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WO2025225134A1 - Amélioration de l'hypofonction rénale - Google Patents

Amélioration de l'hypofonction rénale

Info

Publication number
WO2025225134A1
WO2025225134A1 PCT/JP2025/004984 JP2025004984W WO2025225134A1 WO 2025225134 A1 WO2025225134 A1 WO 2025225134A1 JP 2025004984 W JP2025004984 W JP 2025004984W WO 2025225134 A1 WO2025225134 A1 WO 2025225134A1
Authority
WO
WIPO (PCT)
Prior art keywords
renal function
lactitol
stage
suppressing
decline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/JP2025/004984
Other languages
English (en)
Japanese (ja)
Inventor
高橋 祥子 神本
憲司 齋藤
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taz Inc
Original Assignee
Taz Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taz Inc filed Critical Taz Inc
Publication of WO2025225134A1 publication Critical patent/WO2025225134A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the present invention relates to providing a new means for suppressing renal function decline and improving renal function in the body using lactitol. More specifically, the present invention relates to providing a new means for suppressing renal function decline using lactitol.
  • CKD Chronic kidney disease
  • the objective of the present invention is to provide a new means for suppressing kidney function decline that can fundamentally improve diseases accompanied by kidney function decline, including chronic kidney disease (CKD).
  • CKD chronic kidney disease
  • the inventors of the present invention have solved the above-mentioned problem by providing a new means for inhibiting renal function decline in the body, using lactitol or a derivative thereof to inhibit and improve renal function decline. More specifically, the present invention has solved the above-mentioned problem by providing an agent for inhibiting renal function decline, which contains lactitol or a derivative thereof.
  • the present invention can provide a new means for suppressing renal function decline in the body and improving renal function.
  • FIG. 1 is a graph showing the change in serum creatinine levels in a subject (male, 47 years old) before and after one month of lactitol intake.
  • Figure 2 is a graph showing the change in eGFR value calculated based on the serum creatinine value obtained in Figure 1 in a subject (male, 47 years old) before and after one month of lactitol intake.
  • FIG. 3 is a graph showing serum creatinine (CRE) levels after 21 days of lactitol intake in a test mouse (male, 60 weeks old) with a renal failure model induced by feeding adenine to the test mouse.
  • CRE serum creatinine
  • FIG. 4 is a graph showing blood urea nitrogen (BUN) levels after 21 days of lactitol intake in a test mouse (male, 60 weeks old) with a renal failure model induced by feeding adenine to the test mouse.
  • FIG. 5 is a graph showing blood lactate dehydrogenase (LDH) levels after 21 days of lactitol intake in a test mouse (male, 60 weeks old) with a renal failure model induced by feeding adenine.
  • FIG. 6 is a graph showing blood creatine kinase (CK) levels after 21 days of lactitol intake in a test mouse (male, 60 weeks old) with a renal failure model induced by feeding adenine to the test mouse.
  • FIG. 7 is a graph showing blood albumin (ALB) levels after 21 days of lactitol intake in a test mouse (male, 60 weeks old) with a renal failure model induced by feeding adenine to the test mouse.
  • ALB blood albumin
  • the inventors of the present invention have conducted extensive research and development, and hypothesized that by having individuals with impaired kidney function ingest lactitol, a type of sugar alcohol, the decline in kidney function may be suppressed or improved. They decided to conduct human trials in subjects with high blood creatinine levels to verify the effect on markers of renal failure.
  • lactitol can suppress and improve renal function decline in the body, and demonstrated that lactitol or its derivatives can provide a new means for suppressing renal function decline. More specifically, the present invention provides an agent for suppressing renal function decline, which comprises lactitol or a derivative thereof.
  • lactitol or its derivatives when orally administered, they can efficiently reduce blood creatinine levels, a marker of kidney function decline. Therefore, in the present invention, lactitol or its derivatives can suppress and improve kidney function decline in the body, and more specifically, improve chronic kidney disease (CKD).
  • CKD chronic kidney disease
  • lactitol is used as the active ingredient, but its derivatives can also be used as active ingredients.
  • lactitol derivatives refer to compounds created by changing a small portion of the molecular structure of lactitol, and refer to compounds that maintain the basic structure and properties of lactitol while undergoing modifications such as the introduction of functional groups, oxidation, reduction, or atom substitution in part of the structure.
