[Clinical significance of measurement of urinary leukotriene E4 in asthmatic patients without attack].

To evaluate clinical significance of measurement of urinary leukotriene E4 (LTE4) in asthmatic patients without attack, we measured urinary LTE4 in 68 asthmatic patients without attack and investigated its correlation with severity of asthma, % FEV1, bronchial hyperresponsiveness and peripheral eosinophil counts. Values of urinary LTE4 were significantly higher in the asthmatic patients (113.6 +/- 9.7 pg/mg.cr) than in healthy control subjects (67.8 +/- 4.7, n = 31), and the level of urinary LTE4 was in proportion to the severity of disease. Urinary LTE4 showed significant negative correlation with % FEV1 in atopic patients (Rs = -0.43, p = 0.025, n = 28), which was not recognized in non-atopic patients. Urinary LTE4 showed no significant correlation with bronchial hyperresponsiveness and peripheral eosinophil counts. Our findings suggested that basal LTE4 in urine reflected chronic airway inflammation of asthma.

[Long-term prognosis of asthmatic patients treated with low-dose beclomethasone dipropionate].

To clarify the prognosis of asthmatics treated with low-dose of inhaled beclomethasone dipropionate (BDP), we retrospectively assessed 43 patients treated with initial dose of 200 or 400 micrograms/day for 5 years, and obtained the following results. 1) 15 patients achieved step-down therapy (group A), 17 patients maintained initial dose of BDP (group B), and 11 patients required step-up therapy of BDP or daily use of oral prednisolone (group C). 2) There was no significant difference in age, sex, duration of disease, severity of disease, peripheral eosinophil counts, %FEV1 and histamine PC20 before BDP treatment among three groups. The percentage of atopic asthmatics was significantly higher in group C than in group A. 3) There was no significant difference in symptom and histamine PC20 between after 1 year state and after 5 years state in three groups. 4) After 1 year from the start of BDP treatment, only 18% patients got symptom free and neither patients exceeded 20,000 micrograms/ml of histamine PC20 in group C. Long-term treatment of low-dose BDP inhalation was effective on mild/moderate asthmatics. Patients requiring step-up therapy had not got sufficient improvement in bronchial hyperresponsiveness after one-year treatment.

Therapeutic effect of a new synthetic lipid A analog (ONO-4007) on a tumor implanted at different sites in rats.

The therapeutic effect of ONO-4007, a new lipid A analog, was examined on the 13762NF mammary adenocarcinoma in the F-344 rat system. Intravenous administration of ONO-4007 (2.5 mg/kg) had a very potent effect on subcutaneously (s.c.) inoculated 13762NF tumor cells, but none at all on intravenously (i.v.) or intraperitoneally (i.p.) inoculated ones. Also no beneficial therapeutic effect of ONO-4007 was observed on i.v. or i.p. inoculated tumor cells when it was combined with anticancer drugs such as carboplatin (CBDCA) or cyclophosphamide (CY). The therapeutic efficacy of ONO-4007 (2.5 mg/kg, 3 times a day for 6 days) for s.c. inoculated tumor cells was greater than that of CBDCA (20-30 mg/kg x 1), and it was also shown to stimulate spleen cells to produce tumor necrosis factor alpha (TNF-alpha) in vitro in a dose-dependent manner. These results suggest that enhanced production of TNF-alpha may be responsible in part for the beneficial effect of ONO-4007 against s.c. inoculated tumor cells. ONO-4007 may in the future become a useful modality for the treatment of human cancers.

Therapeutic effect of clarithromycin on a transplanted tumor in rats.

