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Novel application of pyrazolo[1, 5-a]pyridine compound and composition for treatment of Mycobacterium abscessus infection

A mycobacterial and pyrazolo technology is applied in the directions of medical preparations containing active ingredients, antibacterial drugs, organic active ingredients, etc. Effect

Active Publication Date: 2017-10-13
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In vivo experiments, pyrazolo[1,5-a]pyridine compounds can effectively inhibit the growth of Mycobacterium tuberculosis in mice at a dose of 20 mg / kg / d; however, existing studies have found that the lowest inhibitory effect on Mab Bacterial concentration exceeds 50μg / mL, it can be judged that it cannot be used alone to treat Mab infection

Method used

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  • Novel application of pyrazolo[1, 5-a]pyridine compound and composition for treatment of Mycobacterium abscessus infection
  • Novel application of pyrazolo[1, 5-a]pyridine compound and composition for treatment of Mycobacterium abscessus infection
  • Novel application of pyrazolo[1, 5-a]pyridine compound and composition for treatment of Mycobacterium abscessus infection

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0049] Experimental example 1, graded inhibitory concentration experiment of CFZ and TB47

[0050] 1. Experimental grouping

[0051] The graded concentration of TB47 is 12.5μg / mL, 6.25μg / mL, 3.12μg / mL, 1.56μg / mL, 0.78μg / mL, 0μg / mL;

[0052] The graded concentration of CFZ (CFZ) is 10μg / mL, 5μg / mL, 2.5μg / mL, 1.25μg / mL, 0.62μg / mL, 0μg / mL;

[0053] According to the graded concentrations of the above two drugs, they are combined and administered in combination one by one;

[0054] The CFZ and TB47 used above were dissolved in dimethyl sulfoxide (DMSO) for use.

[0055] 2. Experimental steps

[0056] (1) Mab cultivation

[0057] Insert the self-luminescent Mab into 5mL 7H9 liquid medium for culture, add glass beads to break up, and cultivate to the OD of the bacterial solution 600 When reaching 0.6-0.8, dilute the bacterial solution by 10 -6 , take 0.5mL plated 7H11 solid medium, and culture at 37°C for 14 days; pick a single colony from the plate and use a luminescence detec...

experiment example 2

[0062] Experimental example 2. Synergistic experiment of low concentration TB47 on CFZ anti-Mab

[0063] 1. Experimental grouping

[0064] Utreated group: give equal volume of DMSO as a control

[0065] TB47-0.078 group: administer TB47 at a concentration of 0.078 μg / mL;

[0066] CFZ-2 group: administer CFZ at a concentration of 2 μg / mL;

[0067] CFZ-2+TB47-0.02 group: the administration concentration is TB47 0.02μg / mL and CFZ 2μg / mL;

[0068] CFZ-2+TB47-0.078 group: the administration concentration is TB47 0.078μg / mL and CFZ 2μg / mL;

[0069] The CFZ and TB47 used above were dissolved in DMSO for use.

[0070] 2. Experimental steps

[0071] (1) Mab cultivation

[0072] Insert the self-luminescent Mab into 5mL 7H9 liquid medium for culture, add glass beads to break up, and cultivate to the OD of the bacterial solution 600 When reaching 0.6-0.8, dilute the bacterial solution by 10 -6 , take 0.5mL plated 7H11 solid medium, and culture at 37°C for 14 days; pick a single co...

experiment example 3

[0077] Experimental example 3, detection of intracellular activity of the composition of the present invention

[0078] 1. Experimental grouping

[0079] Untreated group: given an equal volume of dimethyl sulfoxide as a control;

[0080] TB47 group: administer TB47 at a concentration of 1 μg / mL;

[0081] CFZ group: administer CFZ at a concentration of 2 μg / mL, which is the minimum inhibitory concentration in vitro;

[0082] CLR group: CLR was administered at a concentration of 4 μg / mL, which was the minimum inhibitory concentration in vitro;

[0083] ROX group: Administer ROX at a concentration of 4 μg / mL, which is the minimum inhibitory concentration in vitro;

[0084] CFZ+TB47 group: CFZ 1 μg / mL and TB47 2 μg / mL;

[0085] CLR+AMK group: administration of CLR4μg / mL and AMK8μg / mL;

[0086] CFZ+TB47+CLR group: CFZ 1 μg / mL, TB47 2 μg / mL and CLR 4 μg / mL;

[0087] CFZ+TB47+ROX group: CFZ 1 μg / mL, TB47 2 μg / mL and ROX 4 μg / mL;

[0088] The CLR, ROX, CFZ, and TB47 used above ...

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Abstract

The invention discloses novel application of a pyrazolo[1, 5-a]pyridine compound and a composition for treatment of Mycobacterium abscessus infection. The pyrazolo[1, 5-a]pyridine compound can be used for preparation of an anti-Mycobacterium abscessus synergist of clofazimine, combined use of the two can reach a synergistic effect, and a low concentration pyrazolo[1, 5-a]pyridine compound can reinforce the anti-Mycobacterium abscessus effect of clofazimine. The active components of the composition for treatment of Mycobacterium abscessus infection provided by the invention contain clofazimine and / or macrolide antibiotic, and the pyrazolo[1, 5-a]pyridine compound serving as a synergist. The composition has the characteristics of rapid effect, no relapse after treatment, and efficacy significantly superior to the combined use of clarithromycin and amikacin, and overcomes the shortcomings of easy generation of induced drug-resistance and poor long-term treatment effect in existing macrolide antibiotic clinical treatment.

Description

technical field [0001] The invention belongs to the field of compositions, and more specifically relates to a composition for treating mycobacterium abscessus infection. Background technique [0002] Mycobacterium abscessus (Mab) is a rapidly growing fungus belonging to the classification of nontuberculous mycobacteria (NTM), which mainly causes lung, skin and subcutaneous soft tissue infections, and can be treated in immunocompromised patients It can cause pulmonary diseases including cystic fibrosis, fibrotic bronchiectasis, and chronic obstructive pneumonia. Relevant investigations and studies have shown that Mab infection accounts for 82% of lung diseases caused by NTM. Mab can cause sporadic and explosive epidemics, and has become an important pathogen of nosocomial infections in recent years. It has been reported that in the past ten In the middle of the year, the number of infections due to Mab was on the rise in China, the United States, and Australia. [0003] Mab...

Claims

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Application Information

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IPC IPC(8): A61K31/4545A61K31/498A61K31/7048A61K31/7052A61P31/04
CPCA61K31/4545A61K31/498A61K31/7048A61K31/7052A61K2300/00
Inventor 张天宇刘洋谭守勇刘健雄李昕洁王邦兴周佩佩蔡杏珊郭玲敏刘燕刘志永唐运祥高亚敏姜火凤
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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