WO2017114095A1 - 可利霉素在抗结核分枝杆菌感染中的应用 - Google Patents
可利霉素在抗结核分枝杆菌感染中的应用 Download PDFInfo
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- WO2017114095A1 WO2017114095A1 PCT/CN2016/108502 CN2016108502W WO2017114095A1 WO 2017114095 A1 WO2017114095 A1 WO 2017114095A1 CN 2016108502 W CN2016108502 W CN 2016108502W WO 2017114095 A1 WO2017114095 A1 WO 2017114095A1
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- WIPO (PCT)
- Prior art keywords
- tuberculosis
- mycobacterium tuberculosis
- colimycin
- drugs
- kelimycin
- Prior art date
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the invention relates to the use of macrolide antibiotics in the treatment of Mycobacterium tuberculosis infection.
- Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB) infection, which mainly affects the lungs. It is the single most common cause of death among infectious diseases. Tuberculosis is more common in immunocompromised populations and is the most common AIDS-related opportunistic infection. According to the World Health Organization (WHO), there are 8 million to 10 million new cases of tuberculosis every year in the world, and 3 to 4 million people die of tuberculosis, and they are more likely to be in developing countries. It is also predicted that about 1 billion people will be infected and 3-5 million will die of tuberculosis between 2000 and 2020.
- WHO World Health Organization
- MTB resistance has increased year by year and will become a major threat to global tuberculosis control.
- China is one of the 22 countries with high incidence of tuberculosis in the world.
- the number of active tuberculosis patients ranks second in the world, and the epidemic characteristics are high infection rate, high prevalence rate, high drug resistance rate and high mortality rate. 2 million MTB nationwide. More than a quarter of the positive patients were tuberculosis-resistant patients.
- the first-line drugs commonly used in the treatment of tuberculosis include: rifampicin, isoniazid, streptomycin, ethambutol and pyrazinamide.
- these drugs have many adverse reactions, limited bactericidal effects, and long course of treatment, usually used for more than 6 months, and poor patient compliance.
- Second-line anti-tuberculosis drugs include: capreomycin, ethionamide, p-aminosalicylic acid, cycloserine, ciprofloxacin, amikacin and kanamycin Etc., and these drugs have large adverse reactions, longer treatment time (18 to 24 months), expensive, and lower cure rate. It is noteworthy that clinical studies have shown that first-line anti-tuberculosis drugs can cause damage to the liver.
- the adverse reactions of isoniazid are peripheral neuritis, hepatotoxicity, central nervous system disorders and allergic reactions; the adverse reactions of rifampicin are Hepatotoxicity, digestive tract discomfort, nervous system symptoms and allergic reactions; adverse reactions of ethambutol are mainly optic neurotoxicity; pyrazinamide adverse reactions are yellowing of skin and increased blood uric acid; streptomycin toxicity and bacterial resistance Sexual problems severely limit their use, because the combination with other drugs can reduce the incidence of bacterial resistance, although not much clinical application, but still used as a first-line drug against tuberculosis. [Zhu Shanmei Strait Pharmacy 2010, 22(2): 123-125].
- the new macrolides clarithromycin, azithromycin and roxithromycin are derivatives of fourteen-membered erythromycin, and their antibacterial mechanism is different from that of the first-line and second-line anti-tuberculosis drugs.
- the 50S subunit reversibly binds to interfere with protein synthesis. It has been reported in China that the MIC of clarithromycin against sensitive M. tuberculosis is 0.25-2.0 ⁇ g/ml, the MIC of resistant bacteria is 2.0-32 ⁇ g/ml, and the MIC of azithromycin against M.
- tuberculosis is 128 ⁇ g/ ML [Tang Shenjie, the latest advances in anti-tuberculosis drug research, China National Defense Magazine, 2006 28-volume supplement 1-3 pages].
- the MIC of clarithromycin against M. tuberculosis H37Rv (ATCC 27294) is 6 ⁇ g/ml; the MIC of azithromycin is 95 ⁇ g/ml [Kanakeshwari Falzari et al: In vitro and in vivo activities o macrolide derivatives against Mycobacterium tuberculosis Antimicrob. Agents and Chemother. 2005, 49(4): 1447-1454]; MIC of roxithromycin ⁇ 64 ⁇ g/ml.
