East-West development: understanding the usability and acceptance of foreign data in Japan.

The introduction in Japan of New GCP regulations, as well as the internationalization of clinical trials under the ICH process (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use), has meant that the system is now faced with a number of serious challenges. This is shown by the dramatic decrease in registration of new drugs. Identifying the actors in the new context is essential. We shall first define precisely what is the Regulatory Authority in Japan, and which are the Regulatory Requirements to be fulfilled. We shall then describe the new process for evaluation of foreign clinical data. One of the major issues will be to determine in which cases a complete clinical data package will be sufficient to support regulatory submission, and in which cases additional clinical studies or bridging studies, and what kind of bridging studies will be required.

Survey of recognition and utilization of guidelines for the diagnosis and management of bronchial asthma in Japan.

BACKGROUND: In Japan in 1993, the Japanese Society of Allergology (JSA) developed guidelines for diagnosis and management of asthma (JGL), which were based on the concept that asthma is a chronic inflammatory disorder of the airway. METHODS: This survey study was intended to investigate the recognition and utilization of JGL among physicians who had treated asthma. The survey comprised two methods: a quantitative mail survey and a qualitative door-to-door survey conducted by trained interviewers. RESULTS: In the mail survey, a total of 1028 physicians responded; 552 members of the JSA and 476 nonmembers. Ninety-four percent of JSA members were aware of adult asthma management guidelines, while 53% of nonmembers were aware of them. Although approximately half of the physicians, both members and nonmembers, found differences between the asthma management policies in JGL and their previous policies, most of them utilized JGL once they read it. In the qualitative door-to-door survey, 80-90% of physicians evaluated JGL as good after they read it. CONCLUSIONS: JGL was recognized and utilized by most JSA members, but only half of nonmember physicians were aware of JGL, although they utilized JGL after they read it. Further action to implement JGL among nonspecialist physicians is needed to improve management of asthma.

Irinotecan (CPT-11) in combination with weekly administration of cisplatin (CDDP) for non-small-cell lung cancer.

PURPOSE: CPT-11 (60 mg/m2 on days 1, 8 and 15) in combination with CDDP (80 mg/m2 on day 1) has shown promising antitumor activity for non-small-cell lung cancer (NSCLC), but dose-limiting toxicities (DLT) are leukopenia and diarrhea, with a wide variation among patients. To estimate weekly CDDP administration in combination with CPT-11, a phase I study for patients with advanced NSCLC was conducted. METHODS: Patients were treated with CPT-11 at a fixed dose of 60 mg/m2 together with CDDP at 27 mg/m2 (level 1, 6 patients), 33 mg/m2 (level 2, 12 patients), and 40 mg/m2 (level 3, 6 patients) with 1600 ml hydration on days 1, 8 and 15 over 4 weeks. During the treatment course, drug was not administered on the day it was due in the presence of leukopenia (< 3000/ml) and/or diarrhea. RESULTS: The planned administration was completed in 5 of 6 patients at level 1, 6 of 12 patients at level 2, and 2 of 6 patients at level 3. The most common toxicity observed was leukopenia (five patients with grade 3 and one patient with grade 4). Leukopenia was considered to be a DLT, and the maximum tolerated dose (MTD) was level 2. Although there were patients who suffered from diarrhea (four patients with higher than grade 2), diarrhea was judged not to be a DLT with this weekly regimen. Nausea and vomiting were mild. Pharmacokinetic analysis of free platinum from CDDP demonstrated that the area under the curve (AUC) from 33 mg/m2 CDDP was 0.92 +/- 0.29 microg/ml h. In 13 patients evaluated for response, the response rate was 54%. CONCLUSION: The value of weekly administration of CDDP in combination with CPT-11 was shown by (1) diarrhea not being dose-limiting, (2) mild nausea, (3) well-maintained AUC of free platinum, and (4) promising activity.

[A case of refractory bronchial asthma improving with treatments of sleep apnea syndrome].

