Use of r-enantiomer beta2-agonists for prevent and treatment of pulmonary inflammation and inflammatory remodeling for reduced adverse effects

A technology of toxic side effects and agonists, which is applied in the direction of medical preparations containing active ingredients, respiratory diseases, organic active ingredients, etc., and can solve problems such as weakening, reduced therapeutic effect, and immunomodulatory activity to be determined

Pending Publication Date: 2021-12-31
谭文
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the relative contribution of β2-agonists used as bronchodilators in the treatment of asthma to the ultimate immunomodulatory activity and their overall therapeutic effect remains to be determined
[0012] Furthermore, possible conflicting effects between the R and S enantiomers of β2 agonists are not well documented clinically
When using a racemic β2 agonist, the possible therapeutic effect of the R-enantiomer is reduced or attenuated by the opposite effect of its S-enantiomer

Method used

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  • Use of r-enantiomer beta2-agonists for prevent and treatment of pulmonary inflammation and inflammatory remodeling for reduced adverse effects
  • Use of r-enantiomer beta2-agonists for prevent and treatment of pulmonary inflammation and inflammatory remodeling for reduced adverse effects
  • Use of r-enantiomer beta2-agonists for prevent and treatment of pulmonary inflammation and inflammatory remodeling for reduced adverse effects

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] OVA sensitization / challenge Asthma model mice were sensitized and challenged with ovalbumin (OVA) or saline. Briefly, mice were sensitized on days 0 and 14 by intraperitoneal injection of 0.2 mL of 2% aluminum hydroxide (alum) gel containing 10 μg of OVA antigen. On the 21st day, the 22nd day and the 23rd day, 1% OVA saline (0.01 g / mL) was nebulized by a nebulizer (PARI Turbo boy) for induction for 20 minutes. On day 26, the rats were stimulated by nebulizing normal saline (0.05 g / mL) containing 5% OVA for 20 minutes. The control group was intraperitoneally injected with 0.2 mL of normal saline containing 2% alum on days 0 and 14, and then nebulized normal saline without OVA for 20 minutes on days 21, 22, 23 and 26.

Embodiment 2

[0061] Methods: Measurement of Airway Responsiveness to Methacholine

[0062] Airway responsiveness to methacholine (MchCH) was assessed in conscious, freely moving, spontaneously breathing mice on day 28 by whole body plethysmography (Buxco Electronics Inc.). Mice were challenged with ultrasonic nebulization inhalation of normal saline or increased Mch concentration (2, 10, 20 mg / mL) for 2 min. Before Mch challenge, mice were inhaled with 20 μL of drug or saline aerosol due to the short-acting bronchodilation effect of terbutaline. The degree of bronchoconstriction is expressed as the airway constriction index (PenhENH), a calculated dimensionless value that correlates with measures of airway resistance, impedance, and intrathoracic pressure. The Penh value within 4 minutes was recorded and averaged after each atomization stimulation.

[0063] Sample Collection and Whole Blood Analysis

[0064] After methacholine stimulation, mice were anesthetized and blood was collected ...

Embodiment 3

[0092] Effects of R- and D-(S)-terbutaline on PAS staining in lung tissue

[0093] The present invention discloses that in OVA-sensitized / stimulated asthmatic mice, there is a marked inflammatory response and exacerbation of histopathological changes, including increased secretion of connective tissue, mucin, fibroblasts, smooth muscle and collagen, and alveolar and cellular The septal thickness of the bronchial walls increases. In addition, the bronchioles were also markedly constricted. Dextro(S)-terbutaline further enhanced these symptoms. Treatment with L(R)-terbutaline significantly improved these changes.

[0094]

[0095] Figure 5, Periodic acid Schiff (S grade) staining of lung tissue (x200).

[0096] Samples from saline (control), OVA, OVA+R-, S or RS terbutaline treated mice. Subepithelial matrix glycoproteins, collagen, fibroblasts, and inflammatory infiltration (model) were further deteriorated in the dextro(S)-terbutaline group. L(R)-Terbutaline significan...

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PUM

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Abstract

This invention disclosed new use of R-terbutaline and other R-enantiomer [beta]2-agonists as immune-modulators for treatment of bronchia-lung inflammatory symptoms or inflammatory fibrosis remolding. This invention also disclosed new use of R-terbutaline and R-[beta]2-agonists for reduced adverse effects related to racemic or S-enantiomer [beta]2-agonists including airway hyper responsiveness and airway fibrosis.

Description

[0001] Cross references to related patent applications [0002] This patent application claims priority to U.S. Provisional Patent Application No. 62844398, filed May 7, 2019. [0003] This patent application is also a partial continuation of International Application No. PCT / US19 / 50120 on September 7, 2019 (a continuation of US Patent Application No. 62728800 on September 9, 2018). [0004] field of invention [0005] The present invention discloses L-(R)-terbutaline enantiomer and other similar L-(R)-enantiomer β2 receptor agonists as immunomodulators for treating lung-bronchial inflammation and / or inflammatory remodeling, Novel uses for simultaneously reducing toxic side effects associated with long-term use of racemic (RS)-β2 receptor agonists. [0006] Background of the invention [0007] Terbutaline is a beta2 agonist that has been used for more than 30 years in the treatment of asthma and in some countries for anti-tocolytic treatment of preterm birth. Terbutaline mol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/167A61K31/44A61K31/56A61P11/08
CPCA61K31/137A61K9/00A61K45/06A61K31/46A61P11/00A61K2300/00A61K31/138A61K31/167A61K31/27A61K31/40A61K31/439A61K31/44A61K31/4704A61K31/538A61K31/5386A61K31/55A61K31/573
Inventor 谭文
Owner 谭文
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