  • lactitol or its derivatives as active ingredients, other substances that have been shown to have an inhibitory effect on kidney function decline can be used in combination.
  • the intake amount of lactitol or its derivatives in the present invention can be any amount commonly used.
  • the intake amount of lactitol or its derivatives can be 5 to 40 g per day.
  • the intake schedule for lactitol or its derivatives can be any, and for example it can be ingested once a day, three times a day, or it can be ingested less frequently, such as once a week or once a month.
  • the agent for suppressing kidney function decline of the present invention may contain, in addition to the active ingredient lactitol or its derivatives, various additives commonly used in foods or pharmaceuticals.
  • the suppression of decline in renal function includes bringing the values of renal function markers in plasma closer to the normal range, etc.
  • renal function markers in plasma include: - Glomerular injury markers: albumin, type IV collagen, ceruloplasmin, creatinine, serum cystatin C - Renal tubule damage markers: NGAL, ⁇ 1-MG, KIM-1, L-FABP, angiotensinogen, NAG, ⁇ 2 microglobulin - Inflammatory markers: inflammatory cytokines (IL-6, IL-8, IL-18, IP-10, TNF- ⁇ , TNF- ⁇ receptor), growth factors (TGF- ⁇ , CTGF), adhesion molecules (ICAM-1, VCAM-1), fetuin-A, soluble CD40 ligand, human ⁇ 1 acid glycoprotein, - Oxidative stress markers: 8-OHdG, pentosidine, and blood AGE -
  • CKD markers such as glomerular filtration rate (GFR), cystatin C,
  • the agent for suppressing renal function decline of the present invention is preferably administered to individuals whose serum creatinine level is mildly abnormal, requires reexamination/lifestyle improvement, or requires detailed examination/treatment, based on the reference values for serum creatinine levels shown in Table 1.
  • the agent for suppressing renal function decline of the present invention can be used for any disease in which renal function declines, such as glomerulonephritis and chronic kidney disease (CKD).
  • CKD chronic kidney disease
  • the agent for suppressing renal function decline of the present invention is particularly effective against CKD, and is even more effective against renal function decline selected from early nephropathy stage (Stage 2), overt nephropathy stage (Stage 3A), and renal failure stage (Stage 4).
  • Formula for calculating eGFR based on serum cystatin C (Cys-C (mg/L)): Male: eGFR (ml/min/1.73 m2 ) (104 x Cys-C (mg/L) -1.019 x 0.996 age (years) ) -8
  • Female: eGFR (ml/min/1.73 m 2 ) (104 ⁇ Cy
  • the agent for suppressing renal function decline of the present invention is preferably administered to an individual whose renal function decline is in the state of G2, G3a, G3b, or G4 (i.e., a state in which the GFR value is 15 mL/min/1.73 m2 or more and less than 90 mL/min/1.73 m2 ) based on the GFR classifications shown in Table 2.
  • Suppression of renal function decline when the agent for suppressing renal function decline of the present invention is administered to such an individual includes any case in which the eGFR value increases, for example, when the agent for suppressing renal function decline of the present invention is administered to an individual whose eGFR value falls into the "G3a" category for a certain period of time, resulting in an increase in the eGFR value to a value that falls into the "G2" category, or when the agent for suppressing renal function decline of the present invention is administered to an individual whose eGFR value falls into the "G2" category, resulting in an increase in the eGFR value, although within the range of the "G2" category.
  • composition refers to either a food composition (compositions for general foods and compositions for foods with bioregulatory functions (e.g., foods for specified health uses, foods with nutrient functions, or foods with functional claims)) or a pharmaceutical composition.
  • the present invention can provide a pharmaceutical composition containing lactitol or a derivative thereof for treating diseases accompanied by decreased kidney function.
  • composition of the present invention may contain other ingredients or various additives commonly used in foods or pharmaceuticals, and any type of these other ingredients or various additives is acceptable.
  • lactitol or its derivatives that can be used in the composition of the present invention can efficiently lower serum creatinine levels and improve (increase) eGFR, an index of kidney function.
  • the active ingredient in the composition of the present invention can be contained in an amount commonly used for lactitol or its derivatives.
  • the composition of the present invention can be used to treat any disease in which kidney function declines, such as glomerulonephritis and chronic kidney disease (CKD).
  • kidney function declines such as glomerulonephritis and chronic kidney disease (CKD).
