Effect of adjusting the combination of budesonide/formoterol on the alleviation of asthma symptoms.

BACKGROUND: The combination of budesonide + formoterol (BFC) offers the advantages of dose adjustment in a single inhaler according to asthma symptoms. We analyzed the relationship between asthma symptoms in terms of peak expiratory flow (PEF) and dose adjustment by the patient. METHODS: Twenty-eight patients with asthma who used BFC for alleviation of their symptoms (12 men, 16 women; 60 years old) were instructed that the inhaled BFC dose could be increased to a maximum of 8 inhalations per day according to symptom severity. Patients measured and recorded PEF every morning and evening in their asthma diary along with their symptoms and the dose of drugs taken. RESULTS: Sixteen of the 28 patients increased their dose for asthma symptoms. The time to recovery from the asthma symptoms was significantly shorter when cough was the only symptom present compared with dyspnea or wheeze (1.4 vs. 5.3 or 6.6 days, p < 0.05) and when they had only one symptom compared with two or three symptoms (1.3 vs. 5.7 or 10.5, p < 0.01). The relationship between PEF (% of personal best) when the dose was increased (Y) and the days for the increased dose to achieve a PEF greater than PEF in the symptom-free state (X) was determined to be Y = - 0.591X + 89.2 (r2 = 0.299, p < 0.001). CONCLUSION: As a guide for increasing the BFC dose when patients with mild asthma have asthma symptoms, the dose should be increased when cough is present or PEF is decreased to 88.9% (i.e., X = 0.5).

Chemical synthesis of an indomethacin ester prodrug and its metabolic activation by human carboxylesterase 1.

It is necessary to consider the affinity of prodrugs for metabolic enzymes for efficient activation of the prodrugs in the body. Although many prodrugs have been synthesized with consideration of these chemical properties, there has been little study on the design of a structure with consideration of biological properties such as substrate recognition ability of metabolic enzymes. In this report, chemical synthesis and evaluation of indomethacin prodrugs metabolically activated by human carboxylesterase 1 (hCES1) are described. The synthesized prodrugs were subjected to hydrolysis reactions in solutions of human liver microsomes (HLM), human intestine microsomes (HIM) and hCES1, and the hydrolytic parameters were investigated to evaluate the hydrolytic rates of these prodrugs and to elucidate the substrate recognition ability of hCES1. It was found that the hydrolytic rates greatly change depending on the steric hindrance and stereochemistry of the ester in HLM, HIM and hCES1 solutions. Furthermore, in a hydrolysis reaction catalyzed by hCES1, the Vmax value of n-butyl thioester with chemically high reactivity was significantly lower than that of n-butyl ester.

Riluzole-induced lung injury in two patients with amyotrophic lateral sclerosis.

Riluzole has recently been proven as the first effective drug for the treatment of amyotrophic lateral sclerosis (ALS). We report two rare cases of lung injury caused by riluzole therapy in patients with ALS. Chest radiographs showed bilateral lower lobe, dorsal-dominant ground glass opacity, and/or consolidation. A drug lymphocyte stimulation test (DLST) of peripheral blood or bronchoalveolar lavage cells was positive for riluzole. Histopathological examination of lung biopsy specimens revealed lung injury without fungoid granuloma, vasculitis, or diffuse alveolar damage. To the best of our knowledge, this is the first report of riluzole-induced lung injury with positive DLST results.

Relationship between sensitivity to dyspnea and fluctuating peak expiratory flow rate in the absence of asthma symptoms.

