JP2021165276A - Chemical pool medicament, injection formulation, internal use formulation, infusion formulation and dialysis device - Google Patents

Abstract

To provide a chemical pool medicament capable of exhibiting an elimination ability of reactive oxygen species (especially, free radical), and complementing a reduction ability to an oxidation type biological molecule subjected to oxidation reaction.SOLUTION: There is provided a chemical pool medicament including at least one of: an acceptor molecule capable of capturing a free radical which is generated in a body of a patient subjected to blood cleaning treatment by a blood cleaning device; and a donor molecule which may inhibit oxidation reaction by giving a hydrogen atom and/or an electron as an electron element, to an oxidation type biological molecule which is subjected to oxidation reaction in the body of the patient subjected to the blood cleaning treatment by the blood cleaning device. After capturing the free radical, or after giving the electron, by the blood cleaning device, the chemical pool medicament is discharged to outside of the body of the patient, and using a length (hr) of a treatment intermittent period in the blood cleaning treatment and weight (kg) of the patient subjected to the blood cleaning treatment, the chemical pool medicament is administered by chemical equivalent of 0.001 mEq/(hr kg) or greater.SELECTED DRAWING: Figure 1

Description

The present invention relates to a chemical pool drug, an injectable preparation, an oral preparation, an infusion preparation and a dialysis machine.

In hemodialysis and similar methods (hereinafter collectively referred to as blood purification treatment or blood purification method) performed as a renal replacement treatment for chronic dialysis patients, various substances accumulated in the blood are purified while performing extracorporeal circulation. The semitransparent film of the vessel is permeated and removed. There are three main removal principles. The first is hemodialysis, in which blood and dialysate are refluxed to both sides of a semipermeable membrane to cause transmembrane mass transfer due to a substance concentration gradient between the two. Second, hemofiltration involves applying pressure to the blood to cause transmembrane filtration, discarding the filtrate altogether and supplying an equal volume of replacement fluid. Thirdly, hemodiafiltration using the former two in combination can be mentioned. Such a blood purification method has been put into practical use as a treatment for chronic maintenance hemodialysis. Further, as a subsequent principle of removal, adsorption of dissolved blood molecules to the semipermeable membrane of the blood purifier can be mentioned. Subsequent removal principles are also utilized in some blood purification treatments. By continuing blood purification treatment 3 times a week for 4 to 6 hours, the minimum required uremic toxin removal, electrolyte and acid-base balance correction are achieved, and chronic dialysis patients can survive for more than 40 years. It is possible.

As a treatment for chronic renal failure, blood purification methods complement the excretory function of glomerular filtration, but cannot complement renal tubular reabsorption and excretion and endocrine function in the renal stroma. Therefore, bone marrow erythroblast stimulating hormone (erythropoietin and its derivatives), antihypertensive agents, adsorbents that suppress the absorption of electrolyte phosphorus from the intestinal tract, and calcium receptor agonists for the purpose of suppressing parathyroid function, etc. It is customary to combine drug administration with blood purification.

Furthermore, the blood purification method has not sufficiently complemented the function of scavenging active oxygen species and free radicals generated in the metabolism of life activities. It is said that about 1% of oxygen molecules are not reduced to water molecules but change to active oxygen in the process of respiration. Therefore, harmful free radicals with high chemical reactivity are constantly generated in the metabolic process. As a result, in the body of chronic dialysis patients, the deterioration of various biopolymers is accelerated by the chain reaction of free radicals (oxidative stress-enhanced state). It has been shown that some reduction reactions, such as intramolecular oxidation structures such as disulfide bonds -S-S-, can also be reduced to -SH by blood purification treatment. However, its reducing action is limited, and its complementary ability such as elimination of free radicals and reduction of oxidizing molecules (oxidized biomolecules used in the oxidation reaction that proceeds in the body) is poor. In addition, the blood purification treatment given to chronic dialysis patients is repeated 3 times a week for 4 to 6 hours each time. Therefore, out of 168 hours a week, there are 156 to 150 hours of non-treatment. The interval between the treatment session on the weekend and the treatment session at the beginning of the next week is 66 to 68 hours, and the interval between other sessions is about 42 to 44 hours. During the time when such treatment is not performed, the radical chain reaction due to the molecular attack of free radicals proceeds. As a result, cell damage is caused, the polymer responsible for the function and construction of the living body is deteriorated, and finally the pathological conditions such as arteriosclerosis and muscular atrophy are exacerbated.

The number of chronic dialysis patients in Japan continues to increase, exceeding 330,000 as of 2018, and long-term survivors exceeding 40 years are not uncommon (see Non-Patent Document 1). With the long-term survival of chronic dialysis patients, deterioration of biopolymers, gene deterioration, and cell function deterioration due to a decrease in the ability to scavenge active oxygen species and free radicals in a chronic renal failure state progresses. As a result, complications such as muscular atrophy and motor dysfunction, arteriosclerosis, canceration, and accelerated aging occur as visible pathological conditions. With the increase in the number of chronic dialysis patients and the aging of the population, it is feared that these problems will become more serious in both number and quality in the future. Conventional blood purification treatments are insufficient to improve the pathological condition of renal failure such as decreased ability to scavenge active oxygen species and free radicals generated in the metabolic process due to defects in performance and lack of time, and long-term conditions such as arteriosclerosis and muscular atrophy. The complications have not been prevented.

Japan Dialysis Medical Association, "Illustrated Current Status of Chronic Renal Failure in Japan" (http://www.jsdt.or.jp/overview_confirm.html)

To improve conventional blood purification treatment, a chemical pool drug capable of complementing the ability to scavenge reactive oxygen species (particularly free radicals) and the ability to reduce oxidized biomolecules subjected to an oxidation reaction is provided. The purpose is. That is, it is an object of the present invention to provide a chemical pool drug capable of adding a function of blocking the progress of a chain reaction of harmful free radicals having high chemical reactivity to conventional blood purification therapy.

Another object of the present invention is to provide an injectable preparation, an oral preparation and an infusion preparation containing a chemical pool drug (acceptor drug or donor drug) used for such complementation.

Furthermore, it is an object of the present invention to provide a dialysis apparatus configured to supply the infusion preparation.

Such an object is achieved by the present invention of the following (1) to (13).

(1) Acceptor molecules that can capture free radicals generated in the body of patients undergoing blood purification treatment with a blood purifier, or
Oxidation by donating electrons as hydrogen atoms and / or electrons to the oxidized biomolecules subjected to the oxidation reaction in the body of the patient to whom the blood purification treatment is performed by the blood purifier. A chemical pool drug containing at least one of the donor molecules capable of blocking the reaction.
The chemical pool drug is configured to be removed from the patient's body by the blood purifier after capturing the free radicals or donating the electrons.
The chemical pool drug is 0.001 mEq / (hr · kg) or more using the length of the treatment intermittent period (hr) in the blood purification treatment and the weight (kg) of the patient to whom the blood purification treatment is performed. A chemical pool drug characterized by being administered in a chemical equivalent of.

(2) The chemical pool drug according to (1) above, wherein the total amount of the chemical equivalents per one blood purification treatment is 0.001 to 20 mEq / (hr · kg).

(3) The chemical pool drug according to (2) above, which is administered in a larger amount than the total amount of the chemical equivalent.

(4) Any of the above (1) to (3), wherein the acceptor molecule after capturing the free radical and the donor molecule after donating the electron have a stable period of at least 3 hours. The chemical pool drug described in.

(5) The chemical pool agent according to any one of (1) to (4) above, which comprises at least one of a small molecule compound having a molecular weight of 1000 D or less or a large molecular compound having a molecular weight of 20 kD or more.

(6) The chemical pool agent according to (5) above, wherein the small molecule compound contains at least one of reduced ascorbic acid or reduced glutathione.

(7) The chemical pool agent according to (5) above, wherein the small molecule compound contains a peptide consisting of 2 or 3 residues of D-type amino acid.

(8) The chemical pool agent according to (5) above, wherein the large molecular compound contains a recombinant α1-m.

(9) The chemical pool drug according to (8) above, wherein the recombinant α1-m contains at least one of the original recombinant α1-m or the mutant recombinant α1-m.

(10) An injectable preparation comprising the chemical pool agent according to any one of (1) to (9) above.

(11) An oral preparation comprising the chemical pool drug according to any one of (1) to (9) above.

(12) An infusion preparation comprising the chemical pool agent according to any one of (1) to (9) above.

(13) A blood purifier, an extracorporeal circulating blood circuit connected to the blood purifier to circulate blood, a supply means connected to the extracorporeal circulating blood circuit, and a dialysate supplied to the blood purifier. A dialysis machine that includes a dialysate circuit.
The dialysis apparatus, wherein the supply means is configured to supply the infusion preparation according to the above (12) to the extracorporeal circulating blood circuit.

According to the present invention, a chemical pool capable of complementing the ability to scavenge active oxygen species (particularly free radicals) and the ability to reduce oxidized biomolecules subjected to an oxidation reaction to conventional blood purification treatments. Drugs can be provided. In addition, it is possible to provide an injectable preparation, an oral preparation and an infusion preparation containing a chemical pool drug (acceptor drug or donor drug) used for such complementation. Further, it is possible to provide a dialysis apparatus configured to supply the infusion preparation (for example, a rinse solution containing the drug).

It is explanatory drawing of the chemical pool dialysis in the treatment of chronic renal failure. It is explanatory drawing which schematically showed the chemical reaction progress state of the molecule of the chemical pool drug in the chemical pool dialysis. It is explanatory drawing which shows the compartment model which defines the movement balance of the chemical pool drug among three fractions (extracellular fluid, cytoplasm, and mitochondria) in the body to which a chemical pool dialysis is performed. It is explanatory drawing which showed the concentration transition of the chemical pool drug in the chemical pool dialysis by the fraction of extracellular fluid, cytoplasm, and mitochondria. It is explanatory drawing which showed the transition of the chemical pool size when the intrinsic clearance value is different as an index of ineffective metabolism after administration of a chemical pool drug. It is explanatory drawing which showed the carrying-out method of the chemical pool dialysis in the acute blood purification treatment. It is explanatory drawing which showed the relationship between the clearance value of blood purification and the removal of a chemical pool drug. It is explanatory drawing which showed the carrying-out method of the chemical pool dialysis which administers the chemical pool drug in an intermittent period in a chronic blood purification treatment. It is explanatory drawing which shows an example of the molecule of a chemical pool drug. It is explanatory drawing which shows an example of the molecule of a chemical pool drug. It is the schematic which shows the structural example of the dialysis apparatus which comprises the rinse liquid containing a chemical pool agent.

Hereinafter, the dialysis apparatus, the acceptor drug, the donor drug, the rinse solution, and the method of use as the rinse solution of the present invention will be described in detail based on the preferred embodiments shown in the accompanying drawings. Prior to these explanations, the background to the present invention will be briefly described.

(History of invention)
As described above, chronic dialysis patients (patients with chronic renal failure, etc.) are in a state of increased oxidative stress. It is speculated that impaired mitochondrial function is involved in the decline in defense against oxidative stress in patients with chronic renal failure. Mitochondria are organelles essential for the metabolic activity of life. The mitochondria are composed of electron transporters NADH (nicotinamide adenine dinucleotide) and NADPH (nicotinamide adenine dinucleotide phosphate) and ATP (nicotinamide adenine dinucleotide phosphate), which are compounds with high energy bonds, through metabolic circuits such as the citric acid cycle and electron transport chain. It is responsible for the production of adenosine triphosphate). NADH is used for the production of ATP in mitochondria, but NADH and NADPH are also essential for the elimination of reactive oxygen species in the whole body including mitochondria. However, when mitochondrial function declines in chronic renal failure, the absolute amount of NADH and NADPH involved in the reduction reaction is insufficient, resulting in insufficient elimination of reactive oxygen species and harmful chain reactions of free radicals. It works. In addition, the action of reducing oxidizing substances is diminished, and oxides and peroxides accumulate.

