FUTURE PHARMACOLOGICAL DIRECTIONS FOR ASTHMA AND COPD

Vasoactive intestinal peptide analogs

Vasoactive intestinal peptide (VIP) is a potent relaxant of constricted human airways in vitro but it is degraded in the airway epithelium and ineffective in asthmatic patients. A more stable cyclic analogue of VIP (Ro-25-1553) has a more prolonged effect in vitro ad in vivo and is effective in asthmatic patients by inhalation.

Prostaglandin E₂

PGE agonists that are selective for lung receptor subtypes are being considered for exploration as bronchodilator/anti-inflammatory drugs.

Atrial natriuretic peptides (ANP)

Intravenous infusion of ANP produces a significant bronchodilator response and protects against bronchoconstriction induced by inhaled broncoconstrictors such as methacholine. ANP, however, is a peptide and subject to rapid enzymatic degradation. A related peptide, urodilatin, is less susceptible to degradation and has a longer duration of action. It is as potent as salbutamol when given intravenously.

Phosphodiesterase 4 (PDE4) inhibitors

Based on the actions of theophylline, there has been interest in developing PDE4 inhibitors. In animal models of asthma, PDE4 inhibitors reduce eosinophil infiltration and airway hyperresponsiveness to allergens. The PDE4 inhibitor cilomilast has been clinically tested in COPD, but the drug causes emesis, which is a common side effect with this drug class (this could be due to inhibition of PDE4D). There is hope that selective inhibitors of PDE4B might have more therapeutic potential.

Pharmacogenomics

Current data suggest that the 16^th amino acid position of the ₂ adrenergic receptor is associated with a major, clinically significant pharmacogenomic effect, namely down regulation of the receptor and responsiveness of patients using -agonists. Investigations of the effect of this and other polymorphisms on the response to long-acting -agonists is currently being conducted.

Category: Pharmacology Notes