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The nasal drug application has drawn much attention as the strategy for the delivery route of many drug modalities such as the poorly absorbed drugs, peptides, nucleic acid, and central nervous system drugs. The absorption of drug after intranasal (IN) application depends on the nasal residence time of applied drug, affected by mucociliary clearance (MC). MC is a decisive factor in the nasal absorption of drug. We describe the establishment of in vitro evaluation system of nasal MC via the moving velocity of a marker particle on nasal mucosa, and the development of the pharmacokinetic model to which in vitro parameters on nasal MC was incorporated to enable the prediction of drug absorption after IN application. Moreover, the pharmacokinetics of norfloxacin after IN application was investigated using MC-modified rats pretreated with MC modulators. Nasal absorption fluctuated due to changes in the nasal residence time of drug in response to changes in MC. The prediction system enables quantitative evaluation of changes in drug absorption associated with MC fluctuations. In addition, for a precise prediction system for drug absorption after IN application from the drug absorption model, the relationships between in vitro drug permeability through Calu-3 layers, in vivo transnasal permeation of drug and in vivo bioavailability after IN application were evaluated. The significant correlations between these parameters were obtained, suggesting that transnasal permeability and drug absorption after IN application can be predicted from in vitro membrane permeability.

Nasal application of powder formulations has garnered attention because of its significant potential for systemic drug delivery. Because a powder drug must first diffuse from the formulation and dissolve in the nasal cavity fluid before transepithelial permeation, dissolution and diffusion are distinct but important factors for nasal drug absorption. Since the formulation is directly administered onto the nasal mucosal surface, the effect of excipients on drug absorption may be significant. Therefore, the influence of excipients on nasal drug absorption was evaluated. Three types of hydroxypropyl cellulose (HPC) [HPC (SL), HPC (M), and HPC (H)], lactose, and sodium chloride (NaCl) were used as excipients. Warfarin (WF), piroxicam (PXC), sumatriptan (STP), and norfloxacin (NFX) were selected as model drugs. HPC (M) enhanced the absorption of PXC, while both HPC (M) and HPC (H) enhanced the absorption of STP. All three HPCs failed to enhance the absorption of WF. An increase in the polymerization degree of HPCs decreased the diffusion of drugs in HPC solutions, but prolonged their nasal retention. Lactose and NaCl increased the fluid volume on the nasal mucosal surface by increasing the osmotic pressure, thereby enhancing the nasal absorption of PXC and NFX; however, lactose and NaCl accelerated the nasal clearance of these. These results indicate that nasal drug absorption from powder formulations can be controlled by excipients.

The human body is a hostile environment for Aspergillus species, which originally live outside the human body. There are lots of elimination mechanisms against Aspergillus inhaled into the human body, such as high body temperature, soluble lung components, mucociliary clearance mechanism, or responses of phagocytes. Aspergillus fumigatus, which is the primary causative agent of human infections among the human pathogenic species of Aspergillus, defend itself from the hostile human body environment by various mechanisms, such as thermotolerance, mycotoxin production, and characteristic morphological features. Here we review mechanisms of defense in Aspergillus against elimination from the human body.

Nitric oxide (NO) stimulates the ciliary motility of the airway epithelium, thereby assisting in the regulation of mucociliary transport in the respiratory tract. In the present study, to elucidate a possible involvement of NO in mucociliary disturbance in diffuse panbronchiolitis (DPB), we measured nasal clearance time (NCT) using the saccharin test, NO concentration in the exhaled air with a chemiluminescence analyzer, and electrolyte concentration in the sputum. Compared with healthy nonsmokers and smokers, patients with DPB showed a lower NO concentration in the exhaled air (p < 0.05), prolonged NCT (p < 0.01), and a higher Cl concentration in the sputum (p < 0.05). Among these variables, exhaled NO concentration was negatively correlated with NCT (p < 0.01) and sputum Cl concentration (p < 0.05). These results suggest that the inhibition of NO generation associated with an elevated Cl concentration in the airway surface liquid may contribute to airway mucociliary dysfunction in DPB.

