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The effect of a selective thromboxane synthetase inhibitor, OKY-046, and a selective 5-lipoxygenase inhibitor, AA-861, on bronchial responsiveness to acetylcholine was studied in 23 asthmatic subjects. The provocative concentration of acetylcholine producing a 20% fall in forced expiratory volume in one second (PC20 FEV1) was measured before and after oral administration of OKY-046 (3000 mg over four days) and AA-861 (1100 mg over four days) and inhalation of OKY-046 (30 mg) in 10, 10, and nine asthmatic subjects respectively. Baseline values of FEV1 and forced vital capacity (FVC) were not altered by oral OKY-046, oral AA-861, or inhaled OKY-046. The geometric mean value of PC20 FEV1 increased significantly from 0.55 to 2.24 mg/ml after oral OKY-046, but was unchanged after inhalation of OKY-046 and after oral administration of AA-861. These results suggest that thromboxane A2 may play a part in bronchial hyperresponsiveness to acetylcholine. [ABSTRACT FROM PUBLISHER]

Background: There is limited evidence for pulmonary arterial hypertension (PAH)-targeted therapy in patients with pulmonary hypertension associated with respiratory disease (R-PH). Therefore, we conducted a multicenter prospective study of patients with R-PH to examine real-world characteristics of responders by evaluating demographics, treatment backgrounds, and prognosis., Methods and results: Among the 281 patients with R-PH included in this study, there was a treatment-naïve cohort of 183 patients with normal pulmonary arterial wedge pressure and 1 of 4 major diseases (chronic obstructive pulmonary diseases, interstitial pneumonia [IP], IP with connective tissue disease, or combined pulmonary fibrosis with emphysema); 43% of patients had mild ventilatory impairment (MVI), whereas 52% had a severe form of PH. 68% received PAH-targeted therapies (mainly phosphodiesterase-5 inhibitors). Among patients with MVI, those treated initially (i.e., within 2 months of the first right heart catheterization) had better survival than patients not treated initially (3-year survival 70.6% vs. 34.2%; P=0.01); there was no significant difference in survival in the group with severe ventilatory impairment (49.6% vs. 32.1%; P=0.38). Responders to PAH-targeted therapy were more prevalent in the group with MVI., Conclusions: This first Japanese registry of R-PH showed that a high proportion of patients with MVI (PAH phenotype) had better survival if they received initial treatment with PAH-targeted therapies. Responders were predominant in the group with MVI.

Background: Obstructive sleep apnea (OSA) is characterized by augmented sympathetic nerve activity. In our previous study, patients with OSA and an apnea-hyperpnea index (AHI)>55events/h showed increased single-unit muscle sympathetic nerve activity compared to patients with OSA and AHI of 30-55events/h. However, the prognostic impact in these patients remains unclear., Methods: Ninety-one OSA patients were included. All patients who had indication for continuous positive airway pressure (CPAP) were treated with CPAP. Patients were divided into three groups: mild/moderate OSA (S), AHI<30events/h (n=44); severe OSA (SS), AHI 30-55events/h (n=29); and very severe OSA (VSS), AHI>55events/h (n=18). The primary endpoint was a composite outcome composed of death, cardiovascular events, stroke, and heart failure with hospitalization., Results: In the 5-year follow-up, the primary event rate in the SS group [3 events (7%)] was the same as that in the S group [3 events (10%)]. However, the VSS group showed a significantly higher primary event rate among the three groups [6 events (33%), p<0.05]. In Cox regression analysis, the VSS group had the highest hazard ratio compared to other risk factors., Conclusions: CPAP was effective for preventing cardiovascular disease in patients with severe OSA, however patients with very severe OSA still had a high event rate, indicating that CPAP treatment might be insufficient to reduce the OSA-related risk burden in patients with very severe OSA. Additional systemic medical treatment for CPAP might be needed in patients with very severe OSA., (Copyright © 2020. Published by Elsevier Ltd.)