BACKGROUND: Exacerbation of asthma has a negative impact on quality of life and increases the risk of fatal asthma. One of the known risk factors for patients with a history of near-fatal asthma is reduced sensitivity to dyspnea. OBJECTIVE: We aimed to identify patients with such risk before they experienced severe exacerbation of asthma. METHODS: We analyzed asthma symptoms and peak expiratory flow rate (PEFR) values of 53 patients recorded daily in a diary over a mean period of 274 days. Patients matched their symptoms to one of eight categories ranging in severity from 'absent' to 'severe attack'. We then analyzed the relationship between PEFR and asthma symptoms by dividing the PEFR value by the values of clinical parameters, including asthma symptom level. RESULTS: Average PEFR was 75.2% (50.5-100%) in the 'absent' symptom category, 64.5% (36.6-92.6%) in 'wheeze', 57.3% (25.0-94.7%) in 'mild attack' and 43.6% (20.4-83.1%) in 'moderate attack', with the personal best reading taken as 100%. Thus, differences in PEFR in patients in the same symptom category varied widely. PEFR in wheeze, mild attack and moderate attack did not correlate significantly with duration of asthma, forced expiratory volume in one second or proportion of personal best to standard predicted PEFR values. These PEFRs showed no significant difference in groups divided by type of regular treatment, but showed a significant negative correlation with the coefficient of variation (CV) of PEFR when asthma symptoms were absent. CV for absent symptoms should be between +4.0 and -4.0% when using regression analysis to measure PEFR if the decreased PEFR is in agreement with guidelines. CONCLUSION: To determine which patients have reduced sensitivity to dyspnea, CV of PEFR should be considered when asthma symptoms are reported as absent. When patients present with more than 8% fluctuation in PEFR, we should intervene in their treatment, even when they claim to be stable.

[Clinical investigation of weekly cisplatin and vinorelbine with concurrent radiation therapy for locally advanced non-small cell lung cancer].

Concurrent combination therapy with chemotherapy(cisplatin(CDDP)and vinorelbine(VNR))and thoracic radiotherapy was administered to patients with unresectable locally advanced non-small cell lung cancer. The subjects were 19 patients with stage III non-small cell lung cancer, PS 0-1. They were able to undergo thoracic radiotherapy, had not received previous therapy, and had maintained main organ functions. CDDP(40mg/m / 2)and VNR(20mg/m2)were administered on days 1, 8, 22, and 29, and thoracic radiotherapy was performed every day except for those on which chemotherapy was conducted, 5 days a week at 2 Gy/day(total: 60 Gy). Four subjects were stage III A, 15 were stage III B, and their ages ranged from 42 to 75 years(median age: 65 years). The subjects were 18 males and 1 female, and concerning their histological types, 12, 5, and 2 were diagnosed squamous cell, adeno- and adenosquamous carcinoma, respectively. Regarding the therapeutic efficacy, 0, 14, and 5 subjects were clinically CR, cPR, and cSD, respectively, and their response rate was 73. 7%. The median survival time was 27. 2 months, and the one-year survival rate was 71. 2%. Concerning≥grade 3 adverse effects, 14 and 12 cases had leukocytopenia and neutropenia, respectively. However, no esophagitis was observed, and only one case experienced≥grade 3 nausea and vomiting. Radiation pneumonitis(≥grade 3)was observed in one case, but there was no severe liver or renal dysfunction, and no treatment-related death. It was suggested that this treatment reduces the occurrence of renal toxicity and digestive symptoms, and that a marked antitumor effect can be expected from its administration.

Patients in whom active tuberculosis was diagnosed after admission to a Japanese university hospital from 2005 through 2007.

