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WO2017155053A1 - Agent thérapeutique pour la stéatose hépatique non alcoolique et la stéatohépatite non alcoolique - Google Patents

Agent thérapeutique pour la stéatose hépatique non alcoolique et la stéatohépatite non alcoolique Download PDF

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WO2017155053A1
WO2017155053A1 PCT/JP2017/009538 JP2017009538W WO2017155053A1 WO 2017155053 A1 WO2017155053 A1 WO 2017155053A1 JP 2017009538 W JP2017009538 W JP 2017009538W WO 2017155053 A1 WO2017155053 A1 WO 2017155053A1
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lansoprazole
nash
nafld
examples
expression
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Japanese (ja)
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悠太 山本
敬司 上山
利男 西
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Wakayama Medical University
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Wakayama Medical University
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Definitions

  • the present invention relates to a novel pharmaceutical use of lansoprazole known as a proton pump inhibitor. More specifically, the present invention relates to a preventive and / or therapeutic agent for nonalcoholic fatty liver disease / nonalcoholic steatohepatitis containing lansoprazole.
  • non-alcoholic steatohepatitis (hereinafter referred to as “NASH”), which exhibits liver tissue findings such as fat accumulation, inflammatory necrosis, and fibrosis despite the absence of alcohol consumption due to increased obesity and insulin resistance accompanying lifestyle changes. ” May be abbreviated as“. ”An increase in patients has been reported (Non-patent Document 1). Chronic progressive liver disease of non-drinkers who have fatty liver and whose cause is unknown is collectively called non-alcoholic fatty liver disease (hereinafter sometimes abbreviated as “NAFLD”), of which liver lesions are highly active and cirrhosis.
  • NAFLD non-alcoholic fatty liver disease
  • NASH is defined as one that has a high frequency of transition to liver disease or death related to liver disease (Japanese Society of Gastroenterology NAFLD / NASH Clinical Practice Guidelines 2014; hereinafter, in this specification, general NAFLD typified by NASH is shown. (In some cases, “NAFLD / NASH” may be used as an abbreviation.)
  • the main features of the clinical pathology of NAFLD / NASH include an increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • NASH patients have a high risk of progressing to fatal diseases such as cirrhosis and liver cancer, and NAFLD / NASH prevention, improvement, and development of treatment methods are important medical issues.
  • the onset mechanism of NAFLD / NASH is still unclear, and safe and highly effective drugs and treatment methods for NAFLD / NASH
  • Lansoprazole (trade name: Takepron (registered trademark)) has a proton pump inhibitory action on gastric wall cells (Patent Document 1) and is a highly safe compound that is commercially available as a therapeutic agent for peptic ulcer.
  • the present inventors have induced oxidative stress tolerance of organs by inducing lansoprazole in the first phase drug metabolism system (Ahr-Cyp1a1) and the second phase drug metabolism system (Nrf2-HO-1). It has been reported that it has a therapeutic effect on drug-induced acute hepatitis (Patent Document 2, Non-Patent Document 2).
  • lansoprazole is effective for the prevention and / or treatment of NAFLD / NASH.
  • TGF- ⁇ transforming growth factor- ⁇
  • An object of the present invention is to provide a safe and useful preventive and / or therapeutic agent for nonalcoholic fatty liver disease / nonalcoholic steatohepatitis for which no effective drug therapy is currently known.
  • lansoprazole suppresses liver fibrosis and suppresses the progression of NAFLD / NASH by subcutaneous administration to NAFLD / NASH model animals. I found. Interestingly, it was found that this suppressive effect was not due to the action of lansoprazole to induce the expression of antioxidant stress gene. Hepatic fibrosis is deeply involved in the accumulation of extracellular matrix (ECM) such as type I collagen ⁇ 1 chain (Col1a1), which is a downstream factor of TGF- ⁇ .
