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Type IV phosphodiesterase (PDE IV) is expressed in many tissues including airway smooth muscle and inflammatory cells, suggesting that this isozyme has a regulatory role in the pathogenesis of bronchial asthma. We investigated the effect of a novel selective PDE IV inhibitor, T-440, on immediate asthmatic reaction (IAR), late reaction (LAR) and leukocyte infiltration into the airways after allergen challenge in guinea pigs. Inhalation of ovalbumin by sensitized guinea pigs induced an immediate increase in specific airway resistance that peaked at 15 min. LAR was only produced in combination with chronic treatment with metyrapone, an inhibitor of the biosynthesis of adrenocortical steroids, and was suppressed by administration of dexamethasone, suggesting that the expression of LAR is dependent on an intrinsic steroid hormone. These reactions were accompanied by increases in the number of eosinophils and neutrophils recovered in bronchoalveolar lavage fluid. Oral administration of T-440 significantly inhibited IAR, LAR and the infiltration of eosinophils, whereas it suppressed neutrophil accumulation with relative low potency. These findings imply that the inhibition of PDE IV activity is a reasonable target for the management of obstructive airway diseases associated with airway inflammation such as asthma.

Pulmonary resection of metastatic lesions from colorectal cancer was performed in 19 patients. The cumulative 5-year survival after thoracotomy was 39%. Patients with either one or two metastases has a significantly better survival, with a 5-year survival of 55%, than did those with a greater degree of metastases. Other factors had no apparent influence on postthoracotomy survival. Therefore, the number of metastases should be carefully considered when pulmonary resection is considered for metastatic colorectal cancer.

We demonstrated the effect of a novel selective type IV phosphodiesterase (PDE) IV inhibitor, T-440 (1-[1-(2-methoxyethyl)pyrid-2-one-4-yl]-2,3-bis (hydroxymethyl)-6,7-diethoxynaphthalene), on antigen- and chemical mediator-induced bronchoconstrictions in anesthetized guinea pigs in vivo. Intravenously (i.v.) administered T-440 inhibited antigen-induced bronchoconstriction dose-dependently in passively sensitized guinea pigs (ED50 = 2.3 mg/kg). Histamine-, leukotriene (LT) D4-, U-46619-, acetylcholine (ACh)-, neurokinin A- and endothelin-1-induced bronchoconstrictions were also inhibited by i.v. injected T-440. Most potent suppression was produced against the bronchoconstriction induced by LTD4 (ED50 = 0.89 microgram/kg), whereas the effect against ACh was very weak (ED50 = 1.8 mg/kg). Additionally, T-440 inhibited histamine-induced bronchoconstriction by intraduodenal and intratracheal administration (ED50 and EC50 = 1.6 mg/kg and 0.50 mg/ml, respectively). Bronchoconstrictions induced by antigen and chemical mediators were also suppressed by theophylline. However, all of these anti-spasmolytic effects of theophylline were less potent than those of T-440 (1.8-110 times). Our results indicate the importance of PDE IV in bronchodilation, and PDE IV inhibitors may have potential as anti-asthma drugs.

The effect of T-440, a selective type IV phosphodiesterase (PDE IV) inhibitor on interleukin (IL)-5 production by peripheral blood mononuclear cells (PBMCs) of atopic asthmatic subjects was investigated. PBMCs produced IL 5 following challenge with specific allergen in vitro. T-440 suppressed allergen-induced IL-5 production significantly at a concentration of 1 microgram/ml. T-440 inhibited cyclic AMP-phosphodiesterase (PDE) activity in a concentration dependent manner and raised the intracellular cyclic AMP level of PBMCs significantly. Dibutyryl cyclic AMP suppressed IL-5 production by PBMCs in a similar way to T-440, suggesting that the increase of intracellular cyclic AMP caused by T-440 reduces IL-5 production. T-440 may be an effective agent to treat atopic diseases associated with eosinophilic inflammation, e.g. asthma and atopic dermatitis.

We examined the relationship between ozone (O3)-induced airway hyperresponsiveness (AHR) and inflammation in guinea pigs. Inhalation of methacholine (MCh) was adopted in the time course study of AHR that was assessed by measuring pulmonary inflation pressure after O3 exposure (3 ppm, for 2 hr) because the degree of AHR detected by inhalation of MCh was greater than that detected by i.v. administration. AHR was detected up to 5 hr after O3 exposure and was not observed at 24 and 48 hr. In the bronchoalveolar lavage (BAL) study, the numbers of neutrophils, eosinophils, lymphocytes and macrophages in BAL fluid (BALF) reached maximum at 24 hr or later. On the other hand, the number of airway epithelial cells in the BALF significantly increased at 2 and 5 hr. In the histological study, disorder and impairment of the airway epithelium in the trachea and lung were observed at 2 and 5 hr. Changes in the airway epithelium were recovered at 48 hr, although an increase in leukocytes was observed in the lung. These results indicate that O3-induced AHR in guinea pigs is most probably associated with impairment of the epithelium rather than with infiltration of inflammatory cells in the airway.