A 29-year-old woman of the bronchial asthma was admitted to our hospital. Her asthmatic symptoms were refractory in spite of the administration of 30 mg of daily-oral prednisolone. During the asthma-attack, marked arterial oxygen desaturation was noted. So we doubted that she had obstructive sleep apnea complicated with obesity. Sleep Apnea Monitor revealed her nocturnal desaturation and frequent sleep apnea. To avoid the desaturation, we recommended her to keep prone position during the sleep. And both desaturation and asthmatic symptoms were dramatically improved. Nasal-CPAP also had been effective for them. These findings suggest that sleep apnea mediated oxygen desaturation may be one of the promotor of asthmatic symptoms.

[Allergic bronchopulmonary aspergillosis in a patient without bronchial asthma who had chronic airway infection with Pseudomonas aeruginosa].

A 25-year-old man was admitted to the hospital because of uncontrollable coughing and sputum production. He had been suffering from coughing and sputum production since he was 7 years old. He was given a diagnosis of bronchiectasis and persistent airway infection with Pseudomonas aeruginosa when he was 16 years old. One year of treatment with erythromycin and another year of treatment with roxithromycin were not effective. After he was referred to our hospital in 1993, he was given clarithromycin together with tosufloxacin for two years as an outpatient. The treatment was not very effective, but some prophylactic effect was seen with regard to prevention of acute exacerbations of Pseudomonas aeruginosa airway infection. Examination after admission revealed a high level of serum IgE (3703 U/ml), a strong skin reaction to aspergillus allergen, and marked central bronchiectasis in both upper lobes. He had no history of eosinophilia or of attacks of dyspnea. Our diagnosis was acute exacerbation of long-standing allergic bronchopulmonary aspergillosis and chronic airway infection. Treatment with oral prednisolone (30 mg per day) together with intravenous cefsulodin for three weeks resulted in marked relief symptoms and improvement in pulmonary function. The delay in correct diagnosis seems to have been caused by the lack of an obvious episode of asthma, and by the fact that the chronic productive coughing was thought to have been due to bronchiectasis, and to chronic bacterial infection. The characteristic bronchiectasis of this patient prompted us to examine the allergic reaction to aspergillus and let us to the correct diagnosis.

[Esophagobronchial fistula and empyema resulting from esophageal carcinoma].

A 59-year-old woman was admitted to the hospital with a one-month history of hemoptysis, generalized fatigue, and a high fever. A chest X-ray film obtained on admission showed a massive right-sided pleural effusion. Examination of an aspirate showed a high level of amylase, and bacteria that were the same as oral bacteria. Closed drainage yielded ichorous pus and food residues, which led us to the diagnosis of empyema caused by esophageal perforation. Esophagography and fiberoptic esophagoscopy revealed that an esophagobronchial fistula related to an advanced esophageal carcinoma had caused the empyema. Surgical resection was done, and the patient was alive at the time of this writing, 7 months after she was first treated. Esophageal carcinoma is sometimes accompanied by esophagobronchial fistula. Patients with this condition usually have severe respiratory symptoms; those presenting with empyema are rare. Esophageal carcinoma must be carefully ruled out as the cause of empyema.

[Allergic bronchopulmonary aspergillosis (ABPA)].

The entity of allergic pulmonary aspergillosis includes various diseases of the lung which are caused by not only allergic reactions to aspergillus but also destructive inflammations due to saprophytic infection of aspergillus in lower respiratory tracts. We focus our discussion on ABPA with our own experience of 11 cases and overview of the disease. First of all, We propose that the entity of ABPA should be expanded from one that has been defined by the diagnostic criteria established by Rosenberg et al in 1977. We have to consider stage of ABPA, the existence of ABPA without asthma and ABPA complicated with chronic bacterial infection in lower respiratory tracts and the progression of ABPA to infectious and invasive aspergillosis. It is important for the diagnosis of ABPA to study not only allergic reactions to aspergillus but also chest HRCT which reveals the central bronchiectasis and mucus plugging that are thought characteristic of the disease. Systemic steroid therapy is indispensable in the acute stage of the disease. Bronchial toileting for the removal of mucoid impaction is also important. In the chronic stage of the disease, antifungal drugs and inhaled steroid therapy should be considered in intractable cases on recurrence to prevent the disease progression and lung injuries.

