WO2012020821A1 - 非アルコール性脂肪肝炎の予防または治療剤 - Google Patents
非アルコール性脂肪肝炎の予防または治療剤 Download PDFInfo
- Publication number
- WO2012020821A1 WO2012020821A1 PCT/JP2011/068344 JP2011068344W WO2012020821A1 WO 2012020821 A1 WO2012020821 A1 WO 2012020821A1 JP 2011068344 W JP2011068344 W JP 2011068344W WO 2012020821 A1 WO2012020821 A1 WO 2012020821A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- liver
- fatty liver
- ibudilast
- therapeutic agent
- nash
- Prior art date
Links
- ZJVFLBOZORBYFE-UHFFFAOYSA-N CC(C)C(c1c(cccc2)[n]2nc1C(C)C)=O Chemical compound CC(C)C(c1c(cccc2)[n]2nc1C(C)C)=O ZJVFLBOZORBYFE-UHFFFAOYSA-N 0.000 description 1
Images
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
- A61K31/33—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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to a preventive or therapeutic agent for nonalcoholic fatty liver disease, particularly nonalcoholic steatohepatitis, containing ibudilast as an active ingredient.
- Nonalcoholic fatty liver disease All fatty liver diseases that include fatty liver similar to alcoholic liver damage that occurs in non-drinkers are called nonalcoholic fatty liver disease (NAFLD). Fatty acid synthesis in the liver of patients with NAFLD is always activated. Activation of fatty acid synthesis in the liver is considered to be one important factor for fatty liver formation caused by metabolic syndrome (Non-patent Document 1).
- Non-patent Document 2 SREBP-1, which is a transcription factor that is a key for fatty acid synthesis in the liver.
- NAFLD is generally divided into simple fatty liver, which is generally considered to have a good prognosis, and nonalcoholic steatohepatitis (NASH), which is considered to have a poor prognosis due to inflammation and fibrosis in simple fatty liver.
- NASH is considered to be a severe form of NAFLD (Non-patent Documents 4-7).
- Non-Patent Document 4 Two-hit theorem means that simple fatty liver develops based on lifestyle and genetic factors as first hit, and oxidative stress and inflammatory cytokines derived from fatty liver act as second hits in this state. The theory is that NASH develops and progresses (Non-Patent Documents 8 and 9).
- Non-Patent Document 4 Since the treatment of metabolic syndrome as a disease background of NASH is important, insulin resistance improving drugs, antioxidants, antihyperlipidemic drugs, liver protection drugs and angiotensin II receptor antagonists are used in this aspect. (Non-Patent Document 4).
- Non-Patent Document 10 the insulin resistance improving drug pioglitazone was expected as a NASH therapeutic drug, but according to the results of Phase III (PIVENS), there was no improvement effect on fibrosis and the initial criteria could be cleared. No (Non-Patent Document 10). Moreover, pioglitazone is concerned about side effects such as fracture risk, weight gain, worsening or onset of heart failure (Non-patent Document 11).
- ibudilast is widely used in clinical settings as a cerebrovascular disorder ameliorating agent, bronchial asthma therapeutic agent and allergic conjunctivitis therapeutic agent, and its safety has been confirmed.
- the action of ibudilast the action of prostacyclin (PGI 2 ) to enhance the cerebral vascular relaxation action (Non-patent Document 12), the effect of inhibiting platelet aggregation (Non-Patent Document 13), the airway contraction inhibiting action, the leukotriene antagonizing action, Various actions such as leukotriene release inhibitory action (Non-patent Document 14), PDE inhibitory action (Patent Document 1) and migration inhibitory factor (MIF) activity inhibitory action (Non-patent Document 15) are known. No effects on liver disease, NAFLD, NASH and fatty liver were known.
- the object of the present invention is to provide a preventive or therapeutic agent for fatty liver disease that is effective against NAFLD, particularly NASH.
- ibudilast improves all of fatty liver, liver inflammation and liver fibrosis, which are the main pathologies of NASH, and completed the present invention.
