A Preliminary Study On The Cholesterol-lowering Effect And The Mechanism Of The New Drug R-bambuterol

Hyperlipidemia is a modifiable risk factor for a variety of cardiovascular and cerebrovascular diseases,which pose serious threats to human life.Bambuterol is a racemic drug normally prescribed for the treatment of asthma.The R-form bambuterol(R-BMB)is the levorotatory isomer of bambuterol,it is proved to be safer and more potent than its racemic mixture.A phase I clinical trial had showed that R-BMB is effective in reducing blood lipids.Nevertheless,the mechanism of action of R-BMB is still unknown and further investigation is needed.1)Clinical data analysis showed that R-BMB can effectively reduce the concentrations of TC and LDL-C in blood,showing good therapeutic effect against high blood lipid disorder.Analysis of blood lipid collected at 24 h after administration of R-BMB indicated that R-BMB reduces the concentration of LDL-C through reducing the number of sd-LDL particles.The results also showed that R-BMB effectively inhibited the activity of BuChE.Moreover,the changes in enzyme activity of BuChE were related to the changes in concentrations of Apo B and sd-LDL.2)Hyperlipidemia rabbit models were established using a high fat diet containing 1%(w/w)cholesterol in three weeks and employed to estimate the lipid reduction effect of R-BMB.The results showed that high doses of R-BMB could effectively reduce the concentrations of TC and LDL-C,showing a similar therapeutic effect with atorvastatin,and the effects on reducing high blood lipids of R-BMB was dose dependent.Compared with the hyperlipidemia control group,the BuChE inhibitor ISO-OMPA alone can effectively reduce blood lipid concentrations.The ?2 receptor agonist R-terbutaline,which is the prodrug of R-BMB,had no effect on blood lipids.The main reason for the lipid-lowering effect of R-BMB was the inhibition of BuChE activity.3)After measuring the BuChE activity in plasma of the blank control group,model group,high dose of R-BMB group and ISO-OMPA group,we found that the plasma BuChE activity of the high dose R-BMB group and ISO-OMPA group were significantly inhibited.The results also showed that the activity of BuChE and the concentration of R-BMB in plasma had a negative correlation,and it maybe connected with the reducing blood lipid concentration.The activity of BuChE showed that R-BMB and ISO-OMPA can effectively reduce the activity of free and membrane-bound BuChE in liver and heart compared with the model group.After measuring the activity of ALT and AST in plasma,the results showed that the atorvastatin can raise the concentration of ALT but R-BMB cannot.The results also showed that R-BMB can reduce the concentration of blood glucose,but have no effects on serum kalium.HE staining analysis of the liver and heart of the blank group,model group,R-BMB high dose group and atorvastatin group found that heart slices showed there are no obvious changes between groups,but liver slices showed that the R-BMB had some protective effects on these tissues.In conclusion,R-BMB had protective effects on the liver.