Neisseria species other than N. meningitidis and N. gonorrhoeae are generally regarded as commensal bacterial flora of the oropharynx, and little is known regarding cases of these non-pathogenic Neisseria species in the lower respiratory tract. We clinically examined respiratory tract infections from which non-pathogenic Neisseria species were isolated by transtracheal aspiration (TTA). The incidence of non-pathogenic Neisseria isolated was 54 (15.7%) out of 344 episodes of respiratory tract infections with isolated microorganisms from TTA, and was 17.6%, 15.8%, 14.3% for pneumonia, acute bronchitis, and chronic lower respiratory tract infection, respectively. All 54 episodes were isolated with other microorganisms such as alpha-Streptococcus spp. (75.9%), Haemophilus influenzae (25.9%) and anaerobics (22.2%). The isolation ratio according to the age group increased at 45 years of age or more, but did not increase with the advance of age. Predisposing factors were identified such as overt aspiration, iatrogenic procedure and heavy smoking. Cases without overt aspiration that had fevers of 38 degrees C or more or hypoxemia of less than PaO2 70 torr when detecting non-pathogenic Neisseria were observed more frequently in the aged than the non-aged. The findings suggest the detection of non-pathogenic Neisseria by TTA is influenced by the host state that the fall of microorganisms from the upper to lower respiratory tract cannot be defended or excluded by mucociliary transportation disorder due to underlying disease and smoking, or deterioration of physical status other than overt or silent aspiration.

Although excessive production of sputum is one of the characteristic features of acute and chronic respiratory infections, bronchiectasis, diffuse panbronchiolitis, chronic bronchitis and asthma, pathophysiological mechanisms underlying airway hypersecretion remain uncertain. The increase in intraluminal mucus may lead to impairment of airway mucociliary clearance and deterioration of bronchial obstruction. Airway surface fluid is composed of mucus glycoprotein released from submucosal glands and goblet cells and water from airway epithelial cells, and the secretory function can be regulated by autonomic nervous system and a variety of chemical mediators. It is thus important to select mucoregulating drugs after understanding the mechanisms of hypersecretion and impaired mucociliary transport under individual conditions.

Young's syndrome is characterized by chronic sinopulmonary infections and obstructive azoospermia due to systemic mucociliary transport failure. We gave anesthesia to four adult male patients with Young's syndrome for microsurgical epididymovasostomy or epididymal sperm aspiration. Preoperatively, all patients had no or mild clinical manifestation of the lung disease. Intraoperatively, however, three of four patients had voluminous tracheal discharge and two of them showed low arterial oxygen tension. Postoperatively, massive sputa secretion continued. In anesthesia for the patients with Young's syndrome, although they show no or little respiratory symptoms before anesthesia, attention should be paid to lung complication during and after anesthesia.

Mucociliary transport (MCT) was studied in 22 patients with atypical mycobacteriosis (Group I : 16 with M. avium-intracellulare complex (MAC), Group II : 6 with M. kansasii) by aerosol inhalation cine-scintigraphy. In most of the patients, the MCT was abnormally slow both in the main bronchus and in the trachea, while in healthy controls the transport of the inhaled aerosol in the bronchus and the trachea were rapid and smooth. In both groups, the tracheal MCT was impaired in two thirds of the patients, while the MCT in the main bronchus was impaired in all except one in Group I and in two-thirds in Group II. The results indicate that the grade of bronchial impairment was higher in MAC than in M. kansasii infections. In atypical mycobacteriosis, especially in MAC infections, such impairment of MCT could be closely related to the disruption of local defence mechanisms in the airways.

