Bronchodilation by an inhaled VPAC2 receptor agonist in patients with stable asthma

Abstract

Background: The synthetic vasoactive intestinal peptide (VIP) analogue Ro 25-1553 is a selective VIP-PACAP type 2 (VPAC 2 ) receptor agonist that causes a bronchodilatory effect in guinea pigs in vivo. The effect of Ro 25-1553 given by inhalation to patients with asthma was studied and compared with that of a long acting β 2 adrenoceptor agonist. Methods: Twenty four patients with moderate stable asthma participated in a double blind, randomised, placebo controlled, crossover study. The primary variable was bronchodilatory effect (increase in forced expiratory volume in 1 second, FEV 1 ) after inhalation of Ro 25-1553 (100 µg or 600 µg) and formoterol (4.5 µg), respectively. Putative side effects were characterised by monitoring sitting blood pressure, serum potassium, electrocardiography and echocardiography. Results: Inhalation of 600 µg Ro 25-1553 caused a rapid bronchodilatory effect (geometric mean increase in FEV 1 compared with placebo) within 3 minutes of 6% (95% CI 4 to 9), as did inhalation of formoterol (8% (95% CI 5 to 10)). The corresponding maximum bronchodilatory effect during 24 hours was similar for 600 µg Ro 25-1553 (7% (95% CI 4 to 10)) and the reference bronchodilator formoterol (10% (95% CI 7 to 12)). However, for both doses of Ro 25-1553 the bronchodilatory effect was attenuated 5 hours after inhalation whereas formoterol still had a bronchodilatory effect 12 hours after inhalation. Neither Ro 25-1553 nor formoterol produced any clinically relevant side effects. No drug related difference in adverse events was observed. Conclusion: Inhalation of a synthetic selective VPAC 2 receptor agonist constitutes a promising approach for bronchodilation in patients with asthma.

Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts

“…Because RA appears to be a more rational target disease than OA for the development of antiinflammatory neuropeptides, the use of stable VPAC 2 receptor agonists is an attractive alternative to the use of parenteral short-lived neuropeptides (43). In this regard, the VPAC 2 agonist used in this study (RO25-1553) was recently tested in patients with asthma, without significant toxicity (44).…”

The selective PAC1 receptor agonist maxadilan inhibits neurogenic vasodilation and edema formation in the mouse skin

“…Plasma VIP level of patients with acute asthmatic exacerbations was found to be significantly lower compared to the controls and showed correlation with the response to therapy, suggesting that bronchodilatory and vasodilatory actions of the peptide are essential in this regard (Cardell et al, 1994;Said, 1982). Even in a human study, VPAC2 receptor was shown to exert inhibitory action against bronchial asthma (Lind en et al, 2003). After conjunctival allergic challenge, VIP was found to be elevated in allergic patients similarly to the lesional skin of patients with atopic dermatitis, indicating an immunomodulatory action of the peptide (Giannetti et al, 1992;Sacchetti et al, 2011).…”

Severe refractory asthma: an update

“…Vasoactive intestinal peptide analogues and potassium channel openers, i.e. agonists of bitter taste receptors (TAS2Rs), have shown bronchodilator effects [44][45][46]. Unfortunately, these drugs have had more potent vasodilator than bronchodilator effects.…”