  • ECM extracellular matrix
  • ECM is lysed by matrix metalloproteinases (MMPs), but when the activity of MMPs is inhibited by a tissue inhibitor of MMPs (Timp1), liver fibrosis occurs. Therefore, the present inventors examined whether lansoprazole suppresses the expression of these liver fibrosis-related genes, and none of the gene expression was significantly suppressed. It was found that protein expression (ie, activation of TGF- ⁇ ) was remarkably suppressed. Although the involvement of reactive oxygen species (ROS), MMP2 and MMP9 has been reported as a mechanism of TGF- ⁇ activation, lansoprazole did not increase HO-1 expression in NAFLD / NASH model animals.
  • ROS reactive oxygen species
  • TGF- ⁇ activation was inhibited by inhibiting.
  • NASH is caused by inflammation following fat accumulation
  • the present inventors examined the influence of lansoprazole administration on the expression of proinflammatory cytokines in NAFLD / NASH model animals. As a result, it was revealed that lansoprazole suppresses IL-6 gene and protein expression. From the above, the present inventors have found that lansoprazole is useful for the treatment of NAFLD / NASH, and that the therapeutic effect involves cytokines, not antioxidant stress proteins, and completed the present invention. I came to let you.
  • the present invention is as follows.
  • a preventive and / or therapeutic agent for NAFLD / NASH comprising lansoprazole.
  • the agent according to [1] which is used so that 5 mg to 150 mg of lansoprazole is administered per day for an adult.
  • a TGF- ⁇ expression inhibitor comprising lansoprazole.
  • An IL-6 expression inhibitor comprising lansoprazole.
  • NAFLD / NASH can be prevented and / or treated by administering lansoprazole at a dose that has been confirmed to be safe as an existing drug.
  • A shows the tissue of the liver of a NAFLD / NASH model rat in which collagen (I and III) fibers are stained with Picrosirus® Red.
  • B shows the result of scoring using the NAFLD / NASH stage criteria (Brunt criteria). The result of having investigated the density
  • the result of having investigated the expression change of Nrf2, HO-1, Ahr, and Cyp1a1 gene in the liver of a NAFLD / NASH model rat by lansoprazole administration by RT-PCR is shown.
  • the black bar shows the results of the CDAA 5w + LAP 4w group administered with lansoprazole, and the white bar shows the results of the control CDAA 5w group.
  • the result of having investigated the expression change of the liver fibrosis related gene (Timp1, Col1a1, Tgfb1) in the liver of a NAFLD / NASH model rat by lansoprazole administration is shown.
  • TGF- (beta) protein in the liver of a NAFLD / NASH model rat by lansoprazole administration is shown.
  • the present invention provides a prophylactic and / or therapeutic agent for NAFLD / NASH (hereinafter sometimes abbreviated as “the prophylactic and / or therapeutic agent of the present invention”) comprising lansoprazole.
  • Lansoprazole which is an active ingredient in the present invention, is a compound represented by the following structural formula (2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole).
  • Lansoprazole in the present invention may be a racemate or an optically active form such as an R-form or S-form, but (R) -2-[[[3-methyl-4- (2 , 2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole and the like are preferred.
  • lansoprazole in the present invention may be a compound represented by the above structural formula or a pharmaceutically acceptable salt of an optically active substance thereof. Examples of such salts include salts with inorganic bases, salts with organic bases, salts with basic amino acids, and the like.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt and the like.
  • Suitable examples of salts with organic bases include, for example, alkylamines (trimethylamine, triethylamine, etc.), heterocyclic amines (pyridine, picoline, etc.), alkanolamines (ethanolamine, diethanolamine, triethanolamine, etc.), dicyclohexylamine.
  • salts with N, N′-dibenzylethylenediamine and the like Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like. Of these salts, alkali metal salts or alkaline earth metal salts are preferable. The sodium salt is particularly preferable.
  • lansoprazole Since lansoprazole is unstable to acids, it can be provided in the form of an acid-stable prodrug to prevent degradation by gastric acid when administered orally. Examples thereof include prodrugs described in US Pat. No. 6,093,734.