- the present invention is as follows. 1. A preventive or therapeutic agent for fatty liver disease containing ibudilast as an active ingredient. 2. 2. The preventive or therapeutic agent according to 1 above, wherein the fatty liver disease is non-alcoholic fatty liver disease. 3. 3. The preventive or therapeutic agent according to 2 above, wherein the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis. 4). 3. The preventive or therapeutic agent according to 2 above, wherein the non-alcoholic fatty liver disease is simple fatty liver.
- the preventive or therapeutic agent for fatty liver disease of the present invention can suppress all of fatty acid synthesis, fatty liver, liver inflammation and liver fibrosis in the liver, and NAFLD, particularly NASH It can be effectively prevented or treated.
- FIG. 6 shows the effect of ibudilast (10, 30 and 100 mg / kg, administered twice a day) on hepatic IL-1 ⁇ mRNA expression level.
- the preventive or therapeutic agent for fatty liver disease of the present invention contains ibudilast as an active ingredient.
- Ibudilast is a known compound represented by the following formula (1) and can be produced according to a known production method (for example, Japanese Patent Publication No. Sho 52-29318).
- fatty liver disease is a general term for diseases in which neutral fat is deposited in hepatocytes and causes liver damage, and alcoholic liver damage and non-alcoholic fatty liver disease (nonalcoholic fatty liver disease). NAFLD).
- nonalcoholic fatty liver disease is synonymous with nonalcoholic fatty liver and nonalcoholic liver steatosis.
- Non-alcoholic fatty liver disease includes non-alcoholic steatohepatitis (nonalcoholic steatohepatitis; NASH) and simple fatty liver.
- Nonalcoholic fatty liver disease for example, is a liver characterized primarily by large droplets of liver fat, similar to alcoholic liver damage, although liver tissue findings are similar to alcoholic liver damage It is defined as a disease concept including simple fatty liver with a good prognosis and progressive NASH ["NASH / NAFLD clinical guide” (edited by the Japanese Society of Liver Science, Bunkodo, August 2006)].
- NAFLD non-alcoholic fatty liver disease
- Non-alcoholic steatohepatitis is defined, for example, as follows ["NASH / NAFLD medical care guide” (edited by the Japanese Society for Liver Science, Bunkodo, August 2006)].
- Matteoni (Mattoni, CA, et al. 1999. Gastroenterology. 116: 1413-1419) classifies NAFLD into type 4.
- Type 1 Simple fatty liver
- Type 2 steatohepatitis
- Type 3 Fatty liver necrosis (with balloon-like degeneration)
- Type 4 Hepatocyte necrosis with Mallory body or fibrosis (with balloon-like degeneration) .
- Non-alcoholic steatohepatitis is designated as type 3 and type 4 in which the frequency of progression from examination of long-term prognosis to cirrhosis and liver-related death is significantly high.
- NASH Non-alcoholic steatohepatitis
- stage 1 center of leaflet (Zone 3)
- stage 2 1 + portal vein area
- stage 3 bridge formation
- stage 4 cirrhosis.
- “simple fatty liver” refers to a case in which only fat deposition of hepatocytes is observed among fatty liver diseases and necrosis / inflammation or fibrosis of hepatocytes is not involved.
- the fatty liver disease to which the preventive or therapeutic agent of the present invention is applied is preferably nonalcoholic fatty liver disease (NAFLD), more preferably nonalcoholic steatohepatitis (NASH) or simple fatty liver, and nonalcoholic Steatohepatitis is particularly preferred.
- NAFLD nonalcoholic fatty liver disease
- NASH nonalcoholic steatohepatitis
- simple fatty liver simple fatty liver
- nonalcoholic Steatohepatitis is particularly preferred.
- Trorhosis is a theory that NASH develops and progresses by the following mechanism of onset and development. First, accumulation of liver fat (fatty liver) occurs as First hit. Furthermore, NASH develops and progresses when liver inflammation and fibrosis develop due to oxidative stress or inflammatory cytokines derived from fatty liver as second hit. As NASH develops and progresses, cirrhosis and liver cancer develop and progress.
- ibudilast suppresses liver fat accumulation by suppressing liver fat synthesis activity and liver triglyceride content, and first suppresses fatty liver.
