Imbalance between vascular endothelial growth factor and endostatin levels in induced sputum from asthmatic subjects

BACKGROUND: Angiogenesis has recently attracted considerable attention as a component of airway remodeling in bronchial asthma. Vascular endothelial growth factor (VEGF) is highly expressed in asthmatic airways, and its contribution to airway remodeling has been reported. Although angiogenesis is regulated by a balance of angiogenic and antiangiogenic factors, the relative levels of antiangiogenic factors in asthmatic airways have not been evaluated. OBJECTIVE: We sought to determine whether an imbalance between angiogenic and antiangiogenic factors exists in asthmatic airways. METHODS: We simultaneously measured VEGF and endostatin levels and evaluated their correlation and balance in induced sputum from 18 steroid-naive asthmatic subjects and 11 healthy control subjects. After initial sputum induction, asthmatic subjects underwent 8 weeks of inhaled beclomethasone dipropionate (BDP; 800 microg/d) therapy, and sputum induction was then repeated. RESULTS: VEGF and endostatin levels in induced sputum were significantly higher in asthmatic subjects than in control subjects (P <.001). There was a significant correlation between VEGF and endostatin levels in both control subjects (r = 0.995, P <.001) and asthmatic subjects (r = 0.923, P <.001). Moreover, the VEGF/endostatin level ratio in asthmatic subjects was significantly higher than that in control subjects (P <.0001). After 8 weeks of inhaled BDP therapy, the VEGF level in induced sputum in asthmatic subjects was significantly decreased (P <.001), whereas the endostatin level was not. A correlation between VEGF and endostatin levels existed even after BDP therapy (r = 0.861, P <.001). Moreover, the VEGF/endostatin level ratio was significantly decreased to the same level as in the control subjects after BDP therapy (P <.0001). CONCLUSION: There was an imbalance between VEGF and endostatin levels in induced sputum from asthmatic subjects. This imbalance might play an important role in the pathogenesis of bronchial asthma through its effects on angiogenesis.     

Effects of inhaled beclomethasone dipropionate and alternate-day prednisone on pituitary-adrenal function in children with chronic asthma.

Two corticosteroid regimens, alternate-day prednisone and inhaled beclomethasone dipropionate, have been more acceptable than daily oral corticosteroids for treatment of chronic asthma. To compare the effect of these regimens on hypothalamic-pituitary-adrenal function, 20 children with asthma were evaluated while receiving 20 to 40 mg of prednisone on alternate mornings or 400 to 800 microgram per day of inhaled beclomethasone dipropionate in divided daily doses; seven children requiring only non-corticosteroid medication served as controls. Early-morning serum cortisol concentration, urinary free-cortisol excretion and the 11-desoxycortisol response to metyrapone were decreased to a similar degree among children receiving both corticosteroid regimens in comparison with the control patients and were lowest when alternate-day prednisone and inhaled beclomethasone dipropionate were given together. Thus, inhaled beclomethasone dipropionate appears similar to alternate-day prednisone in its effect on hypothalamic-pituitary-adrenal function when used alone; the effect is additive when the two are used together.     

Increased levels of vascular endothelial growth factor in induced sputum in asthmatic patients

