Comparison of bronchodilating and antiinflammatory activities of oral formoterol and its (R,R)-enantiomers.
OBJECTIVE
To compare the bronchodilating and antiinflammatory effects of oral racemic formoterol (rac-FMT) and (R,R)-formoterol (R,R-FMT).


METHODS
The changes of lung resistance (RL), dynamic lung compliance (Cdyn), and the accumulation of inflammatory cells in bronchoalveolar lavage fluids (BALF) induced by ovalbumin aerosol in sensitized guinea pigs and mice were investigated in vivo.


RESULTS
Mean value increase of RL and mean value reduction of Cdyn from 1 to 30 min after antigen challenge were up to 101 %+/-34 % and 42 %+/-7 %, respectively. rac-FMT 0.5, 1.0, and 2.0 mg/kg, and R,R-FMT 0.25, 0.5, and 1.0 mg/kg ig, induced dose-related inhibition of the bronchoconstrictive responses to aerosolised ovalbumin. ID50 (95% confidence limits, 95 % CL) value of rac-FMT on RL maximal increase and Cdyn maximal reduction at 5 min were 0.64 (0.54-0.76) and 1.02 (0.88-1.18) mg/kg, respectively. For R,R-FMT they were 0.46 (0.40-0.53) and 0.52 (0.45-0.61) mg/kg, respectively. ID50 (95 % CL) value of rac-FMT on RL mean increase and Cdyn mean reduction from 1 to 30 min were 0.96 (0.86-1.07) and 1.59 (1.32-1.92) mg/kg, respectively. For R,R-FMT they were 0.52 (0.45-0.59) and 0.43 (0.37-0.51) mg/kg, respectively. Ovalbumin-aerosol challenge induced an increase of inflammatory cells in BALF in sensitized mice. rac-FMT and RR-FMT caused a dose-dependent and almost complete inhibition at 2.0 mg/kg. ID50 (95 % CL) of rac-FMT on the number of total inflammatory cells and eosinophil in BALF were 1.48 (1.22-1.81) and 0.80 (0.62-1.04) mg/kg, respectively. ID50 (95 % CL) of RR-FMT were 0.80 (0.57-1.13) and 0.60 (0.43-0.83) mg/kg, respectively.


CONCLUSIONS
R,R-FMT protected lung against increase of RL and reduction of Cdyn induced by bronchial challenge of ovalbumin in the asthma model of guinea pigs, and inhibited airway inflammation in the sensitized mice. Efficacy of R,R-FMT was approximately 2-fold than that of rac-FMT.
Xie
Qiang-Min
QM
Zhejiang Respiratory Drugs Research Laboratory of State Drugs Administration of China, Medical School of Zhejiang University, Hangzhou 310031. xieqm@zju.edu.cn
Chen
Ji-Qiang
JQ
Shen
Wen-Hui
WH
Yang
Qiu-Huo
QH
Bian
Ru-Lian
RL
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001249:Asthma / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004804:Eosinophils / Q000473:pathology; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D000068759:Formoterol Fumarate; D006168:Guinea Pigs; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D007958:Leukocyte Count; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D051379:Mice; D010047:Ovalbumin; D013237:Stereoisomerism
D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D004983:Ethanolamines; D010047:Ovalbumin; D000068759:Formoterol Fumarate