Objective We aimed to identify obstructive sleep apnea syndrome (OSAS) severity indices reflecting the anthropometric and metabolic characteristics of patients with OSAS. Methods A total of 76 patients with OSAS underwent nasal continuous positive airway pressure (nCPAP). We also investigated the effects of nCPAP on OSAS-associated muscle sympathetic nerve activity (MSNA), risk for cardiovascular diseases, and insulin secretion and sensitivity. Results Among the OSAS severity indices, HbA1c was significantly correlated with the apnea-hypopnea index, whereas HOMA-beta, HOMA-IR, and hepatic insulin resistance were significantly correlated with % SpO 2 <90%, independent of age, gender, and body mass index (BMI). Burst incidence of MSNA was independently associated with only a 3% oxygen desaturation index. nCPAP therapy significantly lowered the OSAS severity indices and reduced the burst rate, burst incidence, and heart rate. Conclusion The OSAS severity indices reflecting apnea/hypopnea are associated with glycemic control, whereas those reflecting hypoxia, particularly % SpO 2 <90%, are associated with hepatic insulin resistance independent of obesity. Both types of OSAS severity indices, especially the 3% oxygen desaturation index (reflecting intermittent hypoxia), are independently associated with MSNA, which is dramatically lowered with the use of nCPAP therapy. These findings may aid in interpreting each OSAS severity index and understanding the pathophysiology of OSAS in clinical settings.

Background: Obstructive sleep apnea syndrome (OSAS) is associated with augmented sympathetic nerve activity and cardiovascular diseases. However, the interaction between coronary artery plaque characteristics and sympathetic nerve activity remains unclear. The purpose of this study was to clarify the relationships between coronary artery plaque characteristics, sleep parameters and single- and multi-unit muscle sympathetic nerve activity (MSNA) in OSAS patients. Methods and Results: A total of 32 OSAS patients who underwent full-polysomnography participated in this study. The coronary plaque volume was calculated with 320-slice coronary computed tomography (CT). Single- and multi-unit MSNA were obtained during the daytime within 1 week from full-polysomnography. Patients were divided into 2 groups according to their apnea-hypopnea index (AHI) score (mild-moderate group, AHI <30; and severe group, AHI ≥30). There were no group differences in risk factors for atherosclerosis; however, severe AHI patients showed significantly high single-unit MSNA, and low- and intermediate-attenuation plaque volumes. In regression analysis, the plaque volume of any CT value was not associated with single- or multi-unit MSNA; only AHI significantly correlated with low-attenuation plaque volume (R=0.52, P<0.05)., Conclusions: Our findings provided the evidence that AHI is an independent predictor for low-attenuated, vulnerable plaque volume, but not daytime MSNA, in patients with OSAS.

Introduction: High quality sputum helps increase the sensitivity of the diagnosis of pulmonary tuberculosis., Objectives: To evaluate the efficiency of the acoustic device (Lung Flute; LF) in sputum induction compared with the conventional method, hypertonic saline inhalation (HSI)., Methods: In this crossover study, patients with presumed pulmonary tuberculosis submitted 3 consecutive sputa: the first sputum without induction and the second and third ones using LF and HSI. We compared the efficiency of the 2 induction methods., Results: Sixty-four participants were eligible. Thirty-five (54.6%) patients had negative smears on the first sputum without induction. Among those patients, 25.7% and 22.9% patients were smear-positive after using LF and HSI, respectively (P = .001). The positive conversion rate was not significantly different between the methods. The first samples without induction yielded 65.7% positive cultures, whereas 71.4% and 77.1% of the samples from LF and HSI were positive, respectively (P = .284). Similar results were observed in the nucleic acid amplification test [no induction (60.0%), LF (72.0%) and HSI (60.0%); P = .341]. In 29 smear-positive patients on the first sputum without induction, we observed no significant increase in smear grade, culture yield and nucleic acid amplification test positivity with either method. LF tended to induce fewer adverse events; desaturation (3.1% vs 11.1%; P = .082) and throat pain (1.5% vs 9.5%; P = .057). LF showed significantly fewer total adverse events (15.8% vs 34.9%; P = .023)., Conclusions: Our study showed LF had similar sputum induction efficiency to HSI with relatively fewer complications., (© 2017 The Authors. The Clinical Respiratory Journal Published by John Wiley & Sons Ltd.)