- the test results show that colimycin is effective against Gram-positive bacteria, especially some resistant bacteria (such as ⁇ -lactam-resistant Staphylococcus aureus, erythromycin-resistant Staphylococcus aureus, etc.), and has no obvious cross with similar drugs.
- the main steps of the present invention are to determine the activity of colimycin against Mycobacterium tuberculosis by using the absolute concentration method for the clinically isolated Mycobacterium tuberculosis, and to use the anti-tuberculosis first-line drugs isoniazid and rifampicin as clinical controls.
- the results showed that there were 172 strains of colimycin in the clinical isolates of 240 strains of Mycobacterium tuberculosis, the total effective rate was 71.66%, and 37 of them were better than isoniazid, accounting for the effective number of bacteria. 21.5%; 39 strains with better activity than rifampicin, accounting for 22.7% of the effective bacteria; 23 strains with better activity than both, accounting for 13.4% of the effective bacteria count.
- the results of the present invention suggest that colimycin is expected to exploit new uses in the treatment of M. tuberculosis infections resistant to isoniazid and rifampicin.
- the invention also provides the use of a composition comprising colimycin as an active ingredient and a pharmaceutically acceptable carrier for the preparation of a medicament for the prevention of tuberculosis infection.
- the use of the present invention may be in the form of an oral dosage form, or an injectable dosage form or any other suitable dosage form.
- the first-line drug related to tuberculosis commonly used in clinical practice is used as a control.
- a series of studies on the activity of lixinomycin against Mycobacterium tuberculosis showed that the effective number of the colimycin showed activity in clinically isolated Mycobacterium tuberculosis was superior to the control group. It is used in the treatment of certain drug-resistant Mycobacterium tuberculosis infections.
- PBS pH 6.8 was added to 40 mL, and centrifuged at 3000 g for 20 minutes, and then the supernatant was discarded to leave a precipitate. 2 mL of PBS (pH 6.8) was added to prepare a suspension. The treated specimen inoculated medium was subjected to solid culture.
- composition of the medium is shown in Table 1.
- the ingredients were added to distilled water at the doses listed and fully dissolved; boiled for 30 minutes or at 121 ° C for 15 minutes.
- Mycobacterium tuberculosis culture-positive bacteria for a little moss, apply it evenly on the glass slide, fix it on the flame, dye it with stone carbonate reddish solution, heat on the flame for 5 minutes, decolorize with 3% hydrochloric acid alcohol for about 1 minute, rinse with water, then After counterstaining with alkaline melanin solution for 1 minute, rinse with water, absorb water, and observe under oil microscope.
- the stained red is Mycobacterium tuberculosis.
- Colimycin standard product from China National Institute for the Control of Pharmaceutical and Biological Products; reference drug: isoniazid, rifampicin using Sigma standard products.
- Anti-tuberculosis drugs are formulated into mother liquor at a certain concentration, and then added to the medium in a certain amount to prepare the required dose (Table 2).
- the strains isolated from the clinical specimens were smeared as cultures of acid-fast bacteria, diluted with physiological saline containing 10% Tween 80, and turbid with McFarland standard turbidity tube (Guangdong Huan Kai Microbiology Co., Ltd.), preparation 10 - 2 mg/mL of bacterial solution was inoculated into the medium containing the test drug.
- Negative and positive controls were set for each batch of trials.
- the negative control was unmedicated medium.
- the positive control was M. tuberculosis standard strain H37Rv.
- the inoculum size per tube was 0.1 mL.
- the cultured medium after inoculation was cultured at 37 °C.
- the bacterial liquid was observed once on the third day after inoculation, and then observed once a week, and the results were reported in 4 weeks.
- Control no drug medium. All isolated strains grew 4+ in drug-free medium.
- Colimycin is superior to 250 ⁇ g/ml of rifampicin in certain clinical Mycobacterium tuberculosis activities.
