JP2018127435A - Uremia preventing or ameliorating agents - Google Patents

Abstract

[PROBLEMS] To effectively reduce or reduce the concentration of a uremic substance in blood, or a preventive or ameliorating agent for uremia having an action of effectively improving symptoms or diseases caused by accumulation of a uremic substance in blood ( To provide a reducing agent for blood uremic substances having an action of reducing (reducing). When a peptide comprising the amino acid sequence represented by SEQ ID NO: 1, preferably linaclotide, is administered by a method such as oral administration, prevention of symptoms or diseases caused by accumulation (increase) of uremic substances in blood or Improvement (treatment) can be performed. [Selection figure] None

Description

  The present invention comprises a peptide consisting of the amino acid sequence shown in SEQ ID NO: 1; and an amino acid sequence in which one or two amino acids are added, substituted, deleted and / or inserted in the amino acid sequence shown in SEQ ID NO: 1. And one or two or more peptides selected from the group consisting of peptides having the action of reducing the concentration of blood uremic substances; (hereinafter, these may be collectively referred to as “the present peptides”) Uremic prophylaxis or amelioration agent (hereinafter sometimes referred to as “the prevention / amelioration agent”) or blood uremic substance reduction agent (hereinafter referred to as “the reduction agent”). Is).

  The kidney is an organ that regulates homeostasis (balance) in the body. One of the renal functions is to take in waste products and toxins (uremic substances) in the blood, send them into the urine and excrete them outside the body. When such renal function is reduced, uremic substances that should be excreted by the kidneys tend to accumulate in the body, causing symptoms such as nausea and decreased appetite, as well as damage to cells in the kidneys, causing further reduction in renal function. In addition, it is known that a person with impaired renal function has a higher risk of suffering from stroke or myocardial infarction than a healthy person. Furthermore, trimethylamine-N-oxide (TMAO), which is one of uremic substances, has been reported to contribute to the deterioration of arteriosclerosis (Non-patent Document 1). Therefore, preventing or treating symptoms and diseases caused by accumulation of such uremic substances (uremia) not only treats symptoms such as nausea and decreased appetite, and worsening kidney damage, but also strokes, It is also necessary from the viewpoint of preventing or treating heart disease, arteriosclerosis and the like.

  As a preparation having a function of adsorbing uremic substances, a kind of activated carbon, spherical adsorbed charcoal cremedin (registered trademark: Kureha Chemical) is known (Patent Documents 1 and 2). Cremedin is a black spherical particle obtained by oxidizing and reducing spherical microporous carbon derived from petroleum hydrocarbons at high temperature, adsorbing harmful substances present in the digestive tract without being absorbed into the body, It is used for the purpose of eliminating (reducing) blood uremic substances and suppressing lowering of renal function by excretion with feces. In addition, carbon nanotubes (Patent Document 3), uremic substance-specific recognition polymers (Patent Document 4), and the like are known as reducing agents for blood uremic substances having a uremic substance adsorption function. In addition, the present inventors have reported that tyrosine has an action of reducing the concentration of uremic substances in blood (Japanese Patent Application No. 2006-213703).

  Meanwhile, Linzes (registered trademark) (linaclotide) is a therapeutic agent for constipation-type irritable bowel syndrome containing a peptide having the amino acid sequence shown in SEQ ID NO: 1 as an active ingredient. However, it has not been known so far that the peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 has a preventive or therapeutic effect on uremia.

Japanese Examined Patent Publication No. 62-29368 Japanese Examined Patent Publication No. 63-60009 Japanese Patent Laid-Open No. 2006-8602 JP 2004-131406 A

Tang WH et al. N Engl J Med. 2013; 368: 1575-84.

  An object of the present invention is to effectively prevent or improve a uremic agent having an action of effectively improving a symptom or disease caused by accumulation of uremic substances in blood, or to effectively reduce the concentration of uremic substances in blood. An object of the present invention is to provide a blood uremic substance reducing agent having an action of reducing (decreasing) the blood.

  The present inventor has continually studied to solve the above problems. In the process, the present peptides were found to have an action of effectively reducing the concentration of the blood uremic substance. It has been reported that TMAO, which is one of uremic substances specifically shown in this example, contributes to the deterioration of arteriosclerosis (Non-patent Document 1). Therefore, in consideration of such prior art, it is considered that the present peptides have a preventive or therapeutic effect on uremia such as cardiovascular abnormalities (eg, arteriosclerosis) caused by TMAO. The present invention has been completed based on these findings.