[A case of desquamative interstitial pneumonia with increased numbers of eosinophils in the bronchoalveolar lavage fluid].

A 76-year-old man was admitted to our hospital with a diffuse reticulo-nodular shadow on chest X-ray. He had no symptoms. Transbronchial lung biopsy specimens revealed alveolitis and small numbers of lymphocytes. Bronchoalveolar lavage fluid (BALF) analysis revealed an increased number of eosinophils. Few eosinophils were seen in the alveolar lumen on biopsy. The patient had no symptoms, and was discharged without therapy. He was followed as an outpatient. Dyspnea on effort gradually developed June 1995. The diffuse infiltrative shadows on chest CT worsened and the patient was again admitted. Laboratory data revealed an elevation of serum LDH. Tumor markers were negative. Desquamative interstitial pneumonia (DIP) was diagnosed on open lung biopsy. Corticosteroid therapy (1 mg/kg/day) was administered. After treatment with corticosteroid, chest CT findings and pulmonary function tests improved remarkably. DIP is less common in Japan than elsewhere. The characteristic findings of BALF taken from patients with DIP are still inperfectly characterized. Our patient exhibited an increased number of eosinophils. To the best of our knowledge, BALF findings were reported for six cases of DIP in Japan. In five out of the seven cases (including our case), BALF findings demonstrated an increased number of eosinophils. This finding may be one of the characteristic features in patients with DIP.

[A comparison of asthma deaths and near-fatal asthma attacks].

This study compares the characteristics of fatal asthma patients and those of near-fatal asthma patients who had experienced severe life threatening attacks. Data from 67 fatal asthma patients and 80 near-fatal asthma patients were analyzed. The mean age of fatal asthma cases were older than near-fatal asthma cases, 51.9 yrs and 44.3 yrs, respectively. Similarities of the two cases were seen in sex, type of asthma and severity of asthma. The experiences of previous life-threatening asthma did not differ in both groups (43.3% of fatal vs 40.0% of near-fatal). From the viewpoint of type of development of severe exacerbation, rapid exacerbation was more frequent in fatal cases than near-fatal cases, but acute exacerbation after unstable asthma was more in near-fatal asthma. Seventy-six percent of all asthma deaths occurred at home or on the way to the emergency department. The rate of delay of receiving medical care was significantly higher in fatal cases (72%) than near-fatal cases (26%). There was no significant difference in the frequency of medical management before fatal or near-fatal episode such as oxygen therapy, mechanical ventilation. Use of ambulance, visiting emergency department, previous hospitalization between the two groups. The profile of fatal cases was almost same to that of near-fatal cases except delay of receiving medical care. In conclusion, the analysis of near-fatal cases was very important to make clear the causes of asthma death.

[Repeated pneumonia in the middle lobe caused by congenital bronchoesophageal fistula].

A 52-year-old woman was admitted to our hospital because of repeated episodes of pneumonia in the middle lobe. She had also experienced coughing during meals. The history and chest CT findings suggested the presence of a bronchoesophageal fistula. An upper GI series revealed a fistula between an esophageal diverticulum and the superior segment bronchus of the right lower lobe. Fiberoptic bronchoscopy done immediately after the upper GI series revealed barium sulfate leaking from the superior segment bronchus of the right lower lobe into the middle lobe bronchus. These findings indicated that the repeated pneumonia in the middle lobe was caused by a congenital bronchoesophageal fistula. Examination of the resected fistula showed that it was a Braimbridge type I bronchoesophageal fistula. Although of at least 49 cases of congenital bronchoesophageal fistulas with esophageal diverticula have been reported in the Japanese medical literature, we know of no previous case in which such a fistula was associated with middle-lobe pneumonia.