The detection of lesions of the paranasal sinuses as incidental findings during magnetic resonance imaging of patients suspected of intracranial disease who have no nasal symptoms has been far more common than we expected. The present study was performed on 325 patients a mean age of 60.7 years. Medical histories were taken whether they had any nasal symptoms or not. Asymptomatic sinus disease was present in 41.6% of the 257 patients who had no nasal symptoms, and 9.7% of the patients had either marked mucosal thickening, excessive fluid or polyps in the maxillary sinuses. Although the mean age of these patients was comparatively high, we can infer that 1 in 10 have relatively severe sinus lesions. Mucociliary transport time was measured using the saccharin method in 15 patients who had sinus disease but no nasal symptoms. The mean transport time was 15.6 minutes and within normal limits. Routine ENT examination revealed no lesions in the nasal cavity of any of the subjects. We classified the patients with asymptomatic sinus disease into two groups; group A: patients with sinus disease associated with some nasal manifestations but who do not complain about them, group B: patients who have sinus disease but do not have any nasal problems. Group B represents genuine asymptomatic sinus disease in the narrow sense. Most asymptomatic patients in this study appeared to belong to group B. They had some sinus disease, but because their mucociliary function in their nasal cavity was normal, they did not have any nasal symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical studies were made over 7 years on 9 cases to whom long-term chemotherapy with EM was administered for chronic airway infection. 1) Clinical effectiveness: Highly effective in 8 cases; Improvement in QOL was observed in 8 cases. Bacteriological effect: In 7 cases, pathogenic bacteria disappeared. 2) No side effects were observed. 3) Changes in PaO2 levels with the passage of time: In most cases, PaO2 reached a plateau within 1 year. Although in some cases, there was subsequent elevation. 4) The frequency of catching cold over the 7 years period was low with an average of 1.2 times/year per subject. In only 2 cases were subject hospitalized due to acute exacerbation triggered by a cold. 5) Mucociliary transport improved in 7 out of 8 cases examined. However, only 4 of these recovered normal transport. The effect of EM in the other cases in which clinical improvement was not demonstrated was deemed slightly effective. On the basis of the above findings, it was suggested that long-term chemotherapy using EM was clinically efficacious. This is based on the fact that its efficacy, including amelioration of QOL appeared within one year of the initiation of therapy, and continued without decline for over 7 years.

Williams-Campbell syndrome is a unique type of bronchiectasis which shows ballooning during expiration and collapse during inspiration. Its etiology is thought to be a congenital decrease in bronchial cartilage. We experienced two adult cases of Williams-Campbell syndrome. Since the mucociliary transport system was normal in both cases and neither case had chronic sinusitis, these cases differed from sino-bronchial syndrome. Cases of Williams-Campbell syndrome reported in Japan show characteristic bronchography, but a decrease in bronchial cartilage may or may not be present and its congenital nature is very difficult to demonstrate. We therefore advocate referring to such cases of bronchiectasis with these bronchographic characteristics Williams-Campbell-type bronchiectasis, even if a decrease in bronchial cartilage is not observed.

There has been growing appreciation of the significant role played by the mucociliary transport system in the body. The mucociliary transport system is an important defense mechanism by which the human body usually maintains its "homeostasis" by protecting the body against invading particles, including bacteria. This system includes two major functional mechanisms; i.e., ciliary transport and mucous secretional systems, each of which is usually complimentary and cooperative. Three hereditary disorders, primary ciliary dyskinesia (immotile-cilia syndrome), cystic fibrosis and Young's syndrome, have been shown to be systemically associated with mucociliary transport failure, leading to male infertility and chronic sinopulmonary infections. Localized mucociliary transport failure, however, is observed in respiratory diseases, especially chronic sinusitis, chronic bronchitis, bronchiectasis and bronchial asthma. We aim, in this review, to draw together those developments in the study of ciliary transport and mucous secretion, the interactions between them and their pathophysiology that can provide a better understanding of the mucociliary transport system of the human body.