That is, the present invention is as follows.
[1] A peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 and an amino acid sequence shown in SEQ ID NO: 1 consisting of an amino acid sequence in which 1 or 2 amino acids are added, substituted, deleted and / or inserted, A preventive or ameliorating agent for uremia characterized by containing as an active ingredient one or more peptides selected from the group consisting of peptides having an action of reducing the concentration of a blood uremic substance.
[2] The preventive or ameliorating agent as described in [1] above, which is orally administered.
[3] The preventive or ameliorating agent according to [1] or [2], wherein the peptide is linaclotide.
[4] The above [1] to [1], wherein the uremic substance is one or more substances selected from trimethylamine-N-oxide, indoxyl sulfate, creatinine, phenyl sulfate, indole, and phenol. [3] The preventive or improving agent according to any one of [3].
[5] The preventive or ameliorating agent according to any one of [1] to [4], wherein the uremia is a circulatory system abnormality caused by trimethylamine-N-oxide.
[6] The preventive or ameliorating agent according to [5], wherein the circulatory system abnormality is arteriosclerosis.
[7] A peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 and the amino acid sequence shown in SEQ ID NO: 1 consisting of an amino acid sequence in which 1 or 2 amino acids are added, substituted, deleted and / or inserted, A reducing agent for a blood uremic substance, comprising one or more peptides selected from the group consisting of peptides having an action of reducing the concentration of the blood uremic substance as an active ingredient.
[8] The reducing agent according to [7] above, which is orally administered.
[9] The reducing agent according to [7] or [8] above, wherein the peptide is linaclotide.
[10] The above [7] to [7], wherein the uremic substance is one or more substances selected from trimethylamine-N-oxide, indoxyl sulfate, creatinine, phenyl sulfate, indole, and phenol. [9] The reducing agent according to any one of [9].

  Since the peptides have the action of decreasing (suppressing) or preventing the increase (increase) in the blood uremic substance concentration, the blood uremic substance concentration is adjusted to the normal value, and the blood uremic substance concentration It is useful for the prevention or improvement (treatment) of symptoms or diseases caused by accumulation (increase).

“Control group” of healthy mice (n = 8), “0-CKD group” (n = 7) of adenine-induced chronic kidney disease (CKD) mice not administered with linaclotide (n = 7), 10 μg / kg / day Plasma samples were prepared from “10-CKD group” (n = 8) of CKD mice administered linaclotide and “100-CKD group” (n = 9) of CKD mice administered 100 μg / kg / day of linaclotide. FIG. 2 is a graph showing the results of measuring the concentrations of TMAO (FIG. 1A) and indoxyl sulfate (Ind-S) (FIG. 1B) in plasma (mean ± standard deviation [SD]). . “*” And “**” in the figure indicate that there is a statistically significant difference (P <0.05 and P <0.01, respectively) by Wilcoxon signed rank test. . Plasma samples from “control group” (n = 8), “0-CKD group” (n = 7), “10-CKD group” (n = 8), and “100-CKD group” (n = 9) The figure which shows the result (mean value +/- standard deviation [SD]) which prepared and measured the density | concentration of creatinine (Creatinine) (FIG. 2A) and phenyl sulfate (PS) (FIG. 2B) in plasma. It is. “*” And “**” in the figure indicate that there is a statistically significant difference (P <0.05 and P <0.01, respectively) by Wilcoxon signed rank test.

  In another embodiment of the present invention, one or more peptides selected from the present peptides are administered to a patient in need of reduction of a blood uremic substance to prevent or reduce uremia. One or two or more peptides selected from the present peptides for use as a method for improving (treating) or preventing or improving (treating) uremia, or preventing or improving (treating) uremia One or two or more peptides selected from the present peptides for use in the present invention, or one or two selected from the present peptides for producing a preventive or ameliorating (treating) agent for uremia Mention may be made of the use of more than one peptide.

  This preventive / ameliorating agent is an agent containing the peptide of the present invention, which has a limited use of “to prevent or ameliorate uremia”, as an active ingredient, and the reducing agent is an agent for reducing uremic substances in blood. It is an agent containing the peptides of the present invention, which have a limited use of “to reduce”, as an active ingredient (these agents may be collectively referred to as “the present agent”).