The free radical chain reaction is a special redox reaction in which radical electrons move between molecules one after another. This chain reaction involves cleavage, cleavage, intramolecular rearrangement, glycation, carbonylation, carbamylation, nitration, methylation, oxidation, peroxidation, cross-linking, and others, depending on the properties of the molecule targeted for attack. Causes chemical modification and the like. Moreover, in this chain reaction, a series of reaction rates is fast, and most of the reaction fields are intracellular. Therefore, there are few intermediate metabolites in the chain reaction that can be removed by blood purification treatment. Therefore, the activity that occurs every moment even if the time and frequency of blood purification treatment is increased, the administration of drugs (various fat-soluble vitamins) for the purpose of removing active oxygen species in the blood, and continuous treatment are performed. It does not have enough complementary capacity to process oxygen species normally.

In this way, in the blood purification method for treating chronic dialysis patients, from the viewpoint of not only prolonging life but also preventing long-term complications, the function of scavenging active oxygen species and oxidation, which are insufficiently improved by the current blood purification method, and oxidation. It is required to complement the reducing ability of the oxidized biomolecule to be subjected to the reaction. One of the inventions whose main purpose is such complementation is a dialysis apparatus capable of using a chemical pool drug administration different from the usual drug administration in combination with the current blood purification method. Hereinafter, prior to the description of the dialysis apparatus of the present invention, the acceptor drug and the donor drug of the present invention (hereinafter, also referred to as “chemical pool drug”) will be described. The chemical pool drug means a drug used as a chemical pool, and a detailed description of the definition of the chemical pool and the like will be described later. In addition, the blood purification method (referred to as "chemical pool dialysis" in the following description and figures) in which the administration of the chemical pool drug of the present invention is used in combination acts protectively against oxidative stress and satisfies predetermined requirements. It combines the administration of the drug with existing blood purification methods.

(Chemical pool drug)
Pool is a biomedical term and is a concept that means the space in which a substance can be distributed in the body. Normally, the size of a pool is expressed in volume, and the amount of substance is the product of this volume and the concentration of substances dissolved in the pool.

A chemical pool is a space constructed in the body by dissolving and distributing the drug in the body. The actual chemical pool spans three fractions, extracellular fluid, cytoplasm, and mitochondria, which mainly consist of plasma and interstitial fluid, but the volume of each fraction is different. For example, in a human of 60 kg, the volume of extracellular fluid is 12 L, the volume of cytoplasm is 18 L, and the volume of mitochondria is about 6 L. In addition, the administered drug is distributed unevenly in each fraction. Therefore, the concentration of the drug in each fraction is also different. Therefore, for a unified understanding, the size of the chemical pool existing in the body is expressed not by volume but by chemical equivalent. That is, in the present invention, the chemical pool is a group of a plurality of compartments in the body (that is, about 12 L of extracellular fluid, about 18 L of cytoplasm, about 6 L of mitochondria) in which the administered drug is dissolved and distributed. The total amount is expressed as a chemical equivalent (unit: mEq). A drug used as a chemical pool is called a chemical pool drug.

Therefore, the size of the chemical pool constructed is the chemical equivalent of the chemical pool drug administered. For example, if a chemical pool drug of 50 mEq is administered into the body and it is not decomposed in the body, it is considered that a chemical pool having a size of 50 mEq is constructed in the body. Blood purification treatment removes the chemical pool drug and reduces the size of the chemical pool.

An example of administration of a chemical pool drug will be briefly described. As shown in "Fig. 1", the administration of the chemical pool drug is repeated after each completion of the blood purification treatment. The administered chemical pool drug constitutes a chemical pool in the body. In this example, the size of the chemical pool, that is, the chemical equivalent of the chemical pool drug to be administered, assumes the chemical equivalent of an active oxygen species that occurs during the intermittent period of blood purification treatment and cannot be processed by the protective action of the living body. In the schematic diagram of "FIG. 1", the length of the treatment intermittent period is shown shorter than the actual length of the blood purification treatment time.

The chemical pool agent of the present invention is a free radical supplementary substance or a reducing substance having chemical reactivity as shown in "Table 1". That is, the chemical pool drug is either an acceptor molecule (acceptor drug) capable of capturing free radicals (unpaired electrons) from a radical molecule, or an oxidized biomolecule (Table 1) that is subjected to an oxidation reaction that proceeds in the body. It is a donor molecule (donor drug) capable of donating an electron to a reducing action body) that is not a radical represented by Y. In the case of a donor molecule, the mode of donating an electron is a reaction of donating one electron as a hydrogen atom, a reaction of donating two electrons as two hydrogen atoms in two molecules, and a reaction of donating one electron as a single electron in one molecule. There is a reaction in which one molecule donates one electron as a hydrogen atom and another electron as a single electron. The chemical pool drug before and after the reaction, with the acceptor molecule or donor molecule in the state before each chemical reaction as the active molecule (unchanged form) and the acceptor molecule or donor molecule after the chemical reaction as the inactive molecule (variant form). To distinguish. In the chemical pool, various proportions of active and inactive molecules are present, and the proportion of inactive molecules increases over time (“FIG. 2”). In the blood purification treatment, the chemical pool drug is not sorted into active molecules and inactive molecules, but is equally removed.

After administration, the molecule of the chemical pool drug becomes a radical molecule or an oxidized molecule after exerting its action by a chemical reaction in the living body. Unless these radical molecules and oxidized molecules are surely removed in the next blood purification, the free radicals will not be removed or the reducing action will not be exerted as a balance of treatment. Therefore, the chemical pool drug must meet the following three requirements. First, it is a requirement that the chemical equilibrium constant in "Table 1" is larger than 1 (chemical reactivity). Secondly, it is a requirement that the chemical pool drug is not decomposed in the body for a certain period of time (preferably 72 hours or more) and exists stably (stability). This is because when the chemical pool drug is decomposed in the body, the administration of the chemical pool drug becomes meaningless due to the resumption of the radical chain reaction and the progress of the oxidation reaction of other molecules. Thirdly, it is a requirement that radical molecules or oxidized molecules, which are reaction products of chemical pool drugs, are removed by blood purification (removability).

As described above, the chemical pool drug administration of the present invention differs from the usual drug administration in that the acceptor drug or donor drug of the present invention exists as an active molecule and an inactive molecule after administration. That is, only by removing inactive molecules that are considered to be harmful in the next dialysis, the effect of correcting the target oxidative stress and inducing homeostasis in the body to favorable reducing property is exhibited. It is a point. Without removal by dialysis, the acceptor agent or donor agent of the present invention cannot exert a reducing action. This is because the free radicals are excreted from the body and the reduced state remains in the body only when the molecules of the acceptor drug and the molecules of the donor drug after the reaction are removed by blood purification. Therefore, the chemical pool drug of the present invention requires chemical reactivity, post-reaction stability, and removability as essential requirements (essential 3 requirements). Hereinafter, in addition to the detailed description of these three requirements, more preferable requirements (non-bonding, liquid compatibility, reachability and non-metabolism) will be described.

(Chemical reactivity)
In order to be a suitable acceptor drug or donor drug as the chemical pool drug of the present invention, it is essential that the chemical reaction shown in "Table 1" is biased to the right, that is, the equilibrium constant of the reaction is larger than 1. .. Preferably, when the equilibrium constant is 1000 or more, the competitive action of blocking the chain reaction of free radicals is strong and ideal.

(Stability)
Further, in the chemical pool drug of the present invention, a molecule of an acceptor drug (radical type molecule) that captures free radicals after the reaction and a molecule of a donor drug that has been changed to an oxidized form (oxidized type molecule) are stably present in the body. Is required. The stable period of stable presence of acceptor drug molecules and donor drug molecules after the reaction is at least 3 to 9 hours (for example, the period until the detoxification reaction in the case of acute blood purification treatment reaches an equilibrium state). Yes, preferably 48 to 72 hours (eg, intermittent treatment until the next blood purification in the case of chronic blood purification treatment). When the equilibrium constant of the chemical reaction shown in "Table 1" is 1000 or more, the molecule of the acceptor drug that has captured the free radicals after the reaction and the molecule of the donor drug that has changed to the oxidized form continue to exist stably. Contribute.

(Removability)
Since it is premised that the chemical pool drug can be removed by blood purification treatment, it is necessary to guarantee the dialysis property or the filterability by the blood purifier. When the hemodialysis method is selected as the blood purification method constituting the chemical pool dialysis, the molecular weight of the chemical pool drug is preferably 1000D or less, more preferably 500D or less. The molecular weight of the monomer of the product that becomes a dimer after the reaction (for example, the donor drug “Table 1” that forms the dimer after the reaction) is preferably 500D or less. This is because the removal efficiency by blood purification decreases as the molecular weight increases. When a hemodiafiltration method, a hemofiltration method, or a plasma exchange method, which is excellent in removing large molecules, is selected as the blood purification method constituting the chemical pool dialysis instead of the hemodialysis method, the molecular weight is large in the region of 20 to 40 kD. Since the removal of molecules is also possible, the above requirement for removability is relaxed.

Further, in order to efficiently remove the chemical pool drug after the reaction and construct a new chemical pool by administering a new chemical pool drug, the chemical pool drug easily permeates the dialysis membrane as described later. Therefore, it is preferable that the clearance value indicating the removal performance of the blood purifier (removal performance of the artificial kidney) is set to 200 mL / min or more.

(Nonbonding)
Further, it is preferable that the chemical pool agent of the present invention does not bind to a protein molecule having a large molecular weight, a cell membrane, or an extracellular matrix. This is because it becomes difficult to remove the molecules of the chemical pool drug bound to these by blood purification.

Specifically, it is preferable that the molecule of the chemical pool drug does not bind to a circulating medium molecule having a molecular weight of 10 kD or more or a tissue-building polymer existing in the living body. In the former case, the removal efficiency by blood purification decreases as the molecular weight increases, and in the latter case, removal is virtually impossible.

(Liquid compatibility)
As mentioned above, the chemical pool agent of the present invention must be removed with high efficiency by blood purification. Therefore, as a molecule of a chemical pool drug, a molecule exhibiting lipophilicity (hydrophobicity) or amphipathicity that dissolves in the membranes of cell membranes and intracellular organs and is incorporated into those membranes due to its nature. Molecules that are not are preferred. This is because the molecules of the chemical pool drug incorporated into the cell membrane or the like and immobilized are not removed by blood purification. For example, Vitamin E, known to be a potent radical scavenger, is fat-soluble. For this reason, vitamin E is mainly incorporated into the cell membrane and is difficult to remove by blood purification. A drug composed of such fat-soluble molecules cannot be used as the chemical pool drug of the present invention.

(Reachability)
Reactive oxygen species can occur in all fractions including cytoplasm and plasma in vivo, but most occur in mitochondria. For this reason, mitochondria are most susceptible to free radical damage. Mitochondria also produce NADH, the most important reducing substance. The product of the free radical chain reaction that has not been processed by mitochondria leaks into the cytoplasm, and the product of the chain reaction that has not been processed by the cytoplasm also escapes to the outside of the cell. Therefore, the most important target of the chemical pool agent of the present invention is mitochondria. Therefore, the chemical pool agent of the present invention preferably penetrates the outer mitochondrial membrane to reach the inside of the mitochondria (including the matrix that has penetrated the inner membrane). For each chemical pool drug, a drug in which 10% or more of the administered content (chemical equivalent) reaches the inside of mitochondria shall satisfy the reachability requirement.