Obstructive sleep apnea syndrome (OSAS) is associated with augmented sympathetic nerve activity, as assessed by multi-unit muscle sympathetic nerve activity (MSNA). However, it is still unclear whether single-unit MSNA is a better reflection of sleep apnea severity according to the apnea-hypopnea index (AHI). One hundred and two OSAS patients underwent full polysomnography and single- and multi-unit MSNA measurements. Univariate and multivariate regression analysis were performed to determine which parameters correlated with OSAS severity, which was defined by the AHI. Single- and multi-unit MSNA were significantly and positively correlated with AHI severity. The AHI was also significantly correlated with multi-unit MSNA burst frequency (r = 0.437, p < 0.0001) and single-unit MSNA spike frequency (r = 0.632, p < 0.0001). Multivariable analysis revealed that SF was correlated most significantly with AHI (T = 7.27, p < 0.0001). The distributions of multiple single-unit spikes per one cardiac interval did not differ between patients with an AHI of <30 and those with and AHI of 30-55 events/h; however, the pattern of each multiple spike firing were significantly higher in patients with an AHI of >55. These results suggest that sympathetic nerve activity is associated with sleep apnea severity. In addition, single-unit MSNA is a more accurate reflection of sleep apnea severity with alternation of the firing pattern, especially in patients with very severe OSAS.

Aim: Obstructive sleep apnea syndrome (OSAS) has been associated with high cardiovascular morbidity and mortality, and patients suffer from repeated episodes of hypoxia. Platelet-derived microparticles (PDMPs) are released via platelet activation by various agonists, including inflammatory cytokines or high shear stress. Plasminogen activator inhibitor -1 (PAI-1) is a fibrinolytic marker and soluble fibrin (SF) is a coagulation activation marker. We examined plasma levels of PDMPs, PAI-1 and SF in patients with OSAS. We also examined the effects of continuous positive airway pressure (CPAP) on plasma levels of PDMPs., Methods: Full polysomnography (PSG) monitoring was performed on 27 patients. The apneahypopnea index (AHI) of 5 events/h or less than 30 events/h indicated mild to moderate OSAS, and an AHI of 30 events/h or more indicated severe OSAS. Plasma levels of PDMPs were measured using an ELISA kit, and PAI and SF were determined by a latex immunoassay. In addition, the effects of CPAP treatment were studied in 7 patients., Result: The plasma level of PDMPs was significantly higher in patients with severe OSAS (15.8±10.4 U/mL) than normal controls (10.8±7.1 U/mL, p < 0.05) and patients with mild to moderate OSAS (9.2±3.5 U/mL, p < 0.05). The plasma levels of PDMPs correlated with the AHI (r = 0.39, p < 0.05). In addition, CPAP treatment decreased the plasma level of PDMPs (11.9±5.6 U/mL to 6.7±3.2 U/mL, p < 0.05)., Conclusions: Patients with OSAS might be at increased cardiovascular risk due to elevated PDMPs. Moreover a decrease in the plasma level of PDMPs by treatment with CPAP might reduce cardiovascular risk.

Background: Chronic cough is the only symptom of cough variant asthma (CVA) and atopic cough (AC). Cysteinyl leukotriene receptor antagonists have been shown to be effective in CVA, but there are no reports on their effectiveness in AC. To evaluate the antitussive effect of montelukast, a leukotriene receptor antagonist, in CVA and AC., Methods: Seventy-five patients with chronic cough received diagnostic bronchodilator therapy with oral clenbuterol hydrochloride for 6 days. Of the 75 patients, 48 and 27 met the simplified diagnostic criteria for CVA and AC, respectively. Patients with CVA were randomly divided into 3 groups: montelukast, clenbuterol, and montelukast plus clenbuterol. Patients with AC were randomly divided into 2 groups: montelukast and placebo. The efficacy of cough treatment was assessed with a subjective cough symptom scale (0 meant "no cough" and 10 denoted "cough as bad as at first visit"). The cough scale, pulmonary function test, and peak expiratory flow rate (PEF) were evaluated before and after 2 weeks of treatment., Results: In patients with CVA, 2-week treatment with montelukast, clenbuterol, and montelukast plus clenbuterol all significantly decreased cough scores and treatment with montelukast plus clenbuterol was superior to treatment with montelukast alone. In the montelukast plus clenbuterol group, PEF values in the morning and evening significantly increased after 2 weeks compared with values before treatment. In patients with AC, scores on the cough scale did not differ significantly between the montelukast group and the placebo group., Conclusions: Montelukast was confirmed to suppress chronic non-productive cough in CVA, whereas it was not effective in non-productive cough in AC.