  As the present peptides, a peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 or an amino acid sequence in which 1 or 2 amino acids are added, substituted, deleted and / or inserted in the amino acid sequence shown in SEQ ID NO: 1 The peptide is not particularly limited as long as it is a peptide having a function of reducing the concentration of a uremic substance in blood, and may include a modified amino acid and / or a stable isotope-labeled amino acid. Such amino acid modifications include, for example, acetylation, acylation, ADP ribosylation, amidation, biotinylation, disulfide bond (S-) at the main chain, amino acid side chain, amino terminus, and / or carboxyl terminus of the peptide bond. S bond), sugar chain addition, phosphorylation and the like.

  As the present peptides, in the amino acid sequence shown in SEQ ID NO: 1, the first cysteine (C) residue and the sixth C residue are disulfide bonded, and the second C residue and the tenth C Peptides in which the C residue is disulfide bonded and the fifth C residue and the 13th C residue are disulfide bonded, that is, linaclotide represented by the following structural formula are preferred.

  The method for producing the present peptides is not particularly limited, and can be produced according to known peptide synthesis methods based on the amino acid sequence information of the present peptides. The peptide synthesis method may be, for example, either a solid phase synthesis method or a liquid phase synthesis method. When producing the peptides using the solid phase synthesis method, for example, using the solid phase synthesis method such as the Fmoc method (fluorenylmethyloxycarbonyl method) or the tBoc method (t-butyloxycarbonyl method), the peptide The desired peptides of the present invention can be produced by condensing a peptide or amino acid capable of constituting a group with the remaining part and removing the protective group (when the product has a protective group). For solid phase synthesis, APEX396 (manufactured by Advanced Chemtech), 433A (manufactured by Applied Biosystems), PS3 (manufactured by Protein Technologies), 9050 (manufactured by Perceptive), PSSM-8 (manufactured by Shimadzu Corporation), etc. Commercially available peptide synthesizers can be used. The resin used in the solid phase synthesis method is not particularly limited, and examples thereof include “Rink amide AM Resin”, “Fmoc-AA-Wang Resin”, and “AA-2-Cl-Trt Resin”. Moreover, when producing the present peptides using a liquid phase synthesis method, the present peptides can be produced by a method of condensing N-protected amino acid derivatives step by step step by step. Depending on the presence or absence of a protecting group, a method such as a dicyclohexylcarbodiimide (DCC) method, an active ester method, or a mixed acid anhydride method can be used. In addition, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HCl), (1H-benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP) reagent, diisopropyl The peptides can also be produced by a method using a condensing agent such as carbodiimide (DIPCDI). Commercially available products such as Linzes (registered trademark) (linaclotide) (manufactured by Astellas) can also be used as the peptides.

  In addition to pharmaceutical products (preparations for the prevention or improvement [treatment] of uremia, preparations for reducing blood uremic substances), this drug has specific functions such as health supplements, health functional foods, and supplements. Also included are pharmaceutical-like (food) compositions and functional foods consumed for the purpose of maintaining health.

  The uremic disease that is the disease to be prevented or improved by the preventive / ameliorating agent of the present invention is not particularly limited as long as it is a symptom or disease caused by a uremic substance. Examples of such symptom or disease include anorexia, nausea, Gastrointestinal abnormalities such as vomiting, bad breath, stomatitis, enteritis; nervousness abnormalities such as greed, indifference, poor memory, depression, somnolence, coma, polyneuritis, (developmental) coordination disorder, anorexia Arteriosclerosis (eg, atherosclerosis, arteriole sclerosis, medial calcification sclerosis), anemia, erythropoiesis disorder, hypertension, ischemic heart disease, pericarditis, myocarditis, (blood) coagulation Abnormalities, heart failure, cardiovascular disorder, myocardial infarction, cardiomyopathy, arrhythmia, arteriosclerotic renal artery stenosis, arteriosclerotic nephropathy, cerebral infarction, cervical vascular stenosis, etc .; pigmentation, pruritus (sensation), Skin such as subcutaneous bleeding, skin atrophy, infection, atopy, hair loss Abnormal (disease): albuminuria, acute renal failure, acute tubular necrosis, renal anemia, chronic renal failure, tubulointerstitial disorder, acute nephritis, chronic nephritis, nephrosis, diabetic nephropathy, renal osteopathy ( (For example, renal osteodystrophy), renal dysfunction such as flooding; stroke; cancer; autism; immunodeficiency; bone dysfunction; hyperparathyroidism; insulin resistance; Symptoms or diseases involving LPS (Lipopolysaccharide) such as nephropathy, cystic kidney, liver dysfunction (eg, fulminant hepatitis, fatty liver, NASH, NAFLD), cancer (eg, bile carcinogenesis); ulcerative colitis, clone Inflammatory bowel diseases such as diseases; autoimmune diseases such as lupus, scleroderma and rheumatism; obesity; metabolic syndrome; diabetes; autism; Parkinson's disease; Alzheimer's disease;

