Uridine 5'-triphosphate (UTP) is a naturally occurring agonist for P2[Ysub2] receptors forward the apical surface of ciliated respiratory epithelium.
Uridine 5'-triphosphate (UTP) is a naturally occurring agonist for P2[Ysub2] receptors forward the apical surface of ciliated respiratory epithelium. UTP stimulates salt and water transport and cilia beat oftenness in human airway epithelium in vitro. Single, inhaled doses of UTP stimulate mucociliary clearance in conscious, intubated sheep and in patients with mild chronic bronchitis (smoker and former smokers) suggesting that UTP may be useful for obtaining deep-lung sputum specimens suitable for diagnostic purposes
consideration objective: UTP is being unraveled for the cytologic diagnosis of lung cancer in a less degree than the compound number INS316 Solution for Inhalation (Inspire Pharmaceuticals; Durham, NC) Its ability to improve the quality of expectorated sputum was experimented in the current study.
Design: Placebo-controlled, double-blind, escalating two-period cross-over study
Setting: Outpatient volunteers
Patients or participants: Twenty-six patients with mild chronic bronchitis.
Intervention: Patients attempted to expectorate a specimen spontaneously, following a single inhaled dose of INS316 (10 to 180 mg) and following placebo.
Measurements and results: Sputum weight, sputum confined apartment content, spirometry, and oxyhemoglobin saturation. barely 28% of these patients were able to expectorate a macrophage-containing, deep-lung specimen spontaneously or following inhalation of placebo. In contrast, 85% of the patients were able to make a specimen following inhalation of INS316. The average weight of the sputum expectorated was increased fourfold by way of placebo and 10-fold by INS316. A mild transient decrease in pulmonary function was observ following INS316 administration.
Conclusion: A single dose of INS316 safely improves the ability of patients with mild chronic bronchitis to expectorate a deep-lung sputum specimen suitable for cytologic evaluation.
guide words: diagnostic tests; lung neoplasms; mucociliary clearance; purinergic P2; receptors; uridine triphosphate
Abbreviations: MMEF = maximal mid-expiratory follow rate; UTP = uridine 5'-triphosphate
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The P2Y family of receptors is comprised of 7-transmembrane G-protein-coupled receptors for which the naturally occurring ligands appear to be purine and pyrimidine nucleotides. The P2[Ysub2] receptor is construct on the apical (lumenal) surface of a variety of airway epithelia, including the ciliated epithelial enclosed spaces and goblet cells of the trachea, bronchi, and bronchioles. Evidence is accumulating indicating that this receptor coordinates various activities involved in mucociliary clearance in the lung Nucleotide agonists of the P2[Ysub2] receptor, as it was as uridine 5'-triphosphate (UTP), have been shown to stimulate chloride secretion (and water, secondarily) in a concentration-dependent manner in primary refinements of human airway epithelial enclosed spaces (1,2) These nucleotides also stimulate mucin secretion from goblet confined apartments of perfused explants of human nasal and tracheobronchial tissues, (3) increase cilia beat oftenness in human airway epithelial solitary abode; squalids in a concentration-dependent manner, (4) and increase tracheal mucus velocity and whole-lung mucociliary clearance in vivo in sheep. (5) lately UTP has been shown to stimulate mucociliary clearance in patients with chronic bronchitis (6) and cough clearance in patients with primary ciliary dyskinesia. (7) This pharmacologic activity profile of UTP recommends that P2[Y.sub.2] receptor agonists may have therapeutic potential in individuals in whom mucociliary clearance is impaired, as it is as in chronic bronchitis (89) or cystic fibrosis. (10) However, UTP is rapidly degraded enzymatically within sputum (11) and at airway epithelial cells, (12) and thus may not be suitable as a therapeutic agent in the treatment of these chronic diseases. Other enzymatically resistant, longer-acting P2[Ysub2] agonists are being exhibited for these indications by Inspire Pharmaceuticals (Durham, NC) UTP on virtue of its rapid storm of action and rapid degradation, may be ideally suited as an agent for obtaining deep-lung sputum specimens suitable for diagnostic projects Inspire Pharmaceuticals is developing UTP solutions for inhalation for like indications under the compound number INS316.
Because lung tumors and other preneoplastic lung lesions shed lonely dwellings that can be identified in sputum specimens, sputum cytology has become united component in the diagnosis of lung cancer. The reliability of the be the effects of sputum cytology is highly unable to exist without on the quality of the specimen obtained on the clinician. For the diagnosis of lung cancer, the ideal sputum specimen contains a large number of small cavitys from deep within the lung because so specimens are more likely to contain exfoliated enclosed spaces from lesions.
Many patients have difficulty spontaneously producing similar evaluable sputum specimens, which has been recognized at any time since the earliest attempts at developing screening protocols. (13) Various [i]modus operandi[/i]s and procedures have been enlist in one's serviceed over the years to enhance the quality and quantity of sputum expectorated for diagnostic designs Among these is inhalation of hypertonic saline solution or heated hypertonic saline solution at concentrations ranging from 3 to 15% sodium chloride, with or without added propylene glycol (14-19) The safety of this process has not been rigorously assessed however has been reported to cause significant acute decreases in pulmonary function. (16-19) Another way is to have the subdue collect multiple early-morning spontaneous expectorations at domicile (20) or to pool these collections for a period of [greater than or equal to] 3 days, (131621) which can involve complicated breathing and coughing maneuvers. (13) Because these techniques are not reliable and are ofttimes unsuccessful, more invasive and of great price procedures such as bronchoscopy are frequently performed to obtain evaluable specimens.
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