A 47-year-old man visited his family doctor because of chronic productive cough. Though there were no abnormal chest X-ray film findings, he was diagnosed as tuberculosis on the basis of a sputum examination. Therefore, he was introduced to our hospital and as tracheobronchial tuberculosis was diagnosed by the bronchofiberscopic findings, showing ulceration with a white nodules from the lower part of trachea to the left main bronchus. By treatment, the ulcer change was improved, but the left main bronchus narrowed to pinhole size. Furthermore, the flow-volume curve became worse, and stridor appeared. We inserted Dumon stent in the left main bronchus 4 months later. As a result, his symptoms and flow-volume curve were improved, and we removed the stent 4 years and 6 months later. In this valuable case, we could observe the progress of the post-tuberculosis bronchial stenosis respiratory physiologically.

A 72 year-old man. He was diagnosed with rheumatoid arthritis in 2002. In January 2005 he noted productive cough and fever; he was diagnosed as eosinophilic pneumonia (EP). We discontinued administration of bucillamine and methotrexate and started to treat with oral prednisolone 30 mg daily. To rule out drug-induced EP, prednisolone was tapered by 10 mg per week. Consolidation occurred in the right lower lobe when prednisolone was decreased to 5 mg daily. After increasing the dose of prednisolone to 30 mg daily again, consolidation was promptly resolved. It was considered to be important to rule out drug-induced EP.

A 65-year-old asymptomatic man was admitted to our hospital because a chest abnormal shadow had been pointed out on a medical examination. Our investigation resulted that the consolidation in the left lung had been initially documented in 2002, and had been expanding every year. Bronchofiberscopy showed flare, swelling and stenosis of the left B8, B9 and B10. Because the biopsy specimen from the B9 showed a mass of bacteria and surrounding granulation tissue, pulmonary actinomycosis was diagnosed. Pulmonary actinomycosis should be considered in the differential diagnosis of abnormal chest shadows regardless of the absence of symptoms.

Background: Because the investigation of epidermal growth factor receptor gene (EGFR) status as a predictor of gefitinib efficacy in Japanese patients has shown promise, the authors evaluated EGFR mutations and gene amplification in biopsy specimens from Japanese patients with nonsmall cell lung cancer (NSCLC) who received treatment with gefitinib to analyze the correlation between EGFR gene status and clinical outcome., Methods: Fifty-nine patients were enrolled in this study. EGFR gene amplification was evaluated by fluorescence in situ hybridization (FISH), and EGFR mutations in exons 18, 19, and 21 were analyzed by polymerase chain reaction and direct sequencing., Results: EGFR mutations were detected in 17 patients (28.8%). FISH-positive results were observed in 26 patients (48.1%). The response rate was significantly higher in the patients with EGFR mutations than in the patients without mutations (58.8% vs 14.3%; P=.0005). No significant difference in the response rate was observed between FISH-positive patients and FISH-negative patients (31.8% vs 21.4%; P=.4339). EGFR mutation was correlated with both a longer time to progression (TTP) (7.3 months vs 1.8 months; P=.0030) and longer overall survival (OS) (18.9 months vs 6.4 months; P=.0092). No significant differences in TTP or OS were observed between FISH-positive patients andFISH-negative patients. The results from a multivariate analysis indicated that EGFR mutations maintained a significant association with longer TTP and longer OS., Conclusions: The results of this study suggested that EGFR mutations may serve as predictors of response and survival and that the role of EGFR gene amplification is not a predictor of gefitinib efficacy in Japanese patients with NSCLC., (Copyright (c) 2007 American Cancer Society)

We report a case of pulmonary proteinosis detected at an early stage and followed up on chest CT. A 49-year-old man underwent detailed examinations because of abnormal shadows on chest CT taken on a routine medical examination. The chest CT revealed almost symmetrical ground glass opacities (GGOs) in both lungs with thickened alveolar septa. We could not make a definitive diagnosis even with bronchoalveolar lavage and transbronchial lung biopsy, but after about half a year, the GGOs increased. VATS-biopsy demonstrated alveoli filled with PAS-positive granular materials, and we made a diagnosis of pulmonary alveolar proteinosis. This case was found at an early stage and we were then able to follow up the disease.

