WO2014185650A1 - Pharmaceutical composition for treating tuberculosis, containing fenofibrate - Google Patents
Pharmaceutical composition for treating tuberculosis, containing fenofibrate Download PDFInfo
- Publication number
- WO2014185650A1 WO2014185650A1 PCT/KR2014/003962 KR2014003962W WO2014185650A1 WO 2014185650 A1 WO2014185650 A1 WO 2014185650A1 KR 2014003962 W KR2014003962 W KR 2014003962W WO 2014185650 A1 WO2014185650 A1 WO 2014185650A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tuberculosis
- fenofibrate
- pharmaceutical composition
- treatment
- treating tuberculosis
- Prior art date
Links
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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Definitions
- the present invention relates to a pharmaceutical composition for treating tuberculosis, which contains fenofibrate, which is used as an antihyperlipidemic agent, as an active ingredient.
- Mycobacterium tuberculosis is a rod-shaped acidic bacillus with a very slow growth rate. Most of the tuberculosis bacteria infected through the air are naturally extinguished, but 5 to 10% of those infected develop tuberculosis. About one third of the world's population (about 1.9 billion people) is carriers of Mycobacterium tuberculosis , and it is estimated that about 8 million to 10 million tuberculosis patients die each year and about 3 million tuberculosis patients die.
- Mycobacterium tuberculosis develops after an incubation period for a certain period of time or after infection, and develops acutely without incubation, causing complications associated with inflammation and asthma of the lungs, causing death.
- tuberculosis can be easily transmitted to other people because there is no self-symptom, which is a great difficulty in preventing and treating tuberculosis.
- tuberculosis bacteria should use at least two or more, if possible, four or more drugs because of one mutant strain per approximately 10 6 cell division.
- Fenofibrate is a fibrate family of drugs used primarily for lowering cholesterol.
- Peroxisome proliferator-activated receptors PPARs
- PPAR ⁇ , PPAR ⁇ , and PPAR ⁇ are known.
- Fenofibrate promotes PPAR ⁇ activity to reduce triglycerides while increasing high-density lipoprotein cholesterol.
- Mice lacking PPAR ⁇ do not react with fenofibrate, and thus, expression of target genes is inhibited, resulting in obesity (Costet P et al., J, Edgar A, Galtier P, Pineau T. Peroxisome proliferator-).
- An object of the present invention is to provide a novel use of fenofibrate as a therapeutic agent for tuberculosis, which is used as a therapeutic agent for hyperlipidemia.
- the present invention for achieving the above object relates to a pharmaceutical composition for treating tuberculosis containing fenofibrate as an active ingredient.
- the tuberculosis includes tuberculosis-resistant tuberculosis, pulmonary tuberculosis, tuberculosis, bone tuberculosis, throat tuberculosis, lymphatic tuberculosis, lung disease, breast tuberculosis or spinal tuberculosis.
- the present inventors (A) infecting macrophages with Mycobacterium tuberculosis; (B) processing a sample to measure the anti-tuberculosis efficacy of macrophages infected with Mycobacterium tuberculosis; (C) identifying one or more selected from the group consisting of 1 induction of autophagy, 2 increase in active oxygen species and 3 decrease in tuberculosis viability by treatment of the sample;
- a patent application was filed on March 5, 2012 for a method that can be screened quickly and easily (Application No. 10-2012-22323).
- Macrophages are one of the cells responsible for immunity.
- the antituberculosis ability of fenofibrate was measured based on the above method, and the survival rate of Mycobacterium tuberculosis was significantly decreased from 3 days after the addition of fenofibrate in macrophage infected with Mycobacterium tuberculosis, indicating that fenofibrate has antituberculosis ability. there was.
- Fenofibrate is already widely used for lowering cholesterol and is marketed in various forms in the form of tablets or capsules such as Tricor, Trilipix (Abbott Labs), and Lifibra (Teva).
- the formulation is not limited thereto, and powders, granules, tablets, capsules or the like may be mixed by themselves or by pharmaceutically acceptable carriers, forming agents, diluents or the like by methods known in the pharmaceutical art. It can be prepared and used in the form of an injection or the like.