To identify problems in early diagnosis of tuberculosis and to design countermeasures against the disease, we examined the status of active tuberculosis among patients admitted to a university hospital that did not have an isolation ward for tuberculosis. Between 2005 and 2007, we analyzed demographic characteristics, disease type, chest radiologic findings, and the process leading to diagnosis. Active tuberculosis was diagnosed after admission in 55 patients (34 males and 21 females): pulmonary tuberculosis, 26; tuberculous pleuritis, 13; tuberculous meningitis, 6; miliary tuberculosis, 4; tuberculous pericarditis, 3; lymph-node tuberculosis, 2; and tracheal and bronchial tuberculosis, 1. Although radiographic examinations provided abundant information, chest radiography showed normal findings in 7 patients (12.7%). Computed tomographic scanning was useful for detailed evaluation of abnormalities. Twenty patients (36.4%) were given diagnoses at departments other than ours (Department of Pulmonary Medicine). Numbers of days between hospital admission and diagnosis of tuberculosis (50th percentile/80th percentile) were 8.0/37.8 for miliary tuberculosis, 8.0/8.0 for tracheal and bronchial tuberculosis, 7.5/17.8 for tuberculous pleuritis, 7.0/8.8 for tuberculous pericarditis, 6.0/15.6 for pulmonary tuberculosis, 3.5/4.4 for lymph-node tuberculosis, and 1/1 for tuberculous meningitis. Early diagnosis of tuberculosis requires adherence to the following precautions. Tuberculosis should be suspected in any patient with respiratory symptoms. Sputum tests for acid-fast bacteria should be performed at least three times initially. If findings on chest X-ray films are equivocal, high-resolution computed tomography should be performed to confirm details of shadows and to detect minimal pulmonary shadows or cavitary lesions. Physicians from all specialties should be repeatedly informed about the risk of tuberculosis and should include tuberculosis in the differential diagnosis in patients suspected to have pulmonary diseases.

Relation between the antimicrobial susceptibility of clinical isolates of Pseudomonas aeruginosa from respiratory specimens and antimicrobial use density (AUD) from 2005 through 2008.

OBJECTIVE: To examine the relation between annual trends in the antimicrobial susceptibility of Pseudomonas aeruginosa and drug usage, we compared annual changes in the susceptibility rates of P. aeruginosa clinical isolates during a 4-year period and annual trends in the overall usage of antimicrobials during the same period. METHODS: We studied annual trends in MIC(90)/MIC(50), antimicrobial use density (AUD), and antimicrobial susceptibility rates based on clinical breakpoints for 150 strains of P. aeruginosa isolated from respiratory specimens at Dokkyo Medical University Hospital from 2005 through 2008. RESULTS: The MIC(90)/MIC(50) of antimicrobials effective against P. aeruginosa in years 2005, 2006, 2007, and 2008 were as follows: imipenem, 32/2, 32/1, 8/2, and 16/1 microg/mL; meropenem, 8/1, 8/1, 4/0.5, and 4/0.5 microg/mL; and biapenem, 16/1, 32/0.5, 4/0.5, and 8/0.5 microg/mL, indicating that susceptibility to carbapenems increased slightly. The MIC(90)/MIC(50) was 4/0.25, 2/0.125, 1/0.125, and 2/0.25 microg/mL for ciprofloxacin, 8/4, 8/4, 4/4, and 8/4 microg/mL for amikacin, 64/16, 64/16, 64/16, and 64/16 microg/mL for sulbactam/cefoperazone, 8/2, 16/2, 32/2, and 8/2 microg/mL for ceftazidime, indicating little change. The AUDs of fourth-generation cephalosporins increased from 2005 to 2008 (16.2, 18.4, 28.0, and 23.0), while the AUDs of carbapenems decreased (25.7, 23.7, 10.9, and 12.5). CONCLUSION: The decrease in the AUDs of carbapenems was associated with increased susceptibility rates of P. aeruginosa to carbapenem derivatives. A continuous understanding of trends in the resistance of P. aeruginosa and various other pathogens is essential for designing countermeasures against nosocomial infections, including the proper and effective use of antimicrobials.

A patient with bronchial asthma in whom eosinophilic bronchitis and bronchiolitis developed during treatment.