- Ibudilast suppresses infiltration of lipid droplets and inflammatory cells in the liver, suppresses oxidative stress and inflammatory cytokine levels, and suppresses expression of liver inflammation-related genes and liver fibrosis-related genes in response to Second hit. Suppress liver inflammation and liver fibrosis. By such a mechanism, it is considered that ibudilast can effectively inhibit the onset and development mechanism of NASH.
- the agent for preventing or treating fatty liver disease of the present invention contains ibudilast, and if necessary, known pharmacologically acceptable additives can be blended.
- Additives that can be optionally blended vary depending on the dosage form, dosage form, etc., for example, excipients, binders, disintegrants, lubricants, flavoring agents, flavoring agents, coloring agents, etc.
- An agent or sweetener may be used.
- the preventive or therapeutic agent for fatty liver disease of the present invention can be used in various pharmacologically acceptable forms.
- forms for example, forms such as capsules, scattered, tablets, fine granules, granules, injections, liquids, ointments or patches can be suitably listed.
- the prophylactic or therapeutic agent for fatty liver disease of the present invention can be administered to patients in the form of oral administration or parenteral administration.
- oral preparations are preferable in consideration of ease of use by patients.
- the amount of ibudilast in the preventive or therapeutic agent for fatty liver disease of the present invention can be appropriately changed depending on the age, weight, symptoms, administration route, etc. of the patient.
- 10 mg to 200 mg per dose is preferably used, and 10 mg to 60 mg per dose is more preferably used 2 to 3 times a day.
- Example 1 Ibudilast's inhibitory effect on fatty liver (evaluation using fatty liver model)
- NAFLD activation of hepatic fatty acid synthesis is believed to be one important factor in fatty liver formation (Shinji, T., et al. 2005. J. Clin. Invest. 115: 1139-1142).
- Delzenne et al. (Delzenne, NM, et al. 1997. J Hepatol. 26: 880-885.)
- Tsuchida et al. Tsuchida, A., et al. 2004. J. Biol. Chem. 279: 30817).
- the effect of ibudilast on fatty liver was examined using refeeding mice with increased hepatic fatty acid synthesis with reference to the method of -30822).
- the standard meal (CE-2, Nippon Claire Co., Ltd.) was fed again 30 minutes after oral administration 48 hours after fasting, and dissection was performed 4 hours after refeeding.
- the triglyceride content and fatty acid synthesis in the collected liver were measured.
- Triglyceride extraction from the liver was performed by improving the method of Folch et al. (Folch, J., et al. 1957. J. Biol. Chem. 226: 497-509.).
- the tissue was homogenized using a chloroform-methanol mixture 2: 1 (v / v).
- the homogenate was shaken for 1 hour to extract the lipid fraction, and the supernatant obtained by centrifugation was dried. Extraction was performed twice from the tissue sediment by the same operation, and they were combined and dried. The dried extract was dissolved in 4% (v / v) Triton X-100, and the triglyceride concentration was measured using Liquitec TGII reagent (Roche Diagnostics). The results are shown as mean ⁇ standard error. Statistical analysis was performed using Williams' multiple comparison test, with a significance level of less than 5%.
- Liver fatty acid synthesis was determined by measuring fatty acid synthesis from acetic acid. Tissue 95% (v / v) O 2, 5% (v / v) CO 2, 0.5mM acetate (0.25 ⁇ Ci / mL, [1- 14 C] acetic acid), 0.2% (v / v ) After incubating in BSA-containing Krebs Ringer / Phosphate / Hepes buffer (pH 7.4) at 37 ° C. for 2 hours, an ethanol solution containing 15% (w / v) potassium hydroxide was added at 85 ° C. Incubated for 2 hours to saponify.
- the lower chloroform layer obtained by centrifugation was dried and dissolved in methanol, mixed with a scintillator, and the radioactivity was measured with a liquid scintillation counter (Tri-Carb 1900CA, PerkinElmer). The results are shown as mean ⁇ standard error. Statistical analysis was performed using Williams' multiple comparison test, with a significance level of less than 5%.
- Ibudilast reduced hepatic fatty acid synthesis, which is believed to be important for fatty liver formation in NAFLD (FIG. 1). Furthermore, the liver triglyceride content, which is an indicator of fatty liver, was also significantly reduced (FIG. 2). As a result, it was shown that ibudilast is excellent in fatty acid synthesis in the liver and an inhibitory effect on fatty liver.