  In this specification, “uremic substances (also referred to as“ uremic toxins ”)” are substances excreted by normal kidneys (waste products, toxins, etc.) due to some cause such as decreased renal function. It means a substance that increases (accumulates) in the blood and causes uremia symptoms or diseases when the excretory function is reduced.

Examples of the uremic substance include trimethylamine-N-oxide (TMAO), 1-methyladenosine, 1-methylguanosine, 1-methylinosine (1 -methylinosine), ADMA (Asymmetric dimethylarginine), α-keto-δ-guanidinovaleric acid, α-N-acetylarginine, arabitol, arginine Argininic acid, Benzylalcohol, β-guanidinopropionic acid, β-lipotropin, creatine, creatinine, cytidine, dimethylglycine (Dimethylglycine), erythritol, γ-guanidinobutyric acid, guanidi (Guanidine), guanidinoacetic acid (Guanidinoacetic acid), guanidino succinic acid (Guanidonosuccinic acid), hypoxanthine (Hypoxanthine), malondialdehyde (Malondialdehyde), mannitol (Mannitol), methyl guanidine (Methylguanidine), myo-inositol (Myoinositol), N ^{2, N 2} - dimethyl-guanosine ^{(N 2, N 2 -dimethylguanosine)} , N 4 - acetyl cytidine ^{(N 4 -acetylcytidine), N 6} - methyl adenosine ^{(N 6 -methyladenosine), N 6} - threonyl carbamoyl adenosine (N ^6- threonylcarbamoyladenosine, Orotic acid, Orotidine, Oxalate, Phenylacetylglutamine, Pseudouridine, SDMA (Symmetric dimethylarginine), Sorbitol, cyamine ) Threitol, Thymine, Uracil, Urea, Uric acid, Uridine, Xanthine, Xanthosine, Adrenomedullin, Atrial natriuretic peptide (Atrial natriuretic peptide; ANP), β 2 - microglobulin (β ₂ -microglobulin), β- endorphin (β-endorphin), cholecystokinin (cholecystokinin), CC16 (Clara cell protein), complement factor D (Complement factor D), cystine C (Cystatin C), degranulation inhibiting protein 1 (Delta-sleep inducing peptide), endothelin (Endothelin), hyaluronic acid (hyaluronic acid), inter Interleukin-1β, Interleukin-6, κ-Ig light chain (κ-Ig li ght chain), λ-Ig light chain, leptin, methionine-enkephalin, neuropeptide, parathyroid hormone, retinol-binding protein (Retinol) -binding protein), tumor necrosis factor (TNF) -α (Tumor necrosis factor-α), 2-methoxyresorcinol, 2-deoxyglucosone, CMPF (3-Carboxy-4- methyl-5-propyl-2-furanpropionate, fructoselysine, glyoxal, hippuric acid, homocysteine, hydroquinone, indole-3-acetic acid (Indole-3-acetic acid) acetic acid, Indoxyl sulfate or its precursor (Indole), Kinurenine, Kynurenic acid d), leptin, melatonin, methylglyoxal, N-carboxymethyllysine, p-Cresyl sulfate or its precursor (p-) Cresol [p-Cresol]), Pentosidine, Phenyl sulfate or its precursor (Phenol), P-OH-hippuric axid, Putrescine, Quinolic acid (Quinolinic acid), retinol binding protein (Retinol-binding protein), spermidine (Spermidine), spermine (Spermine) etc. can be mentioned.

  The uremic substance is preferably one or more substances selected from TMAO, indoxyl sulfate and its precursor (indole), creatinine, and phenyl sulfate and its precursor (phenol). As the disease, circulatory system abnormality caused by TMAO is preferable, and arteriosclerosis caused by TMAO is more preferable.

  In the present specification, "reduction of blood uremic substance" means by suppressing the production (generation) of uremic substance or its precursor, promoting the discharge of uremic substance or its precursor outside the body, etc. It means that the concentration of uremic substances contained in the blood is reduced (decreased).