That is, it is desirable that the chemical pool agent of the present invention has a property of having a high degree of reach or distribution to mitochondria, which is a generation site of reactive oxygen species. This degree of achievement is medically related to the permeability coefficients of the outer and inner mitochondrial membranes. The higher the permeability coefficient of the chemical pool drug, the smaller the chemical equivalent to be administered, and the more the effect can be exhibited. An acceptor or donor drug that meets at least the three essential requirements and also meets the mitochondrial reachability requirement is called a "mitochondrial reachable chemical pool drug". An acceptor or donor drug that meets at least the three essential requirements but does not meet the mitochondrial reachability requirement is called a "mitochondrial non-reachable chemical pool drug". In addition, the mitochondrial non-reachable chemical pool drug is one that reaches the cytoplasm (first mitochondrial non-reachable chemical pool drug) and one that does not reach the cytoplasm (second mitochondrial non-reachable chemical pool drug). However, both can be used as the chemical pool agent of the present invention.

(Non-metabolic)
When the chemical pool agent of the present invention is administered to a chronic dialysis patient, the chemical pool agent for constructing the chemical pool is required to exert its effect during the treatment intermittent period of 48 to 72 hours. For this reason, it is preferable that the chemical pool drug can exist without being decomposed unrelated to the desired chemical reaction. Degradation unrelated to the desired chemical reaction is called ineffective metabolism, and in the presence of ineffective metabolism, it is necessary to increase the dose of the chemical pool drug. For example, if a patient wants to administer a chemical pool drug of 50 mEq of a drug, and if the ineffective metabolic rate of this chemical pool drug is 60% in 72 hours, the initial 50 mEq is reduced to 20 mEq. When administering such a chemical pool drug, the initial dose must be increased to 50 / (1-0.6) = 125 mEq to ensure the expected intensity of action. The lower the ineffective metabolic rate of the chemical pool drug of the present invention, the smaller the dose. FIG. 5 is an explanatory diagram comparing the influence on the size of the chemical pool by expressing the magnitude of the ineffective metabolic rate using the endogenous clearance as an index. Specifically, reference numeral 6 in FIG. 5 indicates a change in the size of the chemical pool (mEq) when the intrinsic clearance value is 1 mL / min, and reference numeral 7 is a change in the case where the intrinsic clearance value is 2 mL / min. The change in the size of the chemical pool (mEq) is shown, and the symbol 10 shows the change in the size of the chemical pool (mEq) when the intrinsic clearance value is 12 mL / min. On the other hand, reference numeral 11 in FIG. 5 indicates a change in the amount of chemical pool drug (mEq) present in mitochondria when the endogenous clearance value is 1 mL / min, and reference numeral 12 indicates a change in the amount of the chemical pool drug present in the mitochondria when the endogenous clearance value is 2 mL / min. Indicates a change in the amount of chemical pool drug present in mitochondria (mEq), with reference numeral 15 indicating a change in the amount of chemical pool drug present in mitochondria (mEq) at an endogenous clearance value of 12 mL / min. .. As is clear from FIG. 5, the smaller the endogenous clearance of the living body to the chemical pool drug, the smaller the endogenous clearance of the living body to the chemical pool drug because more chemical pool drugs continue to exist in the body (mitochondria). Is preferable.

Examples of the chemical pool drug of the present invention include a peptide consisting of 2 to 3 residues of type D amino acid as a candidate for an acceptor drug and a donor drug. More specifically, dipeptides consisting of two residues of D-type amino acids (eg, D-lysyl tyrosine, D-tyrosyl lysine, D-tyrosyl cysteine, D-tryptophanyl tyrosine, D-glycyl tyrosine, etc.), Or tripeptides consisting of 3 residues of D-type amino acids (eg, D-lysyl, tyrosine, cysteine, D-tyrosyl, tryptophanyl, lysine, etc.) are candidates for acceptor and donor agents. Among these, as the chemical pool drug, a dipeptide or tripeptide consisting of 2 to 3 residues of type D amino acids shown in Table 2 below is preferable.

Further, as an example of the acceptor drug of the present invention, 2- (α-D-glucopyranosyl) (methyl) methyl-2,5,7,8-tetramethylchroman-6-ol shown in FIG. 9 can be mentioned. After administration as a chemical pool drug, this methyl TMG shown in FIG. 9 modifies the methyl group next to the ether bond between glucose and the chromane ring so that it is not hydrolyzed by α-glycosidase in the body. , It is designed to keep the active center of the enzyme away from each other due to steric hindrance. The TMG without this modified methyl group is easily hydrolyzed and cannot survive stably in the body. Further, 2- (α-D-glucopyranosyl) (isopropyl) methyl-2,5,7,8-tetramethylchroman-6-ol shown in FIG. 10 is also mentioned as an example of the acceptor agent of the present invention. Alkyl group-modified TMGs (TMGs with an alkyl group at the center) such as methyl TMG in FIG. 9 and isopropyl TMG in FIG. 10 are suitable as acceptor agents of the present invention.

However, the chemical pool drug of the present invention is not limited to the above description, and for example, a water-soluble vitamin E modified molecule (acceptor drug) and glutathione (donor drug) can also be used. In addition, reduced ascorbic acid can be a candidate for the chemical pool drug of the present invention from the viewpoint of chemical reactivity, but it is necessary to consider that ineffective metabolism is not small and the radical type releases radicals next. .. That is, reduced ascorbic acid alone does not meet the stability requirements of chemical pooled drugs. Therefore, it is conceivable to use a donor drug (for example, glutathione) in combination so as to compensate for the shortcoming in the stability of reduced ascorbic acid. Thereby, the reduced ascorbic acid can be used as a drug that serves as a chemical pool of the present invention. That is, when a plurality of chemical drug species including chemical drug species that do not meet the essential 3 requirements satisfy the essential 3 requirements as a whole, the entire plurality of such chemical drug species can be regarded as the chemical pool drug of the present invention. can. It is also necessary to consider that reduced ascorbic acid does not reach mitochondria. Glutathione also reaches mitochondria, although it should be considered that ineffective metabolism is not small. Therefore, the combined use of reduced ascorbic acid and glutathione is preferable from the viewpoint of supplementing mitochondrial reachability. As described above, reduced ascorbic acid is not suitable as a chemical pool drug by itself because it does not reach mitochondria and its stability is not sufficient, but on the other hand, it has an extremely high radical abduction ability, so that it is an adjunct to the chemical pool drug. It can be said that it is useful as. For example, reduced ascorbic acid can deprive radicals that have sunk into membrane lipids, which are solid phases, and transfer them to chemical pool agents (eg, glutathione). In general, receiving an electron means that the molecule is reduced, but reduced ascorbic acid is a hydrogen atom (H) composed of one proton and one electron when receiving one radical. Since it loses two, it becomes a deducted oxidation type.

Here, after explaining the abundance (mEq) of the chemical pool for each of the three fractions of extracellular fluid, cytoplasm, and mitochondria, specific chemical equivalents for each application of the chemical pool agent of the present invention will be described. “Fig. 3” is a diagram of a compartment model showing the balance of movement of extracellular fluid, cytoplasm, and chemical pool drug inside and outside mitochondria, which are three fractions of the chemical pool. The chemical pool drug changes the active molecule by a chemical reaction and becomes an inactive molecule. For chemical pool drugs administered into the body, the rate of change from active molecules to inactive molecules is Qe mEq / min for extracellular fluid, Qc mEq / min for cytoplasm, and Qm mEq / min for mitochondria. In each fraction, active molecules decrease at these rates of change and inactive molecules increase at these rates of change. The intermittent period of blood purification treatment may be 2 days (about 43 hours) and 3 days (about 67 hours), so the dose of the chemical pool drug at the beginning of each period is A1, A2 (A1 <A2). Let it be mEq. The permeation rate defined by the concentration difference at both ends of the cell membrane that separates the extracellular fluid from the cytoplasm is Kc mL / min. The permeation rate defined by the concentration difference at both ends of the outer mitochondrial membrane that separates the cytoplasm and mitochondria is Km mL / min. The clearance indicating the removal performance of the artificial kidney is Kd mL / min. The in vivo metabolism of a molecule of a chemical pool drug, which has nothing to do with the change of the chemical pool drug from an active molecule to an inactive molecule and is removed by blood purification, is called ineffective metabolism. The index indicating this ineffective metabolism is defined as the endogenous clearance Ki mL / min, and it is assumed that the ineffective metabolism is performed from the cytoplasm. Forty percent of the body weight of patients undergoing chemical pool dialysis (chronic dialysis patients) is considered intracellular fluid, of which 75% is considered cytoplasmic volume Vc and 25% is considered mitochondrial volume Vm. The extracellular fluid of chronic dialysis patients is 20% of the body weight in the standard state, but it increases in the intermittent period due to oliguria or anuria, and the increase is corrected by removing water from blood purification treatment. Considering that the body fluid increases at a constant rate during the intermittent period, the extracellular fluid volume can be regarded as a function v (t) of time. For active and inactive molecules, let the concentration of the three compartments be a function of time. The time-dependent changes in extracellular fluid, cytoplasm, and mitochondria are calculated by numerical solutions of simultaneous differential equations of "Equation 1" in the intermittent period of blood purification treatment, for example, in the intermittent period starting after blood purification treatment at the beginning of the week. .. Further, regarding the blood purification treatment, for example, during the blood purification treatment in the middle of the week, the concentration transition of extracellular fluid, cytoplasm, and mitochondria with respect to time is calculated by the numerical solution of the simultaneous differential equations of "Equation 2". A 2-week concentration profile obtained by substituting the final value of the previous section into the initial value of the next section is obtained.

The result of multiplying the concentration profile thus obtained by the capacity of each fraction is shown in "FIG. 4". FIG. 4 shows the transition of the abundance (mEq) of the chemical pool drug for each fraction of the chemical pool. Here, the combined abundance of the active molecule of the chemical pool drug and the inactive molecule after the reaction is shown. The arrival of chemical pool drugs into the deep pool of mitochondria and the slowest purification of mitochondria, which is the reverse mass transfer. If the removal efficiency of the chemical pool drug is low, the concentration transition curve shifts upward.

In the mathematical formula, α [t] is a notation indicating that α is a function of the variable t. D [β [t] v [t], t] means to differentiate β [t] v [t] by t. The same applies to others. In addition, α [t] represents the concentration (mEq / mL) of the active molecule in extracellular fluid. γ [t] represents the concentration (mEq / mL) of the active molecule in the cytoplasm. ε [t] represents the concentration of active molecule in mitochondria (mEq / mL). e [t] represents the abundance (mEq) of the active molecule in the extracellular fluid. β [t] represents the concentration (mEq / mL) of the inactive molecule in the extracellular fluid. δ [t] represents the concentration (mEq / mL) of the inactive molecule in the cytoplasm. ζ [t] represents the concentration of inactive molecule in mitochondria (mEq / mL). f [t] represents the abundance (mEq / mL) of the inactive molecule in the extracellular fluid.

The values of the calculation results are α [2580] = α2580, γ [2580] = γ2580, ε [2580] = ε2580, e [2580] = e 2580, β [2580] = β2580, δ [2580] = δ2580, respectively. If ζ [2580] = ζ 2580 and f [2580] = f 2580, these values (actually numerical values) are substituted into the initial values of the next time interval (“Equation 2”).

The chemical pool drug of the present invention is mainly assumed to be administered to chronic dialysis patients (combined with chronic blood purification treatment), but patients with acute renal failure, patients with drug or toxic poisoning, patients with severe infections, patients with burns, etc. It is also expected to be administered to patients with post-ischemic reperfusion injury, severe pregnancy toxins, chronic skin ulcers, cerebral hemorrhage ventricular perforation, patients with severe hemolytic disease, etc. (combined with acute blood purification treatment). The case where the chemical pool drug is administered to a chronic dialysis patient will be described. First, the required amount of chemopool drug is administered to chronic dialysis patients at the end of the usual blood purification treatment session, which is scheduled three times a week. Then, the molecules of the chemical pool drug, which constructs the chemical pool during the treatment intermittent period until the next blood purification treatment, capture free radicals by a chemical reaction or exert reducibility. Next, the radical type molecule and the oxidized type molecule of the chemical pool drug after the reaction are stably present without causing the next chemical reaction. Finally, the molecules of the chemical pool drug, which are stably present in the radical or oxidized form, are removed by the next blood purification treatment. As a result, harmful free radicals and oxidants (oxidized molecules) can be excreted from the body. Then, after the blood purification treatment, the cycle of administering the chemical pool drug again is repeated.

