Dual bronchodilatory and pulmonary anti‐inflammatory activity of RO5024118, a novel agonist at vasoactive intestinal peptide VPAC₂ receptors

Abstract

Vasoactive intestinal peptide is expressed in the respiratory tract and induces its effects via its receptors, VPAC1 and VPAC2. RO5024118 is a selective VPAC2 receptor agonist derived via chemical modification of an earlier VPAC2 agonist, RO0251553. In the present studies, we characterized the pharmacological activity of RO5024118. EXPERIMENTAL APPROACHStability of RO5024118 to human neutrophil elastase was assessed. Bronchodilatory activity of RO5024118 was investigated in guinea pig and human isolated airway smooth muscle preparations and in a guinea pig bronchoconstriction model. Pulmonary anti-inflammatory activity of RO5024118 was investigated in a lipopolysaccharide mouse model and in a porcine pancreatic elastase (PPE) rat model. KEY RESULTSRO5024118 demonstrated increased stability to neutrophil elastase compared with RO0251553. In human and guinea pig isolated airway preparations, RO5024118 induced bronchodilatory effects comparable with RO0251553 and the long-acting b-agonist salmeterol and was significantly more potent than native vasoactive intestinal peptide and the short-acting b-agonist salbutamol. In 5-HT-induced bronchoconstriction in guinea pigs, RO5024118 exhibited inhibitory activity with similar efficacy as, and longer duration than, RO0251553. In a lipopolysaccharide-mouse model, RO5024118 inhibited neutrophil and CD8 + cells and myeloperoxidase levels. In rats, intratracheal instillation of PPE induced airway neutrophilia that was resistant to dexamethasone. Pretreatment with RO5024118 significantly inhibited PPE-induced neutrophil accumulation. CONCLUSIONS AND IMPLICATIONSThese results demonstrate that RO5024118 induces dual bronchodilatory and pulmonary anti-inflammatory activity and may be beneficial in treating airway obstructive and inflammatory diseases.

Effect of the Mixed Phosphodiesterase 3/4 Inhibitor RPL554 on Human Isolated Bronchial Smooth Muscle Tone

“…The use of human isolated bronchial rings to investigate the actions of bronchodilator drugs is well established and considered predictive of the effectiveness of such drugs clinically, and we, as well as a number of other laboratories, have previously demonstrated a range of studies with different drug classes in this model (Matera et al, 2009(Matera et al, , 2011aTannu et al, 2010;Calzetta et al, 2011;Cazzola et al, 2011;Hewson et al, 2012;Rogliani et al, 2013). The inhibitory effect of RPL554 was maintained for up to 5 hours after termination of drug exposure, confirming the long duration of action of this compound in human airways, which we have subsequently confirmed in patients with asthma or chronic obstructive pulmonary disease (COPD) when this drug is nebulized to patients, confirming the predictability of our model (Cazzola et al, 2013;Franciosi et al, 2013).…”

Beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide: Synergy of triple combination therapy on human airway smooth muscleex vivo

“…In the control groups, cumulative concentrations of vehicle were administered and used as time control. At the end of the experiments, papaverine plus atropine (both 100 μM) was added to the baths to determine the maximal relaxant response achievable for each isolated airway and thus provide a standard to which the relaxation induced by the treatments in each tissue can be compared (Tannu et al, ). These experiments were carried out in both medium isolated organ bath and PCLS systems, in order to evaluate the relaxant response associated with the ASM strength in medium bronchi and related to the increasing of intra‐luminal area of small airways (Matera et al, ).…”

Impact of enteral nutrition on postoperative immune function and nutritional status

“…The IL-6 levels in the study group were lower than in the control group on the tenth day after the operation (P < 0.05; Table 4). stages after surgery (Bonekamp et al, 2010;Tannu et al, 2010;Crowther et al, 2012). In this study, gastric cancer patients received EN support with different nutritional preparations during different perioperative periods, which were chosen depending on functional conditions of the digestive tract (Ichimaru et al, 2012).…”