The therapeutic antitumor effect of clarithromycin (CAM) was examined with the 13762NF mammary adenocarcinoma and F-344 rat system. When CAM treatment at a dosage of 2 mg/kg of body weight orally for 21 days was commenced after inoculation of the tumor, no significant decrease in death rate was observed, although the loss in body weight was less than that in the untreated group. When tumor-bearing (TB) rats were treated with CAM in combination with carboplatin or cyclophosphamide, a significant decrease in the death rate was obtained, although neither treatment alone proved to be effective. A beneficial effect was also observed when CAM treatment was combined with surgical treatment. CAM showed no direct cytotoxicity to this tumor in vitro according to the MTT (3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay. Spleen cells obtained from TB rats receiving CAM treatment showed a stronger tumor-neutralizing activity than those from rats which had not received CAM treatment (Winn assay). Enhanced induction of cytotoxic cells to allogeneic tumor was also observed in rats immunized with allogeneic tumor cells together with CAM treatment (51Cr release assay). The 13762NF tumor produces transforming growth factor-beta (TGF-beta), tumor necrosis factor alpha, and matrix metalloproteinase-9, and treatment of tumor cells with CAM in vitro for 24 h significantly inhibited the expression of the genes coding for these proteins (reverse transcription-PCR). Levels of expression of the TGF-beta and interleukin-6 genes of spleen cells obtained from CAM-treated TB rats were both significantly lower than those of spleen cells from CAM-untreated TB rats. This study suggests that CAM has biological response modifier activities resulting in a beneficial therapeutic antitumor effect and might be useful for the treatment of human cancers.

Diuretic response to cyclophosphamide in rats bearing a matrix metalloproteinase-9-producing tumour.

When cyclophosphamide (CY) (100-120 mg kg(-1)) was administered intravenously (i.v.) to normal F-344 rats, oliguria occurred over the 5-day observation period. Conversely, in rats bearing matrix metalloproteinase-9 (MMP-9) producing 13762NF mammary adenocarcinoma (MTLn3 clone), polyuria occurred chiefly during the first 24 h after CY treatment. In parallel with urine volume, a decrease in the urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) was observed during the first 5 days after CY treatment in normal rats, but it increased in MTLn3-bearing rats. No elevation in blood urea nitrogen (BUN) or serum creatinine (Cr) values was observed for either group. Both urine volume and urinary excretion of NAG after CY treatment were lower in rats bearing the MTC clone (lower production of MMP-9) than for those bearing the MTLn3 clone. In the case of treatment with cisplatin (CDDP, 4-6 mg kg(-1)), urine volume, urinary NAG excretion and BUN and serum Cr values all increased in normal rats and were all found to be higher in MTLn3-bearing rats than in normal rats. The diuretic response to these drugs in tumour-bearing (TB) rats may be associated with MMP-9 produced by the tumour cells. This report suggests that the nephrotoxicity due to anti-cancer drugs may change when the drugs are used for the treatment of patients bearing a MMP-9-producing tumour.

Correlation among urinary eosinophil protein X, leukotriene E4, and 11-dehydrothromboxane B2 in patients with spontaneous asthmatic attack.

Various kinds of cells and their mediators are thought to be involved in the pathogenesis of bronchial asthma. However, changes in each mediator or relationship among mediators during an asthmatic attack have not been well documented. In this study, to clarify whether eosinophil protein X (EPX) is a marker which is distinct from leukotriene E4 (LTE4), or 11-dehydrothromboxane B2 (11DTXB2), we measured the urinary excretion of EPX, LTE4, and 11DTXB2 in 14 asthmatics who were admitted to the hospital with either an acute asthmatic attack or status asthmaticus. These patients included eight atopic and six non-atopic types of bronchial asthma, with a median age of 34.0 years. Urinary excretion of EPX was significantly high on admission with the asthmatic attack, and returned to control levels 175 [122 -384] microg/day when the patients were in the improved state (1036-317 microg/day, P < 0.01). Similar findings were observed in LTE4 (155-59 ng/day, P < 0.01) and 11DTXB2 (991-442ng/day, P<0.01). No significant differences in values were observed between atopic and non-atopic types of asthma in all three substances. When the individual data during the attack state were analysed, a significant correlation was observed between changes (%) in urinary EPX and those in urinary LTE4, but no such relationship was observed between changes (%) in urinary EPX and those in urinary 11DTXB2. These results suggest that measuring urinary EPX levels may be a useful marker for the understanding and management of the disease.