  • Lansoprazole can be produced by a method known per se, for example, the method described in JP-A-61-50978, US Pat. No. 4,628,098, JP-A-10-195068, WO98 / 21201, or the like. Manufactured by.
  • the optically active substance can be obtained by an optical resolution method (fractional recrystallization method, chiral column method, diastereomer method, method using a microorganism or enzyme, etc.), asymmetric oxidation, and the like. In this case, it can also be produced according to the methods described in WO00 / 78745, WO01 / 83473, WO01 / 87874 and WO02 / 44167.
  • TGF- ⁇ () TGF- ⁇ involved in promoting fibrosis in the NAFLD / NASH pathology
  • TGF- ⁇ meaning the expression of active TGF- ⁇ protein.
  • IL-6 () pro-inflammatory cytokine IL-6 gene expression and protein expression
  • Lansoprazole has low toxicity and is a pharmaceutical composition mixed with a pharmacologically acceptable carrier as it is or according to a method known per se, such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules and capsules. (Including soft capsules), orally disintegrating tablets, liquids, injections, suppositories, sustained-release agents, patches, etc., for humans or other mammals, orally or parenterally (eg, Topical, subcutaneous, rectal, intravenous administration, etc.) can be safely administered.
  • a pharmacologically acceptable carrier as it is or according to a method known per se, such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules and capsules. (Including soft capsules), orally disintegrating tablets, liquids, injections, suppositories, sustained-release agents, patches, etc., for humans or other mammals, orally or parenterally (eg, Topical, subcutaneous, rectal
  • lansoprazole can exert an action of suppressing the pathological condition of NAFLD / NASH at a dose that has already been confirmed in animal experiments as a therapeutic agent for gastric ulcer and duodenal ulcer. Therefore, the preventive and / or therapeutic agent of the present invention can also be effectively administered to NAFLD / NASH patients in an amount of active ingredient equivalent to the dose as an existing therapeutic agent for gastric ulcer and duodenal ulcer.
  • the content of lansoprazole in the preventive and / or therapeutic agent of the present invention is about 0.01% to 100% by weight of the total composition.
  • the dose of the preventive and / or therapeutic agent of the present invention varies depending on the administration subject, administration route, severity of disease, etc., but for example, when administered orally to an adult (60 kg), the amount of active ingredient About 0.5 to 1500 mg / day, preferably about 5 to 150 mg / day, and most preferably 30 mg / day. When administered parenterally (for example, subcutaneously), the amount of the active ingredient is about 0.5 to 1500 mg / day, preferably about 5 to 150 mg / day, and most preferably 30 mg / day.
  • Lansoprazole may be administered once a day or divided into 2-3 times.
  • Examples of the pharmacologically acceptable carrier that may be used for the production of the preventive and / or therapeutic agent of the present invention include various organic or inorganic carrier substances that are commonly used as pharmaceutical materials. Agents, lubricants, binders, disintegrants, water-soluble polymers, basic inorganic salts; solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents, etc. in liquid preparations It is done. Further, if necessary, additives such as ordinary preservatives, antioxidants, colorants, sweeteners, sour agents, foaming agents, and fragrances can be used.
  • excipient examples include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, titanium oxide and the like.
  • lubricant examples include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose, starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, low-substituted hydroxypropylcellulose, and the like.
  • disintegrant examples include (1) crospovidone, (2) disintegrants called super disintegrants such as croscarmellose sodium (FMC-Asahi Kasei), carmellose calcium (Gotoku Pharmaceutical), (3) carboxymethyl Examples include starch sodium (eg, Matsutani Chemical Co., Ltd.), (4) low-substituted hydroxypropylcellulose (eg, Shin-Etsu Chemical Co., Ltd.), (5) corn starch and the like.
  • the “crospovidone” is crosslinked with a chemical name of 1-ethenyl-2-pyrrolidinone homopolymer, including those called polyvinylpolypyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer.