- the dosage of the active ingredient according to the present invention is appropriately selected depending on the absorption of the active ingredient in the body, the rate of water activation and excretion, the age, sex and condition of the patient, the severity of the disease to be treated, etc.
- the compound may be administered once to several times in an amount of 1 to 100mg per 1kg of body weight.
- composition containing fenofibrate of the present invention as an active ingredient can significantly reduce the survival rate of Mycobacterium tuberculosis and can be used as a new tuberculosis therapeutic agent.
- 1 is a graph showing the anti-tuberculosis efficacy of fenofibrate against intracellular survival of Mycobacterium tuberculosis.
- Macrophage was collected from bone marrow of 8-week-old wild type C57BL / 6 mice. Collected bone marrow cells were cultured (DMEM (Gibco-BRL, Grand Island, NY, USA) with 10% fetal bovine serum (Gibco-BRL), sodium pyruvate, nonessential amino acids, penicillin G (100 IU / ml) and streptomycin ( 100 mg / ml)] was suspended at a concentration of 1 ⁇ 10 5 / ml and attached to a 10-cm petri dish at 37 ° C. and 5% CO 2 . After 2 hours the cells were collected and centrifuged.
- DMEM Gibco-BRL, Grand Island, NY, USA
- fetal bovine serum Gibco-BRL
- nonessential amino acids penicillin G (100 IU / ml)
- streptomycin 100 mg / ml
- Macrophage colony-stimulating factor (M-CSF) was added to the cell medium at a concentration of 25 ng / ml, and the cells were differentiated into macrophages for 3 to 4 days and used for experiments. Lymphocytes, not differentiated macrophages, were removed by mechanical destruction.
- Mycobacterium tuberculosis ( M. tuberculosis ), a pathogenic Mycobacterium tuberculosis bacterium, prepared in 1) was added so that the multiplicity of infection (MOI) per cell of culture was 1: 1 to 1:10. Infected for 4 hours. After infection fenofibrate was treated to a concentration of 50 mM. Solvent 0.1% DMSO was used as a control.
- 7H10 medium was used, and after culturing for 14 days in a 37 ° C incubator, colony forming unit (CFU) was measured to confirm intracellular survival (ICS).
- ICS intracellular survival
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pulmonology (AREA)
Abstract
The present invention relates to a composition for treating tuberculosis, and more specifically, to a pharmaceutical composition for treating tuberculosis containing fenofibrate, which is used as a hyperlipidemia treatment agent, as an active ingredient.
Description
본 발명은 고지혈증 치료제로 사용하고 있는 페노피브레이트(fenofibrate)를 유효성분으로 함유하는 결핵 치료용 약학 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for treating tuberculosis, which contains fenofibrate, which is used as an antihyperlipidemic agent, as an active ingredient.
결핵균은 증식속도가 매우 느린 막대 모양의 항산성 간균이다. 공기를 통해 폐에 감염된 결핵균은 대부분은 자연 소멸되지만 감염자 중 5~10%는 결핵환자로 발전하게 된다. 세계적으로 인구의 약 1/3(약 19억명)이 결핵균(Mycobacterium tuberculosis) 보균자이며, 매년 약 800~1,000만명의 결핵환자가 발생하고 약 300만명의 결핵환자가 사망하는 것으로 추정된다. Mycobacterium tuberculosis is a rod-shaped acidic bacillus with a very slow growth rate. Most of the tuberculosis bacteria infected through the air are naturally extinguished, but 5 to 10% of those infected develop tuberculosis. About one third of the world's population (about 1.9 billion people) is carriers of Mycobacterium tuberculosis , and it is estimated that about 8 million to 10 million tuberculosis patients die each year and about 3 million tuberculosis patients die.
결핵으로 인한 사망률은 90년대 이후 다시 증가하고 있는데 이는 다약제내성(multi-drug resistant; MDR) 결핵균에 의한 감염 증가와 HIV/TB 동시감염의 증가가 주원인으로 판단된다. 현재 전 세 계적으로 약 5000만명의 다약제내성 결핵 환자가 있지만, 이에 대한 치료효율은 50% 정도 밖에 되지 않는다. 또한, 현재 전 세계적으로 약 600만명의 HIV/TB 동시 감염환자가 있으며 대부분이 결핵으로 사망하는 것으로 추정되고 있다(WHO Report 2011. Global Tuberculosis Control, World Health Organization. 2011). The mortality rate from tuberculosis has increased again since the 1990s, mainly due to increased infections caused by multi-drug resistant MDR tuberculosis and increased HIV / TB infection. There are currently about 50 million MDR-TB patients worldwide, but the treatment efficiency is only about 50%. In addition, there are currently about 6 million people living with HIV / TB infection worldwide, most of whom are estimated to die from tuberculosis (WHO Report 2011. Global Tuberculosis Control, World Health Organization. 2011).