[A fundamental study on clinical significance of measuring eosinophil protein X in spot urine in asthmatics].

To define the clinical significance of measuring eosinophil protein X (EPX) in spot urine in asthmatics, we undertook the fundamental study in 32 stable asthmatics having anti-asthmatic agents and 10 normal healthy controls, and obtained the following results. 1) Peripheral eosinophil counts, urinary EPX (u-EPX), urinary leukotriene E4 (u-LTE4), and serum eosinophil cationic protein (s-ECP) values were significantly higher in asthmatics than those in the controls. 2) U-EPX values were not associated with the type of asthma and severity of the disease. 3) A significant correlation was observed between u-EPX values and peripheral eosinophil counts, but not between s-ECP values and peripheral eosinophil counts. Furthermore, no correlation was observed between u-EPX and s-ECP values. 4) U-EPX values did not correlate with either u-LTE4, %FEV1, or histamine PC20 values. Accordingly, EPX value in spot urine may be a useful maker to assess the activation of eosinophils in asthmatics.

Urinary excretion of leukotriene E4 and 11-dehydrothromboxane B2 in patients with spontaneous asthma attacks.

BACKGROUND: Cysteinyl leukotrienes (LTs) and thromboxane A2 (TXA2) are known to play an essential role in the pathogenesis of atopic asthma. However, their role in nonatopic asthma has not as yet been clarified. The objectives of this study were to define (1) the participation of LTs and TXA2 in nonatopic asthma and (2) the relationship between LTs and TXA2 in asthma attacks. METHODS: Urinary excretion of leukotriene E4 (LTE4) and 11-dehydrothromboxane B2 (11DTXB2) was measured in 10 atopic and 10 nonatopic asthmatics who were admitted to hospital with either an acute asthma attack or status asthmaticus. RESULTS: In atopic asthmatics, urinary excretion of LTE4 and 11DTXB2 was significantly higher on admission with an asthma attack, and returned to control levels when the patients were in the improved state (179+/-29 to 65+/-16 ng/day in LTE4, 1,085+/-250 to 440+/-90 ng/day in 11DTXB2). Similar findings were observed in nonatopic asthmatics (148+/-13 to 61+/-11 ng/day in LTE4, 1,089+/-206 to 457+/-60 ng/day in 11DTXB2). However, when the individual data during the attack were analyzed, there was no correlation between urinary excretion of LTE4 and that of 11DTXB2 in both types of asthma. CONCLUSION: Both LTs and TXA2 may be implicated in the pathogenesis of the nonatopic as well as the atopic type of asthma, but no correlation between these two metabolites was observed in the individuals.

Therapeutic effect of pranlukast, a selective cysteinyl leukotriene receptor antagonist, on bronchial asthma.

This study was undertaken to evaluate whether the therapeutic effect of pranlukast, a selective cysteinyl leukotriene (LT) C4/D4/E4 receptor antagonist, can be observed in patients with the non-atopic or atopic type of asthma, or in asthmatics taking oral steroids. Twenty-two patients with moderate to severe bronchial asthma receiving an inhaled corticosteroid (beclomethasone dipropionate) were treated with pranlukast (225 mg b.i.d.) for 4 weeks, and their peak expiratory flow (PEF) and asthmatic symptoms were monitored during the treatment period. In the patients with the non-atopic type of asthma (n = 13), an increase in their PEF was observed both in the morning and evening following a 4-week administration ofpranlukast, but the degree was slightly inferior to that in patients (n = 9) with the atopic type of asthma. On the other hand, no significant increase was observed in the patients (n = 6) taking oral prednisolone (PSL, 5-15 mg/day). Changes in the symptom score at the end of the 4-week treatment period were closely associated with those in the PEF values; namely, a significant improvement in symptom score was observed for patients with the atopic and non-atopic type of asthma, but no improvement for the patients taking oral PSL. Pranlukast, a selective LT receptor antagonist, will be a valuable asset in the treatment of bronchial asthma, especially asthma requiring no oral steroids.

