WO2016197442A1 - Utilisation de la bestatine dans la préparation d'une préparation pharmaceutique pour la prévention et le traitement de maladies inflammatoires et de maladies infectieuses associées à une inflammation - Google Patents

Utilisation de la bestatine dans la préparation d'une préparation pharmaceutique pour la prévention et le traitement de maladies inflammatoires et de maladies infectieuses associées à une inflammation Download PDF

Info

Publication number
WO2016197442A1
WO2016197442A1 PCT/CN2015/086002 CN2015086002W WO2016197442A1 WO 2016197442 A1 WO2016197442 A1 WO 2016197442A1 CN 2015086002 W CN2015086002 W CN 2015086002W WO 2016197442 A1 WO2016197442 A1 WO 2016197442A1
Authority
WO
WIPO (PCT)
Prior art keywords
inflammation
pharmaceutical preparation
bestatin
lps
active ingredient
Prior art date
Application number
PCT/CN2015/086002
Other languages
English (en)
Chinese (zh)
Inventor
钱峰
戈梅
何慧琼
罗敏玉
夏兴
饶敏
Original Assignee
上海来益生物药物研究开发中心有限责任公司
上海交通大学
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 上海来益生物药物研究开发中心有限责任公司, 上海交通大学 filed Critical 上海来益生物药物研究开发中心有限责任公司
Publication of WO2016197442A1 publication Critical patent/WO2016197442A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to the use of umbrel as an active ingredient in the preparation of a pharmaceutical preparation for the prevention and treatment of inflammatory diseases and infectious diseases associated with inflammation.
  • Inflammation is a very common and important basic pathological process. Any factor that can cause tissue damage, such as infection, non-infectious tissue damage (such as trauma, surgery, etc.) can lead to inflammation, and these inflammations have A lot of similar features (Barton GM. A calculated response: control of inflammation by the innate immune system. J. Clin. Invest., 2008, 118: 413-420)
  • LPS Lipopolysaccharides
  • TLRs Toll-like receptors
  • LPS Acting on the TLRs receptors on the cell membrane, the expression of cascaded genes changes through intracellular signaling. LPS can stimulate the synthesis and release of inflammatory factors (such as NO, TNF- ⁇ , IL-6, IL- ⁇ ).
  • LPS can be regarded as the main pathogenic factor of bacteria and plays an important role in
  • Ubenimex also known as Bestatin
  • Bestatin is a common anti-tumor adjuvant that enhances immunity. Function, for anticancer chemotherapy, adjuvant therapy for radiotherapy, etc.
  • Bestatin an inhibitor of aminopeptidase B, produced by actinomycetes, (29). Pp. 97-99; Muskardin, DT, Voelkel. NF & Fitzpatrick, FA (1994). Modulation of pulmonary leukotriene formation and perfusion pressure by bestatin, an inhibitor of leukotriene A4 hydrolase. (48).
  • umbrel has a good in vivo immune enhancement, such as enhancing the activity and function of T cells and killer NK cells, but has not yet played a role in acute inflammation such as bacterial arches. See the report.
  • the inventors of the present invention found in the further study of the function of Bestatin that it has a significant inhibitory effect on acute inflammation caused by LPS. Accordingly, it is an object of the present invention to provide a novel use of Bestatin as an active ingredient in the preparation of a pharmaceutical preparation for preventing and treating inflammatory diseases and infectious diseases associated with inflammation.
  • a first aspect of the present invention provides a use of Bestatin as an active ingredient in the preparation of a pharmaceutical preparation for preventing and treating inflammatory diseases and infectious diseases associated with inflammation,
  • the chemical structural formula of Bestatin is:
  • the inflammatory disease and infectious diseases associated with inflammation include bacterial infection, uncomplicated cystitis, bronchitis, trauma, postoperative inflammatory reaction, accidental injury, myocardial infarction, tuberculosis or sarcoidosis, Sepsis, metastatic tumors, active rheumatoid arthritis, seronegative spinal arthritis, immune vasculitis, rheumatic polymyopathy, Crohn's disease, inflammation of deep vein thrombosis, etc.
  • the inventors established a mouse model of acute lung injury induced by bacterial endotoxin LPS, intraperitoneal administration of Bestatin, the effect of drugs on acute lung injury caused by LPS, and detection of LPS-induced inflammation.
  • a second aspect of the present invention provides a pharmaceutical preparation for preventing and treating an inflammatory disease and an infectious disease associated with inflammation, comprising a therapeutically effective amount of the active ingredient and a pharmaceutically acceptable carrier or excipient
  • the active ingredient is Bestatin, an optical isomer thereof or a pharmaceutically acceptable
  • the pharmaceutical preparation comprises a tablet, a capsule, an oral solution, a granule or an injection (such as a lyophilized powder injection).