When treating a patient with chronic renal failure according to the present invention, the size of the chemical pool to be administered, that is, the total amount of chemical equivalents of the chemical pool drug, is the weight (kg) of the patient with chronic renal failure and the length of the treatment intermittent period (hr). It is preferably 0.001 to 0.05 mEq / (hr · kg), more preferably 0.01 to 0.05 mEq / (hr · kg). This is the chemical equivalent of the active oxygen species produced in the body that can escape the intrinsic scavenging effect and be the starting point of harmful chain reactions, taking into account the results of the above formula. It is a value assumed to be neutralized. Thus, the chemical pool drug will be administered in large quantities. Therefore, it is a natural requirement for use as a chemical pool drug that it is not toxic to the human body even when a large amount of the chemical pool drug is administered into the body. Judging from the transition of blood concentration, it is misunderstood that the removal of the chemical pool drug is almost completed. However, as can be seen from "Fig. 4", it is considered that a certain amount of chemical pool drug remains in the cytoplasm and mitochondria even at the end of blood purification and reaches a steady state. For this reason, chemical pool agents preferably do not have cytotoxicity due to chronic exposure.

Other applications of chemical pool drugs include patients with acute renal failure, patients with drug or toxic poisoning, patients with severe infections, patients with burns, patients with post-ischemic reperfusion injury, patients with severe pregnancy poisoning, chronic skin ulcers, cerebral hemorrhage ventricular perforation. Explain the administration of chemical pool drugs to ruptured patients and patients with severe hemolytic disease. First, the chemical pool drug is administered to the patient, with a balancing time of hours to days. After that, blood purification treatment for removing the captured free radicals and oxidized molecules from the body is performed once or several times. The chemical pool agent of the present invention can also be used in such treatments. "Fig. 6" shows one course of this treatment method. The size of the chemical pool is divided into a white area (chemical equivalent of the remaining active molecule of the chemical pool drug) and a filled area (chemical equivalent of the inactive molecule after the chemical reaction). Shown. Since the purpose of treatment here is to save lives, unlike the prevention of complications in the case of chronic renal failure, the dose of the chemical pool drug is higher than in the case of chronic renal failure. Repeat the above cool several times as needed.

The chemical pool agent of the present invention can be used in patients with acute renal failure, patients with drug or toxic poisoning, patients with severe infections, patients with burns, patients with post-ischemic reperfusion injury, patients with severe pregnancy poisoning, patients with chronic skin ulcers, and cerebral hemorrhage ventricular perforation. When administered to patients, patients with severe hemolytic disease, the size of the chemical pool to be administered, that is, the total amount of chemical equivalents of the chemical pool drug, is determined by using the patient's weight (kg) and the length of the treatment intermittent period (hr). It is preferably 0.1 to 20 mEq / (hr · kg). This is higher than the dose for the treatment of patients with chronic renal failure. The reason for this is that it is taken into consideration that the invasion of diseases and adverse events into the living body increases the production of reactive oxygen species.

As the chemical pool drug of the present invention, it is preferable to use a plurality of chemical species to be administered as the chemical pool drug in combination. For example, as a chemical pool drug, it is preferable to use an acceptor drug that captures free radicals and a donor drug that is an H donor in combination. Further, it is more preferable that the chemical species to be administered as the chemical pool drug contains at least one mitochondrial reachable chemical pool drug such as glutathione. This makes it possible to block the chain reaction of free radicals at multiple stages. That is, oxidative stress in extracellular fluid, cytoplasm and mitochondria can be effectively reduced. As a result, the blocking rate of harmful chain reactions in the living body can be improved. When the chemical pool drug is composed of a plurality of drug species including at least the mitochondrial chemical pool drug, the content (chemical equivalent) of the mitochondrial chemical pool drug is the total of the other drug species. It is preferable that the content is large with respect to the content of. In other words, it is preferable that the chemical pool agent mainly contains a mitochondrial reaching chemical pool agent.

(Administration method of chemical pool drug)
As a method of administering a chemical pool drug, the dose is usually several tens to several hundreds of mEq, so it is customary to administer intravenously to ensure the administration. For example, in an infusion preparation in which 100 mEq of a chemical pool drug is dissolved in 200 mL of water, the osmotic pressure ratio of the infusion preparation to physiological saline is 100x (1000/200) / 308 = 1.6. Intravenous administration of such an infusion preparation is easy. If an injectable product dissolved in 10 mL of water is made, the osmotic pressure ratio of this injectable product to saline is 16, which is quite high. Chronic dialysis patients have an internal shunt or indwelling catheter to maintain blood flow in the extracorporeal circulation. Therefore, it can be said that chronic dialysis patients can tolerate injection of an infusion preparation having an osmotic pressure higher than that in the case of a normal peripheral cutaneous vein (the osmotic pressure ratio is limited to 3). However, in general, it can be said that the occurrence of side effects is less when the drug is slowly administered as an infusion preparation having a larger volume than the one-shot intravenous injection.

As a method for administering the chemical pool drug of the present invention, administration by an oral preparation is also conceivable. In this case, in consideration of the burden of oral administration to the patient, divided doses are administered once or several times a day during the intermittent period of blood purification treatment (“FIG. 8”). In oral administration, the chemical equivalent of a chemical pool drug that actually enters the body to build a chemical pool is reduced due to the effects of decomposition in the intestinal tract and absorption rate in the intestinal tract. In consideration of this point, it is necessary to adjust the chemical equivalent of the chemical pool drug taken internally.

As the method for administering the chemical pool drug of the present invention, the above-mentioned intravenous administration at the end of blood purification is suitable. When administered at once, the concentration gradient increases between the extracellular fluid on the surface layer, the cytoplasm in the deep layer, and the mitochondria in the deep layer. As a result, diffusion also increases the driving force for the chemical pool drug to reach deeper layers. In addition, it takes time for the chemical pool drug to reach the deep layer. Therefore, it is also advantageous to administer the chemical pool drug at the beginning of the treatment intermittent period and utilize the entire intermittent period as the reaction time to develop the therapeutic effect.

In particular, when the chemical pool drug of the present invention is administered to a chronic dialysis patient, the chemical equivalent of the chemical pool drug required for neutralizing reactive oxygen species generated in the intermittent period is collectively intravenously administered at the end of blood purification. Is the first choice. This is because the amount of chemical pool drug that reaches the deep mitochondria to which it is desired to be distributed increases as the concentration gradient increases and the time available for migration increases.

(Rinse liquid)
The rinse solution is used to push the blood left in the extracorporeal circulation blood circuit back into the internal circulation (intravascular) at the end of blood purification and return the blood. The rinse solution of the present invention is configured to contain the above-mentioned chemical pool drug and a solvent such as water or physiological saline. When an infusion preparation is selected as the dosage form of the chemical pool drug as described above, this infusion preparation can also be used as a rinse solution. This can reduce the volume load of the chemical pool drug on the patient. When the chemical pool drug is also used as the rinse solution, the volume of the rinse solution (infusion preparation of the chemical pool drug) is preferably 200 mL to 1000 mL, more preferably 200 to 400 mL. The rinse solution is preferably administered in its entirety over several minutes or longer. The osmotic pressure ratio of the rinse solution to the physiological saline solution is preferably 0.5 to 8, more preferably 0.5 to 5.

Furthermore, the rinse solution may contain an auxiliary agent such as an L-type amino acid. When an L-type amino acid is used as an auxiliary agent, the total content of the L-type amino acid is preferably 1 g to 20 g, and more preferably 3 g to 15 g in total. Amino acid excretion from muscles is inevitable during blood purification treatment. Therefore, the physiological amino acids administered immediately after the blood purification treatment are taken into the muscle again and exert an effect of suppressing the progression of muscular atrophy. Therefore, when the rinse solution contains L-type amino acids, a synergistic effect can be expected with the prevention of muscular atrophy through the mitochondrial protection function of the chemical pool agent of the present invention. In the present invention, as a result of seeking highly efficient removal of molecules (small molecules) of chemical pool drugs, amino acid loss in body fluids also increases correspondingly, and it is inevitable that the amount of amino acids released from muscle increases. Concomitant administration of L-type amino acids is also effective in alleviating this adverse effect.

When the rinse solution contains an L-type amino acid as an auxiliary agent, the osmotic pressure ratio of the rinse solution to the physiological saline solution is preferably 2 to 8. In the range of such an osmotic pressure ratio, slow administration (recovery operation) over several minutes or more is particularly required. Hereinafter, the dialysis apparatus of the present invention capable of supplying the chemical pool drug into the body as a rinse solution will be described in detail based on the preferred embodiments shown in the accompanying drawings.

(Dialysis machine)
FIG. 11 is a schematic view showing a configuration example of a dialysis machine including a rinse solution containing a chemical pool drug. The dialysis apparatus 100 of the present invention enables hemodialysis, hemofiltration, hemodiafiltration and plasma exchange already used in clinical practice, but in the following description, hemodialysis will be described as an example. That is, the dialysis apparatus 100 has the same basic configuration as the fully automatic dialysis apparatus, and can perform blood purification treatment using a general automatic dialysis apparatus.

The dialysis apparatus 100 of the present invention has, as a basic configuration, a blood purifier (dialyzer) D, a dialysate circuit 200 connected to the blood purifier D, an extracorporeal circulating blood circuit (blood circuit) 300, and an artery of a patient's blood vessel. A replenisher supply circuit 400 connected to the blood circuit 300 is provided so as to branch on the side.

The blood purifier D includes a plurality of straw-shaped thin tubes D1. Each capillary D1 is formed of a semipermeable membrane (dialysis membrane), and the semipermeable membrane has a plurality of pores. The blood purifier D is configured so that blood flows into each capillary D1 while dialysate flows outside each capillary D1. As a result, the blood and the dialysate come into contact with each other via the semipermeable membrane. By such contact, harmful substances in the blood and the like are transferred to the dialysate.

In the blood purifier D, it is necessary to remove radical molecules and oxidized molecules which are reaction products of the chemical pool drug from the body with high efficiency. Therefore, the blood purifier D preferably has a clearance value of 150 mL / min or more, preferably 200 mL / min, as a removal performance for small molecules having a molecular weight of 1000 D or less (see “FIG. 7”). Reference numeral 16 in FIG. 7 indicates a change in the chemical pool size (mEq) when the clearance value is 100 mL / min, which is the removal performance of the blood purifier D, and reference numeral 17 is a change in the clearance value of the blood purifier D of 150 mL / min. The change in the chemical pool size (mEq) in the case is shown, and reference numeral 20 indicates the change in the chemical pool size (mEq) when the clearance value of the blood purifier D is 300 mL / min. As is clear from FIG. 7, when the clearance value of the blood purifier D is in the range of 100 mL / min to 300 mL / min, the higher the clearance value of the blood purifier D, the more chemical pool drug is removed. Therefore, the blood purifier D preferably has a clearance value of 100 mL / min or more and 300 mL / min or less, which is a removal performance for small molecules having a molecular weight of 1000 D or less, and is preferably 150 mL / min or more and 300 mL / min or less. More preferably, it is 200 mL / min or more and 300 mL / min or less. In the chemical pool, the purification of the extracellular fluid in the surface layer precedes, and the deep cytoplasm and the deep mitochondria are purified later. Purification of deep pools is time-determined. The blood purification treatment time that is generally used in clinical practice is 4 to 5 hours, but the longer the treatment time, the higher the degree of purification of the chemical pool.