A 71-year-old man was found to have right hydropneumothorax by chest X-ray film on a regular checkup. Thoracic drainage and bullectomy by thoracoscopy did not improve the pneumothorax, so pleurodesis with OK-432 was done. Pneumothorax recurred twice, requiring thoracic drainage and pleurodesis. Although pneumothorax was treated successfully, increased pleural effusion, pleural thickening and subcutaneal tumor at the thoracic drainage suture site developed. The concentration of hyaluronic acid in the pleural fluid was very high. The histological examination of the biopsied subcutaneous tumor showed mixed type malignant pleural mesothelioma. Chemotherapy with gemcitabine and vinorelbine could not control the progression.

To determine the optimum dose of OK-432 for intrathoracic administration, a multicenter randomized phase II trial was conducted in patients with malignant pleural effusion due to non-small cell lung cancer. Patients with histologically- or cytologically-proven malignant pleural effusions were randomized to arm A (10 Klinische Einheit (KE) of OK-432) or arm B (1 KE of OK-432). OK-432 was injected intrapleurally over 30 min on days 1 and 3 and the chest tube was clamped for 6 h. If control was inadequate on day 8, 10 KE was administered on days 8 and 10 in each treatment arm. Forty patients were enrolled and 38 patients were eligible (19 in arm A and 19 in arm B). The effusion control rate on day 8 was 79% in arm A and 53% in arm B, while control rates on day 28 were 74% and 84%, respectively. The median drainage time after administration was significantly shorter in arm A (4.0 +/- 1.2 days) than in arm B (7.0 +/- 1.7 days). The total drainage volume was also significantly less in arm A than in arm B. No grade 4 toxicities or treatment-related deaths were observed in either treatment arm. Intrathoracic injection of OK-432 is a feasible treatment for malignant pleural effusion. Although the malignant pleural effusion control rate was equivalent in each treatment arm, faster control and less drainage were achieved in arm A. A dose of OK-432 10 KE/body is, therefore, recommended for further trial.

Background: The authors evaluate the efficacy and safety of gefitinib monotherapy in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). A secondary endpoint is to evaluate the relationship between clinical manifestations and epidermal growth factor receptor (EGFR) mutation status., Methods: Japanese chemotherapy-naive NSCLC patients were enrolled. They had measurable lesions, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ and bone marrow function. Patients received 250 mg of oral gefitinib daily. EGFR mutations in exon 18, 19, and 21 of DNA extracted from tumor and serum were analyzed by genomic polymerase chain reaction and direct sequence., Results: All 30 patients were eligible for the assessment of efficacy and safety. An objective response and stable disease were observed in 10 patients (33.3%) and nine patients (30.0%), respectively. The median time to progression was 3.3 months and the median overall survival was 10.6 months. The 1-year survival rate was 43.3%. Grade 3 toxicities were observed in seven patients. EGFR mutation was observed in four of 13 (30.8%) tumors, and two of them achieved partial response. In serum samples, three of 10 patients with EGFR mutations in the serum before treatment had a response to gefitinib. EGFR mutation was observed in 10 of 27 and significantly more frequently observed in the posttreatment samples from patients with a partial response or stable disease than in those from patients with progressive disease (p = 0.006)., Conclusions: Gefitinib monotherapy in chemotherapy-naive NSCLC patients was active, with acceptable toxicities. These results warrant further evaluation of gefitinib monotherapy as a first-line therapy. The EGFR mutation in serum DNA may be a biomarker for monitoring the response to gefitinib during treatment.

Objective: A prospective multicentre study was conducted to elucidate the causes of chronic cough in Japan., Methodology: All consecutive and unselected patients complaining of cough lasting 8 weeks or more, who visited our clinics from 1 June to 31 December 2001, were registered. The causes of chronic cough were diagnosed based on the criteria for definite and probable causes of cough as recommended by the Japanese Cough Research Society., Results: Of the 248 patients enrolled, 72 patients (29.0%) were unavailable for follow up before their diagnostic assessment had been finalized. Among the 176 patients who were adequately assessed, a diagnosis was made in 165 patients (93.7%) either as single cause or as one of two causes: atopic cough in 48 (29.1%) and 11 patients (6.7%); cough variant asthma in 46 (27.9%) and nine patients (5.5%); cough predominant asthma in 14 (8.5%) and three patients (1.8%); and sinobronchial syndrome (SBS) in 28 (17.7%) and 14 patients (8.5%), respectively. A diagnosis of gastro-oesophageal reflux-associated cough was made in a total of four patients (2.4%)., Conclusion: Atopic cough, asthmatic cough consisting of cough variant asthma and cough predominant asthma, and SBS are major causes of chronic cough in Japan.