  • Pharmaceutically acceptable salts can be both pharmacologically and pharmaceutically acceptable.
  • the pharmacologically and pharmaceutically acceptable salt thereof may be an alkali metal or alkaline earth metal salt, preferably a sodium salt, a potassium salt, a magnesium salt or a calcium salt.
  • the pharmaceutical preparations involve enteral (e.g., oral, sublingual or rectal administration), parenteral or topical (e.g., transdermal pharmaceutical formulations) dosage forms.
  • An organic or inorganic substance which does not react with the active ingredient may be used as a carrier such as water, oil, benzyl alcohol, polyethylene glycol, triacetin or other fatty acid glycerides, gelatin, lecithin, cyclodextrin, lactose or A sugar such as starch, magnesium stearate, talc or cellulose.
  • the oral administration is preferably a tablet, a dragee, a capsule, a powder, a syrup, a concentrate or a drop, a suppository for rectal administration, an aqueous solution or an oil solution for parenteral administration, or a lyophilizate.
  • Suspensions, emulsions or implants may also be employed, and patches or creams may be used for topical administration.
  • Pharmaceutical preparations for parenteral administration comprise sterile aqueous or anhydrous injections of the active compound, preferably a solution which is isotonic with the blood of the recipient.
  • These pharmaceutical preparations may contain a stabilizer, an additive that controls the release of the pharmaceutically active compound, an antioxidant, a buffer, a bacteriostatic agent, and an adjuvant for preparing an isotonic solution.
  • Aqueous and anhydrous sterile suspensions may contain suspending additives and thickening agents.
  • the pharmaceutical preparation may be dispensed in a single or multiple dose container such as a sealant bottle, or may be stored as a lyophilized product, if desired, in a sterile liquid such as water or a salt solution. Sterile powders, granules or tablets can also be used in the same manner.
  • the pharmaceutical preparation can be used for the prevention and treatment of diseases related to inflammation and inflammation in humans and animals.
  • MPO myeloperoxidase
  • FIG. 2A and FIG. 2B are graphs showing the results of detection of total protein content in lung lavage fluid in a model of LPS-induced acute lung injury in mice; wherein, FIG. 2A is a total of lung lavage fluid after 4 hours of administration of LPS. Protein concentration determination, Figure 2B is the determination of the total protein concentration of the lung lavage fluid after 12 hours of LPS administration.
  • Figure 3A is a graph showing the results of two immunoblotting results of iNOS protein expression in LPS-induced Raw264.7 cells.
  • 3B is a quantitative analysis chart of iNOS protein expression in LPS-induced Raw264.7 cells
  • C57/BL mice were grouped into groups of at least 5, weighed, and administered intratracheally with saline (negative control group) and 5 mg/kg LPS (inflammation group), respectively, before LPS injection.
  • saline negative control group
  • LPS inflammation group
  • Xiaoyan 10 minutes later, and 12 hours later, intraperitoneal injection of Bestatin (except for the negative control group), 0, 4, 24 hours later, the heart was taken, and the lungs were repeatedly washed with 1 ml of PBS.
  • the lung tissue was collected after collecting the lavage solution, and the total protein content in the lung lavage lotion was detected, and the activity of myeloperoxidase (MPO) in the lung tissue was detected.
  • MPO myeloperoxidase
  • Trizol lysed cells extracted RNA, and reverse-transcribed PCR to obtain cDNA, which was used as a template for real-time PCR to examine DNA transcription levels of inflammation-related cytokines and inflammatory molecules induced before and after drug action.
  • the cells were lysed and collected, denatured, SDS electrophoresis 80V 2 ⁇ , transfected 80V 1 ⁇ , 5% milk blocked half ⁇ , 4°C incubation primary overnight, TBST buffer (Tris-Buffered Saline and Tween 20) Wash the membrane 3 times, incubate the secondary antibody for 1 hour at room temperature, wash the membrane 3 times with TBST, observe the change of the expression level of nitric oxide synthase iNOS protein induced by the drug before and after the action on the Odyssey far-infrared observer.
  • TBST buffer Tris-Buffered Saline and Tween 20
  • NO easily forms NO 2 - in an aqueous solution, and under acidic conditions, NO 2 - reacts with a diazonium salt sulfonamide to form a diazo compound, and further undergoes a coupling reaction with naphthyl vinyl diamine.
  • the product concentration has a linear relationship with the N 0 2 -concentration and a maximum absorption peak at 540-560 nm. Using this principle, the amount of NO released from the cell supernatant can be detected.