결핵균은 감염 후 일정 기간 동안 잠복기를 거친 후 발병되거나 또는 잠복기 없이 급성으로 발병하여 폐의 염증과 천식을 동반하는 합병증을 일으켜 감염자를 사망시킨다. 결핵균 단순 보균자의 경우, 자각증상이 없으므로 결핵을 타인에게 쉽게 전염시킬 수 있어 결핵의 예방 및 치료에 큰 어려움이 있는 실정이다.Mycobacterium tuberculosis develops after an incubation period for a certain period of time or after infection, and develops acutely without incubation, causing complications associated with inflammation and asthma of the lungs, causing death. In the case of simple carriers of tuberculosis bacteria, tuberculosis can be easily transmitted to other people because there is no self-symptom, which is a great difficulty in preventing and treating tuberculosis.
현재 결핵에 대한 치료방법으로 화학요법(항결핵제)이 있다. 초기 결핵치료를 위한 1차 항결핵제는 약제의 병합요법(isoniazid, rifampin, pyrazinamide 및 ethambutol)으로 약 85% 정도의 결핵 치료율을 나타내는 매우 효과적인 결핵 치료 방법임에도 불구하고, 최소 6개월 이상 지속적인 투여가 필요하고, 상당한 부작용을 초래하며, 비용이 많이 들 뿐만 아니라 다약제 내성 결핵에 대해서는 효능이 불투명하다는 문제가 있다. 특히 결핵균은 약 106세포분열마다 한 개의 돌연변이주가 출현하기 때문에 최소한 2종 이상, 가능하면 4종 이상의 약제를 병용해야 하는데, 그럼에도 하나의 약제에 대한 내성이 생기는 경우 특별한 대처방법이 없다는 것이 화학요법의 가장 큰 문제점이다. 현재 전 세 계적으로 약 5000만명의 다약제내성 결핵 환자가 있지만, 이에 대한 치료효율은 50% 정도 밖에 되지 않는다. 실제로 결핵으로 인한 사망률은 90년대 이후 다시 증가하고 있는데 이는 다약제내성(multi-drug resistant; MDR) 결핵균에 의한 감염 증가와 HIV/TB 동시감염의 증가가 주원인으로 판단된다(Lienhardt C 등, Efficacy and safety of a 4-drug fixed-dose combination regimen compared with separate drugs for treatment of pulmonary tuberculosis: the Study C randomized controlled trial. JAMA. 305, 1415-1423, 2011). Currently, chemotherapy (anti-tuberculosis drug) is a treatment for tuberculosis. The primary anti-tuberculosis agent for the initial treatment of tuberculosis is a combination of drugs (isoniazid, rifampin, pyrazinamide and ethambutol), which is a very effective method for treating tuberculosis with an estimated 85% treatment of tuberculosis. In addition, the drug has significant side effects, is expensive, and has a problem of opacity for multi-drug resistant tuberculosis. In particular, tuberculosis bacteria should use at least two or more, if possible, four or more drugs because of one mutant strain per approximately 10 6 cell division. However, if there is resistance to one drug, there is no special treatment. Is the biggest issue. There are currently about 50 million multi-drug-resistant tuberculosis patients worldwide, but the treatment efficiency is only about 50%. Indeed, tuberculosis mortality has increased again since the 1990s, mainly due to increased multi-drug resistant (MDR) tuberculosis and increased HIV / TB infection (Lienhardt C et al., Efficacy and safety of a 4-drug fixed-dose combination regimen compared with separate drugs for treatment of pulmonary tuberculosis: the Study C randomized controlled trial.JAMA.305, 1415-1423, 2011).
