Chest
P2Y2 Receptor Agonists: A New Class of Medication Targeted at Improved Mucociliary Clearance
Section snippets
Pharmacology of P2Y2 agonists
The role of purinergic receptors and the description of their pharmacology were originally proposed by Burnstock and colleagues14,15 by way of describing responses that previously had been defined as nonadrenergic and noncholinergic. Adenosine triphosphate (ATP) was proposed as the natural ligand of these receptors. On further study, it was proposed that purinergic receptors should be subdivided into P1 receptors, which respond to adenosine and are coupled to adenylate cyclase, and P2
Clinical Studies With P2Y2 Agonists
The promising results in preclinical models led to a number of pilot human studies evaluating the effects of P2Y2 receptor agonists on sputum production and MCC as well as the therapeutic potential in a variety of airway disorders including CF and primary ciliary dyskinesia. Initial studies were performed using the endogenous ligand compound UTP. The administration of UTP in doses varying from 20 to 180 mg via nebulizer resulted in significant increases in the amount of sputum produced by
Challenges in Developing P2Y2 Agonists
As was alluded to in the introduction, the clinical development of mucoactive drugs for chronic bronchitis has been marked by several ambitious efforts without success. Perhaps the paramount challenge is that there are currently no direct, noninvasive objective methods with which to assess the quantity, character, and distribution of airway secretions in humans. As a result, indirect measures such as sputum volume, lung function, and MCC have been used as surrogate markers. These indirect
Conclusion
In conclusion, P2Y2 receptor agonists are a new class of compounds that are being developed for the treatment of a variety of conditions in which MCC is impaired, including chronic bronchitis and CF. Early research to date shows promise that dose-related increases in MCC and sputum production can be achieved with either UTP or INS365. Although the benefits of enhanced MCC will likely be improved symptoms and possibly even lower long-term exacerbation rates, the short-term pharmacologic actions
REFERENCES (33)
- et al.
A controlled trial of ambroxol in chronic bronchitits
Chest
(1987) - et al.
Orally administered N-acetylcysteine may improve general well-being in patients with mild chronic bronchitis
Respir Med
(1994) The National Mucolytic Study: results of a randomized, double-blind, placebo-controlled study of iodinated glycerol in chronic obstructive bronchitis
Chest
(1990)- et al.
Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease
Cell
(1998) - et al.
Synthesis and P2Y receptor activity of a series of uridine dinucleoside 5′-polyphosphates
Bioorg Med Chem Lett
(2001) - et al.
Optimal assessment and management of chronic obstructive pulmonary disease (COPD)
Eur Respir J
(1995) - et al.
Prevention of acute exacerbations of chronic obstructive bronchitis with carbocysteine lysine salt monohydrate: a multicenter, double-blind, placebo-controlled trial
Respiration
(1996) - et al.
Evaluating the efficacy of mucoactive aerosol therapy
Respir Care
(2000) Oral N-acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airways obstruction
Thorax
(1985)Long-term oral acetylcysteine in chronic bronchitis, a double-blind controlled study
Eur J Respir Dis
(1980)