The dialysate circuit 200 includes a plurality of pumps to circulate the dialysate and supply it to the blood purifier D. The plurality of pumps are composed of a dialysate feed pump P1, a dialysate drainage pump P2, and a third dialysate pump P3. The dialysate feed pump P1 and the dialysate drainage pump P2 have a function of constantly circulating the dialysate at the same feed rate. That is, the dialysate feed pump P1 and the dialysate drainage pump P2 have a function of forming an equal flow rate system. On the other hand, the third dialysate pump P3 is configured to be entangled with the inside of the uniform flow rate system. Specifically, the third dialysate pump P3 is configured to rotate in both forward and reverse directions, and can perform forward drainage or reverse fluid injection.

The blood circuit 300 includes an arterial blood circuit 310 and a venous blood circuit 320 via a blood purifier D. The arterial blood circuit 310 is provided with an electromagnetic opening / closing clamp C2 and a blood pump P4 that rotates in both forward and reverse directions. By rotating the blood pump P4 forward, the blood taken out from the artery is supplied to the blood purifier D, comes into contact with the dialysate, and then returned to the vein through the venous blood circuit 320. When blood is flowing in this way, the electromagnetic opening / closing clamp C2 is in the open state. On the other hand, when such a blood flow is stopped, the electromagnetic opening / closing clamp C2 is in a closed state. When supplying the replacement fluid described later, the electromagnetic opening / closing clamp C2 is in the closed state. In the arterial blood circuit 310, a replacement fluid supply circuit 400 is connected between the electromagnetic opening / closing clamp C2 and the blood pump P4.

The replacement fluid supply circuit 400 includes replacement fluid. The replacement fluid contains an electrolyte solution such as pure water or saline, and in this embodiment further comprises a chemical pool agent. Further, the replacement fluid supply circuit 400 is provided with an electromagnetic opening / closing clamp C1 capable of stopping the supply of the replacement fluid. The replacement fluid is supplied to the blood circuit 300 by rotating the blood pump P4 forward with the electromagnetic opening / closing clamp C1 in the open state and the electromagnetic opening / closing clamp C2 in the closed state.

The dialysis apparatus 100 of the present invention includes an electromagnetic opening / closing clamp C1 capable of electromagnetic opening / closing control, an electromagnetic opening / closing clamp C2, a blood pump P4 capable of both forward and reverse rotation, and a third dialysate pump P3 capable of both forward and reverse rotation. As a result, the same amount of water is removed from the blood circuit 300 or the same amount of fluid is replenished to the blood circuit 300 via the semipermeable membrane of the blood purifier D. It can be said that the dialysis apparatus 100 of the present invention is characterized in that each of the dialysate circuit 200 and the blood circuit 300 is provided with at least one pump capable of both forward and reverse rotation. Further, the dialysis apparatus 100 can be provided with various elements (for example, a control unit and a sensor) in addition to the above-mentioned basic configuration. The control unit can programmatically control the opening / closing of the electromagnetic opening / closing clamp C1 and the electromagnetic opening / closing clamp C2, and the rotation direction and speed of the third dialysate pump P3 and the blood pump P4 to arbitrary values at any time.

(Method of using a solution containing a chemical pool drug as a rinse solution)
In the following, with reference to FIG. 11, a method of using the replacement fluid containing the chemical pool drug of the present invention as the rinse solution R for blood recovery of the extracorporeal circulating blood circuit 300 in the dialysis apparatus 100 will be described. Two specific examples are shown below.

(Specific example 1)
As a replacement fluid, 200 to 300 mL of a rinse solution R consisting of an aqueous solution containing the chemical pool drug of the present invention is connected to the replacement fluid supply circuit 400, which is a branch of the blood circuit 300. During hemodialysis, the electromagnetic opening / closing clamp C1 is in the closed state, the electromagnetic opening / closing clamp C2 is in the open state, the blood pump P4 is in the forward rotation (direction from s to v), and the third dialysate pump P3 is in the forward direction (water removal). It's working. The above is the pre-recovery process. The following series of steps is operated at the end of the blood purification treatment (usually, when the specified treatment time has expired and the specified amount of water removed has expired). 1) Stop the dialysate feed pump P1 and the dialysate drainage pump P2. 2) The electromagnetic opening / closing clamp C1 is opened, the electromagnetic opening / closing clamp C2 is closed, the blood pump P4 is rotated forward at a speed of 10 to 100 mL / min, and the entire amount of the rinse solution R is injected into the blood circuit 300 from t. This injection amount is a value obtained by multiplying the flow velocity of the blood pump P4 by the operating time. After that, the forward rotation of the blood pump P4 is stopped. At this point, the blood from t to v is returned to the body, and the same part is replaced with the rinse solution R (that is, the aqueous solution containing the chemical pool drug). 3) The electromagnetic opening / closing clamp C1 is closed, the electromagnetic opening / closing clamp C2 is opened, the third dialysate pump P3 is in the reverse direction (replenishment direction) at a speed of 10 to 100 mL / min, and the blood pump P4 is in the third. Operate in the opposite direction at an arbitrary speed smaller than the dialysate pump P3. As a result, the dialysate reverse-filters the semipermeable membrane and is injected into the blood circuit 300. Further, the dialysate is distributed at an arbitrary ratio in the two directions of s and v. As a result, the blood remaining in the portion from s to t of the blood circuit 300 is returned from s, and the rinse solution R (aqueous solution containing the chemical pool drug) remaining in t to v is replaced with the dialysate. It is injected into the body. From the above, the administration of the chemical pool drug and the blood return process are completed at the same time.

(Specific example 2)
The blood return step using an aqueous solution containing a chemical pool drug under another program control is shown. The pre-recovery step is the same as that of Specific Example 1. 1) Stop the dialysate feed pump P1 and the dialysate drainage pump P2. 2) With the electromagnetic opening / closing clamp C1 closed and the electromagnetic opening / closing clamp C2 open, the third dialysate pump P3 is moved in the reverse direction (replenishment direction) at a speed of 10 to 100 mL / min, and the blood pump P4 is the same. Operate in the opposite direction at speed. As a result, dialysate equivalent to the volume of the blood circuit 300 from s to u is back-filtered through the semipermeable membrane and injected into the blood circuit 300 side. As a result, the blood in the portion from s to u of the blood circuit 300 is returned from s first. 3) The third dialysate pump P3 is stopped, the electromagnetic opening / closing clamp C1 is opened, the electromagnetic opening / closing clamp C2 is closed, and the blood pump P4 is operated in the forward direction at a speed of 10 to 100 mL / min. As a result, the entire amount of the rinse solution R (an aqueous solution containing the chemical pool drug) is injected. As a result, the blood remaining in the blood circuit 300 from u to v is returned from v. This injection amount is a value obtained by multiplying the flow velocity of the blood pump P4 by the operating time. 4) The electromagnetic opening / closing clamp C1 is closed, the blood pump P4 is stopped, and the third dialysate pump P3 is operated in the reverse direction (replenishment direction) at a speed of 10 to 100 mL / min. As a result, the aqueous solution containing the chemical pool drug remaining in the u to v parts of the blood circuit 300 is replaced with a dialysate having the same volume (or 0.5 to 1.5 times the volume) of the blood circuit 300 in the same part. It is injected into the body. The replacement amount by back filtration is a value obtained by multiplying the flow rate of P3 by the operating time.

In the second embodiment, the blood in the s to t portions of the blood circuit 300 is returned earlier than in the case of the first embodiment, so that there is less risk of blood coagulation in the same portion during the recovery process. However, a small amount of the chemical pool drug aqueous solution may remain in the circuit of the blood circuit 300 from t to u.

As described above, the dialysis apparatus of the present invention enables chemical pool dialysis (a blood purification method in which administration of the chemical pool drug of the present invention is used in combination). The chemical pool drug administered by chemical pool dialysis preferably permeates the cell membrane from the superficial extracellular fluid to reach the deep cytoplasm and further to the deepest mitochondria. By performing chemical pool dialysis using the dialysis apparatus of the present invention, a chemical pool can be formed in these three compartments. Molecules of the chemical pool drug dissolved in this chemical pool capture free radicals in mitochondria, which are the source of reactive oxygen species, and exhibit reducibility to reactive oxygen species to reduce oxygen damage. Therefore, the present invention contributes to the recovery of impaired mitochondrial function in patients with chronic renal failure. Restoration of mitochondrial function restores the production of the electron carrier NADH and the high-energy binding compound ATP. Therefore, the recovery of mitochondrial function improves the intrinsic defense against reactive oxygen species and also improves the energy supply to cells. In this way, skeletal muscle motor ability and muscle atrophy, which are reduced in chronic dialysis patients, can be prevented, and muscle atrophy and muscle atrophy called sarcopenia, locomotive syndrome or frail, in which the pathological condition of chronic renal failure and the aging process progress together, can be prevented. Symptoms consisting of atrophy and motor dysfunction can be prevented. Heart failure, which is an important cause of death in patients with chronic renal failure, is also associated with myocardial damage more than ischemia, and the present invention can be expected to improve heart failure. In addition, inhibition of the development of free radical chain reactions in the most upstream mitochondria reduces oxidative stress in the downstream cytoplasm.

The molecule of the chemical pool drug distributed in the cytoplasm captures the free radical of the chain reaction product of the free radical leaked from the mitochondria to the cytoplasm and reduces the molecule. As a result, deterioration of intracellular organelles, cytoskeleton, and cell membrane can be prevented.

The cytoplasm is a place where various reaction products are produced in addition to the radical chaining, radical amplification, and peroxide formation of the initial free radical chain reaction. For example, reactive oxygen species attack protein molecules and eventually cause peroxidation-type molecular deterioration called AOPP (advanced oxidation protein products) and carbonylation-type molecular deterioration. In addition, hydroxyl radical (・ OH) in the early stage of the chain reaction and peroxynitrite (ONOO ・) generated after that generate carboxymethyl lysine (CML), which is an advanced glycation end product (AGE) of the saccharification reaction. Facilitate. CML degrades biopolymers by cross-linking. In addition, hydroxynonenal (4-HNE) is produced as a highly reactive activated carbonyl compound from the alkoxyl radical (LO ·) and alkylperoxy radical (LOO ·) produced by the lipid being attacked by free radicals. NS. 4-HNE shows activity on various cells, and when it acts on DNA and mitochondria, it can lead to cell death. Furthermore, 3-deoxyglucosone (3DG), which is produced by attacking reducing sugars with active oxygen, is also a highly reactive intermediate, and in addition to acting on cells, it crosslinks and deteriorates protein molecules. Reactive oxygen species also have the effect of attenuating the demethylation reaction that restores DNA methylation, interfering with the posterior modification mechanism of genes and participating in canceration and aging processes. From the above, according to the present invention, there is an effect of preventing cross-linking of biopolymers, preventing deterioration of construct molecules, and physiologically restoring the cellular environment. As a result, the long-term prognosis is expected to be a decrease in the incidence of cancer and a decrease in the aging rate promoted in patients with chronic renal failure.

In addition, patients with acute renal failure, patients with drug or toxic poisoning, patients with severe infections, burns, patients with post-ischemic reperfusion disorder, patients with severe pregnancy poisoning, patients with chronic skin ulcers, patients with cerebral hemorrhage ventricle penetration, severe hemolytic diseases As an emergency treatment in patients, the blood purification method combined with the administration of the chemical pool drug of the present invention is carried out once or several times to stop the chain reaction and oxidation reaction of free radicals that increase the lethality rate, and to reduce the survival rate. It is expected to contribute to improvement.

The method of using the dialysis apparatus of the present invention, the chemical pool drug (acceptor drug and donor drug), the rinse solution containing the chemical pool drug, and the solution containing the chemical pool drug as the rinse solution will be described based on the illustrated embodiment. However, the present invention is not limited to this. For example, each part constituting the dialysis machine can be replaced with an arbitrary configuration capable of exerting the same function. Further, the present invention may be a combination of any two or more features.