- Example 2 Inhibitory effect of ibudilast on fatty liver (evaluation using fatty liver model with obesity) Obesity and insulin resistance are considered as the main underlying pathology in NAFLD (Kristina, M., et al. 2006. J Clin Endocrinol Metab. 91: 4753-4761). Therefore, it has obesity / insulin resistance and exhibits fatty liver. B6. The effect of ibudilast on fatty liver was examined using V-Lep ob / J (ob / ob; Charles River Japan Co., Ltd.) mice.
- mice 7-week-old male ob / ob mice (Nippon Charles River Co., Ltd.) were used.
- 2% (v / v) PEG-60 hydrogenated castor oil (NIKKOL HCO-60, Nikko Chemicals Co., Ltd.) was used for the solvent group as a comparative control, and 2% (v / v) PEG-60 hydrogenated was used for the ibudilast group.
- Ibudilast 10, 30 or 100 mg / kg dissolved in castor oil was orally administered twice a day.
- Triglyceride extraction from the liver was performed by improving the method of Folch et al. (Folch, J., et al. 1957. J. Biol. Chem. 226: 497-509.).
- the tissue was homogenized using a chloroform-methanol mixture 2: 1 (v / v).
- the homogenate was shaken for 1 hour to extract the lipid fraction, and the supernatant obtained by centrifugation was dried. Extraction was performed twice from the tissue sediment by the same operation, and they were combined and dried. The dried extract was dissolved in 4% (v / v) Triton X-100, and the triglyceride concentration was measured using Liquitec TGII reagent (Roche Diagnostics). The results are shown as mean ⁇ standard error. Statistical analysis was performed using Williams' multiple comparison test, with a significance level of less than 5%.
- Ibudilast significantly reduced the triglyceride content of the liver, which is an indicator of fatty liver, in ob / ob mice, which are obese / insulin resistant fatty liver models (FIG. 3). Thereby, it was clearly shown that ibudilast has an excellent improvement effect on fatty liver of patients with obesity and insulin resistance.
- Example 3 Liver inflammation and liver fibrosis-suppressing effect of ibudilast Liver inflammation and liver of ibudilast were observed in mice loaded with methionine-choline deficient diet (MCD diet) that induced liver inflammation and fibrosis observed in human pathologies such as NASH. The effect on fibrosis was examined.
- MCD diet methionine-choline deficient diet
- TNF ⁇ , MCP-1, IL-1 ⁇ , TGF ⁇ and col1a1 mRNA were measured by quantitative real-time PCR using the collected liver.
- expression level of 18S rRNA mRNA was measured as an internal standard by quantitative real-time PCR.
- RNA from the liver was performed using TRIzol reagent (Invitrogen). DNAase treatment of the extracted RNA was performed using RNase-Free DNase Set (Qiagen) and RNeasymini kit (Qiagen).
- RNA Reverse transcription of RNA was performed using High-Capacity cDNA Reverse Transcribation Kit with RNase inhibitor (Applied Biosystems).
- Quantitative real-time PCR was performed using TaqMan Fast Universal PCR mastermix (Applied Biosystems) and Applied Biosystems 7500 Fast Real-Time PCR System (Applied Biosystems).
- Taqman probes and primers were obtained as an assay set of each mRNA (TaqMan Gene Expression Assays, Applied Biosystems). Specifically, mouse TNF ⁇ (Mm00443258_m1), MCP-1 (Mm99999056_m1), IL-1 ⁇ (Mm00434228_m1), TGF ⁇ (Mm01178819_m1), col1a1 (Mm00801666_g1) and 18s rRNA (Hs99999999_s1) were used.
- Each operation related to the quantitative real-time PCR method was in accordance with the instructions attached to each reagent, kit and apparatus.
- the mRNA expression level of the target gene was expressed as a relative value using 18S rRNA as an internal standard. The results are shown as mean ⁇ standard error. Statistical analysis was performed using Williams' multiple comparison test, with a significance level of less than 5%.
- Ibudilast decreased liver TNF ⁇ , MCP-1 and IL-1 ⁇ mRNA expression levels, which are indicators of liver inflammation, and liver TGF ⁇ and col1a1 mRNA expression levels, which are indicators of liver fibrosis (FIGS. 4 to 8). This showed that ibudilast suppressed liver inflammation and liver fibrosis.