  If necessary, the present agent can be used as a pharmaceutically acceptable carrier, binder, stabilizer, excipient, diluent, pH buffer, disintegrant, isotonic agent, additive, coating agent, Examples may include those in which compounding components such as a solubilizer, a lubricant, a lubricant, a solubilizer, a lubricant, a flavor, a sweetener, a solvent, a gelling agent, and a nutrient are further added. Specific examples of such ingredients include water, saline, animal fats and oils, vegetable oils, lactose, starch, gelatin, crystalline cellulose, gum, talc, magnesium stearate, hydroxypropyl cellulose, polyalkylene glycol, Polyvinyl alcohol and glycerin can be exemplified.

  The dosage form of this preparation includes oral administration in the form of powder, granules, tablets, capsules, syrups, suspensions, etc., and injection or spraying of dosage forms such as solutions, emulsions, suspensions, etc. Examples of the dosage form include parenteral administration administered intranasally, and oral administration is preferred.

  The dosage of the drug is appropriately determined according to age, weight, sex, symptoms, sensitivity to drugs, and the like. Usually in the dosage range of 1 μg to 200 mg / day, preferably in the dosage range of 2 μg to 2000 μg / day, more preferably in the dosage range of 3 to 200 μg / day, still more preferably 4 to 20 μg / day. In the range of the dose of day, it is administered once or a plurality of times (for example, 2 to 4 times) per day, but the dose may be adjusted according to the state of symptom improvement.

  The subject of administration of this drug is not particularly limited. However, the concentration of the uremic substance in the blood is usually caused by a person who needs to reduce the blood uremic substance, specifically due to a decrease in renal function. Those who have increased (increased) or who have accumulated uremic substances in the body.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, the technical scope of this invention is not limited to these illustrations.

1. Method [Preparation of adenine-induced CKD mice]
C57BL / 6 (7 weeks old, male, manufactured by Claire Japan) was acclimated for 1 week, and grouped so that there was no variation in the weight of each cage. The CKD group was fed 0.2% adenine feed (manufactured by CLEA Japan) for 6 weeks from the age of 8 weeks, and the control group was fed normal feed (CE-2). In order to prevent death due to dehydration, an external water bottle was set in addition to the normal water supply. Breeding was carried out according to the breeding manual of the central building, 4-5 animals / cage, breeding temperature 24 ° C., 12 hours light / dark cycle, constant feeding, and free drinking.

[Preparation of linaclotide stock solution]
To a 15 mL tube, 5 mg of linaclotide (Cat #: L465880, manufactured by Toronto Research Chemicals) was added and dissolved in 5 mL of physiological saline to prepare 1 mg / mL linaclotide and stored at −20 ° C.

[Linaclotide administration test to adenine-induced CKD mice]
After measuring the water intake and body weight of the adenine-induced CKD mice in the CKD group, the linaclotide stock solution was 10 μg / kg (mouse body weight) / day or 100 μg when 100 μL of physiological aqueous solution was administered to the linaclotide stock solution. / Kg / day was adjusted with a physiological aqueous solution, and 100 μL of linaclotide-containing physiological aqueous solution or a control physiological aqueous solution was used as an oral sonde for mice equipped with a 1 mL syringe (disposable feeding needle, FG7202, Administration was continued for 2 weeks using a ball diameter of 2.0 mm and a size of 1.18 × 50 mm.

[Sampling and measurement of plasma samples]
After administration for 2 weeks, heart blood collection (500 μL) and plasma samples were prepared according to a conventional method, and LC-MS / composed of TSQ Quantum Ultra (Thermo Fisher Scientific) and NANOSPACE SI-2 (Shiseido) Using MS, the concentrations of four uremic substances (TMAO, indoxyl sulfate, creatinine, and phenyl sulfate) in plasma were measured.