  • the agent for suppressing kidney function decline of the present invention is particularly effective against CKD, and is even more effective against kidney function decline in the early nephropathy stage (Stage 2), overt nephropathy stage (Stage 3A), and renal failure stage (Stage 4).
  • composition of the present invention is preferably administered to an individual whose renal function is impaired in the GFR category of G2, G3a, G3b, or G4 (GFR value is 15 mL/min/1.73 m2 or more and less than 90 mL/min/1.73 m2 ) .
  • Example 1 Examination of effects on renal function markers (1)
  • lactitol was administered to humans to confirm the effect of lactitol on kidney function.
  • eGFR estimated glomerular filtration rate
  • Serum creatinine (Cr) levels Serum creatinine (Cr), a marker of kidney function, was measured using serum separated from blood collected from a male subject who had been orally taking lactitol (Bussan Food Science Co., Ltd.) for one month. Serum creatinine was measured using a colorimetric method. As a negative control, serum creatinine levels were measured using a blood sample from the same male subject before the lactitol intake.
  • the results are shown in Figure 2.
  • the eGFR estimated from a serum creatinine level of 1.25 mg/dL before intake was 50.3 (ml/min/1.73 m2 ), and after one month of intake, the eGFR estimated from a serum creatinine level of 0.90 mg/dL increased to 72.1.
  • an eGFR of 60 or less is considered to indicate decreased kidney function, and the improvement from 50.3 to 72.1, within the normal range (60 or above), demonstrated that lactitol intake has an effect on improving the treatment of CKD.
  • Example 2 Examination of effects on renal function markers (2)
  • lactitol was administered to animals to confirm the effect of lactitol on kidney function.
  • mice 60-week-old C57BL/6J mice (male, 30 mice (total of 3 groups), hereafter referred to as "subject mice") were used.
  • the subject mice were housed individually in plastic mouse cages (170 W x 240 D x 120 H mm, manufactured by CLEA Japan, Inc.) lined with paper chips and Peperclean (manufactured by Japan SLC Co., Ltd.) bedding that had been autoclaved (121°C, sterilization for 40 minutes, drying for 30 minutes).
  • the temperature and humidity were kept at 20-26°C, humidity at 30-70%, and with a 12-hour lighting schedule (lights on at 7:00 AM, lights off at 7:00 PM) daily. Temperature and humidity were recorded daily and stored as raw data.
  • adenine-induced renal failure model was created using these test mice and used in the experiment. Specifically, the control group (referred to as the "Con group”) was fed AIN-93M (Research Diet), a diet for mice and rats, while the adenine-fed group (referred to as the "Adenine group”) and the adenine-lactitol-fed group (referred to as the "Adenine+L group”) were given AIN-93M supplemented with 0.1% adenine ad libitum.
  • the Con and Adenine groups received home-pumped water supplemented with 0.025% sodium hypochlorite (Tsurukuron, Tsurumi Soda Co., Ltd.), while the Adenine+L group received water supplemented with 5% lactitol (Butsusan Food Science Co., Ltd.) in 100 mL polycarbonate bottles, and both groups were given free access to this water.
  • the experimental group composition is summarized in Table 3 below.
  • the Adenine+L group which was an adenine-induced renal failure model (with the same formulation as the Adenine group), was given 5 g of lactitol orally daily for 21 days (3 weeks).
  • Plasma samples taken from the test mice in each group were used to measure blood creatinine, urea nitrogen, albumin, lactate dehydrogenase, and creatinine kinase at Oriental Yeast Co., Ltd.
  • Statistical analysis was performed using Dunnett's multiple comparison test, and in the figures for each measurement value below, significant differences of p ⁇ 0.05 are indicated between different signs.
  • LDH lactate dehydrogenase
  • the present invention provides an agent for suppressing renal function decline containing lactitol or a derivative thereof, thereby providing a new means for suppressing renal function decline in the body and improving renal function using lactitol or a derivative thereof.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention aborde le problème de la fourniture d'un nouveau moyen de suppression de l'hypofonction rénale, le moyen étant en mesure d'améliorer fondamentalement des maladies associées à une hypofonction rénale, y compris une néphropathie chronique (CKD).　Les inventeurs de la présente invention ont résolu le problème ci-dessus par la fourniture d'un nouveau moyen destiné à supprimer l'hypofonction rénale, le moyen supprimant et améliorant l'hypofonction rénale in vivo à l'aide de lactitol ou d'un dérivé de celui-ci. Plus spécifiquement, la présente invention a résolu le problème ci-dessus par la fourniture d'un agent pour supprimer l'hypofonction rénale qui contient du lactitol ou un dérivé de celui-ci.
PCT/JP2025/004984 2024-04-22 2025-02-14 Amélioration de l'hypofonction rénale Pending WO2025225134A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2024069001 2024-04-22
JP2024-069001 2024-04-22

