咳・痰と気道クリアランスの薬理基盤構築 : 新しい視点からの治療薬開発と治療法改善へのアプローチ

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Disturbance of the normal mucociliary clearance due to hyperproduction of mucus and modification of its physicochemical characteristics is a common finding in airway diseases. Drugs that affect airway secretion have been developed and used to cleanse the respiratory tract for many centuries and in many countries. On the basis of the mechanism of their actions, the mucoactive drugs are classified into several groups. Some mucoactive drugs have direct effects on the production or composition of airway secretions, resulting in increased effectiveness of mucociliary clearance. Other mucoactive drugs do not have a specific action on mucus, but have beneficial effects on airway structure and function, which lead to correction of the pathophysiologic mechanisms that result in abnormal secretions. However, since many drugs have overlapping effects, it is difficult to classify these drugs into groups based on their major actions. Taken together with previous findings on mucoactive drugs, it appears that an antioxidant effect is a common property of mucoactive drugs and that it is a crucial action to exert their effects against airway diseases. In light of this idea, we must use specific experimental models to simulate pharmacologic events in airway inflammation. The development of new techniques has made it possible to identify and measure the mucus components, measure the rheologic parameters more accurately, and evaluate mucociliary clearance precisely in animals and humans. Therefore, with modifications of methods, we have investigated airway-cleansing drugs from various points of view to reflect actions in inflammatory states for more than two decades. Here, I introduce the methods we have used to study many of the parameters involved in airway clearance, including cough reflex, and describe some of the mucoactive-antitussive drugs that we have studied recently. There is an increasing usage of traditional Chinese herbal medicines in clinics and hospitals, because they tend to have moderate side effects and sometimes remarkable efficacy. To renormalize overall defects in airway disorders, Chinese medicines may be adequate, because they are composed of various herbs with weak but ubiquitous pharmacologic activities. We have been investigating Bakumondo-to. Bakumondo-to has been used for the treatment of bronchitis and pharyngitis accompanying severe dry cough. We found that unlike codeine Bakumondo-to had a notable antitussive activity against the cough associated with bronchitis and the cough increased by angiotensin-converting enzyme inhibitors. Recently, we have found that, in alveolar type II cells, Bakumondo-to attenuated phosphatidylcholine secretion increased by oxygen radicals from activated PMNLS. In addition, we found that Bakumondo-to itself stimulated phosphatidylcholine secretion and increased β-adrenoceptor gene expression in rat alveolar type II cells. We studied the mechanism of action and clarified that Bakumondo-to increased glucocorticoid-sensitive promotor activity. The effect may contribute to its ubiquitous effectiveness in the treatment of airway diseases. Various parameters (chemical properties, physical properties, mucus production, surfactant phospholipid production, and mucociliary clearance) are considered to be important for the dynamics and mobilization of airway secretions. Pharmacologic investigation, with appropriate techniques, of the ability of an agent to modify these parameters can provide useful information about its mechanism of action. However, since these parameters are interconnected, it is very complicated to elucidate the precise mechanisms of action of mucoactive drugs. This means that the goal of treatment cannot always be achieved by the modification of a single parameter, but should, more realistically, be aimed at a renormalization of several parameters. On the basis of this idea, glucocorticoids are ideal mucoactive drugs because they exert various pharmacologic effects in the lung. From a polypharmacologic point of view, a traditional Chinese medicine can be classified as a glucocorticoid-like drug because Chinese medicines consist of many types of active components that have various pharmacologic effects. As one future course of research, we believe that efforts to seek compatible actions between glucocorticoids and Oriental medicines may lead to new opportunities for development of ideal airway-cleansing drugs with specific actions, i.e., suppression of gene expression.
公益社団法人日本薬学会の論文
2003-12-01

咳・痰と気道クリアランスの薬理基盤構築 : 新しい視点からの治療薬開発と治療法改善へのアプローチ

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