A 56-year-old woman was referred to our hospital because of dyspnea, wheezing, and a productive cough. Eight years before presentation, bronchial asthma was diagnosed and the patient received inhaled corticosteroids plus antiasthmatic agents (a long-acting inhaled beta2-agonist, leukotriene modifiers, and theophylline). Chest radiography showed small diffuse nodular shadows, and a computed tomographic scan showed thickening of the bronchi and bronchioles, with diffuse centrilobular nodules in both lung fields. A blood test and microscopic examination of the bronchoalveolar fluid revealed marked eosinophilia. Transbronchial lung biopsy and transbronchial biopsy showed eosinophilic bronchitis and bronchiolitis. After treatment with oral prednisolone (40 mg daily) and inhaled corticosteroids, the symptoms, blood eosinophilia, and radiographic findings improved. Recently, several similar cases of eosinophilic bronchiolitis have been reported. Studies of further cases and elucidation of the pathophysiology of eosinophilic bronchiolitis are necessary to establish a concept for this disease and to determine whether it should be classified as a subtype of bronchial asthma or as a distinct entity.

An analysis of characteristics of patients with exacerbation of asthma in a large university hospital in Japan.

BACKGROUND: Considerable progress has been made in the management of asthma with the increasing use of inhaled corticosteroids. However, asthma exacerbation remains a problem. To analyze the characteristics of patients with exacerbation of asthma who visited our hospital in order to better understand the risk factors for fatal asthma. OBJECTIVES: We studied 100 patients who presented at Dokkyo Medical University Hospital (DMUH) with asthma exacerbation. METHODS: Entry sheets were completed by physicians and questionnaires by patients. RESULTS: Before the exacerbation, the severity was assessed as Step 1 in 46% of patients, Step 2 in 15%, Step 3 in 11%, and Step 4 in 18%. With regard to primary care physicians, 45% were treated at DMUH and 36% had no primary care physicians. Among the DMUH group, the largest proportion was aged 60-69 years and was in Step 4 category. According to asthma control test (ACT) scores, disease was poorly controlled in 83%. Patients with no primary care physician were most often aged 20-39 years (p < 0.01), and severity was assessed as Step 1 in 86% (p < 0.01). However, 44% were poorly controlled according to ACT (p < 0.05). CONCLUSION: Patients could be classified into two groups: older patients with severe intractable asthma, treated by a specialist and younger patients considered to have mild asthma, half of whom had poorly controlled asthma and no primary care physician. Systems are needed that allow the emergency physicians to evaluate the need for regular treatment in patients with exacerbation because such patients often visit the hospital at night or on a non-working day.

A case of vertebral artery dissection associated with morning blood pressure surge.

We report a case of a middle-aged man who suffered a cerebral infarction resulting from dissection of a vertebral artery associated with morning blood pressure surge. A 56-year-old man was transferred to our hospital with dizziness and vomiting in the early morning on a cold day in winter. He reported that he had been standing in front of the sink after bathing when he suddenly felt dizzy and fell down. He did not lose consciousness, and by the time he reached the hospital by ambulance, his dizziness had subsided, but he complained of severe headache and vomited 3 times. On admission, he was alert, and there were no neurological or radiological abnormalities (CT, MR angiography) in the brain. However, infarction in the left cerebellar hemisphere was detected by brain MRI on the 5th day of hospitalization. String sign of the left vertebral artery was noted by angiography, confirming the diagnosis of dissection of the left vertebral artery. Ambulatory blood pressure monitoring was performed after discharge. Although the mean 24-h blood pressure was in the normal range, a marked morning blood pressure rise was observed. We speculated that the acute rise of blood pressure in the early morning might have contributed to the dissection of the vertebral artery.

Efficacy and safety of rush immunotherapy in patients with Hymenoptera allergy in Japan.