BACKGROUND: Vascular endothelial growth factor (VEGF) is highly expressed in the airway of asthmatic patients. As VEGF increases airway vascular permeability, consequent thickening of the airway wall mucosa may lead to narrowing of the airway lumen. OBJECTIVE: We evaluated the relationship between VEGF levels in induced sputum and eosinophilic inflammatory profiles, and the degree of airway vascular permeability in asthmatic patients and we evaluated the effect of inhaled corticosteroids on VEGF levels in induced sputum. METHODS: Induced sputum specimens were obtained from 28 glucocorticosteroids free asthmatics and 11 healthy control subjects. We examined VEGF levels and airway vascular permeability index in induced sputum. After the initial sputum induction, 21 asthmatics received 8-week inhaled beclomethasone dipropionate (BDP, 800 micro g/day) therapy, then sputum induction was repeated. RESULTS: The VEGF levels in asthmatics were significantly higher than in healthy control subjects (P < 0.0001). The VEGF levels were negatively correlated with forced expiratory volume of 1 s (FEV1, % predicted, r = - 0.68, P < 0.001), the percentage of eosinophils (r = 0.51, P < 0.01) and ECP levels (r = 0.39, P < 0.05). Moreover, the VEGF levels were significantly correlated with airway vascular permeability index (r = 0.61, P < 0.001). After 8-week inhaled BDP therapy, the VEGF levels were significantly decreased compared to pretreatment levels (P < 0.0001) and the VEGF levels were significantly correlated with airway vascular permeability index even in post-treatment asthmatics (r = 0.62, P < 0.01). CONCLUSION: The VEGF levels in induced sputum were increased in asthmatics and its levels were associated with degree of airway narrowing and airway vascular permeability. These findings provide strong evidence that VEGF may play an important role in the pathogenesis of bronchial asthma.     

Inhaled corticosteroids decrease vascularity of the bronchial mucosa in patients with asthma

BACKGROUND: Increased vascularity in airway mucosa is a distinctive feature of airway remodelling in asthma. While corticosteroids have proved most effective in modifying airway inflammation, the effect of inhaled corticosteroids on increased airway mucosal vascularity in asthmatics has been little studied. OBJECTIVE: We examined the effect of inhaled corticosteroid on airway vascularity in bronchial biopsy specimens taken from asthmatic patients. SUBJECTS AND METHODS: We studied bronchial biopsies from 28 asthmatic patients before and after treatment with inhaled beclomethasone dipropionate (BDP) 800 microg/daily, or placebo, for 6 months in a double-blind manner. Biopsy specimens were evaluated for number of vessels and percentage of area occupied by vessels, using computerized image analysis after staining for type IV collagen in vessel walls. Specimens were also examined for extent of collagen III in the subepithelial basement membrane. In addition, we compared asthmatic specimens with biopsy specimens taken from non-asthmatic control subjects. RESULTS: There was a significant increase in number of vessels (P < 0.01) and percent vascularity (P < 0.001) in the submucosa of asthmatic patients compared with control subjects. After 6 months of treatment, we observed significant improvements in forced expiratory volume in 1 s (FEV1), FEV1% and airway responsiveness (P < 0.05, each) in the BDP treatment group compared with the placebo group. This was accompanied by significant decreases in both vessel number and percent vascularity in the airways of BDP-treated patients (P < 0.05, each). We also observed a significant correlation between change in percent vascularity and change in collagen III thickness in the BDP-treated patients (rs = 0.90, P < 0.001). Furthermore, the change in percent vascularity was inversely correlated with both FEV1 (rs = -0.49, P < 0.05) and airway responsiveness (rs = -0.36, P < 0.05). CONCLUSION: These findings suggest that inhaled corticosteroid treatment of asthma reduced airway wall vascularity during airway remodelling.     

Hypogammaglobulinemia in steroid-dependent asthmatics correlates with the daily dose of oral prednisolone

BACKGROUND: Steroid-induced adverse effects including suppression of humoral immunity should be considered in steroid-dependent severe asthma. Only a few studies have determined the exact steroid dose that could potentially suppress humoral immunity in asthmatics. METHODS: Randomly selected 100 adult asthmatics treated with inhaled beclomethasone dipropionate (BDP) were classified into three groups based on the dose of steroid to determine the serum IgG, IgA and IgM levels by radioimmunoassay. Relationships between serum immunoglobulin levels and the daily dose and duration of oral prednisolone (PSL) therapy were examined. RESULTS: None of the patients on inhaled corticosteroid alone had hypogammaglobulinemia. Patients on oral PSL at a dose >12.5 mg/day for at least 1 year had low serum IgG. There was no significant correlation between the duration of oral PSL therapy and serum IgG. CONCLUSIONS: Oral PSL can potentially suppress humoral immunity in severe asthma. In asthmatics, hypogammaglobulinemia could develop in those on a daily dose of PSL >12.5 mg, but is independent of the duration of such treatment. No suppression of humoral immunity was noted on inhaled corticosteroid therapy alone, either at low or high dose.     