Background: We previously reported that a 6-month low-dose course of ofloxacin combined with long-term low-dose erythromycin therapy (EM therapy) was superior to EM therapy alone for sinobronchial syndrome (SBS), especially during the initial 2 months of treatment. However, there was no data as to whether discontinuation of low-dose ofloxacin after 2 months results in symptom relapse. This study was designed to clarify this issue., Methodology: Twenty-three patients with SBS received a 2-month course of levofloxacin (LVFX) therapy (100 mg once a day) concurrent with a 6-month course of EM therapy (200 mg three times a day) (group A). Eighteen other patients were given the EM therapy alone (group B). Clinical parameters, including quantity of morning sputum, were recorded in a daily symptom diary, and reviewed by each doctor in charge at 2-4 week intervals., Results: The quantity of morning sputum decreased more rapidly in group A than in group B. No relapse of symptoms was recognized after discontinuation of LVFX in group A., Conclusions: A 2-month low-dose course of LVFX in conjunction with long-term EM therapy may be efficacious for the treatment of SBS, as evidenced by rapid improvement of expectoration without any relapse after LVFX discontinuation.

Purpose: Hereditary nonpolyposis colorectal cancer kindreds are frequently associated with cancers in various organs, including endometrium, stomach, and ovary. However, hematologic malignancy has rarely been reported in association with this cancer syndrome. We present here the case of a probable hereditary nonpolyposis colon cancer patient in whom non-Hodgkin's lymphoma developed after curative resection of colon cancer. Our experience with this rare case encouraged us to review the literature for reports indicating a possible relationship between these diseases., Results: A 52-year-old male whose family history was consistent with the criteria for hereditary nonpolyposis colon cancer underwent right hemicolectomy for ascending colon cancer. Histologically the tumor consisted of adenocarcinoma that was moderately differentiated with mucinous foci and that invaded beyond the muscularis propria. Neither metastasis nor lymphoma was found in paracolonic lymph nodes. Eight months after surgery, the patient developed non-Hodgkin's lymphoma of T-cell origin involving the ileum and lungs. Both colon cancer and lymphoma frequently showed microsatellite DNA instability, sharing alteration in a locus of chromosome 7 (D7S501)., Conclusion: A possible association of hematologic malignancy with hereditary nonpolyposis colon cancer reported in the literature, together with a report that MSH2-deficient mice are susceptible to malignant lymphoma, strongly supports the finding that this patient's lymphoma was related to hereditary nonpolyposis colon cancer. Overall, this case manifested a distinct clinical course similar to that observed in an animal model that is deficient in DNA mismatch repair machinery, thus providing scientific and clinical implications for understanding the molecular basis of these tumors and for critical management of hereditary nonpolyposis colorectal cancer patients, respectively.

A 24-year-old woman who visited our hospital because of urticaria had a bronchial asthma attack about 5 min. after receiving Stronger Neo-Minophagen C (SNMC) intravenously. A skin test for SNMC and its components (glycyrrhizin, L-cystein, aminoacetic acid, and sodium sulfite) was positive for SNMC and borderline for sodium sulfite after 15 min. A skin test for mixtures of L-cystein and sodium sulfite was also positive. Inhalation provocation tests for SNMC and mixtures of L-cystein and sodium sulfite were positive after 5 min. An inhalation provocation test for sulpyrin was also positive. The patient's bronchial asthma attack was ascribed to SNMC. Type I allergy to mixtures of L-cystein and sodium sulfite was the suspected cause.

It has been considered that thromboxane A2 (TXA2) is involved in the development of bronchial hyperresponsiveness (BHR), a characteristic feature of asthma. To ensure the involvement of TXA2 in BHR of asthma, effects of a 1-week treatment with two orally active TXA2 antagonists, BAY u 3405 and S-1452, on BHR were examined in 10 and 13 patients with stable asthma, respectively, in two consecutive double-blinded, randomized, placebo-controlled, two-phase crossover studies. Provocative concentration of methacholine causing a 20% fall in FEV1 (PC20-FEV1) with BAY u 3405 (0.78 (GSEM, 1.50) mg/ml) was significantly greater than the value with placebo (0.65 (GSEM, 1.46) mg/ml) (ratio 1.23 times, 95% CI 1.01 to 1.46: P = 0.0401). PC20-FEV1 was also significantly increased with S-1452 (0.43 (GSEM, 1.39) mg/ml) compared with placebo (0.29 (GSEM, 1.27) mg/ml) (ratio 1.75 times, 95% CI 1.05 to 2.45: P = 0.0189). Baseline pulmonary function was not altered by these treatments. These results may ensure that TXA2 is significantly involved in the BHR of asthma while the degree of contribution may be small.

