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…

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  Development of novel synthetic methodologies and their application to synthesis of natural products are described. The first topic is about an extension of the scope of our indole synthesis by radical cyclization of o-alkenylphenyl isocyanides. By utilizing this methodology and nitrogenzenesulfonamide chemistry, an efficient total synthesis of hexacyclic aspidosperma indole alkaloid, aspidophytine, was accomplished. As the second generation indole synthesis, we then developed the method by radical cyclization of o-akenylthioanilides. Synthetic utility of this method was fully demonstrated by a total synthesis of iboga alkaloid, catharanthine. Furthermore, a total synthesis of vinca alkaloid, vinblastine through a practical synthesis of vindoline was achieved, in which the stereochemistry of the crucial coupling reaction of two indole fragments could be completely controlled. In addition to the indole chemistry, exceptionally mild transformations of thiol esters to ketones and alkenyl ketones have been developed. Examples of application of the protocols for the synthesis of natural products are also described.

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  We studied the effects of 0.25% indomethacin (IM) spray as an in-hospital preparation on the pain of stomatitis after hematopoietic stem cell transplantation in 9 patients with various types of leukemia by measuring the change in pain and the decrease in morphine dose. Stomatitis above grade 2 (painful erythema, edema, or ulcers but can eat or swallow) appeared in all patients as white blood cell (WBC) counts declined after transplantation, and clockwise hysteresis was observed between WBC counts and the grade of stomatitis. When the patients used IM spray for the pain of stomatitis and were judged the grade of pain using a face scale of five grades (0—4) before and after the use of this spray, the mean grades of pain at the maximal pain during the appearance of stomatitis declined from 3.4 to 1.8 (n=5). Furthermore, the concurrent intravenous dose of morphine markedly decreased during IM spray use. There was no complaint concerning the taste and convenience of IM spray by patients. The risk of systemic adverse effects was considered relatively low based on the small amounts of IM applied to the mouth mucosa. In conclusion, it is suggested that IM spray is effective for the relief of stomatitis pain in patients who have undergone hematopoietic stem cell transplantation and is a useful preparation for immediate self-medication upon the appearance of stomatitis pain. We considered that the application of IM spray will contribute to the improvement of patient quality of life.

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  Collegenase is widely used in the process of teasing a nerve in order to perform single fiber action potential (SFAP) recordings. In this study, the effects of collagenase on nerve conduction parameters were investigated. To accomplish this, normal compound action potentials (nCAPs) were recorded from isolated frog sciatic nerve at various distances using the suction technique. Then, the same nerve was treated with collagenased Ringer's solution (3.5 mg/ml, Sigma Type XI) for 90 minutes and action potentials (cCAPs) were recorded again. Numerical analysis of these records was performed and the results were compared. Using the nCAP and cCAP recordings, the conduction velocity distributions (CVD) of the individual nerve trunks were determined by a method that we have previously described. Statistical results indicated significant differences (p<0.05) between the nCAP and cCAP CVD data. From these findings it is concluded that, when used for teasing the nerve fibers, collagenase may affect the nerve trunk conduction parameters. Specifically, a significant amount of decrease has been observed in conduction velocities of myelinated fibers having diameters smaller than 8 μm.

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  The utilization of generic drugs has been promoted, but there is concern about the insufficiency of the information provided on generic drugs. To make an objective evaluation of the amount of information supplied by generic drug manufacturers, we tried to quantify the information supply. The information described in the package insert and the interview form were used in the evaluation. We sent a questionnaire to 1000 randomly selected hospitals nationwide to determine the necessity of each information item in medical practice, and weighted the score allotted to each item based on replies from 524 hospitals. We applied these procedures to diclofenac sodium products and found that the score for a branded drug was 60.5 points and that for generic drugs ranged from 1.6 to 58.3 points. This indicates that there were great variations in information supply activities among the manufacturers. The Qua value, which was the ratio of the points of a generic drug per unit price in the drug tariff to the points of the branded drug, ranged from 0.1 to 2.4. We think that these procedures will make it possible to select the appropriate generic drugs in medical practice.

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  Glibenclamide, a sulfonylurea derivative (SU) antidiabetic agent was detected in a health food by three different methods: TLC, HPLC, and liquid chromatography-mass spectrometry (LC-MS). For analysis of SU antidiabetics, the sample was extracted with acetone as a sample solution. TLC analysis of the sample solution showed a specific spot that had the same characteristics as those of glibenclamide standard solution. HPLC analysis monitored using a photo-diode array detector showed that the sample solution had a peak with a unique UV spectrum, with coincided with that of standard glibenclamide. In sample solution, LC-MS analysis in positive and negative modes indicated that the (M+H)⁺ and (M-H)⁻ ions occurred at m/z 494 and m/z 492, respectively. These results indicate that the monoisotopic mass is 493, coincident with that of glibenclamide. Quantitative HPLC analysis showed that the glibenclamide content in the health food was 0.78 mg/capsule (1.55 mg/g of sample contents). Because the initial dosage of glibenclamide for diabetics is 1.25—2.5 mg per day, this health food has sufficient medicinal effect and also has the potential to cause adverse effects.

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