method according to any one of claims 19 to 21, wherein the non-spiked dialysate flows through the dialysate piping at a rate of approximately 500 mL / min to approximately 700 mL / min.

23. The method according to any one of claims 19 to 21, wherein the non-spiked dialysate flows through the dialysate piping at a rate of approximately 600 mL / min.

24. The method according to any one of claims 19 to 21, 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.

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

26. The method according to any one of claims 19 to 25, wherein the pharmaceutical dialysis fluid spiked with thiosulfate ions is used to be administered to the subject together with a low molecular weight drug.

27. The method according to any one of claims 19 to 25, wherein the pharmaceutical dialysis fluid spiked with thiosulfate ions is used to be administered to the subject together with a low molecular weight vitamin.

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