Publications (1)

Publication Number Publication Date
WO2025225134A1 true WO2025225134A1 (fr) 2025-10-30

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Family Applications (1)

Application Number Title Priority Date Filing Date
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Country Link
WO (1) WO2025225134A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6345222A (ja) * 1986-04-18 1988-02-26 Chugai Pharmaceut Co Ltd 腎不全の保存療法剤
WO1997000075A1 (fr) * 1995-06-14 1997-01-03 Institute Of Immunology Co., Ltd. Medicament contre le prurit cutane accompagnant l'insuffisance renale
WO2014088118A1 (fr) * 2012-12-07 2014-06-12 国立大学法人名古屋大学 Marqueur de cardiopathie et son utilisation
CN103961582A (zh) * 2014-05-23 2014-08-06 申立红 治疗肾炎的中药组合物及其制剂和制备方法
JP2020117491A (ja) * 2019-01-18 2020-08-06 亮介 臼井 新規抗ウロモジュリン抗体、その抗体を使用した血中ウロモジュリン濃度の測定方法及び測定キット、並びに、そのキットを用いた腎機能の評価方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6345222A (ja) * 1986-04-18 1988-02-26 Chugai Pharmaceut Co Ltd 腎不全の保存療法剤
WO1997000075A1 (fr) * 1995-06-14 1997-01-03 Institute Of Immunology Co., Ltd. Medicament contre le prurit cutane accompagnant l'insuffisance renale
WO2014088118A1 (fr) * 2012-12-07 2014-06-12 国立大学法人名古屋大学 Marqueur de cardiopathie et son utilisation
CN103961582A (zh) * 2014-05-23 2014-08-06 申立红 治疗肾炎的中药组合物及其制剂和制备方法
JP2020117491A (ja) * 2019-01-18 2020-08-06 亮介 臼井 新規抗ウロモジュリン抗体、その抗体を使用した血中ウロモジュリン濃度の測定方法及び測定キット、並びに、そのキットを用いた腎機能の評価方法

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