For example, the blood purifier included in the dialysis apparatus of the present invention is a concept including a hemodialysis device, a hemodiafiltration device, a hemofilter, and a plasma separator. Specifically, when the dialysis machine is subjected to hemodialysis, the blood purifier is configured as a hemodialyzer or dialyzer, as described based on the embodiments described above. When the dialysis apparatus is subjected to hemodiafiltration, the blood purifier is configured as a hemodiafiltration filter or a hemodiafilter (filtration type blood purifier). When the dialysis machine is used for blood filtration, the blood purifier is configured as a hemofilter or a hemofilter (filtration type blood purifier). Also, when the dialysis machine is subjected to plasma exchange, the blood purifier is configured as a plasma separator or plasma separator.

Therefore, the "blood purification method" in which the administration of the chemical pool drug of the present invention is used in combination is a concept including a hemodialysis method, a hemodiafiltration method, a hemofiltration method and a plasma exchange method. In addition, the dialysis machine of the present invention can carry out these blood purification methods. Further, for convenience, the term "chemical pool dialysis" according to the present invention is used as a general term including chemical pool hemodiafiltration, chemical pool hemofiltration and chemical pool plasma exchange.

Since the hemodiafiltration method or the hemofiltration method uses a large pore size membrane having a large fractionated molecular size, it is excellent in removing large molecular compounds. Specifically, by using a hemodiafiltration method or a hemofiltration method, the concentration reduction rate of a large molecular compound in blood (for example, α1-microglobulin (α1-m)) before and after treatment can be reduced to about 40 to 60%. Can be increased to.

Furthermore, when the plasma exchange method is used as the blood purification method, the removal efficiency of large molecular compounds (for example, α1-m molecule) can be remarkably improved. For example, in blood, about half of α1-m molecules are bound 1: 1 with immunoglobulin A dimer to form macromolecules with a molecular weight of 350 kD. Therefore, in the hemodiafiltration method or the hemofiltration method, the reduction rate of the blood concentration of α1-m molecule before and after the treatment is limited to about 40 to 60%, but according to the plasma exchange method, it is limited. It is also possible to achieve a reduction rate of about 80%. However, the plasma exchange method has a significantly higher treatment cost.

Hemodialysis is the most widely used method of blood purification treatment for patients with chronic renal failure, but the proportion of hemodiafiltration has been increasing in recent years. The latter is superior to the former in removing large molecular compounds having a molecular weight in the region of 20 to 40 kD.

Therefore, by selecting a hemodiafiltration method, a hemofiltration method, or a plasma exchange method, which is excellent in removing large molecule compounds, instead of the hemodialysis method, the chemical pool of the present invention constitutes the chemical pool dialysis. As the drug, a large molecule compound (for example, α1-m molecule) can be used in addition to the small molecule compound described in the above-described embodiment. Hereinafter, the α1-m molecule (also simply referred to as α1-m) will be described in detail.

(Chemical reactivity of α1-m)
α1-m is a protein with a strong ability to scavenge reactive oxygen species and free radicals. Specifically, α1-m is a glycoprotein having a molecular weight of 33 kD, and has physiological functions such as free heme binding ability, capture ability by chemical reaction with radicals, and reducing action.

Such chemical reactivity of α1-m will be described in detail based on the amino acid sequence of α1-m. In the amino acid sequence of α1-m, the amino acid residues important for radical scavenging and exerting a reducing action are C34, Y22, K92, K118, H123, K130, and Y132. Here, C is cysteine, Y is tyrosine, K is lysine, and H is a one-letter abbreviation for the amino acid residue of histidine. The number next to the one-letter abbreviation is the residue number.

The requirements for the amino acid sequence of the α1-m preparation (recombinant α1-m preparation described later) that can be used as the chemical pool agent of the present invention are at least C34, Y22, with the original amino acid sequence as the basic structure (main chain). At least 3 residues of K92, K118, H123, K130, and Y132 are conserved. All α1-m that meet this requirement meet the requirements for chemical reactivity of chemical pool drugs.

Although α1-m also has a free heme binding ability, free heme is a harmful substance that generates free radicals and drives the mechanism of oxidative injury. One molecule of α1-m captures two molecules of heme and up to nine radical molecules.

(Stability of α1-m)
α1-m captures harmful substances such as free heme with chemical bonds. Therefore, α1-m exists as a stable trap once the free heme is trapped. A stable trap means that there is no possibility of refreeration of free radicals or oxidized molecules. That is, α1-m can stably exist in the body as a free radical trap, and therefore satisfies the requirement for stability of the chemical pool drug.

(Removability of α1-m)
Furthermore, by selecting a hemodiafiltration method, a hemofiltration method, or a plasma exchange method as the blood purification method, it is possible to remove a large molecular compound. Therefore, α1-m is a removability of the chemical pool drug of the present invention. Can also meet the requirements of.

(Other requirements for α1-m)
The macromolecule α1-m meets the non-binding, humoral and non-metabolic requirements, but is predominantly distributed in extracellular fluid in the body, with less than 10% distributed intracellularly. It works if α1-m is sprinkled on mitochondria in vitro, but most molecules do not reach mitochondria when administered (eg, injected) into the body. That is, α1-m does not meet the reachability requirement.

From the above, α1-m is a substance having a strong pharmacological action that completely satisfies the three essential requirements of a chemical pool drug. However, regarding the capture (or reduction) and removal of radicals generated from mitochondria, small molecule compounds are overwhelming from the viewpoint of the size of chemical equivalents and the ability to reach deep (deep and deepest layers) (drug delivery). Is excellent.

Regarding the capture of radicals, let us compare the chemical equivalents of a small molecule with a molecular weight of 330 and α1-m with a molecular weight of 33000 per gram. If one radical is supplemented assuming that there is 1 g of a small molecule with a molecular weight of 330, the equivalent is 3 mEq. On the other hand, assuming that there is 1 g of α1-m having a molecular weight of 33000, this can capture 9 radicals, so that the equivalent is 0.27 mEq. Since there is a difference of about 10 times between the two, it is advantageous because the capacity of the small molecule compound is overwhelmingly large at the same dose. In addition, while α1-m has almost 100% stability in the body, it is considered that metabolism cannot be reduced to 0 with small molecule compounds, and the difference in true action is smaller than 10 times.

(Purification of α1-m)
The α1-m preparation purified from the urine of healthy humans already contains many molecules that have deteriorated as radical scavengers, so it has poor radical scavenging ability and reducing ability, and has the action of a chemical pool drug. Not suitable because it does not exist.

Therefore, as the chemical pool drug of the present invention, a refined product of a recombinant protein expressed by introducing a human α1-microglobulin gene into the DNA of another organism (hereinafter referred to as “recombinant α1-m preparation”) is used. It is preferable to use it. The recombinant α1-m preparation can be produced by recombining the human α1-m gene in, for example, Chinese hamster ovary cells. The types of cells and animal species used for gene recombination and production are not limited to these.

(Original and mutant recombinant α1-m preparations)
As the chemical pool agent of the present invention, in addition to the recombinant α1-m preparation having the original sequence, the recombinant α1-m preparation having a mutant sequence in which base substitution is performed with amino acid substitution within the range satisfying the requirements for important residues. Is preferable. In particular, a recombinant α1-m preparation that has been genetically mutated to increase water solubility, a recombinant α1-m preparation that has a sugar chain bound to it, and a recombinant α1-m preparation that does not have a terminal 3.4 residue. However, it is preferable.

Specifically, by substituting the hydrophobic residue existing on the molecular surface of α1-m with hydrophilicity, the water solubility can be enhanced and the preparation of the preparation becomes easy, which is useful. Furthermore, binding a sugar chain to the amino acid side chain also contributes to increasing water solubility. For these reasons, the recombinant α1-m preparation which has been genetically mutated to increase water solubility and the recombinant α1-m preparation to which a sugar chain is bound are preferable as the chemical pool agent of the present invention.

In addition, the recombinant α1-m preparation that does not have the C-terminal 3-residue IPR or 4-residue LIPR in the α1-m amino acid sequence has reduced binding to immunoglobulin A and thus has improved removability. Therefore, the recombinant α1-m preparation having no terminal 3 to 4 residues is preferable as the chemical pool agent of the present invention.

The recombinant α1-m preparation has a very high manufacturing cost due to the characteristics of the biological product. Therefore, from the medical financial point of view, as an application example in which it is considered appropriate to administer a recombinant α1-m preparation in chemical pool dialysis in chronic dialysis patients, a pathological condition that significantly deteriorates the quality of life is complicated, and this is described above. Examples thereof include intractable ones that cannot be improved by the treatment method of chemical pool dialysis described in the above-described embodiment, that is, restless leg syndrome, inflammatory arthralgia, and limited range of motion due to arthritis.

(Example of administration of recombinant α1-m preparation)
When the recombinant α1-m preparation is used in the chemical pool dialysis of a chronic dialysis patient, the replacement fluid containing the recombinant α1-m preparation can be supplied via the replacement fluid supply circuit 400 in the above-mentioned dialysis apparatus 100, but preferably. After blood purification treatment, the recombinant α1-m preparation is administered once or several times. For example, in the dialysis apparatus 100, 0.1 g to 2 g of the recombinant α1-m preparation as an injection preparation is intravenously administered after the blood purification treatment without going through the replacement fluid supply circuit 400. In this case, the dialysis machine 100 may be provided with a drug administration means capable of administering the recombinant α1-m preparation. Further, the dialysis apparatus 100 includes a first chemical pool drug supply means (means for supplying the chemical pool drug via the replacement fluid supply circuit) and a second chemical pool drug supply means (means for supplying the chemical pool drug via the replacement fluid supply circuit). (Means for supplying) may be provided. Further, the dialysis apparatus 100 preferably includes a control unit capable of independently controlling the first and second chemical pool drug supply means. The improving effect of administration lasts for weeks to months. If the inflammatory symptoms recur, repeat chemical pool dialysis using the recombinant α1-m preparation. However, the dose is not limited to this.

Patients with acute renal failure, patients with drug or toxic poisoning, patients with severe infections, patients with burns, patients with post-ischemic reperfusion disorder, patients with severe pregnancy poisoning, chronic skin ulcers, cerebral hemorrhage ventricular perforation In patients and patients with severe hemolytic disease, the radical scavenging ability and reducing ability are reduced or depleted due to the consumption (deterioration) of α1-m molecules in the living body. Therefore, by administering the recombinant α1-m preparation, the severity of these pathological conditions associated with active oxygen injury can be reduced. In these patients, renal function is also reduced, so α1-m molecules (non-functional deteriorated protein molecules) that have changed to traps (deteriorated bodies) by capturing free radicals are not easily excreted in the urine, thus purifying blood. Must be removed by law.

After the onset of these pathological conditions, 0.1 g to 5 g of the recombinant α1-m preparation is intravenously administered in large doses as soon as possible. Hours to days after administration, hemodiafiltration, hemofiltration or plasmapheresis is performed to remove non-functional degraded protein molecules and altered α1-m molecules. This is set as one course, and it is carried out once or several times. The dose per dose is preferably 0.1 g to 5 g, but is not limited to this.

(Application example 1)
From here, an application example using the chemical pool agent of the present invention (for example, solving a problem caused by intravascular hemolysis) will be described. In chronic dialysis treatment, hemolysis in the circuit (that is, in the blood vessel) is generated in a small amount in each external circulation treatment, and free radicals are produced. In chemical pool dialysis, a predetermined total amount of chemical pool drug is administered after each end of external circulation treatment, but the unreacted type of chemical pool drug administered after the end of the previous external circulation treatment is the current external circulation. If it remains at the start of treatment, even if intravascular hemolysis due to external circulation treatment occurs, the remaining unreacted chemical pool drug (residual chemical pool drug) is a free radical caused by intravascular hemolysis. It can suppress harmful effects.