따라서 기존 약제와 작용기전이 다르고 부작용이 상대적으로 적은 새로운 항결핵제의 개발이 매우 시급한 과제이다. Therefore, the development of new anti-tuberculosis drugs with different mechanisms of action and relatively few side effects is an urgent task.
페노피브레이트는 피브레이트 계열의 의약품으로 콜레스테롤을 낮추기 위한 용도로 주로 사용된다. PPARs(peroxisome proliferator-activated receptor)는 핵에 존재하는 호르몬 수용체의 일종으로 지방산의 물질대사를 조절하는데 중요한 역할을 담당하고 있으며, PPARα, PPARβ, PPARγ가 알려져 있다. 페노피브레이트는 PPARα의 활성을 촉진시켜서 중성지방을 감소시키는 반면 고밀도지단백 콜레스테롤은 증가시키는 역할을 수행한다. PPARα가 결핍된 생쥐의 경우, 페노피브레이트와 반응하지 못하고 그로인해 target 유전자들이 발현이 저해됨으로서 결국 비만을 유발하게 된다는 보고가 있다(Costet P 등, J, Edgar A, Galtier P, Pineau T. Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. J Biol Chem 273, 29577-29585, 1998). 이밖에도 당뇨병, 비만, 인슐린 저항성을 가진 실험동물과 고지방 식이를 섭취한 C57BL/6 생쥐에 페노피브레이트를 처리했을 때 몸무게가 감소했다는 보고를 통해서 체지방 감소효과들을 확인 할 수 있었다(Guerre-Millo M 등, Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 275, 16638-16642, 2000). 그러나 아직까지 페노피브레이트가 결핵의 치료에 효과가 있다는 것은 보고된 바 없다.Fenofibrate is a fibrate family of drugs used primarily for lowering cholesterol. Peroxisome proliferator-activated receptors (PPARs) are a type of hormone receptor in the nucleus that plays an important role in regulating the metabolism of fatty acids. PPARα, PPARβ, and PPARγ are known. Fenofibrate promotes PPARα activity to reduce triglycerides while increasing high-density lipoprotein cholesterol. Mice lacking PPARα do not react with fenofibrate, and thus, expression of target genes is inhibited, resulting in obesity (Costet P et al., J, Edgar A, Galtier P, Pineau T. Peroxisome proliferator-). activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis.J Biol Chem 273, 29577-29585, 1998). In addition, the effects of fenofibrate on body weight reduction in experimental animals with diabetes, obesity, insulin resistance and C57BL / 6 mice fed a high-fat diet were confirmed to reduce body fat (Guerre-Millo M et al., Peroxisome). proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity.J Biol Chem 275, 16638-16642, 2000). However, it has not been reported that fenofibrate is effective in the treatment of tuberculosis.
본 발명은 고지혈증 치료제로서 이용되고 있는 페노피브레이트(fenofibrate)의 결핵 치료제로서의 새로운 용도를 제공하고자 하는 것을 목적으로 한다. An object of the present invention is to provide a novel use of fenofibrate as a therapeutic agent for tuberculosis, which is used as a therapeutic agent for hyperlipidemia.
전술한 목적을 달성하기 위한 본 발명은 페노피브레이트를 유효성분으로 함유하는 결핵 치료용 약학 조성물에 관한 것이다. 본 발명에서 결핵이라 함은 상기 결핵은 다제내성 결핵, 폐결핵, 담결핵, 골결핵, 인후결핵, 임파선결핵, 폐허증, 유방결핵 또는 척추결핵 등을 포함한다.The present invention for achieving the above object relates to a pharmaceutical composition for treating tuberculosis containing fenofibrate as an active ingredient. In the present invention, the tuberculosis includes tuberculosis-resistant tuberculosis, pulmonary tuberculosis, tuberculosis, bone tuberculosis, throat tuberculosis, lymphatic tuberculosis, lung disease, breast tuberculosis or spinal tuberculosis.