Clinical role of bone marrow angiogenesis in childhood acute lymphocytic leukemia

PURPOSE: Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are associated with increased angiogenesis, growth, and metastasis in solid tumors. But, until today, the importance of theses factors on leukemia, especially childhood acute lymphocytic leukemia (ALL) has received limited attention. Therefore, this study examined the bone marrow plasma VEGF and bFGF levels in ALL patients and normal controls. PATIENTS AND METHODS: Bone marrow plasmas at diagnosis from 33 ALL patients (median age 5.9 years; range 1.8-13.9 years) were used for analysis. The bone marrow levels of bFGF and VEGF were determined by enzyme-linked immunosorbent assay (R & D Systems) and compared with the bone marrow levels of 7 healthy control subjects (median age 11.98 years; 6 months -13.6 years). RESULTS: Average VEGF was higher in relapse ALL (N=7, 216.6 +/- 79.9pg/mL) compared to standard (N=9, 36.8 +/- 12.1pg/mL) (p=0.013) or high risk ALL (N=17, 80.0 +/- 12.2pg/mL) (p=0.023). bFGF levels were also significantly higher in relapse than standard-, or high-risk ALL patients (relapse ALL; 48.6 +/- 15.4pg/mL, standard risk ALL; 18.9 +/- 5.5pg/mL, high risk ALL; 19.0 +/- 3.5pg/mL, normal control; 18.6 +/- 4.0pg/mL) (p=0.003). Three patients with refractory relapse and death had much higher VEGF and bFGF values (VEGF; 420.0 +/- 81.6pg/ mL, bFGF; 85.6 +/- 3.2pg/mL). CONCLUSION: Our data suggest that the increased levels of VEGF and bFGF in bone marrow may play an important role in prognosis of childhood ALL.     

Interleukin-4 and interleukin-4 soluble receptor alpha levels in bronchoalveolar lavage from children with asthma.

BACKGROUND: In asthma there is increased expression of the Th2-type cytokine interleukin-4 (IL-4). IL-4 is important in immunoglobulin isotype switching to immunoglobulin E and adhesion of eosinophils to endothelium. OBJECTIVE: We hypothesized that levels of IL-4 in bronchoalveolar lavage (BAL) fluid would be increased in stable, atopic asthmatic children compared with controls and that levels of its physiologic inhibitor IL-4 soluble receptor alpha (IL-4sR alpha) would be correspondingly decreased. METHODS: One hundred sixteen children attending a children's hospital for elective surgery were recruited. A nonbronchoscopic BAL was performed, and IL-4 and IL-4sR alpha were measured in the BAL supernatants. RESULTS: There was no significant difference in IL-4 concentrations between atopic asthmatic children, atopic normal controls, and nonatopic normal controls [0.13 pg/mL (0.13 to 0.87) vs 0.13 pg/mL (0.13 to 0.41) vs 0.13 pg/mL (0.13 to 0.5), P = 0.65]. IL-4sR alpha levels were significantly increased in asthmatic patients compared with atopic controls [6.4 pg/mL (5.0 to 25.5) vs 5.0 pg/mL (5.0 to 9.9), P = 0.018], but not when compared with the nonatopic controls [5.2 pg/mL (5.0 to 10.6), P = 0.19]. CONCLUSIONS: Contrary to expectation, IL-4sR alpha levels are increased in BAL from stable asthmatic children compared with nonatopic controls, and we speculate that IL-4sR alpha is released by inflammatory cells in the airways to limit the proinflammatory effects of IL-4.     

Analysis of vascular endothelial growth factor levels in induced sputum samples from patients with cough variant asthma.