In Japan, approximately 40 persons die annually from anaphylaxis caused by Hymenoptera stings. Venom immunotherapy is considered safe and effective for the treatment of allergic systemic reactions caused by Hymenoptera stings in patients with Hymenoptera allergy. We studied the efficacy and safety of rush immunotherapy in patients who had a history of systemic reactions to Hymenoptera stings in Japan. Between 1988 and 2002, 95 patients with a history of systemic reactions to Hymenoptera stings were investigated. The stings originated from honeybees in 5 patients, yellow jackets in 28, wasps in 48, both yellow jackets and wasps in 9, and both yellow jackets and honeybees in 5. All patients had venom-specific IgE antibodies in sera (RAST score > or = 2) and received rush immunotherapy with venom extracts at our hospital. Forty-three patients had 63 field re-stings during immunotherapy. Of these patients, 41 (95.3%) with 59 field re-stings (93.7%) had no systemic reactions. Two patients (4.7%) with four field restings (6.3%) had anaphylactic shock. Although anaphylactic reactions developed in two patients (2.1%) during rush immunotherapy with honeybee venom and one patient (1.1%) during maintenance therapy wasp venom, systemic adverse reactions were mitigated by treatment with antihistamines before venom injection. Our results show that immunotherapy is safe and effective for the prevention of systemic reactions to Hymenoptera re-stings in patients with Hymenoptera allergy. We therefore recommend that patients who are allergic to Hymenoptera venom prophylactically receive immunotherapy.

Effects of CD80 and CD86 on cytokine production in patients with wasp-venom allergy who receive venom immunotherapy.

Several studies have provided evidence that activation of antigen-specific T cells requires interactions between CD28 on T cells and its ligands, CD80 and CD86, on antigen-presenting cells (APCs). However, the effects of CD80 and CD86 on cytokine production in patients with Hymenoptera venom allergy who receive venom immunotherapy remain unclear. We examined the effects of CD80 and CD86 on Th1- and Th2-cytokine production before and after venom immunotherapy in patients with wasp-venom allergy. Peripheral blood mononuclear cells (PBMCs) were isolated from patients with wasp-venom allergy before and after three months of venom immunotherapy. CD4+ T cells and monocytes were isolated as APCs from PBMCs and were cocultured with wasp venom in the presence of anti-CD80 or -CD86 blocking antibodies. Interleukin (IL)-4, IL-10, and interferon (IFN)-gamma were measured by enzyme-linked immunosorbent assay. The expression of CD80 and CD86 on CD14+ PBMCs was detected by fluorescence-activated cell-sorter analysis. The expression of CD86, but not that of CD80, on CD14+ PBMCs cocultured with venom increased after three months of venom immunotherapy, but not before venom immunotherapy. Blockade of CD86 reduced IL-10 production after three months of venom immunotherapy. IL-10 production promoted by CD86 costimulation may be involved in the mechanism of venom immunotherapy in patients with venom allergy.

Prostaglandin D2 reinforces Th2 type inflammatory responses of airways to low-dose antigen through bronchial expression of macrophage-derived chemokine.

PGD2, a lipid mediator released from mast cells, is known to participate in allergic reactions. However, the mechanism by which PGD2 contributes to such reactions remains unclear. We established a novel experimental model of asthma that permitted direct assessment of the role of PGD2 in airway inflammation. Antigen-sensitized mice were exposed to aerosolized prostaglandin D2 (PGD2) 1 d before challenge with low-dose aerosolized antigen. Not only the numbers of eosinophils, lymphocytes, and macrophages but also the levels of IL-4 and IL-5 in bronchoalveolar lavage fluid were higher in PGD2-pretreated mice than in control mice. The expression of macrophage-derived chemokine (MDC), a chemoattractant for Th2 cells, was greater in PGD2-pretreated mice than in control. Injection of anti-MDC antibody into PGD2-pretreated mice markedly inhibited inflammatory cell infiltration as well as Th2 cyto-kine production after antigen challenge. These results indicate that PGD2 accelerates Th2 type inflammation by induction of MDC. Our results suggest that this mechanism may play a key role in the development of human asthma and that MDC might be a target molecule for therapeutic intervention.

Production of TARC and MDC by naive T cells in asthmatic patients.