본 발명자들은 (A) 대식세포에 결핵균을 감염시키는 단계; (B) 결핵균이 감염된 대식세포에 항결핵 효능을 측정하고자 하는 시료를 처리하는 단계; (C) 상기 시료의 처리에 의한 ① 자가포식의 유도 여부, ② 활성산소종의 증가 여부 및 ③ 결핵균 생존률의 감소 여부로 구성되는 군으로부터 선택된 하나 이상을 확인하는 단계;를 포함하여 항결핵제의 효능을 빠르고 간편하게 스크리닝할 수 있는 방법에 대해 2012년 03년 05일자로 특허출원한 바 있다(출원번호 제10-2012-22323호). 대식세포는 면역을 담당하는 세포의 하나로, 대식세포를 항결핵제의 스크리닝에 사용하는 것에 의해 결핵균에 감염된 세포가 면역체계 내에서 효과적으로 제거될 수 있는 지 확인할 수 있다.The present inventors (A) infecting macrophages with Mycobacterium tuberculosis; (B) processing a sample to measure the anti-tuberculosis efficacy of macrophages infected with Mycobacterium tuberculosis; (C) identifying one or more selected from the group consisting of ① induction of autophagy, ② increase in active oxygen species and ③ decrease in tuberculosis viability by treatment of the sample; A patent application was filed on March 5, 2012 for a method that can be screened quickly and easily (Application No. 10-2012-22323). Macrophages are one of the cells responsible for immunity. By using macrophages for the screening of anti-tuberculosis agents, it is possible to confirm whether cells infected with Mycobacterium tuberculosis can be effectively removed from the immune system.
하기 실시예에 기재된 바와 같이 상기 방법에 기반하여 페노피브레이트의 항결핵능을 측정한 결과 결핵균에 감염된 대식세포에서 페노피브레이트의 첨가 3일 후부터 결핵균의 생존율이 유의하게 감소하여 페노피브레이트가 항결핵능이 있음을 알 수 있었다. As described in the Examples below, the antituberculosis ability of fenofibrate was measured based on the above method, and the survival rate of Mycobacterium tuberculosis was significantly decreased from 3 days after the addition of fenofibrate in macrophage infected with Mycobacterium tuberculosis, indicating that fenofibrate has antituberculosis ability. there was.
페노피브레이트는 콜레스테롤을 낮추기 위한 용도로 이미 널리 사용되고 있는 의약품으로 Tricor, Trilipix (Abbott Labs), Lifibra (Teva) 등 정제나 캡슐의 형태로 여러 가지 상표로 출시되고 있다. 그러나, 제형이 이에 한정되는 것은 아니며 약제학적 분야에서 공지의 방법에 의하여, 그 자체 또는 약학적 허용되는 담체(carrier), 부형제(forming agent), 희석제 등과 혼합하여 분말, 과립, 정제, 캡슐제 또는 주사제 등의 제형으로 제조되어 사용될 수 있다. Fenofibrate is already widely used for lowering cholesterol and is marketed in various forms in the form of tablets or capsules such as Tricor, Trilipix (Abbott Labs), and Lifibra (Teva). However, the formulation is not limited thereto, and powders, granules, tablets, capsules or the like may be mixed by themselves or by pharmaceutically acceptable carriers, forming agents, diluents or the like by methods known in the pharmaceutical art. It can be prepared and used in the form of an injection or the like.
본 발명에 따른 유효성분의 투여량은 체내에서 활성성분의 흡수도, 물활성화율 및 배설속도, 환자의 연령, 성별 및 상태, 치료할 질병의 중증정도 등에 따라 적절히 선택되나, 일반적으로 성인에게 1일에 체중 1kg 당 상기 화합물을 1~100mg 의 양으로 1회 내지 수회로 나누어 투여할 수 있다.The dosage of the active ingredient according to the present invention is appropriately selected depending on the absorption of the active ingredient in the body, the rate of water activation and excretion, the age, sex and condition of the patient, the severity of the disease to be treated, etc. The compound may be administered once to several times in an amount of 1 to 100mg per 1kg of body weight.
이상과 같이 본 발명의 페노피브레이트를 유효성분으로 함유하는 조성물은 결핵균의 생존율을 현저하게 감소시켜 새로운 결핵 치료제로 사용될 수 있다. As described above, the composition containing fenofibrate of the present invention as an active ingredient can significantly reduce the survival rate of Mycobacterium tuberculosis and can be used as a new tuberculosis therapeutic agent.