BACKGROUND: We previously found that vascular endothelial growth factor (VEGF) levels in induced sputum samples are increased in patients with classic asthma and are associated with the degree of airflow obstruction and airway microvascular permeability. OBJECTIVE: To examine VEGF levels and the degree of airway microvascular permeability in patients with cough variant asthma (CVA). METHODS: Levels of VEGF in induced sputum samples and airway microvascular permeability were examined in 12 controls, 16 patients with CVA, and 16 patients with classic asthma. We also evaluated the relationship between VEGF level and the clinical features of these 2 disorders. RESULTS: Mean (SD) VEGF levels and airway vascular permeability index values were significantly higher in patients with CVA (VEGF: 2,520 [1,050] pg/mL; P < .001; vascular permeability index: 0.017 [0.006]; P = .003) and classic asthma (4,750 [1,260] pg/mL; P < .001; 0.028 [0.009]; P < .001) than in controls (1,420 [1,230] pg/mL; 0.009 [0.003]). Furthermore, these values were significantly higher in patients with classic asthma vs CVA. We also found significant correlations between VEGF level and airway vascular permeability index in patients with CVA (r = 0.60; P = .02) vs classic asthma (r = 0.83; P = .001). Furthermore, VEGF levels were inversely correlated with the degree of airflow obstruction and airway hyperresponsiveness to methacholine in patients with CVA and classic asthma. CONCLUSIONS: Airway microvascular hyperpermeability induced by elevated VEGF levels contributes to abnormal airway function in CVA and classic asthma, and differences in the clinical features of these 2 disorders may depend on airway VEGF levels.     

Influence of changing from chlorofluorocarbon (CFC)-beclomethasone dipropionate (BDP) to hydrofluoroalkane (HFA)-BDP on pulmonary function in asthmatic children]

The discontinuation of chlorofluorocarbon- beclomethasone dipropionate (CFC-BDP) products has made it necessary to switch to hydrofluoroalkane (HFA)-BDP. We studied the influence of the changing from CFC-BDP to HFA-BDP on pulmonary function in asthmatic children. METHODS: In twenty asthmatic children (mean: 10.5 years of age) who were clinically well-controlled with CFC-BDP for longer than 6 months, CFC-BDP was switched to HFA-BDP, at half the dose of CFC-BDP. We examined the changes in spirometric parameters at 3-6 months after the switch. RESULTS: FEV1.0% ([FEV1.0/FVC]x100) and %V50 ([V50 measured/V50 predicted]x100) were significantly improved (FEV1.0%: pre 81.7+/-4.7-->post 84.1+/-4.1 [p<0.05], % V50: pre 66.9+/-6.9-->post74.4+/-11.3 [p<0.05]). Comparison between patients with greater than 10% improvement in %V50 and those with less than 10% improvement revealed differences in the duration of using CFC-BDP (former 2.8+/-0.9 years, latter 5.2+/-2.4 years [p<0.05]) despite lack of difference in age at initiation of treatment with CFC-BDP. CONCLUSION: The changing from CFC-BDP to HFA-BDP showed the improvement of lung function in a part of asthmatic children. We should keep in mind that there are some differences of efficacy among the inhaled corticosteroid products. The long-term anti-inflammatory medication should be adjusted to normalize the pulmonary function on the basis of the degree of airway inflammation.     

Oral candidiasis associated with inhaled corticosteroid use: comparison of fluticasone and beclomethasone.

