Bronchoprotection by Olodaterol Is Synergistically Enhanced by Tiotropium in a Guinea Pig Model of Allergic Asthma

Abstract

The novel once-daily b 2 -agonist bronchodilator drug olodaterol has recently been shown to be effective in patients with allergic asthma for .24 hours. An increased cholinergic tone common to these patients may decrease the effectiveness of b 2 -agonists. This could provide a rationale for combination therapy with olodaterol and the long-acting anticholinergic tiotropium to aim for a once-daily treatment regimen. In guinea pigs, we evaluated the protective effects of olodaterol, alone and in combination with tiotropium, on airway responsiveness to histamine, which is partially mediated by a cholinergic reflex mechanism. In addition, using a guinea pig model of acute allergic asthma, we examined the cooperative effects of these bronchodilators on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyper-responsiveness (AHR) to histamine, and airway inflammation. It was demonstrated that the protective effect of olodaterol against histamine-induced bronchoconstriction was synergistically enhanced and prolonged in the presence of tiotropium. In addition, tiotropium synergistically augmented both the reversal of and the protection against the allergeninduced AHR after the EAR by olodaterol. Olodaterol and tiotropium were highly effective in inhibiting the magnitude of the allergen-induced EAR and LAR, and both reactions were fully inhibited by the combination of these drugs. It is remarkable that these effects were not associated with an effect on inflammatory cell infiltration in the airways. In conclusion, the results indicate that combination therapy with olodaterol and tiotropium may be highly effective in the treatment of allergen-induced asthmatic reactions and AHR.

Characterisation of a murine model of the late asthmatic response

“…This suggests that airway sensory nerves are not involved in the mechanisms driving the LAR in the mouse model. This is in contrast to previous findings in the more established Brown Norway rat model of LAR, but also in a Guinea-pig model of LAR [11, 33]. When two separate colonies of TRPA1 knockout mice were utilized there was still no attenuation in the LAR response when compared with wildtype controls.…”

Crosstalk between beta-2-adrenoceptor and muscarinic acetylcholine receptors in the airway

“…An increasing number of studies in cell-based and animal models of lung disease combining LAMA and LABA are currently being performed and should be published in the near future. The data at the functional level are encouraging and the molecular mechanisms require further exploration [71;72]. …”

The evidence on tiotropium bromide in asthma: from the rationale to the bedside

“…Eosinophilic recruitment was affected also by a concomitant administration of tiotropium and budesonide or ciclesonide in animal models of asthma [103, 104]. Recent evidences in guinea pig models of asthma demonstrated a synergistic action between olodaterol and tiotropium when administered together; in fact, tiotropium supported and enhanced the protection against allergen-induced hyper-responsiveness, fully inhibiting the early and late asthmatic reaction [105]. The latter mechanism may be explained by the evidence that during charbacol induced inflammation of human fibroblasts, tiotropium seem to sustain olodaterol in restoring c-AMP levels in airway fibroblasts, cooperating to decrease the inflammatory response [93].…”