- the preventive or therapeutic agent for fatty liver disease of the present invention containing ibudilast is useful as a prophylactic or therapeutic agent for NAFLD, particularly NASH.
Abstract
Description
1.イブジラストを有効成分として含有する脂肪性肝疾患の予防または治療剤。
2.脂肪性肝疾患が非アルコール性脂肪性肝疾患である前項1記載の予防または治療剤。
3.非アルコール性脂肪性肝疾患が非アルコール性脂肪肝炎である前項2記載の予防または治療剤。
4.非アルコール性脂肪性肝疾患が単純性脂肪肝である前項2記載の予防または治療剤。
1.明らかな飲酒歴がない(アルコール量:20g以下/日)。
2.ウイルス性(HCV、HBV)、自己免疫性のような成因の明らかな慢性肝疾患は認めない。
3.メタボリックシンドローム、肥満、糖尿病、高脂血症、高血圧、高尿酸血症、睡眠時無呼吸症候群などはリスクファクターである。マルチプルリスクファクターを有す例では単純性脂肪肝<NASHの可能性が高くなる。
4.脂質代謝やミトコンドリア機能の異常をきたす種々の疾患や薬剤も成因となる。
1.Matteoni(Matteoni,C.A.,et al.1999.Gastroenterology.116:1413-1419)はNAFLDを4型に分類。1型:単純性脂肪肝、2型:脂肪性肝炎、3型:脂肪性肝壊死(風船様変性を伴う)、4型:マロリー体ないしは線維化を伴う肝細胞壊死(風船様変性を伴う)。長期予後の検討から肝硬変への進展や肝関連死の頻度が有意に高い3型、4型を非アルコール性脂肪性肝炎(NASH)とする。
2.米国肝臓学会のSingle Topic Conference 2002(Neuschwander-Tetri,B.A.,et al.2003.Hepatology.37:1202-1219.)ではNASHの必須所見として脂肪化(大滴性>小滴性、小葉中心部に多い)、小葉内炎症(軽度、好中球や単核球浸潤)、肝細胞の風船様変性(脂肪化周辺、小葉中心部に多い)を挙げ、NAFLDの3型、4型(Matteoni分類)をNASHとしている。
3.Brunt(Brunt,E.M.,et al.1999.Am.J.Gastroenterol.94:2467-2474)はNASHの進展経過を線維化の程度により4段階に分類。stage 1:小葉中心部(Zone 3)、stage 2:1+門脈域、stage 3:架橋形成、stage 4:肝硬変。
イブジラストの脂肪肝抑制作用(脂肪肝モデルを用いた評価)
NAFLDにおいて、肝脂肪酸合成の活性化が脂肪肝形成の1つの重要な因子であると考えられている(Shinji,T.,et al.2005.J.Clin.Invest.115:1139-1142)。そこで、Delzenneら(Delzenne,N.M.,et al.1997.J Hepatol.26:880-885.)及びTsuchidaら(Tsuchida,A.,et al.2004.J.Biol.Chem.279:30817-30822)の方法を参考にして、肝の脂肪酸合成を増大させた再摂食マウスを用いてイブジラストの脂肪肝に対する効果を検討した。
イブジラストの脂肪肝抑制作用(肥満を伴う脂肪肝モデルを用いた評価)
肥満・インスリン抵抗性は、NAFLDにおいて主要な基礎病態として考えられている(Kristina,M.,et al.2006.J Clin Endocrinol Metab.91: 4753-4761)。そこで、肥満・インスリン抵抗性を有し、かつ、脂肪肝を呈するB6.V-Lepob/J(ob/ob;日本チャールス・リバー株式会社)マウスを用いてイブジラストの脂肪肝に対する効果を検討した。
イブジラストの肝炎症および肝線維化抑制作用
NASHのようなヒトの病態で認められる肝炎症および肝線維化を誘発したメチオニン-コリン欠乏食(MCD食)負荷マウスを用いて、イブジラストの肝炎症および肝線維化に対する効果を検討した。
本出願は、2010年8月12日出願の日本特許出願2010-180656に基づくものであり、その内容はここに参照として取り込まれる。
Claims (4)
- イブジラストを有効成分として含有する脂肪性肝疾患の予防または治療剤。
- 脂肪性肝疾患が非アルコール性脂肪性肝疾患である請求項1記載の予防または治療剤。
- 非アルコール性脂肪性肝疾患が非アルコール性脂肪肝炎である請求項2記載の予防または治療剤。
- 非アルコール性脂肪性肝疾患が単純性脂肪肝である請求項2記載の予防または治療剤。
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2012528712A JPWO2012020821A1 (ja) | 2010-08-12 | 2011-08-11 | 非アルコール性脂肪肝炎の予防または治療剤 |
BR112013003064-0A BR112013003064A2 (ja) | 2010-08-12 | 2011-08-11 | Prevention or the medical treatment agent of non-alcoholic steatohepatitis |
EP11816484.7A EP2604607A4 (en) | 2010-08-12 | 2011-08-11 | AGENT FOR THE PREVENTION AND TREATMENT OF NON-ALCOHOLIC STÉATOHÉPATITE |
RU2013110517/15A RU2013110517A (ru) | 2010-08-12 | 2011-08-11 | Средство для профилактики или лечения неалкогольного стеатогепатита |
CA2808039A CA2808039A1 (en) | 2010-08-12 | 2011-08-11 | Prophylactic or therapeutic agent for non-alcoholic steatohepatitis |
US13/816,252 US20130143913A1 (en) | 2010-08-12 | 2011-08-11 | Prophylactic or therapeutic agent for non-alcoholic steatohepatitis |