  • mice Thirty C57/BL mice were randomly divided into 3 groups, 10 in each group, and weighed, and the following operations were performed respectively: [0036] negative control group: tracheal injection of 0.9% physiological saline 50 ⁇ 1;
  • LPS inflammation group tracheal injection 5mg / kg LPS 50 ⁇ 1;
  • LPS + umbryiz treatment group two times before the tracheal injection of LPS (5 mg / kg, about 50 ⁇ 1) 12 hours and 10 minutes, two intraperitoneal injections of umbrel (10 mg / kg each time, about 200 ⁇ l) ;
  • Figure 1 is a graph showing the results of myeloperoxidase (MPO) activity assay in a model of acute lung injury induced by LPS in mice.
  • MPO myeloperoxidase
  • FIG. 2A and FIG. 2B are graphs showing the results of detection of total protein content in lung lavage fluid in a model of LPS-induced acute lung injury in mice; wherein, FIG. 2A is the total amount of lung lavage fluid after 4 hours of administration of LPS. Protein concentration determination, Figure 2B is the determination of the total protein concentration of the lung lavage fluid after 12 hours of LPS administration.
  • This example uses the Raw264.7 mouse macrophage cell line as an example to compare the effects of Bestatin and its two derivative compounds on the expression of inflammatory factor NO induced by LPS, including 24 hours of LPS stimulation.
  • Raw264.7 cells were seeded in a 12-well plate at a density of 3.5 ⁇ 10 5 /well, cultured overnight with 1640 medium containing 10% fetal bovine serum, and Bestatin was pre-incubated at a concentration of 0.2 mg/ml. For 30 minutes, the control group was an equal volume of medium, and 24 hours of induction was induced by stimulation with Olg/ml of LPS. The supernatant was collected and lysed for immunoblot analysis.
  • Figure 3A shows the results of two immunoblots of iNOS protein expression, ⁇ -actin as a control
  • Figure 3B shows the quantitative analysis of iNOS protein expression, the optical density ratio of iNOS and ⁇ -actin was calculated by Image J software, and three independent experiments were performed. The results were calculated for the mean standard error, and the results of the Bestatin and the LPS group were compared for significant difference analysis, where ** ⁇ ⁇ 0.01.
  • the Griess method was used to detect the amount of NO released from the culture supernatant.
  • the cell culture and stimulation induction were as described in Fig. 3A and Fig. 3B, and the culture supernatant was taken, and the amount of NO released therein was detected by a kit.
  • the mean standard error was calculated from the results of three independent experiments.
  • the results of Bestatin and LPS were compared, and ** ⁇ ⁇ 0.01, *** ⁇ ⁇ 0.005.
  • Bestatin has a protein expression level in LPS-induced Raw264.7 cells and a release amount of LPS-induced inflammatory factor NO. More than 50% reduction
  • the present invention provides a novel use of Bestatin, which is useful as an active ingredient in the preparation of a pharmaceutical preparation for preventing and treating inflammatory diseases and infectious diseases associated with inflammation.
  • the present invention also provides a pharmaceutical preparation for preventing and treating an inflammatory disease and an infectious disease associated with inflammation, comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable carrier or excipient, said activity
  • the ingredient is umbrel, its optical isomer or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical preparation comprises a tablet, a capsule, an oral solution, a granule or a dosage form. Injection (such as lyophilized powder injection).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une nouvelle utilisation de la Bestatine dans la préparation d'une préparation pharmaceutique pour la prévention et le traitement de maladies inflammatoires et de maladies infectieuses associées à une inflammation en tant que principe actif. L'invention concerne également une préparation pharmaceutique pour la prévention et le traitement de maladies inflammatoires et de maladies infectieuses associées à une inflammation, comprenant une quantité thérapeutiquement efficace d'un principe actif et un véhicule ou excipient pharmaceutiquement acceptable, le principe actif étant la Bestatine, un de ses isomères optiques ou un de ses sels pharmaceutiquement acceptables.
PCT/CN2015/086002 2015-06-12 2015-08-04 Utilisation de la bestatine dans la préparation d'une préparation pharmaceutique pour la prévention et le traitement de maladies inflammatoires et de maladies infectieuses associées à une inflammation WO2016197442A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510323381.1 2015-06-12
CN201510323381.1A CN104887655A (zh) 2015-06-12 2015-06-12 乌苯美司在制备用于预防和治疗炎症疾病和与炎症相关的感染疾病的药物制剂中的应用

