The purine-sensitive receptor, P2Y2, has a comprehensive role in the regulation of the steady state of the airway mucus layer. The P2Y2 receptor, when activated, enhances the transmembrane movement of water molecules, thins out mucins and accelerates cilial transport mobility. P2Y2 receptor agonists include purine nucleoside triphosphates, pyrimidine nucleosides and INS Studies have indicated that inhaled pyrimidine nucleosides and INS are capable of accelerating the mucus flow rate in airways and enhancing mucociliary clearance; another P2Y2 agonist, INS, has activity similar to that of pyrimidine nucleosides 68 , With the continued exploration of the role of airway mucus hypersecretion in the pathogenesis of chronic inflammatory airway diseases, the results confirm from an evidence-based medicine point of view that patients with chronic inflammatory airway diseases benefit from treatment with expectorants The crucial role of timely and effective expectorant intervention for the treatment of chronic airway inflammatory disease has been widely accepted by clinicians.
However, controversies remain over the applicable subjects, the reasonable dosage and the duration of treatment, among other therapeutic considerations.
- US8501911B2 - Methods of reducing inflammation and mucus hypersecretion - Google Patents.
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The phenomenon of chronic airway mucus hypersecretion presenting as a cough and expectoration is ubiquitous in all chronic airway inflammatory diseases. Therefore, a study has suggested that therapies targeting mucus hypersecretion in chronic airway inflammation should be recommended regardless of the presence of a chronic cough and expectoration 9. Thus, future studies on the mechanism of expectorant medicines and the exact role expectorant medicines should play in the standard treatment of chronic airway inflammatory diseases are required. The development of novel expectorant medicines and an optimal therapeutic regimen is required.
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Airway hypersecretion in allergic rhinitis and asthma: New pharmacotherapy
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J Am Geriatr Soc. Carbocisteine improves quality of life in patients with chronic obstructive pulmonary disease. Inflamm Allergy Drug Targets. China Journal of Chinese Materia Medica. J Immunol. Weitz-Schmidt G: Statins as anti-inflammatory agents. Trends Pharmacol Sci. Mancini GB, Etminan M, Zhang B, et al: Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease.
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Clin Pharmacol Ther. Drugs Exp Clin Res. Int J Clin Pharmacol Ther. Int Immunopharmacol. Wu H, Li Q, Zhou X, et al: Theaflavins extracted from black tea inhibit airway mucous hypersecretion induced by cigarette smoke in rats. Phytother Res. Accordingly, such inhibitors of components of the mucin secretion signaling pathway find use in methods of inhibiting mucus secretion. The present invention thus provides methods and compositions useful in regulating decreasing or attenuating mucus secretion.
Such methods and compositions are useful in the treatment of medical conditions in which mucus hypersecretion occurs, and are particularly useful in the respiratory tract. Accordingly, the present invention provides methods and compositions for regulating mucus secretion, by regulating attenuating or decreasing the effects of MARCKS protein in the mucus-secretory pathway. Such regulation attenuation can be achieved by administering active fragments of MARCKS protein in pre-determined amounts, or administration of these or other compounds alone or in combination that inhibit the MARCKS-related secretory pathway.
Such compounds include those that block the dephosphorylated MARCKS protein binding event that leads to mucin release. Thus, a method for increasing mucus secretion is to administer to a mucus-secreting cell, a compound that binds to a MARCKS protein inhibitor. It will be desirable, in many therapeutic situations, to maintain some level of mucus secretion i.http://groupdeal349leonardo.dev3.develag.com/875-sony-xperia.php
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Maintenance of basal mucus secretion may be achieved by regulating the dose of the active compound utilized. Additionally, while not wishing to be held to a single theory of the invention, the present inventors suggest that in some secretory epithelia, a basal level of mucus secretion may be maintained by a pathway separate from the MARCKS-related pathway and stimulated mucus secretion.
The present invention provides methods and compositions able to decrease or reduce mucus hypersecretion that occurs in many pathological conditions, including pathological conditions related to inflammatory, viral, bacterial, or genetic causes. In particular, the present methods and compositions provide methods of treating airway diseases in which mucus secretion is increased over that which occurs in the absence of the disease i. Subjects to be treated by the present methods include human and non-human subjects. Non-human subjects include companion animals such as cats and dogs, as well as livestock such as cattle, horses, sheep and swine.
The present methods and compositions may be used to reduce mucus secretion, or to inhibit mucus hypersecretion, in any secretory epithelium, or epithelial cell, including but not limited to airway epithelial cells e. As will be apparent to those skilled in the art based on the subject and the condition being treated, it may be desirable to maintain a basal level of mucus secretion, while reducing hypersecretion of mucus.
As used herein, a treatment that reduces or inhibits mucus secretion refers to a treatment that reduces the amount of secreted mucus compared to that which would occur in the subject in the absence of such treatment. The peptides and compounds of the present invention block mucus secretion in response to known activators of PKC and protein kinase G, and to physiologically relevant stimuli e.
The present invention thus provides methods and compositions for treating epithelial cells or epithelial tissue, where it is desirable to decrease the amount of mucus secreted by those cells or tissue. In particular the present invention provides methods and compositions for treating respiratory conditions where it is desirable to decrease the amount of mucus present in the airways. Conditions suitable for treatment by the present methods include human and animal inflammatory, viral or bacterial airway disease e.
Normal mucus secretion in the lung plays an important role in clearing inhaled foreign particles and pathogens from the airways. Mucus traps inhaled particles, and is then removed from the airways by ciliary action or by coughing. Above-normal levels of mucus secretion hypersecretion in the airways can lead to intraluminal mucus accumulation, resulting in airflow obstruction and an increased susceptibility to infectious agents. Secretory cells in the airways include submucosal glands and superficial epithelial mucus cells goblet cells.
Airway mucus secretion is an important determinant in the prognosis and clinical features of pulmonary diseases. In subjects with chronic bronchitis and bronchial asthma, goblet cell hyperplasia has been observed, with a two- to three-fold increase in the numbers of goblet cells compared to controls. Cutz et al.
Inflammation of the airways may induce mucus hypersecretion by multiple mechanisms, including the release of chemical mediators from surrounding tissues and cells. Airway mucus hypersecretion is a particularly dominant clinical finding in cystic fibrosis, bronchitis, COPD, emphysema, and bronchial asthma.
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The presence of excessive bronchial mucus can lead to bacterial infection and respiratory failure. Lungs of asthmatic patients, at autopsy, often show the presence of excessive bronchial mucus and mucus plugging. Methods of reducing airway mucus secretion would be useful for the treatment of such conditions, as well as in treating bacterial or viral infections e. Various methods are currently in use to reduce mucus secretion when needed in disease states.
Some therapies act to decrease the signals or stimuli that upregulate mucus secretion. For example, inflammatory mediators may upregulate mucus secretion; steroid treatments are often used to decrease inflammation and thus indirectly decrease mucus secretion. Antihistamines are used to block the responses to allergens which can trigger attacks of allergic asthma. The thickened mucus present in patients with cystic flbrosis is removed by compression therapy, and infections occurring due to the thickened mucus are treated with antibiotics.