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  • Bambuterol is a prodrug of the agonist terbutaline


    Bambuterol is a prodrug of the β2-agonist terbutaline. It is commonly prescribed for hif pathway and chronic obstructive pulmonary disease (COPD) with once daily dosing and documented clinical safety (Olsson and Svensson, 1984; D\'Alonzo et al., 1995; Sitar et al., 1993). It has been reported previously that bambuterol increases the level of high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia (FlorÉN et al., 1997) and in patients with type II diabetes mellitus (Bitzén et al., 1993) after six to eight weeks of treatments. However, the cholesterol lowering effect of bambuterol, particularly on the level of LDL-C, was only marginal and inconclusive (FlorÉN et al., 1997; Bitzén et al., 1993). Bambuterol is a chiral drug with R- and S-enantiomers (Gazić et al., 2006). The uncertain LDL-C lowering effect of bambuterol in the previous studies might be related to the inefficacy of racemic bambuterol due to the different biological effects of enantiomers (Waldeck, 1993). Animal study clearly suggested a cholesterol lowering effect of R-bambuterol in the treatment of tyloxapol-induced hyperlipidemia in mice (Cheng and Tan, 2009). In addition, the previously inconclusive effects on plasma lipid of bambuterol were shown in long term studies without a demonstration of a dose relationship.
    Discussion High plasma level of LDL-C is a major risk factor for coronary heart disease. Conventional cholesterol-lowering treatments such as statin are only modestly effective. Bambuterol is a type of β2-agonist commonly used for the treatment of asthma and COPD with the advantage of once daily dosing and favorable side effect profile (Olsson and Svensson, 1984; D\'Alonzo et al., 1995; Sitar et al., 1993). In this open-label, randomized phase I clinical trial, we showed that R-bambuterol significantly lower the plasma levels of LDL-C, and marginally raise the ratio of ApoA1/ApoB, an indicator of HDL-C/LDL-C, in less than 2h after administration and in a dose-dependent manner. We also showed that R-bambuterol is more potent in cholesterol lowering than rac-bambuterol. The lipid-lowing effects of R-bambuterol sustained after 24h of treatment and after multiple doses. R-bambuterol therefore is an attractive alternative or complement for other treatments to decrease plasma LDL-C levels, and would be especially beneficial for those patients who also suffering from COPD. The lipid-lowering effect of R-bambuterol was dose-dependent (Fig. 2). A single dose of R-BMB significantly lowered the levels of LDL-C and marginally raised the ratio of ApoA1/ApoB at Tmax (less than 2h), therefore achieved a favorable lipid lowering effect in a short term. Correlation between Cmax of R-bambuterol and the corresponding lipid levels at Tmax further supported the lipid-lowering effect of R-bambuterol (Suppl. Fig. 1). The lipid-lowering effect of R-bambuterol was also observed at 24h after dosing, which appeared to be weaker. At 24h, the concentration of plasma R-bambuterol was less than one tenth of that at Tmax (Table 2). It indicated that multiple mechanisms underlie the lipid-lowering effects of R-bambuterol, namely the initial effects and the lagging effects. The initial effects were possibly related to the inhibition of butyrylcholinesterase (Gazić et al., 2006). Butyrylcholinesterase activity has been associated with cardiovascular risk factors, including the level of LDL-C (Stojanov et al., 2011). The lagging effects were unlikely to be related to terbutaline since the concentration of terbutaline at 24h after treatment (Table 2) was much lower compared to the previous study (Hooper et al., 1981). In the multiple-dose 5mg R-bambuterol group, the reduction in LDL-C and the increase in ApoA1/ApoB at 24h after dose 6 and dose 7 were comparable to those in the single-dose group. These results suggested potential long-term cholesterol-lowering effects of R-bambuterol. The lipid-lowering effects of R-bambuterol and rac-bambuterol were compared. At Tmax, percentage changes in LDL-C, TC, ApoB and ApoA1 in the 10mg rac-bambuterol group were similar to those in the 5mg R-bambuterol group, but only approximately half of those in the 10mg R-bambuterol group (Fig. 3), suggesting that R-bambuterol was more potent. R-bambuterol made up half of rac-bambuterol. It is possible that R-enantiomer of bambuterol is the eutomer which accounted for most of the observed cholesterol-lowering effects of rac-bambuterol. Similar findings in previous study in guinea pigs showed that the protective effect of R-bambuterol from histamine induced bronchoconstriction is stronger than that of rac-bambuterol (Cheng and Tan, 2009).