BACKGROUND: Inhaled steroids such as fluticasone propionate and beclomethasone dipropionate play a central role in the treatment of bronchial asthma. Fluticasone exhibits excellent clinical effectiveness; however, oral adverse effects can occur. OBJECTIVE: To compare the frequency of oral candidiasis in asthmatic patients treated with fluticasone and beclomethasone, to evaluate the effect of gargling with amphotericin B, and to measure the inhalation flow rate on candidiasis. METHODS: The study consisted of 143 asthmatic patients who were treated with inhaled steroids, 11 asthmatic patients not treated with inhaled steroids, and 86 healthy volunteers. Quantitative fungal culture was performed by aseptically obtaining a retropharyngeal wall swab from these patients. Patients with positive results were treated with gargling using a 1:50 dilution amphotericin B solution. In asthmatic patients treated with fluticasone, the inhalation flow rate was measured using an inspiratory flow meter. RESULTS: The amount of Candida spp. was significantly greater in asthmatic patients taking inhaled steroids compared with those who were not. It was also significantly greater in patients with oral symptoms than asymptomatic patients and significantly greater in asthmatic patients treated with fluticasone than in those treated with beclomethasone. Although the presence of Candida did not correlate with the inhaled dose of beclomethasone, it did increase with the dose of fluticasone. Gargling with amphotericin B was effective in most asthmatic patients with candidiasis. Candidiasis was not due to inappropriate flow rates during inhalation of steroids. CONCLUSIONS: Fungal culture of a retropharyngeal wall swab may be useful for predicting the risk of developing oral candidiasis in asthmatic patients treated with inhaled steroids. The amount of isolated Candida was significantly greater in asthmatic patients treated with fluticasone than in those treated with beclomethasone. Attention to dosage is required as the amount of Candida increased with dose of fluticasone. Gargling with a 1:50 dilution of amphotericin B is effective in treating oral candidiasis of asthmatic patients treated with inhaled steroids.     

Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma

BACKGROUND: A recombinant humanized anti-IgE mAb, omalizumab, forms complexes with free IgE, blocking its interaction with mast cells and basophils; as a consequence, it might be effective in the treatment of asthma. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of omalizumab in the treatment of inhaled corticosteroid-dependent asthma. METHODS: In this phase III, double-blinded, placebo-controlled trial, 525 subjects with severe allergic asthma requiring daily inhaled corticosteroids were randomized to receive placebo or omalizumab subcutaneously every 2 or 4 weeks, depending on baseline IgE level and body weight. Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment and tapered during a further 12-week treatment period. RESULTS: Omalizumab treatment resulted in significantly fewer asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation than placebo treatment during the stable steroid phase (0.28 vs 0.54 [P =.006] and 14.6% vs 23.3% [P =.009], respectively) and during the steroid reduction phase (0.39 vs 0.66 [P =.003] and 21.3% vs 32.3% [P =.004], respectively). Beclomethasone dipropionate reduction was significantly greater with omalizumab treatment than with placebo (median 75% vs 50% [P <.001]), and beclomethasone dipropionate discontinuation was more likely with omalizumab (39.6% vs 19.1% [P <.001]). Improvements in asthma symptoms and pulmonary function occurred along with a reduction in rescue beta-agonist use. Omalizumab was well tolerated, with an adverse-events profile similar to that of placebo. CONCLUSION: The addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use.     

系统性红斑狼疮患者血清IL-18、sVCAM-1和VEGF水平及其意义

目的探讨白细胞介素18（IL-18）、可溶性血管黏附分子-1（sVCAM-1）和血管内皮生长因子（VEGF）水平变化与系统性红斑狼疮（SLE）发病机制的关系。方法采用酶联免疫ELISA法检测SLE患者35例,正常对照组25例血清IL-18、sVCAM-1和VEGF的水平。结果SLE组IL-18（521．23±134．29）pg／mL、sVCAM-1（1179．25±225．57）ng／mL、VEGF（198．85±41．96）pg／mL,较正常对照组IL-18（256．39±59．52）pg／mL、sVCAM．1（538．16±91．21）ng／mL、VEGF（125．62±32．15）pg／mL明显升高,差异有统计学意义（P均〈0．01）。活动期SLE患者IL-18（687．44±158．60）pg／mL、sVCAM．1（1478．14±322．72）ng／mL、VEGF（236．25±48．62）pg／mL与非活动期组sLEIL—18（355．02±109．98）pg／mL、sVCAM-1（881．37±128．30）ng／mL、VEGF（160．47±35．79）pg／ml之间比较,差异有统计学意义（P均〈0．01）。结论SLE患者IL-18、sVCAM-1和VEGF水平增高,且与疾病的活动性相关。     

Increased concentrations of glutathione in induced sputum of patients with mild or moderate allergic asthma.