[Selenium deficiency associated with cardiac dysfunction in three patients with chronic respiratory failure].

We encountered three patients with chronic respiratory failure who had heart failure of cardiac arrhythmias and low levels of serum selenium. All three had tracheostomies and had received long-term parenteral nutrition that had not included selenium. All three also had refractory cardiac dysfunction, which was manifested in edema, heart failure, and various tachycardias. We suspected that selenium deficiency had caused their cardiac dysfunction. Serum selenium concentrations were found to be much lower than normal in all three, so 100 micrograms/day of selenium was administered in addition to their tube feedings. Cardiac function improved after replacement of selenium. These cases show the need for preventing selenium deficiency in patients with chronic respiratory failure during long-term administration of parenteral nutrition.

[Guidelines for the diagnosis and management of bronchial asthma--a comparison of the Japanese guidelines for the adult asthma with GINA and ICR].

Although the concept of asthma management of the Japanese Guidelines is basically similar in the other guidelines including GINA, ICR, of British Thoracic Society, and of the other countries, assuming that asthma is a chronic inflammatory disorder of the airway, the program of stepwise pharmacologic therapy is not the same in various points. Therapy suggested in the Japanese Guidelines is different in 1) oral antiallergic drugs are widely used, 2) patients prefer oral bronchodilators to inhaled bronchodilators, 3) sustained released theophylline in the long term management and intravenous infusion of aminophylline for the treatment of acute exacerbation are accepted and frequently used by the physicians. Also the differences in the choice of medication between GINA, which is characterized by concept of cost, and other guidelines are discussed.

[The usefulness of induced sputum in the diagnosis of pulmonary tuberculosis].

This study was designed to compare the results of culture for tubercle bacilli using induced sputum by an ultrasonic nebulizer and gastric aspirates from same patients who were suspected of having active tuberculosis with little or no sputum and had received no prior chemotherapy. 22 patients included in this series were either culture positive for tubercle bacilli or showed unequivocal radiographic improvement after three months of therapy with three anti-tuberculosis drugs. Induced sputum from 17 patients and gastric aspirates from seven patients were culture positive for M.tuberculosis. This difference is significant (p < 0.01). Paired induced sputum and gastric aspirates were both positive for tubercle bacilli in seven patients. The finding of acid-fast bacilli on microscopy or tubercle bacilli in culture in four of the seven patients were available much earlier with induced sputum than with gastric aspirates. Positive gastric aspirates and negative induced sputum for tubercle bacilli was not seen. These results suggest that induced sputum by an ultrasonic nebulizer is superior to gastric aspirates in terms of high sensitivity and early finding for tubercle bacilli and induced sputum and gastric aspirates do not supplement each other.

[Outbreaks of pulmonary tuberculosis in a family and in a hospital. Analysis of restriction-fragment-length polymorphisms].

Restriction-fragment-length polymorphism, analysis was used to study two outbreaks of pulmonary tuberculosis, one in a family and one in a hospital. The DNA probe was derived from the insertion sequence IS 6110. Two groups of isolates were analyzed, both of which were suspected to be common sources of each infection. Both groups showed identical fingerprints within each group. These results suggest that analysis of restriction-fragment-length polymorphism is useful in epidemiological studies of pulmonary tuberculosis.

[Tracheal carcinoma causing severe tracheal stenosis].

A 47-year-old woman was admitted to our hospital because of shortness of breath. She had wheezed for a long time before admission. A flow-volume curve showed a pattern consistent with a fixed obstruction of the trachea. CT findings also revealed severe stenosis of the trachea caused by a tumor mass. Tracheal carcinoma was diagnosed after transbronchoscopic biopsy. The patient received chemotherapy and radiation therapy concurrently for about six weeks. Her symptoms resolved, and a second flow-volume curve had a normal pattern. Tracheal carcinoma should be included in the differential diagnosis of airway obstruction. In such cases, the flow-volume curve can be useful as a screening test.