도 1는 결핵균의 세포 내 생존률에 대한 페노피브레이트의 항결핵 효능을 보여주는 그래프.1 is a graph showing the anti-tuberculosis efficacy of fenofibrate against intracellular survival of Mycobacterium tuberculosis.
이하 첨부된 실시예를 들어 본 발명을 보다 상세히 설명한다. 그러나 이러한 도면과 실시예는 본 발명의 기술적 사상의 내용과 범위를 쉽게 설명하기 위한 예시일 뿐, 이에 의해 본 발명의 기술적 범위가 한정되거나 변경되는 것은 아니다. 또한 이러한 예시에 기초하여 본 발명의 기술적 사상의 범위 안에서 다양한 변형과 변경이 가능함은 당업자에게는 당연할 것이다. Hereinafter, the present invention will be described in more detail with reference to the accompanying examples. However, these drawings and embodiments are only examples for easily explaining the contents and scope of the technical idea of the present invention, and thus the technical scope of the present invention is not limited or changed. In addition, it will be apparent to those skilled in the art that various modifications and changes can be made within the scope of the present invention based on these examples.
실시예Example
마우스의 대식세포에 결핵균을 감염시킨 후에 페노피브레이트(sigma)를 처리하고 세포 내 결핵균 생존율이 페노피브레이트에 의해 영향을 받는 지 확인하였다. 구체적인 실험방법은 다음과 같다.After infecting Mycobacterium tuberculosis with mice, fenofibrate was treated with sigma, and it was confirmed whether intracellular Mycobacterium tuberculosis survival was affected by fenofibrate. The specific experimental method is as follows.
실시예 1 : 대식세포의 결핵균 감염 및 페노피브레이트 처리Example 1 Mycobacterium Tuberculosis Infection and Fenofibrate Treatment
1) 대식세포 수집 및 배양1) Macrophage Collection and Culture
8주령의 야생형 C57BL/6 마우스의 골수로부터 대식세포(macrophage)를 수집하였다. 수집한 골수세포는 배양액[DMEM(Gibco-BRL, Grand Island, NY, USA) with 10% fetal bovine serum (Gibco- BRL), sodium pyruvate, nonessential amino acids, penicillin G (100 IU/ml) 및 streptomycin (100 mg/ml)]에 1×105/ml의 농도로 부유시켜 37℃, 5% CO2 조건에서 10-cm petri dish에 부착시켰다. 2시간 후에 세포를 수집하고 원심분리하였다. 세포 배지에 대식세포 집락 인자(macrophage colony-stimulating factor, M-CSF)를 25 ng/ml의 농도로 첨가하여 배양액에 3~4일 동안 대식세포로 분화하여 실험에 사용하였다. 분화한 대식세포가 아닌 림프구들은 기계적인 파괴로 제거하였다. Macrophage was collected from bone marrow of 8-week-old wild type C57BL / 6 mice. Collected bone marrow cells were cultured (DMEM (Gibco-BRL, Grand Island, NY, USA) with 10% fetal bovine serum (Gibco-BRL), sodium pyruvate, nonessential amino acids, penicillin G (100 IU / ml) and streptomycin ( 100 mg / ml)] was suspended at a concentration of 1 × 10 5 / ml and attached to a 10-cm petri dish at 37 ° C. and 5% CO 2 . After 2 hours the cells were collected and centrifuged. Macrophage colony-stimulating factor (M-CSF) was added to the cell medium at a concentration of 25 ng / ml, and the cells were differentiated into macrophages for 3 to 4 days and used for experiments. Lymphocytes, not differentiated macrophages, were removed by mechanical destruction.
2) 결핵균 감염 및 페노피브레이트 처리 2) Mycobacterium tuberculosis infection and fenofibrate treatment
1)에서 준비한 마우스 대식세포 배지 내에 병원성 결핵균인 Mycobacterium tuberculosis(M. tuberculosis)를 배양 세포 1개당 감염된 균의 개체 평균수(multiplicity of infection, MOI)가 1:1~1:10이 되도록 첨가하여 2~4시간 동안 감염시켰다. 감염시킨 후에 페노피브레이트를 50 mM의 농도가 되도록 처리하였다. 대조군으로 용매제인 0.1% DMSO를 사용하였다. Mycobacterium tuberculosis ( M. tuberculosis ), a pathogenic Mycobacterium tuberculosis bacterium, prepared in 1) was added so that the multiplicity of infection (MOI) per cell of culture was 1: 1 to 1:10. Infected for 4 hours. After infection fenofibrate was treated to a concentration of 50 mM. Solvent 0.1% DMSO was used as a control.