In order to exert such an effect, each dose of the chemical pool drug is set to a predetermined total amount (for example, 0.001 to 0.05 mEq / (hr · kg) when treating a patient with chronic renal failure). It is preferable to have more than. It is considered that this can more reliably prevent the development of the chain reaction of harmful free radicals in the superficial layer (extracellular fluid), deep layer (cytoplasm) and deepest layer (mitochondria) of the chemical pool. From this point of view, it is more preferable to increase the dose of the chemical pool drug each time by about 1.1 to 2 times the predetermined total amount.

The recombinant α1-m preparation is useful for the purpose of neutralizing radicals and heme in the superficial layer (extracellular fluid) or terminal (viewed from the radical reaction cascade) of the chemical pool. Therefore, if the treatment cost is not taken into consideration, the combined use of the small molecule chemical pool drug and the recombinant α1-m preparation is effective in chronic dialysis patients from the viewpoint of solving the problem caused by the above-mentioned intravascular hemolysis. Conceivable.

(Application example 2)
The pathological conditions in which the combined administration of a small molecule chemical pool drug and a radical α1-m preparation is considered to be particularly effective include pathological conditions in which intravascular hemolysis occurs (hemolytic uremic syndrome, etc.) and extrinsic (outpatient) conditions. There are pathological conditions (toxic poisoning, etc.) in which radical production causes adverse events due to (sex) causes. Both are pathological conditions covered by acute blood purification treatment. Inflammation, microcirculatory disorders, and tissue destruction are common in such pathologies.

As mentioned above, the advantage of α1-m is the ability to capture two heme molecules in addition to the stability after radical scavenging. Heme is hemoglobin that leaks from red blood cells due to hemolysis and decomposes to separate from globin. Heme itself is not a radical, but it is a very harmful molecule that promotes radical production. Fetal-derived hemoglobin F and free heme damage the vascular endothelial cells throughout the mother's body, a disease called eclampsia in severe preeclampsia. Therefore, α1-m is effective in neutralizing heme that produces radicals and radicals in blood and interstitial fluid.

On the other hand, small molecule chemical pool agents may not have the ability to capture heme as much as or greater than themselves, but can act on the neutralization of radicals generated by heme. .. For these reasons, the combined administration of a small molecule chemical pool drug and a recombinant α1-m preparation is considered to be particularly effective for the pathological conditions covered by the acute blood purification treatment.

(Application example 3)
Acute blood purification is usually performed only a few times, so expensive treatment is permitted, but chemical pool dialysis by administration of recombinant α1-m preparation in chronic dialysis patients is partly intractable from the viewpoint of rising medical costs. It may be limited to patients with comorbidities. Therefore, in other patients, it is desirable to practice spontaneous pseudo-chemical pool dialysis due to endogenous α1-m production. That is, it is conceivable to entrust it to pseudo-chemical pool dialysis that removes α1-m in the living body and promotes new production in the liver. Hereinafter, pseudo-chemical pool dialysis will be described after explaining the physiological production and metabolism of α1-m.

In vivo α1-m is produced in the liver. Due to the high rate of renal metabolism and excretion, the half-life in blood is only a few hours, but the rate of production in the liver is also high, and the balance is always maintained at a blood concentration of 10 to 20 mg / L. When renal function is normal, α1-m traps that capture free radicals, etc. are rapidly filtered by the glomerulus of the kidney, and either in their original form or after being reabsorbed in the renal tubules, the decomposed fragments. It is excreted in the urine in the form. Some of the free radicals thus produced in the body are excreted outside the body.

On the other hand, in patients with renal failure, the metabolic and excretory function is deficient, so α1-m, which is a free radical trap, remains in the body. Specifically, in chronic dialysis patients, the blood concentration increases due to the lack of renal metabolic excretion. When the blood concentration rises, the production in the liver is suppressed by feedback control and decreases. Therefore, the blood concentration does not increase indefinitely, and the balance is finally maintained at a concentration of 120 to 150 mg / L. In chronic dialysis patients, there is almost no turnover (new replacement) of α1-m molecule. Therefore, even at a high concentration of 120 to 150 mg / L, the radical scavenging ability and reducing ability of α1-m are already depleted. That is, α1-m in the body of a chronic dialysis patient is a non-functional deteriorated protein molecule. Since α1-m having a molecular weight of 33 kD is hardly removed by normal hemodialysis, this level is maintained and no large fluctuation occurs.

In such chronic dialysis patients, if a hemodiafiltration method or a hemofiltration method, which is superior in removing larger molecules, is practiced instead of hemodialysis, about 200 to 300 mg of α1-m can be obtained by one treatment for 4 to 5 hours. Can be removed. The blood concentration can also be reduced by about 40 to 60%. However, the blood concentration continues to rise within a few days until the next treatment, and eventually returns to the original blood concentration of 120 to 150 mg / L. This means that during the same period, 200 mg of α1-m molecules removed by the previous blood purification method were newly synthesized in the liver to offset the decrease. Since the new α1-m has radical scavenging ability and reducing ability, it is considered that the new α1-m exerts its action by its chemical equivalent. The effects of the endogenous α1-m produced by the liver and the externally administered recombinant α1-m preparation are similar if the chemical equivalents are the same. In blood purification therapy, the active removal of α1-m, a non-functional degraded protein molecule, induces endogenous α1-m production from the liver, a virtually spontaneous pseudochemical pool. It is dialysis.

By practicing the hemodiafiltration method or the hemofiltration method in this way, α1-m, which is a protein having a strong scavenging ability of reactive oxygen species and free radicals, can be molecularly rotated. This is effective in improving the oxidative stress protective action and the cell proliferation inhibitory state in renal failure.

(Application example 4)
Chemical pool dialysis can be applied to the treatment of paraquat poisoning in the area of acute blood purification. First, paraquat addiction will be described. The chemical name for paraquat is 1,1'-dimethyl-4,4'-bipyridinium dichloride. Paraquat is still used today as a pesticide, and if swallowed by mistake, it is absorbed into the body through the intestinal tract, enters cells, and reaches the outer mitochondrial membrane. The paraquat that reaches the outer mitochondrial membrane undergoes one-electron reduction to become a paraquat radical, which induces a strong systemic radical chain reaction. As a result, cells die due to the depletion of NADPH in addition to a large amount of reactive oxygen species damage. Clinical symptoms include vomiting immediately after ingestion, diarrhea, abdominal pain, sores in the mouth, and ulceration over time. In severe cases, renal dysfunction, hepatic dysfunction, and shock progress, and interstitial pneumonia and pulmonary fibrosis also occur, leading to death. The lethal dose of paraquat is tens of mmol.

For such paraquat poisoning, tissue damage due to the generation of active oxygen is the core of the pathological condition, so large doses of α-tocopherol (vitamin E), which is an antioxidant, have been tried conventionally, but organ damage is caused. Lifesaving of the severe cases that develop is almost impossible. This is because vitamin E does not sufficiently block radical chain reactions, vitamin E is fat-soluble and dissolves in the membrane to deteriorate membrane lipids, and vitamin E radicals after the chemical reaction are not excreted from the body. It seems to be related.

From the above relationship considerations, chemical pool dialysis can be applied to the treatment of paraquat poisoning. Specifically, in practice, the protocol for chemical pool dialysis for paraquat poisoning is as soon as possible after exposure, as a chemical pool drug, both reduced ascorbic acid (vitamin C) and reduced glutathione in 10-100 mmol veins, respectively. Administer. However, the chemical pool drug is not limited to these two drugs. Urgent intravenous administration of chemical pool drugs prior to or in parallel with gastrointestinal lavage. Then, within 1 day (preferably within 4 hours), blood purification treatment is performed for 4 to 6 hours to remove the chemical pool drug. At the end of blood purification, administer a second chemical pool drug. Then, within one day, perform a second blood purification therapy. After that, administration of the chemical pool drug and blood purification are repeated for several courses. When continuous blood purification treatment is performed instead of intermittent treatment as blood purification treatment, additional administration of chemical pool drug is performed every 4 to 24 hours during continuous blood purification treatment to compensate for the decrease in the concentration of residual chemical pool drug. I do.

In chemical pool dialysis for paraquat poisoning, the effect of blocking radical chain reaction can be exhibited even if 0.5 to 10 g of the recombinant α1-m preparation alone is administered as a chemical pool drug. However, as a blood purification method for removing chemical pool drugs, a hemodiafiltration method or a hemofiltration method is adopted rather than hemodialysis because the removal efficiency of large molecules is relatively large, and a large pore membrane is selected as the blood purifier. .. In addition, plasma exchange can be added while supplementing the plasma product to remove α1-m molecules more efficiently. As a chemical pool drug, a certain effect can be expected even when the recombinant α1-m preparation is used alone, but a chemical pool drug of a small molecule compound is preferably used in combination. Examples of the chemical pool drug for the small molecule compound used in combination include, but are not limited to, reduced ascorbic acid (vitamin C) and reduced glutathione. The treatment schedule of repeating the administration of the chemical pool drug and blood purification for several courses is the same as the above protocol.

(Application example 5: Treatment of side effects of anticancer drugs)
Another application of chemical pool dialysis in the area of acute blood purification includes the treatment of severe cytotoxic side effects after administration of antineoplastic agents. Anthraquinone (anthracycline) -based anticancer antibiotics represented by adriamycin have a quinone structure in the molecule, so after being taken up into cells, they are reduced by one electron in microsomes to generate semiquinone radicals, which are radicals. Induces a chain reaction. Cardiotoxicity is a well-known serious side effect. When heart failure develops, the condition is irreversibly worsened and often fatal. Start administration of chemical pool drugs as soon as signs of cardiotoxicity appear. The protocol for the treatment is similar to the protocol for the treatment of paraquat addiction.

Hereinafter, examples will be specifically described, but the present invention is not limited to the following examples as long as the gist of the present invention is not exceeded.

(Example 1)
Chemopool dialysis is performed for chronic dialysis patients weighing 60 kg who receive normal blood purification treatment (blood dialysis at 200 to 300 mL / min for 4 to 5 hours) performed three times a week. went. Specifically, as the chemical pool agent of the present invention, 2- (α-D-glucopyranosyl) (methyl) methyl-2,5,7,8-tetramethylchroman-6-ol, which is an acceptor agent that captures free radicals (Fig.) A 200 mL aqueous solution (rinse solution) containing 9) at a chemical equivalent of 10 mEq was prepared. This rinse solution was placed in a dialysis machine equipped with a high-performance membrane (dialysis membrane having a clearance value of 150 mL / min). At the end of the blood purification treatment, this rinse solution was used for blood recovery in the extracorporeal circulating blood circuit of the dialysis machine, and the entire amount was administered to the above-mentioned patient. The administered chemical pool drug was removed from the body by the next blood purification treatment after an intermittent treatment period (43 to 44 hours). This cycle was repeated at the end of blood purification treatment.

(Example 2)
Chemopool dialysis was performed on a chronic dialysis patient weighing 60 kg who was subjected to the same usual blood purification treatment as in Example 1. Specifically, as the chemical pool agent of the present invention, 2- (α-D-glucopyranosyl) (isopropyl) methyl-2,5,7,8-tetramethylchroman-6-ol, which is an acceptor agent that captures free radicals (Fig.) A 300 mL aqueous solution (rinse solution) containing 10) at a chemical equivalent of 200 mEq was prepared. This rinse solution was placed in a dialysis machine equipped with a high-performance membrane (dialysis membrane having a clearance value of 200 mL / min). At the end of the blood purification treatment, this rinse solution was used for blood recovery in the extracorporeal circulating blood circuit of the dialysis machine, and the entire amount was administered to the above-mentioned patients. The administered chemical pool drug was removed from the body by the next blood purification treatment after an intermittent treatment period (43 to 44 hours). This cycle was repeated at the end of blood purification treatment.