To elucidate the mechanisms of acquired resistance to mitomycin C (MMC) in non-small cell lung cancer (NSCLC), we established two MMC-resistant NSCLC sublines by continuous exposure to MMC, using PC-9 as a parent cell line. The sublines, PC-9/MC2 and PC-9/MC4, were 6.4- and 10-fold more resistant to MMC than their parent cell line, respectively, at the IC50 value as determined by MTT assay. They exhibited cross-resistance to EO9, but were not resistant to cisplatin, vindesine, etoposide, carboquone, or KW-2149, a novel MMC derivative. They were collaterally sensitive to adriamycin and menadione. Accumulation of the drug was decreased in the resistant sublines to about 60% of that in the parent cells. Cytosolic DT-diaphorase (DTD) activities were decreased to 13.5 +/- 3.2 in PC9/MC2 and 1.3 +/- 0.6 in PC-9/MC4 from 261.5 +/- 92.7 nmol/min/mg protein in the parent PC-9. NADH:cytochrome b5 reductase activities in both of the resistant cell lines were significantly decreased as compared to that in the parent cell line. Addition of dicumarol resulted in a two-fold increase in IC50 value in PC-9, whereas the IC50 value showed no change in PC-9/MC4. Moreover, dicumarol did not affect the sensitivities to KW-2149 but decreased the sensitivities to EO9 in both the parent and the resistant cell lines. Formation of an alkylating metabolite was significantly decreased in the resistant cells, in parallel to the degree of resistance. We concluded that deficient drug activation due to decreased DTD activity was important as a mechanism of resistance to MMC in PC-9, a relatively DTD-rich NSCLC cell line.

There are some active transport systems in the cell membrane, such as potassium pump, calcium pump, and proton pump. Although it has been reported that sodium/potassium and sodium/calcium pumps of cell membrane play roles in the intracellular accumulation of anticancer agents, the significance of the active transport channels in accumulation of mitomycin C (MMC), one of the most active agents for non-small cell lung cancer (NSCLC) has been unclear. In this study, we evaluated the role of the potassium pump, calcium pump, and proton pump as determinants of the sensitivity to MMC in vitro by using the selective inhibitors, ouabain, verapamil or AG-2000 (an active metabolite of Lansoplazole), respectively. PC-9 and PC-9/MC4 cell lines which are sensitive and resistant to MMC were used for these experiments. PC-9/MC4 was 9.4-fold more resistant to MMC than PC-9 cells. Relative resistance was not significantly changed by co-incubation with a non-cytotoxic dosage of these inhibitors. From these results, it was revealed that the active transport systems in cell membrane do not play a role in determining the sensitivity to MMC and the acquisition of resistance to MMC in PC-9 cell lines. Intracellular bioactivation may be an important factor to determine sensitivity to MMC in NSCLC cells under aerobic conditions.

We report a case of pneumonitis induced by PL granules. A 45-year-old man took PL granules and other drugs for fever and headache. Because he subsequently developed high grade fever, cough and diarrhea, he was admitted to our hospital. His chest X-ray film revealed multiple patchy shadows in both lung fields. Analysis of bronchoalveolar lavage fluid (BALF) disclosed a high number of cells (total), lymphocytes, and a high CD4/CD8 ratio. Microscopic examination of transbronchial lung biopsy (TBLB) specimens showed infiltration of mononuclear cells and thickening of the alveolar wall. After discontinuation of drugs, his condition (symptoms, laboratory data, and chest X-ray findings) promptly improved. Lymphocyte stimulation tests (LST) for PL granules and acetaminophen were positive and an oral challenge test with PL granules was also positive. Based on these findings, we diagnosed this as a case of pneumonitis and enteritis due to PL granules. To our knowledge, this is the first reported case of pneumonitis due to PL granules.