실시예 2 : 결핵균 생존률에 대한 페노피브레이트의 영향 분석Example 2 Analysis of the Effect of Fenofibrate on Mycobacterium Tuberculosis Viability
실시예 1의 2)에 의해 페노피브레이트를 처리한 결핵균 감염 대식세포에 대해 페노피브레이트의 처리 직전, 처리 3일 후 또는 처리 7일 후 대식세포의 배양액을 제거한 후 멸균 증류수를 가하여 대식세포를 터트렸다. 대식세포 내에 존재하는 결핵균을 동정하기 위하여 7H10 배지를 사용하였고, 37℃ incubator에서 14일 정도 배양한 후 집락형성단위(CFU)를 측정하여 세포내 균 생존율(intracellular survival, ICS)을 확인하고 그 결과를 도 1에 도시하였다. 도 1에서 SC는 대조군을, Fenofibrate는 페노피브레이트 50 mM 처리군을 나타낸다.The macrophage cells treated with Mycobacterium tuberculosis infected fenofibrate according to Example 1, 2) were removed immediately after the fenofibrate treatment, 3 days after the treatment, or 7 days after the treatment, and then sterile distilled water was added to burst the macrophages. In order to identify Mycobacterium tuberculosis in macrophages, 7H10 medium was used, and after culturing for 14 days in a 37 ° C incubator, colony forming unit (CFU) was measured to confirm intracellular survival (ICS). Is shown in FIG. 1. In FIG. 1, SC represents a control group, and Fenofibrate represents a fenofibrate 50 mM treatment group.
도 1에서 확인할 수 있듯이 결핵균의 세포 내 생존률은 페노피브레이트의 첨가 3일 후부터 유의하게 감소하는 것을 확인할 수 있었다. As can be seen in Figure 1, the intracellular survival rate of Mycobacterium tuberculosis was confirmed that significantly decreased from 3 days after the addition of fenofibrate.
Claims (1)
- 페노피브레이트 (fenofibrate)를 유효성분으로 함유하는 결핵 치료용 약학 조성물.Fenofibrate A pharmaceutical composition for treating tuberculosis containing (fenofibrate) as an active ingredient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2013-0055030 | 2013-05-15 | ||
| KR1020130055030A KR101344218B1 (en) | 2013-05-15 | 2013-05-15 | Pharmaceutical composition for treatment of tuberculosis containing fenofibrate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2014185650A1 true WO2014185650A1 (en) | 2014-11-20 |
Family
ID=49988945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2014/003962 WO2014185650A1 (en) | 2013-05-15 | 2014-05-02 | Pharmaceutical composition for treating tuberculosis, containing fenofibrate |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR101344218B1 (en) |
| WO (1) | WO2014185650A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101754516B1 (en) | 2015-02-27 | 2017-07-07 | 순천향대학교 산학협력단 | Phenanthrenyl compounds and antituberculosis composition containing the same |
| KR101751930B1 (en) | 2015-05-04 | 2017-06-30 | 충남대학교산학협력단 | Pharmaceutical Composition for Treating Mycobacterium tuberculosis or Mycobacterium abscessus Infection |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007511568A (en) * | 2003-11-20 | 2007-05-10 | イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー | PPAR agonists for the treatment of HCV infection |
| KR20080004600A (en) * | 2005-04-13 | 2008-01-09 | 라이프사이클 파마 에이/에스 | A tablet comprising a fibrate |
| KR20120057664A (en) * | 2002-05-24 | 2012-06-05 | 풔니어 래버러토리 아일랜드 리미티드 | Nanoparticulate fibrate formulations |
| WO2012104655A2 (en) * | 2011-02-04 | 2012-08-09 | Biocopea Limited | Compostions and methods for treating chronic inflammation and inflammatory diseases |
| KR20120095170A (en) * | 2011-02-18 | 2012-08-28 | 충남대학교산학협력단 | Pharmaceutical composition containing fenofibrate for prevention of sepsis |
-
2013
- 2013-05-15 KR KR1020130055030A patent/KR101344218B1/en active IP Right Grant
-
2014
- 2014-05-02 WO PCT/KR2014/003962 patent/WO2014185650A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20120057664A (en) * | 2002-05-24 | 2012-06-05 | 풔니어 래버러토리 아일랜드 리미티드 | Nanoparticulate fibrate formulations |
| JP2007511568A (en) * | 2003-11-20 | 2007-05-10 | イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー | PPAR agonists for the treatment of HCV infection |