  • PVPP polyvinylpolypyrrolidone
  • Specific examples include Kollidon CL (manufactured by BASF), Polyplastidone XL (manufactured by ISP), Polyplaston XL-10 (manufactured by ISP), and Polyplastidone. INF-10 (manufactured by ISP).
  • water-soluble polymer examples include ethanol-soluble water-soluble polymers [for example, cellulose derivatives such as hydroxypropylcellulose (hereinafter sometimes referred to as HPC), polyvinylpyrrolidone, etc.], ethanol-insoluble water-soluble polymers Molecules [for example, hydroxypropylmethylcellulose (hereinafter sometimes referred to as HPMC), cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum, etc.] and the like.
  • HPC hydroxypropylcellulose
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum, etc.
  • Examples of the “basic inorganic salt” include basic inorganic salts of sodium, potassium, magnesium and / or calcium. Preferred is a basic inorganic salt of magnesium and / or calcium. More preferred is a basic inorganic salt of magnesium.
  • Examples of the basic inorganic salt of sodium include sodium carbonate, sodium hydrogen carbonate, disodium hydrogen phosphate and the like.
  • Examples of the basic inorganic salt of potassium include potassium carbonate and potassium hydrogen carbonate.
  • Examples of the basic inorganic salt of magnesium include heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg 6 Al 2 ( OH) 16 ⁇ CO 3 ⁇ 4H 2 O] and alumina hydroxide / magnesium, preferably heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like.
  • Examples of the basic inorganic salt of calcium include precipitated calcium carbonate and calcium hydroxide.
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • dissolution aid examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • the “suspending agent” examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; And hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • hydrophilic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • Examples of the “isotonic agent” include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the “buffering agent” include buffer solutions of phosphate, acetate, carbonate, citrate, and the like.
  • Examples of the “soothing agent” include benzyl alcohol and the like.
  • Examples of the “preservative” include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • antioxidant examples include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • colorant include edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2; edible lake pigments, bengara and the like.
  • sweetening agent examples include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like.
  • sweetening agent examples include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia, thaumatin and the like.
  • sweet agent examples include citric acid (anhydrous citric acid), tartaric acid, malic acid and the like.
  • the “foaming agent” examples include sodium bicarbonate.
  • the “fragrance” may be a synthetic product or a natural product, and examples thereof include lemon, lime, orange, menthol, and strawberry.
  • Lansoprazole is compression-molded by adding a carrier such as an excipient, a disintegrant, a binder or a lubricant according to a method known per se such as JP-A-62-277322 and JP-A-63-301816. Then, if necessary, a preparation for oral administration can be prepared by coating by a method known per se for the purpose of taste masking, enteric property or persistence. In the case of an enteric preparation, an intermediate layer may be provided between the enteric layer and the drug-containing layer by a method known per se for the purpose of separating both layers.
  • a carrier such as an excipient, a disintegrant, a binder or a lubricant according to a method known per se such as JP-A-62-277322 and JP-A-63-301816.
  • a preparation for oral administration can be prepared by coating by a method known per se for the purpose of taste masking, enteric property or persistence.
  • an intermediate layer may be provided between
  • lansoprazole when used as an orally disintegrating tablet, for example, a core containing crystalline cellulose and lactose is coated with lansoprazole and, if necessary, a basic inorganic salt in accordance with WO 99/59544, WO 00/00126, etc.
  • a composition is obtained by coating with a coating layer containing a water-soluble polymer, and the resulting composition is coated with an enteric coating layer containing polyethylene glycol, and then coated with an enteric coating layer containing triethyl citrate, It can be produced by a method of coating with a polyethylene glycol-containing enteric coating layer and finally coating with mannitol to obtain fine particles, mixing the obtained fine particles and additives, and molding.
