[Bronchial asthma due to Stronger Neo-Minophagen C].

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.

Analysis of thrombocytopenia due to carboplatin combined with etoposide in elderly patients with lung cancer.

Thrombocytopenia induced by carboplatin combined with etoposide for elderly lung cancer patients was analyzed in relation to the predicted thrombocytopenia by the equations advocated by Egorin et al. and Taguchi et al. The thrombocytopenia actually observed was strongly correlated with and significantly more severe than that predicted if carboplatin had been administered as a single agent. The AUC (area under the curve) of carboplatin predicted by Calvert's equation significantly affected the degree of thrombocytopenia. These data suggested that dosing of carboplatin should be determined individually on the basis of renal function, as recommended earlier. The reason for the enhancement of thrombocytopenia is yet to be determined in future trials.

Involvement of thromboxane A2 in bronchial hyperresponsiveness of asthma. Kanazawa Asthma Research Group.

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.

Additive effect of continuous low-dose ofloxacin on erythromycin therapy for sinobronchial syndrome.

It has been established that long-term low-dose erythromycin therapy (EM therapy) is very effective for sinobronchial syndrome, a common condition in Japan characterized by chronic upper and lower airway inflammation. The effect does not result from its bacteriocidal activity and the detailed mechanisms are not known. It takes 3-6 months for EM therapy to improve the symptoms. This study was designed to evaluate the additive effect of continuous low dosage or intermittent usual dosage of ofloxacin (OFLX) on EM therapy in patients with sinobronchial syndrome. Patients with sinobronchial syndrome were randomly allocated to receive one of the following four regimens. Patients in Group A received both low-dose OFLX and EM therapy daily for 6 months. Patients in Group B received EM therapy and intermittent treatment of OFLX for 6 months. Patients in Group C underwent EM therapy for 6 months. Patients in Group D received neither OFLX nor EM therapy. All patients were given carbocystein for more than 2 months before starting each treatment and during the study period. In patients receiving OFLX and/or EM therapy, these antimicrobial agents were well-tolerated during the treatment period. Amount of sputum in the morning was significantly less in Group C than in Group D after 3-6 months, and decreased significantly in Group A as compared with Group B after 2 weeks, Group C after 2 weeks to 2 months, and Group D after 2 weeks to 6 months. Other symptoms such as number of expectorations, difficulty of expectoration and severity of cough also improved rapidly in Group A. These findings suggest that it is useful to add low-dose OFLX to EM therapy for sinobronchial syndrome, especially within 1-2 months from starting treatment, and it may be cost-effective as this combination therapy can shorten the treatment period of EM therapy.

Management of disseminated intra-abdominal lymphangiomatosis with protein-losing enteropathy and intestinal bleeding.

We encountered an unusually severe case of intra-abdominal lymphangiomatosis associated with protein-losing enteropathy and intestinal bleeding. A low-fat diet effectively raised the patient's serum levels of hemoglobin and the total serum protein, perhaps by inducing a reduction in intestinal lymph flow and pressure.

Repeated inhalation challenge with exogenous and endogenous histamine released by acetaldehyde inhalation in asthmatic patients.

We previously reported that inhaled acetaldehyde, a metabolite of ethanol and a main factor in alcohol-induced asthma, causes bronchoconstriction indirectly through endogenously released histamine in asthmatic subjects. No study has examined the difference between tachyphylaxis in response to endogenous as opposed to exogenous histamine. Therefore, we examined tachyphylaxis occurring in response to repeated inhalation of histamine or acetaldehyde in nine asthmatic subjects. The mean acetaldehyde concentration causing a 20% decrease in FEV1 increased significantly from 18.4 (geometric standard error of the mean (GSEM = 0.14) to 45.2 (GSEM = 0.14) mg/ml over a period of 1 h (p < 0.002), whereas the mean histamine concentrations causing a 20% decrease in FEV1 were identical. No correlations were observed between the change in bronchial responsiveness to each solution and the change in baseline FEV1. These results suggest that tachyphylaxis in response to histamine is observed only when the latter is released endogenously. We believe that this is the first report suggesting tachyphylaxis caused by endogenous histamine.

Role of sodium pump systems to determine sensitivity to mitomycin C in non-small cell lung cancer cell lines.

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.

Establishment and characterization of non-small cell lung cancer cell lines resistant to mitomycin C under aerobic conditions.

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.

[A case of pneumonitis induced by PL granules].

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.

Effect of proton pump inhibitor on cell growth and sensitivity to cis-diamminedichloroplatinum(II) in non-small cell lung cancer cell lines.

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 case report of rounded atelectasis on MRI].

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.

Role of dt-diaphorase as a determinant of sensitivity to mitomycin analogs in nonsmall cell lung-cancer cell-lines.

DT-diaphorase (DT-D) is regarded as a two-electron reductase that plays an important role in the biotransformation of mitomycin C (MMC) to antitumor metabolites, which is enhanced under hypoxic conditions. To evaluate the role of DT-D as a bioactivator of MMC and its analogue, KW-2149, in non-small cell lung cancer (NSCLC) cell lines under an aerobic or hypoxic condition, we examined the inhibitory effect of dicumarol which was regarded as an inhibitor of DT-D on the sensitivity to these anticancer agents in vitro. In this study, we used an MMC-resistant NSCLC cell line (PC-9/MC4) which was established in our laboratory from a PC-9 cell line as a parent cell line by continuous exposure to MMC. The subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9, the parent cell line, under aerobic conditions, and 5.2-fold more resistant even under hypoxic conditions. PC-9/MC4 cell lines did not show collateral resistance to KW-2149, a newly developed MMC analogue. The IC50 value of PC-9 against MMC significantly decreased by co-incubation with dicumarol under aerobic, but not under hypoxic conditions. KW-2149 was cytotoxic to PC-9/MC4 as well as PC-9 cells, and the sensitivity to KW-2149 was not altered by coincubation with dicumarol or exposure to hypoxia. There were no significant differences in intracellular uptake of MMC and the activities of cytosolic detoxification enzymes, GST and GSH, between PC-9 and PC-9/MC4 cell lines under aerobic conditions. These findings suggest a partial role of DT-D in bioactivation of MMC, but not of KW-2149, under aerobic conditions. However, the detailed mechanisms of drug resistance to MMC under hypoxic conditions are still not clear.

[A case of eosinophilic pneumonia due to tolfenamic acid].

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 multiple nodular shadows on chest roentgenogram].

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.

[A case of chylothorax resulting from malignant lymphoma--pathogenesis of chylothorax: a new concept].

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.

[Inhibitory effects of rhIL-1 beta pretreatment on bleomycin-induced pneumonitis in mice].

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.