Synergistic Bronchodilatory Effects of Dexpirronium and Formoterol in Guinea Pigs

The antimuscarinic agent dexpirronium and the ß2-agonist formoterol are both potent bronchodilators. Aim of this study was to analyse their combined effect in an in vivo model. Guinea pigs were allocated to control (10 mg/kg lactose) and drugs in lactose: dexpirronium (1, 10 μg/kg), formoterol (1, 10 μg/kg) or dexpirronium and formoterol (1 μg/kg each; n = 6/group). The animals were anaesthetized (urethane 2 g/kg ip) and mechanically ventilated over the cannulated trachea. Test drugs were given intratracheally 10 min before 10 μg/kg acetylcholine (ACh) was applied iv. ACh applications were repeated every 10 min. The respiratory back pressure was determined at baseline and after each ACh application. Statistical analysis was done with ANOVA and Dunnett's post hoc test (treatment vs. control). Individually applied compounds in a dosage of 1 μg/kg showed only marginal effects 10, 30 and 60 min after application on the pulmonary resistance (290, 369, 336 cm H2O for dexpirronium and 264, 313, 288 cm H2O for formoterol compared to 289, 481, 546 cm H2O for the control). Ten-fold higher concentrations of dexpirronium and formoterol reduced the resistance at 60 min to 183 and 194 cm H2O (p < 0.05). A concentration of 1 μg/kg of each drug in combination exerted significant protection from bronchoconstriction already at 30 min with 106 cm H2O (p < 0.05) and at 60 min with 91 cm H2O (p < 0.01). The combination of dexpirronium and formoterol interacts in an over-additive manner showing at least same effects with 1 μg/kg as the individual drugs with the 10-fold dosage.