| KR20080004600A (en) * | 2005-04-13 | 2008-01-09 | 라이프사이클 파마 에이/에스 | A tablet comprising a fibrate |
| WO2012104655A2 (en) * | 2011-02-04 | 2012-08-09 | Biocopea Limited | Compostions and methods for treating chronic inflammation and inflammatory diseases |
| KR20120095170A (en) * | 2011-02-18 | 2012-08-28 | 충남대학교산학협력단 | Pharmaceutical composition containing fenofibrate for prevention of sepsis |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101344218B1 (en) | 2013-12-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Guan et al. | Salidroside attenuates LPS-induced pro-inflammatory cytokine responses and improves survival in murine endotoxemia | |
| Döring et al. | BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs | |
| KR20150063056A (en) | Composition for reducing new-onset diabetes | |
| US20170266213A1 (en) | Use of beta-nicotinamide mononucleotide in preparation of anti-aging drugs or health-care products | |
| CN100528222C (en) | Treatment of multiple sclerosis through ingestion or inhalation of copolymer-1 | |
| CN102427727A (en) | Treatment of neurodegeneration and neuroinflammation | |
| AU2023204000A1 (en) | Mast cell stabilizers for treatment of hypercytokinemia and viral infection | |
| CN109419814B (en) | Application of paradisella gordonii to inhibition of fatty liver disease | |
| WO2018090983A9 (en) | Saponin compound for improving intestinal microflora, preparation method and use thereof | |
| Sarmento et al. | Relationship between virulence of Mycobacterium avium strains and induction of tumor necrosis factor alpha production in infected mice and in in vitro-cultured mouse macrophages | |
| WO2014185650A1 (en) | Pharmaceutical composition for treating tuberculosis, containing fenofibrate | |
| Rasheed et al. | Effects of methylsulfonylmethane and neutralizing anti–IL-10 antibody supplementation during a mild Eimeria challenge infection in broiler chickens | |
| CN112694463B (en) | Application of isopentenyl chromone compound in preparation of anti-coronavirus medicines | |
| KR20140032312A (en) | Pharmaceutical composition for treatment of tuberculosis | |
| Jhan et al. | Improvements of cognitive functions in mice heavily infected by Angiostrongylus cantonensis after treatment with albendazole, dexamethasone, or co-therapy | |
| Kubera et al. | The effect of cocaine sensitization on mouse immunoreactivity | |
| CN112245424B (en) | Application of bisabolane sesquiterpene structural analogue in preparation of anti-coronavirus medicines | |
| CN110946862B (en) | Application of sanguinarine in inhibition of growth of multiple drug-resistant enterobacter hopcalis | |
| KR101286743B1 (en) | Pharmaceutical composition containing fenofibrate for prevention of sepsis | |
| CN114081886A (en) | Pharmaceutical composition suitable for treating drug-resistant tuberculosis | |
| WO2020153800A9 (en) | Composition for preventing or treating triple negative breast cancer, containing tumor infiltrating lymphocytes as active ingredient | |
| CN108888628B (en) | Application of ginsenoside GRh2 in preparing anti-toxoplasma gondii compound preparation and medicine thereof | |
| WO2006053487A1 (en) | The use of vegetable anthraquinone derivatives and vegetable polysaccharides for treating human immunodeficiency virus (hiv) | |
| KR20230138735A (en) | Pharmaceutical Anti-Tuberculosis Composition | |
| KR102049526B1 (en) | Pharmaceutical Anti-Tuberculosis Composition Comprising GABA |
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: 14797284 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: 14797284 Country of ref document: EP Kind code of ref document: A1 |