Recently, the importance of the potassium pump in the cellular accumulation of cis-diamminedichloroplatinum(II) (CDDP) has been reported. In this study we evaluated the role of the proton pump as a determinant of the sensitivity to CDDP in non-small cell lung cancer cell lines in vitro by using a selective proton pump inhibitor, AG-2000. PC-9 and PC-9/CDDP cell lines, which are sensitive or resistant to CDDP, were used for these experiments. PC-9/CDDP was 17.4-fold more resistant to CDDP than PC-9 cells. Relative resistance was not altered by co-incubation with a non-cytotoxic dosage of AG-2000. From these studies, it was shown that the proton pump inhibitor AG-2000 did not enhance the sensitivity to CDDP. However, as AG-2000 is not cytotoxic and does not compromise the CDDP-sensitivity in NSCLC cells at the concentration of clinical use for gastroduodenal ulcer, AG-2000 can be used with CDDP in chemotherapy for lung cancer.

A 73-year-old man was admitted to Toyama Red Cross Hospital, because of productive cough and right flank pain. His chest X-ray film and computed tomography (CT) showed pleural effusion and a mass shadow in the right lung area. On CT vessels and bronchi were seen curving toward the mass (comet tail sign), suggesting rounded atelectasis. Transthoracic lung biopsy under CT and echo guidance revealed suppurative pleuritis. MRI also showed the comet tail sign. Moreover, in the lesion, curling hypointense lines were observed on various slices. We describe how MRI facilitates the diagnosis of rounded atelectasis.

We report a case of pneumonitis induced by tolfenamic acid. A 23-year-old woman was admitted to our hospital because of cough and fever. She had been treated with tolfenamic acid and other medications for lumbago. Nine days after the treatment, she developed erythema, fever, cough and dyspnea. Her chest X-ray revealed multiple patchy and micronodular shadows in both lung fields. Bronchoalveolar lavage fluid (BALF) showed increased total cells, lymphocytes, eosinophils and CD4/CD8 ratio. Microscopic examination of transbronchial lung biopsy (TBLB) specimens showed infiltration of mononuclear cells and eosinophils into the alveolar wall and the interstitium. After discontinuation of all drugs, her complaints, laboratory data and chest X-ray findings markedly improved. The lymphocyte stimulation test (LST) and challenge test for tolfenamic acid were positive. Based on these findings, we diagnosed this case as pneumonitis (eosinophilic pneumonia) due to tolfenamic acid. To our knowledge, there has been no reported case of pneumonitis due to this drug in Japan.

An adult case of chickenpox with a chest roentgenogram revealing multiple nodular shadows of 5 to 20 mm in diameter is reported. These shadows were different from those in previously reported varicella pneumonia cases especially with respect to size. Pulmonary function test showed disturbance in diffusion capacity, and bronchoalveolar lavage fluid analysis revealed a decreased CD4/CD8 ratio. Transbronchial lung biopsy showed mild alveolitis and focal exudation and hemorrhage into the alveolar space, which were thought to correspond to the relatively large nodules on the chest roentgenogram. These findings suggest that multiple nodular shadows on the chest roentgenogram may been seen in some patients with chickenpox.

We report a case of chylothorax in a 51-year-old male with non-Hodgkin's lymphoma. Combination chemotherapy reduced the size of mediastinal lymph nodes dramatically, but retroperitoneal lymph nodes remained almost the same, and chylothorax subsequently developed. Lymphangiogram showed reticular spread of contrast material from the thoracic duct downwards but not above the diaphragm. These findings suggest that an obstruction of the infra-diaphragmatic but not the supra-diaphragmatic thoracic duct caused development of collateral lymphatic channels penetrating the diaphragm into the thoracic cavity, with subsequent formation of chylothorax.

We studied the effects of recombinant human interleukin-1 beta (rhIL-1 beta) pretreatment on bleomycin (BLM)-induced pneumonitis in mice. Lung injury was dose-dependently induced by BLM (50 mg/kg, 100 mg/kg, 150 mg/kg i.v.). The mice were pretreated with IL-1 (1 microgram/mouse i.p.) at 0.5, 6, 12 or 24 hours before the administration of BLM. Wet lung weight, lung weight-to-body weight ratio and bronchoalveolar lavage cell findings were analyzed with respect to time, and lung specimens on day 28 after administration of BLM were histopathologically examined. When mice were pretreated with IL-1 at 0.5 hr or 6 hr before the administration of BLM, changes in all the parameters were significantly suppressed. The results indicate that IL-1 pretreatment protects mice from BLM-induced pneumonitis and its effects are time-dependent.