  • enteric coating layer examples include cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, methacrylic acid copolymer [for example, Eudragit® L30D-55 (trade name; Rame Co., Ltd.), Kollicoat MAE30DP (trade name; manufactured by BASF Corp.), Polykid PA30 (trade name; manufactured by Sanyo Kasei Co., Ltd.), etc.], carboxymethyl ethyl cellulose, shellac and other water-based enteric polymer bases; Sustained release bases such as coalescent [eg Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name), etc.]; water-soluble polymer; triethyl citrate, polyethylene glycol, acetylated monoglyceride De, triacetin, include one or consists like a mixture of two or more layers such as a plasticizer such as castor
  • additives examples include water-soluble sugar alcohols (eg, sorbitol, mannitol, maltitol, reduced starch saccharified product, xylitol, reduced palatinose, erythritol, etc.), crystalline cellulose (eg, Theolas KG 801, Avicel PH 101) , Avicel PH 102, Avicel PH 301, Avicel PH ⁇ 302, Avicel RC-591 (crystalline cellulose, carmellose sodium), etc., low-substituted hydroxypropylcellulose (eg, LH-22, LH-32, LH-23, LH) -33 (Shin-Etsu Chemical Co., Ltd.) and mixtures thereof, etc.), binders, acidulants, foaming agents, sweeteners, fragrances, lubricants, colorants, stabilizers, excipients, Disintegrants are also used.
  • water-soluble sugar alcohols eg, sorbitol, mannitol
  • Lansoprazole can be used in combination with other drugs.
  • concomitant drugs include liver protectants, hypoglycemic agents, antihypertensive agents, antioxidants, anti-inflammatory agents and the like.
  • liver protectant include ursodeoxycholic acid and betaine.
  • hypoglycemic agents include insulin and insulin derivatives, sulfonylureas such as tolbutamide, gliclazide, glibenclamide and glimepiride, fast-acting insulin secretagogues such as nateglinide, repaglinide and mitiglinide, and ⁇ such as acarbose, voglibose and miglitol.
  • -Glucosidase inhibitors biguanides such as metformin and phenformin, and thiazolidines such as pioglitazone, rosiglitazone and troglitazone.
  • the antihypertensive agent include an angiotensin converting enzyme inhibitor, an angiotensin receptor inhibitor, and a calcium antagonist.
  • the antioxidant include vitamins such as vitamin C and vitamin E, N acetylcysteine, probucol, icosapentaenoic acid and esters thereof.
  • the anti-inflammatory agent include cytokine production inhibitors such as pentoxifylline.
  • lansoprazole is mixed according to a method known per se, and in one pharmaceutical composition (for example, tablet, powder, granule, capsule (including soft capsule), liquid, injection, suppository, sustained release etc.)
  • pharmaceutical composition for example, tablet, powder, granule, capsule (including soft capsule), liquid, injection, suppository, sustained release etc.
  • both may be formulated separately, and each may be formulated separately and administered to the same subject simultaneously or with a time difference.
  • liver fibrosis The fixed tissue was embedded in paraffin and sliced, and collagen (I and III) fibers were stained using Picroserius Red Stain Kit (Polyscienes). Hepatic fibrosis scoring was performed using the criteria of Brunt (1) (Brunt, EM. Et al., Seminar Liv. Dis., 21: 3-16 (2001)).
  • RNA samples were extracted from tissues soaked in RNAlator using RNeasy mini kit, concentration was measured using Nano Drop 1000 (Thermo Fischer), and then reverse transcription reaction was performed using AMV reverse transcriptase (Roche).
  • AMV reverse transcriptase As an internal control, the housekeeping gene GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was used.
  • the reverse-transcribed sample was quantified by real-time PCR using the primers shown in Table 1 and LightCycler FastStart DNA Master SYBR Green I (Roche) or KAPA SYBR FAST qPCR Kit (KAPA Biosystems).
  • the amplification protocol was 45 cycles of 95 ° C. 5 seconds-60 ° C. 5 seconds-72 ° C. 12 seconds.
  • a calibration curve was prepared by amplifying a series of 10-fold diluted standard cDNA samples using the same protocol.
  • TGF- ⁇ protein was measured by Western blotting.