CN2011800395138A CN103189374A (zh) | 2010-08-12 | 2011-08-11 | 非酒精性脂肪肝炎的预防或治疗剂 |
MX2013001583A MX2013001583A (es) | 2010-08-12 | 2011-08-11 | Agente profilactico para esteatohepatitis no alcoholica. |
KR1020137003533A KR20130097722A (ko) | 2010-08-12 | 2011-08-11 | 비알코올성 지방간염의 예방 또는 치료제 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010180656 | 2010-08-12 | ||
JP2010-180656 | 2010-08-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012020821A1 true WO2012020821A1 (ja) | 2012-02-16 |
Family
ID=45567781
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2011/068344 WO2012020821A1 (ja) | 2010-08-12 | 2011-08-11 | 非アルコール性脂肪肝炎の予防または治療剤 |
Country Status (11)
Country | Link |
---|---|
US (1) | US20130143913A1 (ja) |
EP (1) | EP2604607A4 (ja) |
JP (1) | JPWO2012020821A1 (ja) |
KR (1) | KR20130097722A (ja) |
CN (1) | CN103189374A (ja) |
BR (1) | BR112013003064A2 (ja) |
CA (1) | CA2808039A1 (ja) |
MX (1) | MX2013001583A (ja) |
RU (1) | RU2013110517A (ja) |
TW (1) | TW201211041A (ja) |
WO (1) | WO2012020821A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105039513A (zh) * | 2015-05-29 | 2015-11-11 | 广州市第一人民医院 | 用于非酒精性脂肪肝相关目的基因多态性检测方法及其引物,以及试剂盒 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016085994A1 (en) * | 2014-11-26 | 2016-06-02 | Medicinova, Inc. | Ibudilast and telmisartan for treating non-alcoholic fatty liver disease, non alcoholic steatohepatitis, and advanced non alcoholic steatohepatitis |
WO2017181317A1 (en) * | 2016-04-18 | 2017-10-26 | Eli Lilly And Company | Treatment for nonalcoholic steatohepatitis and fibrosis |
EP3538076A4 (en) * | 2016-11-08 | 2019-11-13 | University of Louisville Research Foundation, Inc. | Encapsulation of phosphodiesterase inhibitors for the treatment of alcoholic liver disease |
CN111686239B (zh) * | 2019-03-11 | 2021-12-24 | 中国科学院微生物研究所 | 抗真菌化合物的应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010180656A (ja) | 2009-02-09 | 2010-08-19 | Takiron Co Ltd | 排水管路構造及びこれに用いる管継手 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004050091A1 (ja) * | 2002-12-03 | 2004-06-17 | Kyorin Pharmaceutical Co., Ltd. | ホスホジエステラーゼ10a阻害剤 |
US20090297496A1 (en) * | 2005-09-08 | 2009-12-03 | Childrens Hospital Medical Center | Lysosomal Acid Lipase Therapy for NAFLD and Related Diseases |
US20100144864A1 (en) * | 2007-04-05 | 2010-06-10 | Ironwood Pharmaceuticals, Inc. | Soluble guanylate cyclase (sgc) modulators for treatment of lipid related disorders |
WO2009109525A1 (en) * | 2008-03-03 | 2009-09-11 | Nycomed Gmbh | Use of a specific pde4 inhibitor for the treatment and/or prophylaxis of non-alcoholic fatty liver disease |
JPWO2009154230A1 (ja) * | 2008-06-17 | 2011-12-01 | 持田製薬株式会社 | 非アルコール性脂肪肝炎の予防/改善・治療薬 |
US20090312302A1 (en) * | 2008-06-17 | 2009-12-17 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating nonalcoholic fatty liver disease-associated disorders |
-
2011