[Allergic bronchopulmonary aspergillosis in a patient with no symptoms of asthma until after bronchial lavage].

An asymptomatic 56-year-old man was admitted to our hospital because of an abnormal shadow on a chest X-ray film. Allergic bronchopulmonary aspergillosis was diagnosed on the basis of five findings: eosinophilia, immediate skin reactivity to Aspergillus antigen, the presence of precipitating antibodies against Aspergillus antigen, a high concentration of IgE in serum, and central bronchiectasis. He had no symptoms of asthma at the time of diagnosis, but did a few days after he underwent bronchial lavage. We speculate that the asthma attack was related to the bronchial Lavage as follows: First, drainage of mucus plugs by bronchial lavage may have exposed the bronchial epithelium, which had already been sensitized, to aspergillus antigens. Second, the scattered antigen may have dose-dependently stimulated the bronchi. Third, the infection may have increased bronchial responsiveness to the antigen. Symptoms of bronchial asthma are not necessary for the diagnosis of allergic bronchopulmonary aspergillosis.

Efficient method for the quantitation of urinary leukotriene E4: extraction using an Empore C18 disk cartridge.

We describe here an efficient procedure for the precise quantitation of leukotriene E4 (LTE4) in a small volume of urine, which was achieved mainly by the use of an Empore extraction disk cartridge. After addition of [3H]LTE4 to 2 ml of urine, an Empore C18 cartridge was used for initial extraction of the urine, which resulted in the extraction of LTE4 in a small volume of solvent. The eluate could then be injected onto a high-performance liquid chromatography column without further concentration. After separation by high-performance liquid chromatography, LTE4 was extracted from the effluent using an Empore C18 cartridge. The concentration of LTE4 was subsequently quantified by enzyme immunoassay. LTE4 can be recovered from urine with sufficient efficiency (69.9+/-4.7%, mean+/-S.D., n=101). The coefficient of variation of the assay procedure was less than 10%. When urine was spiked with different amounts of LTE4, the recovery of LTE4 added to the urine specimen was less than 120%. The concentration of LTE4 in urine from normal healthy subjects was 48.0+/-15.3 pg/mg creatinine (n=15).

Urinary leukotriene E4 and 11-dehydrothromboxane B2 in patients with aspirin-sensitive asthma.

The objective of this study was to define the participation of cysteinyl leukotrienes (LTs) or thromboxane A2 in the pathogenesis of aspirin-sensitive asthma (ASA). Leukotriene E4 (LTE4) and 11-dehydrothromboxane B2 (11DTXB2) values in spot urine were measured in 22 asthmatics with a history of aspirin sensitivity and in 17 without such a history (non-aspirin-sensitive asthma [NASA]) in the outpatient clinic. The urinary LTE4 value was significantly higher in ASA patients than in NASA (340 +/- 47 vs 65 +/- 15 pg/mg.cr, P < 0.001), but there was no significant difference in urinary 11DTXB2 between the two groups (891 +/- 77 vs 657 +/- 90 pg/mg.cr). A high value of LTE4 was not associated with type of asthma, severity of disease, oral prednisolone treatment, sex, or age. A higher value of 11DTXB2 was observed in the atopic type than the nonatopic type in ASA (1086 +/- 111 vs 697 +/- 147 pg/mg.cr, P < 0.05). No correlation was observed between urinary LTE4 and 11DTXB2 in either ASA or NASA. In conclusion, LTs may play an important role in the pathogenesis of ASA, and TXA2 in the pathogenesis of the atopic type in ASA.

[Not Available].