Publications (1)

Publication Number Publication Date
WO2016197442A1 true WO2016197442A1 (fr) 2016-12-15

Family

ID=54020901

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/086002 WO2016197442A1 (fr) 2015-06-12 2015-08-04 Utilisation de la bestatine dans la préparation d'une préparation pharmaceutique pour la prévention et le traitement de maladies inflammatoires et de maladies infectieuses associées à une inflammation

Country Status (2)

Country Link
CN (1) CN104887655A (fr)
WO (1) WO2016197442A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10588880B2 (en) * 2016-09-28 2020-03-17 Eiger Biopharmaceuticals, Inc. Methods and pharmaceutical compositions for the treatment of non-alcoholic steatohepatitis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103910648A (zh) * 2013-12-30 2014-07-09 西安万隆制药股份有限公司 一种盐酸乌苯美司化合物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1943562A (zh) * 2006-10-25 2007-04-11 宛六一 乌苯美司分散片及其制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103910648A (zh) * 2013-12-30 2014-07-09 西安万隆制药股份有限公司 一种盐酸乌苯美司化合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEN, YAXI ET AL.: "Experimental Study on the Effect of Anti-Duck Hepatitis B Virus Bestain (Ubenimex", CHINESE JOURNAL OF HEPATOLOGY, vol. 6, no. 1, 31 March 1998 (1998-03-31) *

Also Published As

Publication number Publication date
CN104887655A (zh) 2015-09-09

Similar Documents

Publication Publication Date Title
Yendt et al. The use of thiazides in the prevention of renal calculi
BR112014027983B1 (pt) Uso de inibidores de aquaporina seletivos
TWI794885B (zh) 全身紅斑性狼瘡之治療
BR112019014924A2 (pt) Composição farmacêutica usada para o tratamento de mielopatia associada ao htlv-1
US20230321056A1 (en) Methods for Treating Metastasis with Cathepsin C Inhibitors
Komiya et al. Adalimumab-induced interstitial pneumonia with an improvement of pre-existing rheumatoid arthritis-associated lung involvement
CN107106580A (zh) 治疗癌症干细胞的组合物
US11524055B2 (en) Methods for treating diseases mediated by ERBB4-positive pro-inflammatory macrophages
CN105517631A (zh) 左西替利嗪和孟鲁司特在治疗创伤性损伤中的用途
JP2016535787A (ja) 新規方法
CN111886026A (zh) 用于治疗或预防高细胞因子血症和重度流感的方法和化合物
Gouveia et al. Organizing pneumonia induced by tocilizumab in a patient with rheumatoid arthritis
WO2016197442A1 (fr) Utilisation de la bestatine dans la préparation d'une préparation pharmaceutique pour la prévention et le traitement de maladies inflammatoires et de maladies infectieuses associées à une inflammation
CN110840906A (zh) 淫羊藿苷在制备治疗缺氧性肺动脉高压药物中的应用
Dowling et al. The treatment of pneumococcic pneumonia with sulfadiazine
WO2016197443A1 (fr) Nouvelle utilisation de 3-amino-2-hydroxy-4-phényl-valyl-isoleucine
RU2348406C1 (ru) Способ лечения бактериальных гнойных менингитов у детей
CN104888189B (zh) 3‑氨基‑2‑羟基‑4‑苯基‑缬氨酰‑异亮氨酸类似物的新应用
CN112494490A (zh) 匹莫范色林酒石酸盐在制备治疗胶质瘤药物中的应用
Kang et al. Hemodynamic changes after propacetamol administration in patients with febrile UTI in the ED
US20210284643A1 (en) Small molecule inhibitors for transcription factors
CN108379585A (zh) Hdac4抑制剂在制备治疗心力衰竭的药物中的应用
KR20120012157A (ko) 실로스타졸 또는 이의 약리학적 허용가능한 염을 유효성분으로 함유하는 패혈증 또는 패혈증성 쇼크 치료 및 예방용 약학조성물
Steinbach et al. The use of aureomycin in pulmonary tuberculosis
Salahuddin et al. Unusual case of non-resolving necrotizing pneumonia: a last resort measure for cure.

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: 15894710

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15894710

Country of ref document: EP

Kind code of ref document: A1