- 2011-08-11 KR KR1020137003533A patent/KR20130097722A/ko not_active Application Discontinuation
- 2011-08-11 US US13/816,252 patent/US20130143913A1/en not_active Abandoned
- 2011-08-11 CN CN2011800395138A patent/CN103189374A/zh active Pending
- 2011-08-11 EP EP11816484.7A patent/EP2604607A4/en not_active Withdrawn
- 2011-08-11 CA CA2808039A patent/CA2808039A1/en not_active Abandoned
- 2011-08-11 TW TW100128762A patent/TW201211041A/zh unknown
- 2011-08-11 WO PCT/JP2011/068344 patent/WO2012020821A1/ja active Application Filing
- 2011-08-11 JP JP2012528712A patent/JPWO2012020821A1/ja active Pending
- 2011-08-11 MX MX2013001583A patent/MX2013001583A/es not_active Application Discontinuation
- 2011-08-11 RU RU2013110517/15A patent/RU2013110517A/ru unknown
- 2011-08-11 BR BR112013003064-0A patent/BR112013003064A2/ja not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010180656A (ja) | 2009-02-09 | 2010-08-19 | Takiron Co Ltd | 排水管路構造及びこれに用いる管継手 |
Non-Patent Citations (11)
Title |
---|
BROWNING, J.D. ET AL., J. CLIN. INVEST., vol. 114, 2004, pages 147 - 152 |
CHO, Y ET AL., PROC. NATL. ACAD. SCI. USA., vol. 107, 2010, pages 11313 - 11318 |
DAY, C. P. ET AL., GASTROENTEROLOGY, vol. 114, 1998, pages 842 - 845 |
HARRISON, S.A. ET AL., HEPATOLOGY, vol. 51, 2010, pages 366 - 369 |
KEN'ICHI IKEJIMA ET AL.: "Shibosei Kan'en ni Taisuru Phosphodiesterase IV Sogaizai no Ensho Oyobi Sen'ika Yokusei Koka", ACTA HEPATOLOGICA JAPONICA, vol. 47, no. SUP.2, pages A353 * |
LUCIEN C.D GIBSON ET AL.: "The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 538, no. IS.1-3, 2006, pages 39 - 42, XP028029297 * |
MITSUO OHASHI, ZENSOKU, vol. 2, 1989, pages 103 - 107 |
OHASHI, M. ET AL., ARCH. INT. PHARMACODYN. THER., vol. 280, 1986, pages 216 - 229 |
OHASHI, M. ET AL., ARCH. INT. PHARMACODYN. THER., vol. 283, 1986, pages 321 - 334 |
SANYAL, A. J. ET AL., N. ENGL. J. MED, vol. 362, 2010, pages 1675 - 1685 |
See also references of EP2604607A4 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105039513A (zh) * | 2015-05-29 | 2015-11-11 | 广州市第一人民医院 | 用于非酒精性脂肪肝相关目的基因多态性检测方法及其引物,以及试剂盒 |
CN105039513B (zh) * | 2015-05-29 | 2018-12-28 | 广州市第一人民医院 | 用于非酒精性脂肪肝相关目的基因多态性检测方法及其引物,以及试剂盒 |
Also Published As
Publication number | Publication date |
---|---|
KR20130097722A (ko) | 2013-09-03 |
TW201211041A (en) | 2012-03-16 |
BR112013003064A2 (ja) | 2018-01-30 |
RU2013110517A (ru) | 2014-09-20 |
EP2604607A4 (en) | 2014-01-01 |
EP2604607A1 (en) | 2013-06-19 |
MX2013001583A (es) | 2013-03-21 |
US20130143913A1 (en) | 2013-06-06 |
JPWO2012020821A1 (ja) | 2013-10-28 |
CN103189374A (zh) | 2013-07-03 |
CA2808039A1 (en) | 2012-02-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Wang et al. | Bergenin, acting as an agonist of PPARγ, ameliorates experimental colitis in mice through improving expression of SIRT1, and therefore inhibiting NF-κB-mediated macrophage activation | |
CN110200981A (zh) | 五环三萜皂苷的医药用途及其药物组合物 | |