[High-dose inhaled beclomethasone in long-term management of chronic severe asthma--usefulness and dose-dependence].

We studied the usefulness of 18 weeks of therapy with two high doses of inhaled beclomethasone dipropionate (BDP) in the management of severe asthma in adults. The patients had asthma symptoms that had not been controlled by combination therapy with BDP (800 micrograms/day) and bronchodilators. They were divided into two groups. Patients in group A (n = 16) were treated with 1800 micrograms/day of BDP and bronchodilators. Patients in group B (n = 10) were treated with 1400 micrograms/day of BDP and bronchodilators. BDP was inhaled via a large spacer (Volumatic). Eleven patients in group A and 6 patients in group B had been given an oral steroid regularly before the study. Asthma symptom scores, peak expiratory flow (PEF), pulmonary function, bronchial reactivity to methacholine, the total amount of oral steroid, and adrenocortical function were recorded. Results. 1) Clinical characteristics before the start of the study did not differ between groups. 2) Asthma symptom scores decreased to a greater extent in patients who received the higher dose of BDP than in those who received the lower dose. 3) Only the higher dose of BDP significantly increased evening and morning % PEF, as measured 6 weeks and 8 weeks after the start of the treatment. 4) Only the higher dose of BDP significantly increased the FEV1 and the PC20 for methacholine. FVC did not increase. 5) Only the higher dose of BDP significantly decreased the total amount of oral steroid needed to control asthma. 6) Results of the rapid ACTH test indicated that neither dose of BDP suppressed adrenocoritical function. Furthermore, the serum cortisol level measured early in the morning increased to within the normal range in the three patients in whom oral steroid therapy could be reduced or stopped after treatment. These data indicate that 1800 micrograms of BDP per day is more effective than 1400 micrograms/day at the beginning of long-term management of severe chronic asthma in adults whose symptoms are not controlled with the combination of 800 micrograms/day BDP and bronchodilators. Therapy with a higher dose (at least 1600 micrograms/day) of an inhaled steroid is more useful and should be promptly begun to treat severe asthma.

[Rigid spine syndrome associated with marked hypoxemia and hypercapnia].

A 48-year-old man was referred to our hospital because of hypoxemia (PaO2 = 43 mmHg), hypercapnia (PaCO2 = 70 mmHg), complete atrio-ventricular block, and heart failure. He also had limitation of spine flexion, scoliosis, deformity of the rib cage, and constriction of the ankle joints, complicated by cor pulmonale. These findings were compatible with rigid spine syndrome. To avoid progressive pulmonary hypertension and hypoxemia, nasal BiPAP and home oxygen therapy (0.5 liters/minute) were begun. Rigid spine syndrome is clinically characterized by limitation of spine flexion, and the limitation of thoracic movement often causes severe constrictive respiratory dysfunction. This syndrome should be considered when evaluating patients who have both thoracic deformity, especially scoliosis, and respiratory failure.

[Standard range of peak expiratory flow in normal, healthy Japanese subjects].

The measurement and analysis of the standard range of peak expiratory flow (PEF) in normal, healthy Japanese is necessary at any cost to facilitate bringing the Japanese Guidelines for Bronchial Asthma smoothly into effect. In a study as part of The Bronchial Asthma Group of the Comprehensive Research Project (Terumasa Miyamoto, Chairman of the Planning and Evaluation Committee) under the auspices of the Ministry of Health and Welfare, we measured PEF in 2,785 healthy Japanese volunteers (1,407 males aged 15-84 years and 1,738 females aged 15-80 years) who had no history of smoking, respiratory and/or thoracic diseases, or wheezing with four different peak flow meters (e.g., mini-Wright, Assess, Personal Best and Vitalograph). As a result of comparing PEF measured by the four meters in the same subjects over a short interval of time, we noted significant differences on analysis of variance. Accordingly, the equation for prediction should account for variables in gender and the type of peak flow meter used. A comparison of cubic equations for prediction suggests that the PEF of both Japanese men and women is similar to that of the British but is different from that of the Chinese.