2. Results The blood TMAO concentration in the 0-CKD group mice was 44.7 μM, which was higher than the blood TMAO concentration in the control group mice of 1.58 μM (see FIG. 1A and Tables 1 and 5). Similarly, the blood indoxyl sulfate concentration (16.7 μg / mL), the creatinine concentration (30.7 μM), and the phenyl sulfate concentration (23.2 μM) in the 0-CKD group mice were also in the blood in the control group mice. Increased compared to indoxyl sulfate concentration (1.01 μg / mL), creatinine concentration (11.7 μM), and phenyl sulfate concentration (3.48 μM) (FIGS. 1B, 2A, and 2B, and Tables 2-5) reference).
On the other hand, the blood TMAO concentration, indoxyl sulfate concentration, creatinine concentration, and phenyl sulfate concentration in 10-CKD group mice and 100-CKD group mice, which are CKD mice administered with linaclotide, are all CKD without linaclotide administration. It decreased compared with the 0-CKD group mouse | mouth which is a mouse | mouth (refer FIG. 1 and 2 and Tables 1-5).
These results indicate that the peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 which is an active ingredient of linaclotide is a uremic substance (TMAO, indoxyl sulfate, creatinine, phenyl sulfate, etc.) accumulated in the blood due to decreased renal function. It has the effect of reducing and shows that it is effective in improving uremia. On the other hand, the TMAO concentration in the blood of an arteriosclerosis model mouse increases as compared with that in a healthy mouse, and when an antibacterial drug is administered to such a model mouse to decrease the number of intestinal bacteria, the increase in the blood TMAO concentration is It has been reported that arteriosclerosis was not worsened (see Non-Patent Document 1). Considering such conventional technology, the peptide consisting of the amino acid sequence represented by SEQ ID NO: 1, which is an active ingredient of linaclotide, is capable of treating circulatory system abnormalities such as arteriosclerosis caused by TMAO by regulating the intestinal bacterial flora. It is fully conceivable to have a prophylactic or therapeutic effect on it. Furthermore, Non-Patent Document 1 also describes that when an antibacterial drug is continuously administered to an arteriosclerosis model mouse, the antimicrobial-resistant intestinal microflora increases and the TMAO inhibitory effect is no longer observed. (See left column on page 1583). On the other hand, since the present agent containing a peptide as an active ingredient instead of an antibacterial agent is unlikely to cause such problems, it is expected that the preventive or therapeutic effect on circulatory system abnormalities such as arteriosclerosis will be sustained.

The “0-CKD group / control group ratio” in the table is “the blood concentration in the 0-CKD group mice” with respect to “the concentration of various uremic substances (TMAO, indoxyl sulfate, or creatinine) in the blood in the control group mice”. The ratio of “various uremic substance concentrations” is shown. In addition, “10-CKD group / 0-CKD group ratio” in the table is “blood uremia substance concentration in 10-CKD group mice” relative to “various uremic substance concentration in blood in 0-CKD group mice”. The ratio is shown. In addition, “100-CKD group / 0-CKD group ratio” in the table is “blood uremia substance concentration in 100-CKD group mice” relative to “various uremic substance concentration in blood in 0-CKD group mice”. The ratio is shown.

  The present invention contributes to prevention or improvement (treatment) of symptoms or diseases (for example, circulatory system abnormalities such as arteriosclerosis) caused by accumulation (increase) of uremic substances (for example, TMAO) in blood. is there.

Claims (10)

A peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 and an amino acid sequence shown in SEQ ID NO: 1 consisting of an amino acid sequence in which one or two amino acids are added, substituted, deleted and / or inserted; A preventive or ameliorating agent for uremia, comprising as an active ingredient one or more peptides selected from the group consisting of peptides having an action of reducing the concentration of a uremic substance.   The preventive or ameliorating agent according to claim 1, which is orally administered.   The preventive or ameliorating agent according to claim 1 or 2, wherein the peptide is linaclotide.   The uremic substance is one or more substances selected from trimethylamine-N-oxide, indoxyl sulfate, creatinine, phenyl sulfate, indole, and phenol. The preventive or ameliorating agent described in 1.   The preventive or ameliorating agent according to any one of claims 1 to 4, wherein the uremia is a circulatory system abnormality caused by trimethylamine-N-oxide.   The preventive or ameliorating agent according to claim 5, wherein the circulatory system abnormality is arteriosclerosis. A peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 and an amino acid sequence shown in SEQ ID NO: 1 consisting of an amino acid sequence in which one or two amino acids are added, substituted, deleted and / or inserted; A reducing agent for a blood uremic substance, comprising as an active ingredient one or more peptides selected from the group consisting of peptides having an action of reducing the concentration of the uremic substance.   The reducing agent according to claim 7, which is orally administered.   The reducing agent according to claim 7 or 8, wherein the peptide is linaclotide.   The uremic substance is one or more substances selected from trimethylamine-N-oxide, indoxyl sulfate, creatinine, phenyl sulfate, indole, and phenol, according to any one of claims 7 to 9. The reducing agent according to 1.