(Example 3)
Chemopool dialysis was performed on a chronic dialysis patient weighing 60 kg who was subjected to the same usual blood purification treatment as in Example 1. Specifically, as the chemical pool agent of the present invention, 100 mEq of D-lysyl tyrosine (dipeptide consisting of 2 residues of D-type amino acid) having a non-physiological optical isomer structure, which is an acceptor agent for capturing free radicals. A 500 mL aqueous solution (rinse solution) containing the chemical equivalent of the above was prepared. This rinse solution was placed in a dialysis machine equipped with a high-performance membrane (dialysis membrane having a clearance value of 150 mL / min). At the end of the blood purification treatment, this rinse solution was used for blood recovery in the extracorporeal circulating blood circuit of the dialysis machine, and the entire amount was administered to the above-mentioned patients. The administered chemical pool drug was removed from the body by the next blood purification treatment after an intermittent treatment period (43 to 44 hours). This cycle was repeated at the end of blood purification treatment. Since the D-type peptide radical that has captured the radical and the D-type peptide that has undergone oxidative modification are not easily decomposed in the body and are stably present during the intermittent treatment period, they can be removed by the next dialysis treatment.

(Example 4)
Chemopool dialysis was performed on a chronic dialysis patient weighing 60 kg who was subjected to the same usual blood purification treatment as in Example 1. Specifically, as the chemical pool agent of the present invention, D-lysyl tyrosyl cysteine (tripeptide consisting of 3 residues of D-type amino acid) having a non-physiological optical isomer structure, which is an acceptor agent that captures free radicals. ) At a chemical equivalent of 100 mEq to prepare a 500 mL aqueous solution. A total of 15 g of proteinogenic L-amino acid was added to this aqueous solution to prepare a rinse solution containing L-amino acid and D-lysyl, tyrosine, and cysteine. This rinse solution was placed in a dialysis machine equipped with a high-performance membrane (dialysis membrane having a clearance value of 150 mL / min). At the end of the blood purification treatment, this rinse solution was used for blood recovery in the extracorporeal circulating blood circuit of the dialysis machine, and the entire amount was administered to the above-mentioned patients. Since the osmotic pressure ratio of the rinse solution to the physiological saline was 3 to 4, slow administration (recovery operation) was carried out over several minutes. The administered chemical pool drug was removed from the body by the next blood purification treatment after an intermittent treatment period (43 to 44 hours). This cycle was repeated at the end of blood purification treatment.

(Example 5)
Chemopool dialysis was performed on a chronic dialysis patient weighing 60 kg who was subjected to the same usual blood purification treatment as in Example 1. Specifically, as the chemical pool drug of the present invention, a 300 mL aqueous solution (rinse solution) containing reduced ascorbic acid and glutathione or glutathione alkyl ester (donor drug as H donor) having a total chemical equivalent of 80 mEq is prepared. bottom. The content ratio of reduced ascorbic acid to glutathione or glutathione alkyl ester was 1: 3 in chemical equivalent ratio. This rinse solution was placed in a dialysis machine equipped with a high-performance membrane (dialysis membrane having a clearance value of 150 mL / min). At the end of the blood purification treatment, this rinse solution was used for blood recovery in the extracorporeal circulating blood circuit of the dialysis machine, and the entire amount was administered to the above-mentioned patients. The administered chemical pool drug was removed from the body by the next blood purification treatment after an intermittent treatment period (43 to 44 hours). This cycle was repeated at the end of blood purification treatment.
The action of glutathione alkyl ester is to act as a substrate for glutathione peroxidase and exert reducibility like glutathione, but in terms of migration, it has better membrane permeability than glutathione and can be more easily reached by mitochondria. It is an advantage.

(Example 6)
Chemical pool dialysis was performed on burn patients weighing 60 kg who required acute blood purification treatment. Specifically, the chemical pool agents of the present invention include 2- (α-D-glucopyranosyl) (methyl) methyl-2,5,7,8-tetramethylchroman-6-ol, which are acceptor agents that capture free radicals. A 500 mL aqueous solution containing glutathione or glutathione alkyl ester (H donor) in a total chemical equivalent of 120 mEq was prepared. The content ratio of 2- (α-D-glucopyranosyl) (methyl) methyl-2,5,7,8-tetramethylchroman-6-ol and glutathione or glutathione alkyl ester was set to 2: 1 in chemical equivalent ratio. Such an aqueous solution was intravenously administered to the above-mentioned patients by a dialysis machine as soon as possible after the occurrence of an adverse event. Then, after the detoxification reaction such as radical supplementation or reduction reaction reached an equilibrium state (usually after several hours to several days have passed), highly efficient blood purification treatment was performed to remove the reaction product. For such removal, the acute blood purification treatment needs to be more efficient in removing small molecule substances than the usual continuous slow-type chronic blood purification treatment. Therefore, the blood purifier of the dialysis apparatus performed blood purification treatment for 4 hours or more using a dialysis membrane having a clearance value of 200 ml / min. When the clearance value is 100 ml / min, it is preferable to perform blood purification treatment for 6 hours or more, and when the clearance value is 150 ml / min, it is preferable to perform blood purification treatment for 5 hours or more. The administration of the chemical pool drug and the subsequent blood purification treatment were set as one course, and three courses were repeated once every three days. In the case of continuous treatment, when the chemical pool drug administered in the body is removed by about 10 to 50% of the chemical equivalent immediately after the administration, administration of an additional chemical pool drug is performed for blood purification treatment. Do it in the middle of.

By the chemical pool dialysis performed in Examples 1 to 5, it was possible to efficiently prevent the progress of the chain reaction of harmful free radicals having high chemical reactivity, which are constantly generated in the metabolic process. According to such chemical pool dialysis, deterioration of biopolymers, gene deterioration, and cell function deterioration due to a vicious cycle of reactive oxygen species scavenging ability and mitochondrial damage in chronic renal failure progresses and is visible. It is expected that the rate of development of complications such as muscular atrophy and motor dysfunction, arteriosclerosis, canceration, and accelerated aging will be reduced, which will contribute to the survival and quality of life of patients. Nationally, preventive medical merits are expected to reduce medical expenses spent on dealing with complications. The reduced ascorbic acid constituting the chemical pool drug used in Example 5 does not reach the mitochondria, but is reduced by glutathione or glutathione alkyl ester after capturing the free radicals leaked outside the mitochondria. In addition, glutathione or glutathione alkyl esters reach the mitochondria. Therefore, it is presumed that the chain reaction of free radicals could be blocked at multiple stages.

In addition, by applying the chemical pool dialysis as in Example 6 to the fields of acute blood purification treatment and emergency treatment, patients with acute renal failure, patients with drug overdose or poisoning, patients with severe infections, patients with burns, imaginary It is expected to improve the survival rate of patients with post-blood reperfusion disorder, severe pregnancy toxins, chronic skin ulcers, cerebral hemorrhage ventricular perforation, and patients with severe hemolytic disease.

1 Blood purification treatment 2 Administration of chemical pool drug 3 Profile of the abundance (mEq) of the drug distributed in the extracellular fluid in the chemical pool 4 Profile of the abundance (mEq) of the drug distributed in the cytoplasm of the chemical pool 5 Chemistry Profile of drug abundance (mEq) distributed in mitochondria in the pool 6 Changes in chemical pool size (mEq) when the endogenous clearance value is 1 mL / min 7 Changes in the chemical pool when the endogenous clearance value is 2 mL / min Change in size (mEq) 8 Change in chemical pool size (mEq) when endogenous clearance value 4 mL / min 9 Change in chemical pool size (mEq) when endogenous clearance value 8 mL / min 10 Intrinsic clearance Change in chemical pool size (mEq) at value 12 mL / min 11 Change in amount of drug present in mitochondria (mEq) at endogenous clearance value 1 mL / min 12 Change in endogenous clearance value 2 mL / min Changes in the amount of drug present in mitochondria (mEq) 13 Changes in the amount of drug present in mitochondria (mEq) when the intrinsic clearance value is 4 mL / min 14 Changes in the amount of drug present in mitochondria (mEq) present in mitochondria when the endogenous clearance value is 8 mL / min Change in drug amount (mEq) 15 Change in drug amount (mEq) present in mitochondria when endogenous clearance value 12 mL / min 16 Chemical pool size (mEq) when blood purification clearance value 100 mL / min Change 17 Change in chemical pool size (mEq) when blood purification clearance value is 150 mL / min 18 Change in chemical pool size (mEq) when blood purification clearance value is 200 mL / min 19 Change in blood purification clearance value 250 mL / min 20 Change in chemical pool size (mEq) when blood purification clearance value is 300 mL / min
C1: Electromagnetic opening / closing clamp
C2: Electromagnetic opening / closing clamp
D: Blood purifier
D1: Thin tube
P1: Dialysate feed pump (equal flow rate system)
P2: Dialysate drainage pump (equal flow rate system)
P3: Third dialysate pump that rotates both forward and reverse
P4: Blood pump that rotates both forward and reverse
R: Rinse solution containing chemical pool drug
s: Connection point between the patient's blood vessel on the blood removal side and the blood circuit
t: Confluence of replacement fluid supply circuit and blood circuit
u: Connection point between blood circuit artery side and blood purifier D
v: Connection point between the patient's blood vessel on the blood return side and the blood circuit 100: Dialysis device 200: Dialysate circuit 300: Extracorporeal circulation blood circuit (blood circuit)
310: Arterial blood circuit 320: Intravenous blood circuit 400: Fluid replacement circuit

Claims (13)

An acceptor molecule that can capture free radicals generated in the body of a patient undergoing blood purification treatment with a blood purifier, or
Oxidation by donating electrons as hydrogen atoms and / or electrons to the oxidized biomolecules subjected to the oxidation reaction in the body of the patient to whom the blood purification treatment is performed by the blood purifier. A chemical pool drug containing at least one of the donor molecules capable of blocking the reaction.
The chemical pool drug is configured to be removed from the patient's body by the blood purifier after capturing the free radicals or donating the electrons.
The chemical pool drug is 0.001 mEq / (hr · kg) or more using the length of the treatment intermittent period (hr) in the blood purification treatment and the weight (kg) of the patient to whom the blood purification treatment is performed. A chemical pool drug characterized by being administered in a chemical equivalent of. The chemical pool drug according to claim 1, wherein the total amount of the chemical equivalents per one blood purification treatment is 0.001 to 20 mEq / (hr · kg). The chemical pool agent according to claim 2, wherein the chemical equivalent is administered in a larger amount than the total amount. The chemical pool agent according to any one of claims 1 to 3, wherein the acceptor molecule after capturing the free radical and the donor molecule after donating the electron have a stable period of at least 3 hours. .. The chemical pool agent according to any one of claims 1 to 4, which comprises at least one of a small molecule compound having a molecular weight of 1000 D or less or a large molecular compound having a molecular weight of 20 kD or more. The chemical pool agent according to claim 5, wherein the small molecule compound contains at least one of reduced ascorbic acid or reduced glutathione. The chemical pool drug according to claim 5, wherein the small molecule compound contains a peptide consisting of 2 or 3 residues of D-type amino acid. The chemical pool drug according to claim 5, wherein the large molecular compound contains a recombinant α1-m. The chemical pool agent according to claim 8, wherein the recombinant α1-m comprises at least one of the original recombinant α1-m or the mutant recombinant α1-m. An injectable preparation comprising the chemical pool agent according to any one of claims 1 to 9. An oral preparation comprising the chemical pool agent according to any one of claims 1 to 9. An infusion preparation comprising the chemical pool agent according to any one of claims 1 to 9. A blood purifier, an extracorporeal circulating blood circuit connected to the blood purifier to circulate blood, a supply means connected to the extracorporeal circulating blood circuit, and a dialysate for supplying dialysate to the blood purifier. A dialysis machine that includes a circuit,
The dialysis apparatus according to claim 12, wherein the supply means is configured to supply the infusion preparation according to claim 12 to the extracorporeal circulating blood circuit.

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