There is amount of epidemiologic, clinical and laboratory evidence to document that viral infection is involved in otitis media with effusion (OME). However, few studies have demonstrated the direct influence of viruses on the tubotympanum. The purpose of this study is to establish the effect of influenza A virus invaded in the tubotympanum, in an attempt to elucidate the possible mechanism by which the virus contributes to the pathogenesis of OME. 80 guinea pigs with normal otoscopic findings were inoculated with 0.2ml suspension of influenza A (3.3 x 10(8)PFU/ml) into their tympanic cavities through their tympanic membranes. To serve as controls, the same number of guinea pigs were injected with 0.2ml of physiologic saline solution into their tympanic cavities. At 3, 7, 14, and 28 days postinoculation, they were used for examination of the mucociliary function. Middle ear effusions were observed only in the animals inoculated with the virus. Mucociliary dysfunction was observed only in the animals inoculated with the virus. The ciliary activity in the bulla was declined at any time examined. On the other hand, the ciliary activity in the eustachian tube and the tympanic orifice was slightly lowered between 7 and 14 days, but the level was not different from that of the control. However, the number of active ciliated cells (showing more than 500 beats/min) was significantly smaller than that of the control. The mucociliary clearance time of the tubotympanum was more prolonged than that of the control at 3, 7, and 14 days, and returned to the control level at 28 days. A variety of morphologic changes were observed in the tubotympanum treated with the virus. Major pathologies observed included a general inflammatory cell infiltration, vacuolation and other degeneration of ciliated cells, and vascular damage and increased vascular permeability. Regeneration of cilia or ciliated cells followed the degeneration, which included an increased number of basal cells and new formed centrioles. However, the viral infection had an influence on the epithelial cells with new centrioles. Our study has demonstrated that viral infection could evoke mucociliary dysfunction of the tubotympanum and create an increased susceptibility to bacteria. Therefore, viral infection could enhance bacterial infectious process in the tubotympanum. Through the failure viruses could contribute to the occurrence of OME.

It is widely accepted that the impairment of tracheobronchial clearance (TBC) are closely related to the development and the progression of chronic bronchial infections. We investigated TBC in patients with chronic bronchial infections (bronchiectasis; 11 cases, diffuse panbronchiolitis; 9 cases and primary ciliary dyskinesia; 3 cases) and also in 6 healthy subjects by a radioactive aerosol (99mTc-human serum albumin, 4.4 +/- 1.4 microns in diameter) inhalation scintigraphy with cough control in order to elucidate the relationships between impaired TBC and chronic bronchial infections. All subjects were not current smokers. After 4-minutes inhalation of radioactive aerosols (tidal volume: 500 ml x 20/min.), radioactivities in whole right lung were measured every 20 seconds for 2 hours serially and then measured at the time of 6 and 24 hours after inhalation. Immediately after the serial recording for 2 hours, single photon emission computed tomography (SPECT) was performed to assess the deposition pattern of radioactive aerosols. During the first 2 hours, all the subjects were instructed to avoid coughing as much as possible to evaluate the mucociliary clearance without cough effect. And then the subjects were allowed to cough between 2 and 24 hours after inhalation. All radiation counts were corrected for background radiation and physical decay of 99mTc. Because it is considered that the deposited aerosols are eliminated much more slowly in alveoli (biological half life: several months) than in airways (biological half life: several hours), the radioactivity remaining at the time of 24 hours was defined as alveolar deposition (ALV). Initial bronchial deposition (Br0) was defined as initial whole lung deposition (L0) minus ALV. We evaluated the TBC with following parameters; 1) Br0/L0 (%):ratio of initial bronchial deposition to initial lung (bronchial and alveolar) deposition. 2) Br2/Br0 (%), Br6/Br0 (%):bronchial retention ratio; the ratio of bronchial deposition at the time of 2 and 6 hours after inhalation to initial bronchial deposition, respectively. 3) TMV (mm/min.):tracheal mucus velocity (rate of shift of radioactive bolus on tracheal mucosa), which was measured during the period of first 2 hours under prohibition of cough. The patients (23 cases) were divided into two groups with regards to cough control for the first two hours of the scintigraphy:cough-controlled group (19 cases) and cough-uncontrolled group (4 cases). The cough-controlled group was subdivided into two subgroups (group A and group B) according to Br0/L0:group A less than 47.9% (mean + SD of Br0/L0 in healthy control) less than or equal to group B.(ABSTRACT TRUNCATED AT 400 WORDS)