- the activity of colimycin was compared with the clinical activity of Mycobacterium tuberculosis resistant to isoniazid and rifampicin. The results showed that the activity of colimycin 20 ⁇ g/ml was better than that of 23 strains of Mycobacterium tuberculosis. ⁇ and 250 ⁇ g / ml rifampicin (Table 6).
- kalliktomycin is not only active against the clinical first-line anti-tuberculosis drugs isoniazid and rifampicin-sensitive bacteria, but also active against some isoniazid and rifampicin-resistant bacteria, and is expected to be clinically New applications have been made in the treatment of drug-resistant M. tuberculosis infections.
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- Health & Medical Sciences (AREA)
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- Organic Chemistry (AREA)
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- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims (6)
- 可利霉素在制备抗结核分枝杆菌感染药物中的应用。
- 以可利霉素为有效成分与药学上可接受的载体组成的组合物在制备抗结核分枝杆菌感染药物中的应用。
- 权利要求1或2所述的应用,其特征是,抗结核分枝杆菌感染治疗采用的可利霉素或可利霉素的组合物制备成口服剂型、注射剂型或其它任何适宜的剂型。
- 一种抗结核分枝杆菌感染的方法,包括给予患者有效量的可利霉素。
- 一种抗结核分枝杆菌感染的方法,包括给予患者有效量的可利霉素与药学上可接受的载体组成的组合物。
- 权利要求4或5所述的方法,其特征是,抗结核分枝杆菌感染治疗采用的可利霉素或可利霉素的组合物制备成口服剂型、注射剂型或其它任何适宜的剂型。
Priority Applications (17)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA3010020A CA3010020A1 (en) | 2015-12-31 | 2016-12-05 | Use of carrimycin in mycobacterium tuberculosis infection resistance |
JP2018553283A JP6770584B2 (ja) | 2015-12-31 | 2016-12-05 | 抗結核感染におけるカリマイシン(Kelimycin)の応用 |
BR112018013327-2A BR112018013327A2 (zh) | 2015-12-31 | 2016-12-05 | Application of Rimycin in Anti - tuberculosis Mycobacterium Infection |
RU2018125622A RU2733382C2 (ru) | 2015-12-31 | 2016-12-05 | Способ применения карримицина против резистентности инфекции, спровоцированной микобактерией туберкулеза |
PL16880885T PL3384915T3 (pl) | 2015-12-31 | 2016-12-05 | Karymycyna do leczenia zakażeń prątkiem gruźlicy |
EP16880885.5A EP3384915B1 (en) | 2015-12-31 | 2016-12-05 | Carrimycin for the treatment of mycobacterium tuberculosis infections |
KR1020187021578A KR20180098624A (ko) | 2015-12-31 | 2016-12-05 | 결핵균 마이코박테리움 터버큘로시스(Mycobacterium tuberculosis) 감염 저항성에서의 켈리마이신의 응용 |
MYPI2018001121A MY191800A (en) | 2015-12-31 | 2016-12-05 | Use of carrimycin in mycobacterium tuberculosis infection resistance |
UAA201808048A UA121159C2 (uk) | 2015-12-31 | 2016-12-05 | Застосування кариміцину при стійкості інфекції мycobacterium tuberculosis |
US16/067,327 US11000708B2 (en) | 2015-12-31 | 2016-12-05 | Use of carrimycin in Mycobacterium tuberculosis infection resistance |
PE2018001212A PE20190210A1 (es) | 2015-12-31 | 2016-12-05 | Aplicaciones de carrimicina en la infeccion por micobacterium tuberculosis resistente |
DK16880885.5T DK3384915T3 (en) | 2015-12-31 | 2016-12-05 | Carrimycin til behandling af mycobacterium tuberculosis-infektioner |
