A Study Of Lipid-lowering Effect Of R-bambuterol In Animal Models And Healthy Chinese Volunteers

Background:Hyperlipidemia is a metabolic disease with abnormally elevated levels of lipids in the blood. The incidence of hyperlipidemia is high among people. However, current pharmacological treatment of hyperlipidemia cannot reach the goals of lipid levels. Therefore, it is a need to develop new candidate drugs for the treatment of hyperlipidemia. R-bambuterol(R-BMB), the levo-enantiomer of BMB, was reported to have better druggability and safety than BMB, and BMB was reported to have effect in regulating blood lipid. So it is significant to investigate the blood lowering effet of R-BMB. Therefore, we studied the lipid-lowering effect of R-BMB, in both animal models and in healthy volunteers.Objectives:To investigate the lipid-lowering effect of R-BMB in animals, Apolipoprotein E knock-out(Apo E-/-) hyperlipidemic mice and high-cholesterol diet induced hyperlipidemic rabbits were used. The lipid-lowering effect of R-BMB was further investigated in a phase I clinical trials in which healthy volunteers were administered with different doses of R-BMB.Methods:(1) ApoE hyperlipidemic mice were gavaged with different doses of R-BMB, and the lipid profiles were measured at different time.(2) Rabbits were fed with high-cholesterol diet to induce hyperlipidemia. The hyperlipidemia rabbits were given normal saline and R-BMB respectively for 4 weeks, and the lipid-lowering effect of R-BMB was analyzed.(3) Blood of the healthy volunteers from a randomized, open-label phase I clinical for R-BMB were collected. The lipid profiles were measured using automatic biochemical analyzer, and the lipid-lowering effect of R-BMB was analyzed.Results:(1) R-BMB had no significant effect on decreasing the levels of TC, TG, LDL-C and HDL-C in Apo E-/- mice.(2) R-BMB decreased the levels of TC and LDL-C in high-cholesterol diet induced hyperlipidemic rabbits, while had no significant effects on TG and HDL-C..(3) After administered with different doses of R-BMB, the levels of LDL-C、TC and HDL-C in the blood of the volunteers decreased at Tmax, with a dose-dependent pattern. R-BMB showed stronger effect than BMB in decreasing LDL-C. The levels of TG were not significantly changed after R-BMB or BMB administration.Conclusion: Although no significant lipid-lowering effect was observed in Apo E-/- mice, R-BMB decreases the cholesterol levels, especially LDL-C in both high-cholesterol diet induced hyperlipidemic rabbits and healthy volunteers. Continued administration of R-BMB showed no effects on the levels of HDL-C and TG. R-BMB showed stronger lipid-lowering effect than BMB.