Relaxant effects of the beta 2-selective adrenoceptor agonist TA-2005 on bronchoconstriction in the anesthetized guinea pig and cat were evaluated in comparison with other known beta 2-adrenoceptor agonists. The ED50 values of intravenously administered TA-2005, procaterol, formoterol, isoproterenol, salbutamol, and salmeterol to inhibit the histamine-induced bronchoconstriction of the guinea pigs were 0.024, 0.053, 0.056, 0.099, 0.23, and 2.00 micrograms/kg, respectively, and those in serotonin-challenged cats were 0.019, 0.037, 0.039, 0.042, 0.13, and 0.52 micrograms/kg, respectively, in the same increasing order. When guinea pigs were passively sensitized with anti-ovalbumin antiserum, the ED50 values of TA-2005, formoterol, procaterol, and isoproterenol to inhibit the antigen-induced bronchoconstriction were 0.09, 0.30, 0.65, and 7.0 micrograms/kg, i.v., respectively, while those of TA-2005, procaterol, formoterol, and salbutamol in actively sensitized animals were 0.24, 0.25, 1.40, and 23.0 micrograms/kg. When TA-2005 was administered by inhalation to guinea pigs or by the intraduodenal route to cats, it exhibited a long-lasting inhibitory effect comparable or superior to the effects of salmeterol and formoterol. These data indicate that, among the known beta 2-adrenoceptor agonists examined, TA-2005 exerts the most potent bronchodilating effects with a long duration of action in vivo, and its potency ratios to the other reference drugs were greater in antigen- than spasmogen-induced bronchoconstriction models.

A 71-year-old male with recurrent colon cancer was admitted to our hospital with obstructive jaundice. Virchow's node metastasis was palpable in his neck. The enlarged intraabdominal lymphnodes due to recurrence and liver metastasis were demonstrated on computed tomography. Bile duct obstruction was treated by expandable metallic biliary endoprosthesis. 5'-DFUR (5'-deoxy-5-fluorouridine) was administered orally at 600 mg daily. Virchow's node metastasis completely disappeared by 46 days after administration of 5'-DFUR. The enlarged intraabdominal lymphnodes and liver metastasis disappeared on computed tomography. No significant side effects from 5'-DFUR were encountered for 18 months. 5'-DFUR appears to be a useful and safe treatment for recurrent colon cancer.

Tracheal relaxing effects and beta 2-selectivity of TA-2005 were investigated by functional experiments and radioligand binding assay in guinea pigs in comparison with those of other beta-agonists, isoproterenol, procaterol, formoterol and salbutamol. The relaxing activity of TA-2005 on histamine-induced contraction in the isolated trachea was most potent among the five agonists, and it was blocked by a beta 2-selective antagonist (ICI 118,551) but not by a beta 1-selective antagonist (bisoprolol). The potency of the relaxing effect was in the order of TA-2005 (pD2 = 9.79) greater than formoterol greater than procaterol greater than isoproterenol greater than or equal to salbutamol. The positive chronotropic effect of TA-2005 was similar to that of isoproterenol; and it was more potent than those of formoterol, procaterol and salbutamol in the isolated atria. The selectivity for tracheal muscle to atria of these agonists were in the order of procaterol greater than greater than or equal to formoterol greater than TA-2005 greater than salbutamol much greater than isoproterenol. A radioligand binding experiment using guinea pig lung and cardiac ventricle as beta 2- and beta 1-adrenoceptor sources, respectively, has also demonstrated that TA-2005 possesses extremely high affinity (IC50 = 1.04 nM) and selectivity (38-fold) to beta 2-adrenoceptors. By addition of GTP, the competition curve of [125I]iodocyanopindolol shifted rightward, indicating the agonist property. These results confirmed that TA-2005 is a highly beta 2-selective agonist that exerts a potent tracheal relaxing effect.

A 61-year-old man was admitted to our hospital because of a left lung cancer. The chest x-ray film showed an irregular mass in the left upper lung field and the ill-defined left upper mediastinal border. A large portion of the aorta seen in the CT section above the aortic arch was understood to be aortic elongation. When a left pneumonectomy was performed, a saccular aneurysm of the distal aortic arch was found and resected under partial aortic clamping. Following the aneurysmectomy mediastinal dissection was performed in the normal way. The patient recovered uneventfully. The pathological specimens showed a pT2N1M0 squamous cell carcinoma with obstructive pneumonia and an arteriosclerotic aneurysm. There was no report of lung cancer associated with aneurysm of the thoracic aorta. In a patient with left lung cancer obliterating the left upper mediastinal border (the "silhouette sign") the aortic arch should be closely examined by MRI and/or angiography.