ES16880885T ES2785644T3 (es) | 2015-12-31 | 2016-12-05 | Carrimicina para el tratamiento de infecciones por Mycobacterium tuberculosis |
AU2016382584A AU2016382584B2 (en) | 2015-12-31 | 2016-12-05 | Applications of kelimycin in mycobacterium tuberculosis infection resistance |
PH12018501394A PH12018501394A1 (en) | 2015-12-31 | 2018-06-28 | Use of carrimycin in mycobacterium tuberculosis infection resistance |
ZA2018/04398A ZA201804398B (en) | 2015-12-31 | 2018-06-29 | Use of carrimycin in mycobacterium tuberculosis infection resistance |
CONC2018/0007133A CO2018007133A2 (es) | 2015-12-31 | 2018-07-09 | Uso de la carrimicina en la infección por micobacterium tuberculosis resistente |
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EP (1) | EP3384915B1 (zh) |
JP (1) | JP6770584B2 (zh) |
KR (1) | KR20180098624A (zh) |
CN (1) | CN105497053B (zh) |
AU (1) | AU2016382584B2 (zh) |
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CA (1) | CA3010020A1 (zh) |
CL (1) | CL2018001804A1 (zh) |
CO (1) | CO2018007133A2 (zh) |
DK (1) | DK3384915T3 (zh) |
ES (1) | ES2785644T3 (zh) |
MY (1) | MY191800A (zh) |
PE (1) | PE20190210A1 (zh) |
PH (1) | PH12018501394A1 (zh) |
PL (1) | PL3384915T3 (zh) |
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CN105497053B (zh) * | 2015-12-31 | 2018-02-13 | 沈阳福洋医药科技有限公司 | 可利霉素在抗结核分枝杆菌感染中的应用 |
CN110545820B (zh) * | 2017-04-06 | 2023-01-10 | 沈阳福洋医药科技有限公司 | 可利霉素及其药学上可接受的盐在制备治疗和/或预防肿瘤药物方面的应用 |
CN110384710B (zh) * | 2018-04-17 | 2023-01-10 | 沈阳福洋医药科技有限公司 | 一种用于预防和/或治疗疼痛的药物、组合产品及其应用 |
CN110384802B (zh) * | 2018-04-17 | 2021-09-17 | 沈阳福洋医药科技有限公司 | 一种用于预防和/或治疗发热的药物、组合产品及其应用 |
WO2021219112A1 (zh) * | 2020-04-30 | 2021-11-04 | 沈阳福洋医药科技有限公司 | 异戊酰螺旋霉素类化合物或其组合物在制备治疗脓毒症疾病药物中的应用 |
CN113577086B (zh) * | 2020-04-30 | 2023-05-02 | 沈阳福洋医药科技有限公司 | 异戊酰螺旋霉素类化合物或其组合物在制备治疗免疫失调的药物中的应用 |
TW202237116A (zh) * | 2020-12-02 | 2022-10-01 | 日商塩野義製藥股份有限公司 | 以組合細胞色素bc1抑制劑與克拉黴素或阿奇黴素為特徵之用於治療分枝桿菌感染之藥物 |
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CN105497053A (zh) | 2016-04-20 |
UA121159C2 (uk) | 2020-04-10 |
PE20190210A1 (es) | 2019-02-07 |
BR112018013327A2 (zh) | 2018-12-04 |
JP6770584B2 (ja) | 2020-10-14 |
AU2016382584B2 (en) | 2022-01-06 |
ES2785644T3 (es) | 2020-10-07 |
EP3384915A1 (en) | 2018-10-10 |
CL2018001804A1 (es) | 2018-09-28 |
AU2016382584A1 (en) | 2018-07-26 |
KR20180098624A (ko) | 2018-09-04 |
EP3384915A4 (en) | 2018-12-19 |
EP3384915B1 (en) | 2020-02-19 |
MY191800A (en) | 2022-07-15 |
RU2018125622A (ru) | 2020-01-31 |
PH12018501394A1 (en) | 2019-02-27 |
US11000708B2 (en) | 2021-05-11 |
CO2018007133A2 (es) | 2018-07-19 |
CA3010020A1 (en) | 2017-07-06 |
PL3384915T3 (pl) | 2020-09-07 |
US20190001160A1 (en) | 2019-01-03 |
JP2019501220A (ja) | 2019-01-17 |
DK3384915T3 (en) | 2020-05-04 |
ZA201804398B (en) | 2019-09-25 |
RU2018125622A3 (zh) | 2020-03-26 |
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