Anti-asthmatic Effect Of β₂ Agonist Eutomer Combined With Ipratropium Bromide On Sensitized Mice

Salbutamol and terbutaline are short-actingβ₂ receptor agonist in clinical therapy.They both have chiral centers R-enantiomer and S-enantiomer.Studies report that the R-enantiomer are active,while S-enantiomers are related to side effects.We compare the therapeutic effects of R-salbutamol with ipratropium bromide and R-terbutaline with ipratropium bromide in airway hyperresponsiveness,airway inflammation and airway remodeling on acuteand chronic asthmatic animol model.The thesis consists of following parts:（Ⅰ）The R-terbutaline of high chemical purity and high optical purity was synthesized.R-terbutaline combined with ipratropium bromide as prepared and detected by high performance liquid chromatography.The detection results showed that the components can be completely separated.The mixture solutions were stabled within 30 minutes.（Ⅱ）In animal models of acute asthma,the therapeutic effect of the combined agent is better than that of single compound agent.The combination of R-salbutamol and ipratropium bromide had the best therapeutic effect,which greatly alleviated the airway hyperresponsiveness caused by methacholine stimulation.The lung histopathological examination showed that bronchospasm,inflammatory cell infiltration,glycogen secretion and collagen deposition were improved by the treatment with combination of R-salbutamol and ipratropium bromide.In addition,the total number of white blood cells and the proportion of eosinophils in the whole blood,the expression levels of OVA-s Ig E in serum,Th2-related inflammatory factors in bronchoalveolar lavage fluid（BALF）,and airway inflammation-related factors NF-κB m RNA were significantly reduced after treatment with combination of R-salbutamol and ipratropium bromide;（Ⅲ）In order to better simulate the situation of clinical administration,in the drug treatment of chronic asthma model,the animal’s mouth and nose were exposed to the self-made atomization chamber.And the drugs were dispersed in the air and delivered into the animal’s lungs through normal tidal breathing.By establishing a detection method to calculate the amount of lung deposition of drugs in mice,the amount of administration in chronic asthmatic mice was clear.（Ⅳ）In the animal model of chronic asthma,various indicators were tested at the points at the second,fourth,and sixth week of administration to monitor the effects of the drugs in different periods of chronic asthma.The results showed that in the 2nd week,the treatment with combination of R-salbutamol with ipratropium bromide showed a dominant effect,but the effect was greatly weakened in the 4th and 6th weeks.In contrast,the combination of R-terbutaline with ipratropium bromide showed a better therapeutic effect than the combination of R-salbutamol with ipratropium bromide from the fourth week.By the 6^th week,compared with the treatment of R-salbutamol combined ipratropium bromide,the proportion of eosinophils in the blood,OVA-s Ig E in serum,Th2 in BALF The expression levels of related inflammatory factors and NF-κB m RNA were significantly reduced by the treatment of R-terbutaline combined ipratropium bromide.In addition,in the lung histopathological,examination the peribronchial inflammatory cell infiltration,bronchospasm and pulmonary fibrosis were also significantly reduced by the administration of R-terbutaline combined ipratropium bromide.We have found that in animal models,the short-actingβ2 receptor agonist euteomer combined with ipratropium bromide has better therapeutic effects than single administration,which is manifested in airway hyperresponsiveness,airway inflammation,and airway remodeling aspect.Secondly,the different advantages are presented in the treatment of acute asthma and chronic asthma between the treatment of R-salbutamol combined ipratropium bromide and R-terbutaline combined ipratropium bromide.