Chest
Volume 121, Issue 5, Supplement, May 2002, Pages 201S-205S
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P2Y2 Receptor Agonists: A New Class of Medication Targeted at Improved Mucociliary Clearance

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Chronic bronchitis is in part characterized by mucus hypersecretion and the inability to clear airways of mucus. Despite years of research in this area, to date there are no pharmacologic therapies available to enhance or promote mucociliary clearance. P2Y2 receptor agonists are a new class of mucoactive compounds that are currently under development for this purpose. This article will review the pharmacology of P2Y2 receptor agonists, review the clinical studies performed to date, and highlight the challenges inherent in the development of therapies with these pharmacologic properties.

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

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