Animal and human studies have shown that various kinds of chemical mediators may participate in the pathogenesis of bronchial asthma. Among these mediators, thromboxane A(2) (TXA(2)) is recognised as important in bronchial responses and the pathogenesis of airway hyperresponsiveness. The reasons are as follows. TXA(2) (or mimetics) is a powerful constrictor of bronchial muscle in vitro and in vivo.Levels of TXB(2), a metabolite of TXA(2), increase in blood or bronchoalveolar lavage fluid after allergen challenge in atopic asthmatic patients.TXA(2) mimetics induce airway hyperresponsiveness to nonspecific stimuli such as acetylcholine or methacholine.TXA(2) synthetase inhibitors or TXA(2) receptor antagonists inhibit asthmatic responses or airway hyperresponsiveness in various animal models and in patients with asthma. In Japan, the TXA(2) synthetase inhibitor ozagrel and the TXA(2) receptor antagonist seratrodast are now used in the treatment of patients with bronchial asthma. In multicentre double-blind studies, these 2 agents were shown to have beneficial effects in adult patients with asthma, and no serious adverse effects were reported. This review deals with the role of TXA(2) in the pathogenesis of bronchial asthma and the clinical potential of anti-TXA(2) agents in the treatment of bronchial asthma.

Grouping of anticancer drugs based on administration method-related toxicity patterns in rats.

As part of the study of the appropriate usage of anticancer drugs, and the effects of the administration method (single dose, or divided doses) on the death rate from toxicity, five anticancer drugs (nimustine hydrochloride = ACNU, cyclophosphamide = CY, carboplatine = CBDCA, mitomycin C = MMC, vindesine = VDS) were studied in F-344 rats. A reduced death rate from toxicity was achieved by divided-dose administration of ACNU and CBDCA (group 1), but it was higher for CY and VDS (group 2), and there was no significant difference with MMC (group 3). In conclusion, the drugs were divided into three groups according to the administration method-related toxicity patterns. Improved knowledge of the properties of anticancer drugs is important for the success of chemotherapy.

Changes in clinical features of fungemia in a Japanese University Hospital over a 12-year period.

Forty-five patients with fungemia during 1982-1993 (periods I = 1982, II = 1986-1989, III = 1990-1993) in a Japanese university hospital were reviewed to follow changes in the clinical features of fungemia. The percentage of fungi among microorganisms isolated from blood cultures was almost constant (6-10%) throughout the study period. Fungemia was highly associated with use of intravascular catheters, and some changes in clinical features were observed: 1) Candida albicans, C. parapsilosis and C. glabrata were the main isolates, and the number of fungal species showed a tendency to increase. 2) The percentage of patients over 65 years old increased from 36 to 50%. 3) The percentage of patients who were treated with anti-fungal agents and/or removal of catheter increased from 50 to 89 and to 86%. 4) The percentage of patients who died within 28 days after isolation of fungus decreased from 64 to 27%. The improved prognosis was thought to be due to the development of new anti-fungal agents and faster removal of intravascular catheter when infection was suspected.

Evaluation of a polymerase chain reaction diagnostic method and risk factors for cytomegalovirus pneumonia.

In order to evaluate the diagnostic methods and risk factors for cytomegalovirus (CMV) pneumonia, 22 patients with suspected CMV pneumonia were examined by means of the polymerase chain reaction (PCR) and serological (Ab) methods (complement fixation test = CF and enzyme-immunoassay = EIA: IgG, IgM). Thirteen patients showed positive for either the PCR or serological method; the PCR method was positive in 77% (10/13) (sputum = 8/10, bronchoalveolar lavage fluid = 3/4, peripheral blood = 3/12, urine = 2/11) and the serological method in 64%(7/11)(CF = 5/10, IgG = 3/11, IgM = 0/11). All patients diagnosed as having CMV pneumonia had underlying disease, most of which were idiopathic interstitial pneumonia and malignancies. Twelve out of 13 patients had been treated with steroids for long- or short (pulse)-periods. The cure rate was high for these patients whose PCR results became negative following anti-CMV treatments. These results indicate that a) the steroid treatment acts as a risk factor for the CMV pneumonia, b) the PCR method is a useful tool not only for early diagnosis but also for assessment of the therapeutic effect on CMV pneumonia, and c) concomitant assays of PCR and Ab may be preferable in making a conclusive diagnosis of CMV pneumonia.