  • the cryopreserved sample was homogenized in PRO-PREP TM (INTRON) buffer and incubated on ice for 20 minutes. Centrifuged at 13,000 xg for 5 minutes at 4 ° C to extract soluble protein. Electrophoresis on SDS-polyacrylamide gel (12.5%), transferred to PVDF membrane (Millipore), and reacted with rabbit anti-TGF ⁇ antibody (CST, 3711S) or rabbit anti-IL-6 antibody (Abnova, PAB16165) as the primary antibody It was.
  • Nrf2 and Ahr expression levels of downstream genes of Nrf2 and Ahr
  • lansoprazole administration significantly increased Nrf2 and Ahr mRNA levels (*: P ⁇ 0.05, analyzed by Student's t test), but downstream HO-1 and Ahr mRAN levels No significant change was observed (FIG. 3). Therefore, it was shown that the prevention and / or treatment effect of lansoprazole on NAFLD / NASH is due to an action different from the antioxidant action of lansoprazole.
  • liver fibrosis-related genes In order to investigate the mechanism of liver fibrosis, the expression levels of three genes (Timp1, Col1a1, Tgfb1) associated with liver fibrosis were measured in the liver of NAFLD / NASH model rats. As a result, the expression of any gene was not significantly changed by lansoprazole administration (FIG. 4).
  • TGF- ⁇ protein In NAFLD / NASH model rats, lansoprazole significantly suppressed the expression of mature TGF- ⁇ protein in the liver (*: P ⁇ 0.05, analyzed by Student's t test) (FIG. 5). On the other hand, the expression of TGF- ⁇ precursor protein was not suppressed by lansoprazole administration. Since TGF- ⁇ protein involved in the promotion of fibrosis is suppressed by lansoprazole, the effect of lansoprazole on liver fibrosis on NAFLD / NASH is the expression of mature TGF- ⁇ (ie, activation of TGF- ⁇ ) It was suggested that it was due to a route through inhibition.
  • proinflammatory cytokines In order to investigate the mechanism of the anti-inflammatory effect of lansoprazole administration, the amount of gene expression of proinflammatory cytokines IL-6 and IL-1 ⁇ in the liver of NAFLD / NASH model rats was measured. As a result, IL-1 ⁇ gene expression was not changed by lansoprazole administration, but IL-6 expression was significantly reduced (FIG. 6A). Similarly, lansoprazole administration also reduced IL-6 protein expression (FIGS. 6B and C).
  • the prophylactic and / or therapeutic agent of the present invention is useful as a safe prophylactic and / or therapeutic agent for NAFLD / NASH.

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Abstract

La présente invention concerne un agent prophylactique et/ou thérapeutique pour la stéatose hépatique non alcoolique (NAFLD) et la stéatohépatite non alcoolique (SHNA) obtenu en incluant du lansoprazole. Le lansoprazole a été utilisé de manière sûre comme agent thérapeutique pour les ulcères gastriques et les ulcères duodénaux, et peut ainsi être un médicament sûr et utile pour traiter une NAFLD ainsi qu'une SHNA.
PCT/JP2017/009538 2016-03-09 2017-03-09 Agent thérapeutique pour la stéatose hépatique non alcoolique et la stéatohépatite non alcoolique Ceased WO2017155053A1 (fr)

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JP2016046340A JP2019077615A (ja) 2016-03-09 2016-03-09 非アルコール性脂肪性肝疾患／非アルコール性脂肪性肝炎の治療剤
JP2016-046340 2016-03-09

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110292577A (zh) * 2019-08-19 2019-10-01 庹必光 泮托拉唑在制备防治非酒精性脂肪肝的药物中的应用
CN110339194A (zh) * 2019-07-31 2019-10-18 沈阳药科大学 拉唑类化合物在制备预防和治疗纤维化疾病药物中的用途
CN110522752A (zh) * 2019-08-19 2019-12-03 庹必光 泮托拉唑在制备防治肝纤维化的药物中的应用
EP3573617A4 (fr) * 2017-11-01 2020-04-22 Aptabio Therapeutics Inc. Agent thérapeutique contre des maladies hépatiques

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