A 81-year-old man was admitted because of left recurrent pneumothorax with pleural adhesion. A drainage tube was inserted through the left lateral thoracic wall. The lung seemed to be fully expanded in the AP chest X-ray film but his dyspnea was not relieved. The CT examination showed severe medial pneumothorax. He was operated on and recovered uneventfully. It is important to note medial pneumothorax in patients in the supine position and/or with pleural adhesion.

The usefulness of preoperative administration of Doxifluridine (5'-DFUR) for treating carcinoma of the colon and rectum was studied through a determination of 5-FU concentration in carcinoma, normal intestine, serum and lymph nodes concerned. 1,200 mg/day of 5'-DFUR was administrated orally to 16 patients with carcinoma of the colon and rectum over four days before surgery, and the specimens obtained by resecting the carcinoma were subjected to the mass spectrometry using a gas chromatography to determine 5-FU concentrations. The time needed for collection of the specimen from the final administration of 5'-DFUR was 3.0 to 20.5 hours (10.7 +/- 6.6 hrs). 5-FU concentrations were as follows: 75.8 +/- 61.2 ng/g in the carcinoma, 39.9 +/- 63.5 ng/g in the normal intestine and 26.8 +/- 52.4 ng/g in the lymph nodes concerned, which were significantly high as compared to serum level of 2.3 +/- 4.9 ng/ml (p less than 0.05). Further, a high level of 90.1 +/- 29.3 ng/g (n = 6) of the carcinoma was sustained even at 12 hours or more since final administration of 5'-DFUR. In view of histological patterns, the levels were 139.5 +/- 69.5 ng/g (n = 5) in well differentiated carcinoma and 46.9 +/- 27.4 ng/g (n = 11) in moderately differentiated carcinoma, the level being significantly high in the former (p less than 0.05). A histologic therapeutical effect was shown in one out of 16 cases, with the improvement that remained the score to grade 1. This was deemed due to the small dosage and a short duration of 5'-DFUR.

A case of a rare giant arteriosclerotic aneurysm of the axillary artery is reported. Reconstruction was successfully performed with end-to-end anastomosis after resection of the aneurysm. The surgical technique is discussed.

Seventeen patients with irregular menstrual periods and androgenic symptoms such as excessive hair growth, acne, and oily skin were treated with spironolactone. The basal levels of serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and luteinizing hormone (LH) were significantly higher in the patients than in the controls. After a 4-week treatment with spironolactone, serum T and DHT showed significant decreases. Before treatment, the serum sex hormone binding globulin (SHBG) levels were significantly lower in the patients than in the controls. After initiation of the spironolactone treatment, the SHBG levels tended to increase but not significantly. Spironolactone treatment resulted in the improvement or disappearance of acne in 4 of 5 patients who suffered from this ailment. Improvement of hirsutism was obtained in 2 of 10 patients. Although 4 oligomenorrheic patients and 6 amenorrheic patients showed anovulatory bleeding but did not ovulate, 2 patients in the amenorrheic group ovulated. Two patients complained of tiredness and weakness, and 2 others of polyuria and polydipsia. Both groups showed only temporary symptoms, so treatment was not interrupted. Spironolactone has beneficial effects on ovarian function and few side effects, so it may prove to be an effective anti-androgen, especially for hyperandrogenic anovulatory patients.

We report a case of successful closure of a postpneumonectomy bronchopleural fistula by means of the transpericardial approach with omentopexy through a median sternotomy incision. This method minimizes problems of infection, healing, and pulmonary function.

A 44-year-old man who had sustained injuries to the chest and left upper extremity was admitted to our hospital. The radial pulse was not palpated at the left wrist. Angiography showed occlusion of the left subclavian artery with mediastinal hematoma. The left vertebral artery filled in a retrograde direction and the distal left subclavian artery could be visualized by filling from the left vertebral artery. He had no ischemic neurological symptom but was immediately operated on to prevent hemorrhage. Through a median sternotomy the injured portion of the left subclavian artery was removed and replaced by a dacron prosthesis. The specimen represented that the artery was completely divided and occluded with thrombus. Recovery was uneventful. This was the seventh case of traumatic subclavian steal syndrome. Vascular repair should be made soon in traumatic subclavian steal syndrome because collateral circulation is poor compared with that in arteriosclerotic obstruction.

A SU-polysaccharide skin test (SU-PS test) has been employed and studied as a parameter for monitoring the immunological status of OK-432 treated patients who had undergone a curative gastrectomy for a gastric cancer in stages II and III. The median diameter of the erythema (SU-PS value) was found to have no relation to the number of lymphocytes and the serum protein level and was depressed by combined chemotherapy. The SU-PS value was significantly higher in patients not given a splenectomy than in patients who had undergone a patients splenectomy. The spleen is considered the essential organ to focus on in OK-432 immunotherapy.