The concentration and activity of neutrophil elastase (NE) in sputa were measured in 24 patients with chronic respiratory diseases such as diffuse pan-bronchiolitis, bronchiectasis and and chronic bronchitis. The results were compared to the clinico-pathophysiological parameters such as clinical impairment score, concentration of albumin and ciliary transport velocity of the sputum. Furthermore, the relationship between the post-therapeutic change of NE in sputum and clinical effect of erythromycin (EM) was investigated in the same cases. Physico-chemical properties of the sputum, including rheological characteristics, mucus transport velocity, phospholipid composition, concentration of albumin and fucose were also analyzed before and after EM therapy. There was a significant positive correlation between NE in sputum and the clinical impairment score, which suggested that the concentration and activity of NE in sputum reflected the clinical severity in such diseases. The concentration and activity of NE also had significant positive and negative correlation to the concentration of albumin and ciliary transport velocity, respectively. Therefore, it was considered that NE in airway could bring the leakage of albumin from serum and interfere with mucociliary transport. The patients were divided into responders (n = 12) and non-responders (n = 12) after EM therapy based on the change of the clinical impairment score. The clinical effect of EM in chronic respiratory diseases was not associated with its bacteriostatic action, but with the quantitative and qualitative suppression of sputum NE. The decrease of the adhesive properties of the sputum, which was observed in responders after administration of EM, was considered to depend on the reduction of the concentration of albumin in sputum. Concerning the phospholipid composition of sputum, sphingomyelin and phosphatidyl-ethanolamine, which had been suggested to be components of serum and cellular membrane, had a tendency to decrease in responders. The proportion of phosphatidylcholine increased in responders. The improvement of ciliary transport velocity of the sputum, which was noted in responders, was probably due to the results mentioned above. In non-responders, these findings were not observed after EM therapy. EM had no influence on the production, release and activity of NE as a result of in vitro experiments using human peripheral neutrophils. Neutrophil chemotaxis was however suppressed after incubation with EM. These results suggest that the mechanisms of the effect of EM is not direct action on NE but through suppression of neutrophil chemotaxis.

A case of immotile cilia syndrome (ICS) is presented. A 34-year-old male, who had suffered from recurrent bronchitis, sinusitis and otitis media since early childhood, was admitted to Keio University Hospital complaining of productive cough and infertility. A saccharin test showed prolonged nasal clearance time, and semen analysis revealed immotile sperm. By electron microscopic observation of cilia of the nasal mucous epithelium and the sperm, inner and outer dynein arm defect, abnormal microtubular arrangement and compound cilia were detected and he was diagnosed as ICS. Thirty eight Japanese cases of ICS collected from the literature were analyzed concerning clinical manifestations, airway clearance, family history and ciliary ultrastructural abnormalities (Table 2, 3). Recurrent bronchitis, male infertility, chronic sinusitis, otitis and decrease in airway clearance were very common in these patients. Female infertility was more common than anticipated. The prevalence rate of situs inversus was more than 50%, probably due to more attention having been paid to Kartagener's syndrome in Japan. Recent studies show that the cilia of this syndrome is not always immotile but characterized by hypomotility or asynchrony, and have attempted to determine the relationship between each ciliary ultrastructural abnormality and motility pattern. It is necessary that more patients including incomplete and mild cases should be investigated.