No significant effect of age of onset on response to anti-asthmatic medications in adult asthmatics.

In order to know the effect of age of onset on response to antiasthmatic medications in adult asthmatics, the changes in bronchial hyper-responsiveness and symptoms were retrospectively assessed following four to five month-treatments in patients with a less than two-year history of asthma. There was no significant difference in regimens among the three groups. The histamine PC20 value increased significantly from 456 to 1015 micrograms/ml in group A (20-39 yrs), 531 to 2363 micrograms/ml in group B (40-59 yrs), and 256 to 1148 micrograms/ml in group C (60 < or =) following the administration of the agents for four to five months. The percentage of patients who became symptom-free also increased significantly in each group along with a decrease in the bronchial hyper-responsiveness. There was no significant difference in the degrees of improvement in bronchial hyper-responsiveness and symptoms. These results suggest that the age of onset of asthma may not be related to the response to anti-asthmatic medications in adult asthmatics.

[A case of rheumatoid arthritis with a remarkable left-right difference in pulmonary lesions and acute exacerbation of pneumonia].

A 59-year-old woman had a four-year history of rheumatoid arthritis. Despite treatment with prednisolone for interstitial pneumonia, her chest X-ray films revealed gradual progression of reticular shadows, mainly in the left lung, and during the third hospitalization she died of respiratory failure due to acute exacerbation of pneumonia. At autopsy, there was a remarkable difference in lung weight: left 250 g, right 510 g. Microscopically, the pulmonary lesion was mild fibrosing interstitial pneumonia, with remarkable luminal organization and macrophages in parts. The features of unilateral interstitial pneumonia with bronchiolitis obliterans organizing pneumonia were clearer in the left lung. The cause of the acute exacerbation and of the difference in interstitial pneumonia between sides could not be identified.

An analysis of bacteraemia in a university hospital in Japan over a 10-year period.

Details of positive blood cultures obtained from 357 inpatients attending the Toyama University Hospital were collected over a 10-year period in order to document changes in microbiological and clinical features of bacteraemia. Fifty-one per cent of patients were over 60 years old, 48% had intravascular catheters in-situ, and 17% had had surgical procedures within 30 days prior to the isolation of organisms from the blood. The proportion of underlying diseases other than malignancies increased over the 10-year period (42-60%, P < 0.05). Patients from surgical departments other than the Academic Department of Surgery increased over the study period (16-55%, P < 0.05). Staphylococcus aureus bacteraemia increased significantly (29 to 49%, P < 0.05) as did pseudomonas and anaerobic bacteraemia. Most bacteria showed no significant changes in their antibiotic sensitivity pattern over the 10 years. Clinical features in patients with bacteraemia varied with the infective organisms and the underlying disease. Mortality was high in patients with haematological malignancy, usually in association with Pseudomonas aeruginosa.

Effect of reduction of inhaled corticosteroid on bronchial hypersensitivity in asthmatics.

We retrospectively assessed the effect of reduction of beclomethasone dipropionate (BDP) inhaler (BDI) on bronchial hypersensitivity in asthmatics whose respiratory threshold of histamine (RT-Hist) once reached a normal level of > or = 10 mg/ml with BDI treatment. In a study period of 1988-1992, 19 out of 44 patients had their RT-Hist of > or = 10 mg/ml, and the reduction of BDI was undertaken in 10 cases. Cessation of bronchodilators did not result in the increase of bronchial hypersensitivity in patients undergoing BDI treatment without the dosage change. When BDI was reduced from 8 puffs/day to 4 puffs/day, the RT-Hist did not drop below 5 mg/ml in 6 out of 8 patients (success rate = 75%). When BDI was reduced from 4 puffsday to 2 puffs/day, the success rate was 37.5% (3/8). Cessation of BDI was unsuccessful in 3 patients (0/3). Conversely, the RT-Hist did not drop below 10 mg/ml in all six cases whose BDI was not reduced. This preliminary study suggested that cessation of BDP would be very difficult in most asthmatics, although its reduction would be successful in some cases.