The helper (Th)2 cell-attracting chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) are ligands for the chemokine receptor CCR4. A number of cellular sources of TARC and MDC have been identified, including not only macrophages, dendritic cells, and natural killer cells, but also bronchial epithelial cells. Recent studies report that TARC and MDC may serve as pivotal chemokines for the development of Th2-dominated experimental allergen-induced asthma. This study was designed to assess TARC and MDC production by CD4+ T cells, including naive T cells and memory/effector T cells, purified from peripheral blood mononuclear cells in patients with asthma. Asthmatic subjects included in this study had mild asthmatic symptoms, positive skin test responses to house dust mite allergen, and elevated level of Dermatophagoides farinae immunoglobulin E in the sera. CD4+ T cells--CD45RA+ CD4+ T cells--as naive T cells and CD45RO+ CD4+ T cells--as memory/effector T cells--were purified by negative selection from peripheral blood mononuclear cells obtained from asthmatic patients (n = 6) and healthy controls (n = 6). These cells and established Th1/Th2 cell lines were then cultured in the presence of both anti-CD3 and -CD28 antibodies. After 48 hr of incubation, concentrations of TARC, MDC, interleukin (IL)-4, IL-5, and interferon-gamma in the supernatants were measured by enzyme-linked immunoadsorbent assay. Reverse transcriptase-polymerase chain reaction was performed to analyze mRNA expression of TARC and MDC. Our results clearly showed that TARC and MDC were produced by activated CD45RA+ CD4+ T cells rather than by activated CD45RO+ CD4+ T cells, and the levels of these chemokines in the asthmatic patients were higher than those in the healthy controls. Furthermore, these chemokines production by Th2 cell lines were greater than those by Th1 cell lines, but the level were smaller than those by naive T cells. Our studies suggest that TARC and MDC are produced by naive T cells rather than by memory/effector T cells, including Th2 cells, in asthmatic patients, and these chemokines were produced at modest levels in any T-cell populations from healthy controls. Taken together, naive T cells in asthma have a peculiar function to produce TRAC and MDC, which contribute to local migration of Th2 cells into lung and lymphoid tissues, along with a function as precursor for memory/effector T cell. This novel function of naive T cells may be implicated in the development of asthma.

Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model.

Numerous in vitro and in vivo studies in both animals and patients with asthma have shown that interleukin (IL)-9 is an important inflammatory mediator in asthma. To examine the effects of IL-9 antagonism on airway inflammation, ovalbumin-sensitized BALB/c mice were intravenously given anti-IL-9 antibody or an isotype-matched control antibody 30 minutes before challenge with aerosolized ovalbumin. Airway response to methacholine was measured, and samples of bronchoalveolar lavage fluid (BALF) were obtained 24 hours after the last antigen challenge. Lung tissue was harvested and examined histopathologically. After ovalbumin challenge, there were significant increases in airway hyperreactivity, the numbers of inflammatory cells in lung, and IL-4, IL-5, and IL-13 production in BALF. Treatment with anti-IL-9 antibody significantly prevented airway hyperreactivity in response to methacholine inhalation. Blockade of IL-9 reduced the numbers of eosinophils (0.3 +/- 0.1 x 10(5) and 23.6 +/- 0.5 x 10(5)/ml, anti-IL-9 antibody/control immunoglobulin G) and lymphocytes (0.2 +/- 0.2 x 10(5) and 0.8 +/- 0.1 x 10(5)/ml) in BALF. Anti-IL-9 antibody treatment also reduced the concentrations of IL-4 (from 70.6 +/- 4.6 to 30.8 +/- 5.2 pg/ml), IL-5 (from 106.4 +/- 12 to 54.4 +/- 6.6 pg/ml), and IL-13 (from 44.2 +/- 7.6 to 30.1 +/- 5.5 pg/ml) in BALF. Macrophage-derived cytokine expression in the airways was also decreased by IL-9 blockade. Taken together, our findings emphasize the importance of IL-9 in the pathogenesis of asthma and suggest that blockade of IL-9 may be a new therapeutic strategy for bronchial asthma.