WO2012020821A1 (ja) | 非アルコール性脂肪肝炎の予防または治療剤 | |
WO2017170434A1 (ja) | Fxrアゴニストとarbの組み合わせ医薬 | |
CA2923090A1 (en) | Methods and pharmaceutical compositions for the treatment of hepatitis b virus infection | |
WO2019024758A1 (zh) | 一种糖苷类化合物在制备用于治疗肝纤维化药物中的应用 | |
Cesaro et al. | Visceral adipose tissue and residual cardiovascular risk: A pathological link and new therapeutic options | |
Hu et al. | Gegen Qinlian decoction ameliorates murine colitis by inhibiting the expansion of Enterobacteriaceae through activating PPAR-γ signaling | |
WO2019227764A1 (zh) | 一种mln4924在制备治疗糖尿病和/或肥胖药物的新用途 | |
US20230045151A1 (en) | Compositions and methods | |
EP3380615B1 (en) | Il-34 antisense oligonucleotides and methods of using same | |
WO2011145340A1 (ja) | 非アルコール性脂肪性肝炎の予防及び/又は治療剤 | |
JP2002516283A (ja) | 核転写因子NF−κBの活性化の阻害剤としての2−ヒドロキシ−4−トリフルオロメチル安息香酸誘導体の使用 | |
Chen et al. | Demethylzeylasteral attenuates hepatic stellate cell activation and liver fibrosis by inhibiting AGAP2 mediated signaling | |
JP7273117B2 (ja) | 藻類プロテオグリカン抽出物含有組成物及びその使用 | |
Arakawa et al. | Efficacy of hydroxychloroquine for treating annular erythema associated with Sjögren’s syndrome | |
Benavides et al. | Phenyl methimazole suppresses dextran sulfate sodium-induced murine colitis | |
Foresi et al. | Inhaled corticosteroids and leukotriene modifiers in the acute treatment of asthma exacerbations | |
Wang et al. | The potential role of FNDC5/irisin in various liver diseases: awakening the sleeping beauties | |
CN112823007A (zh) | 用巴瑞替尼治疗原发性胆汁性胆管炎和原发性硬化性胆管炎 | |
WO2014172857A1 (zh) | 阿可拉定在制备用于治疗原发性肝癌的药物中的用途 | |
CN110099686B (zh) | 非酒精性脂肪性肝病的治疗 | |
Dikopoulos et al. | Bile synthesis in rat models of inflammatory bowel diseases | |
US20230346803A1 (en) | Compositions of berberine ursodeoxycholate and methods thereof for treating primary sclerosing cholangitis | |
Gisondi et al. | Pharmacological treatment of moderate-severe psoriasis in patients with cardio-metabolic comorbidities |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11816484 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2013/001583 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2808039 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13816252 Country of ref document: US Ref document number: 2011816484 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2012528712 Country of ref document: JP Kind code of ref document: A Ref document number: 20137003533 Country of ref document: KR Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2011290156 Country of ref document: AU Date of ref document: 20110811 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2013110517 Country of ref document: RU Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112013003064 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112013003064 Country of ref document: BR Kind code of ref document: A2 Effective date: 20130207 |