BACKGROUND: Oxidative stress is involved in the pathogenesis of allergic inflammatory diseases, such as rhinitis and asthma. Glutathione is a vital intracellular and extracellular protective pulmonary antioxidant. It plays a key role in regulating oxidant-induced lung epithelial cell function and also in the control of proinflammatory processes. OBJECTIVE: To quantify oxidative stress in sputum of asthmatic patients compared with healthy subjects. METHODS: We quantified induced sputum supernatant concentrations of total and oxidized glutathione in 20 patients with mild asthma without inhaled corticosteroid treatment, 19 patients with moderate-persistent asthma treated with inhaled corticosteroids (median dose, 900 microg/d of beclomethasone equivalent), and 15 healthy, nonatopic, nonsmoking subjects. RESULTS: Total glutathione levels were significantly increased in mild and persistent asthma compared with healthy subjects [geometric mean (95% confidence interval), 9.2 microM (7.1-12 microM) and 8.7 microM (5.9-12.5 microM) vs 4 microM (2.7-6 microM); P = .039 and .042, respectively]. In contrast, there were no differences in total and oxidized glutathione levels between steroid-na?ve and steroid-treated asthmatic patients (P > .20 for all comparisons). Persistent, steroid-treated asthmatic patients had higher sputum counts of neutrophils than steroid-na?ve asthmatic patients [geometric mean (95% confidence interval), 35.6% (28.2%-42.7%) vs 17.7% (11.7%-27.1%), P = .04]. There was a positive correlation of total glutathione with sputum total cells (rho = 0.32, P = .02). CONCLUSIONS: Total glutathione is increased in induced sputum of patients with mild and moderate asthma. These data underline the contribution of oxidative stress to the pathogenesis of allergic asthmatic inflammation.     

Effect of anti-asthmatic drugs on the response to inhaled endotoxin.

BACKGROUND: Endotoxin is a pro-inflammatory agent contaminating the dust that has been associated with the risk to develop pulmonary diseases. There is no data on the protective efficacy of anti-asthmatic drugs on the response induced by inhaled endotoxin in human. METHODS: Twelve mildly asthmatic subjects were submitted weekly to bronchial challenge tests with 20 microg endotoxin. The response was evaluated by the changes in FEV1, blood cells count, neutrophils activation (measured with the luminol-enhanced chemiluminescence) and blood concentration in the acute phase proteins, C-reactive protein (CRP) and haptoglobin. In a double-blind randomized cross-over placebo-controlled design, a single dose each of 500 microg beclomethasone dipropionate, 200 microg salbutamol, and 50 microg salmeterol were administered 30 minutes before the endotoxin challenge test. RESULTS: The 20-microg endotoxin challenge test induced a significant decrease in FEV1 and luminol-enhanced chemiluminescence (P < .001 and <.05, respectively). There was an increase in the blood neutrophils count (P < .05), in CRP (P < .02) and in haptoglobin (P < .03) concentrations. Pretreatment with beclomethasone dipropionate did not have any significant effect on the response to inhaled endotoxin. Salbutamol and salmeterol completely prevent the FEV1 decline due to their potent bronchodilatation activity. Salmeterol and salbutamol did not have any significant effect on the blood inflammation induced by endotoxin inhalation. CONCLUSION: The bronchodilating properties of beta2-agonists prevent the lung function response to inhaled endotoxin. When given in a single dose, an inhaled corticosteroid does not have protective activity on the endotoxin-induced blood inflammation.     

A prospective study of respiratory infection in asthmatic patients treated with beclomethasone dipropionate and sodium cromoglycate

A prospective study of forty adult asthmatic patients attending two chest clinics in the City of Liverpool was undertaken. All patients had reversible airways obstruction and were under treatment with either beclomethasone dipropionate or sodium cromoglycate. Satisfactory symptomatic control was achieved in both groups of patients on a subjective basis, but there was a statistically significant (P <0.001) reduction in the number of admissions to hospital in the treatment year compared to the preceding 12 months in the beclomethasone aerosol group. No increased incidence of lower respiratory tract infections or non-specific sore throats was found in either group studied. No cases of clinical oral Candida infection occurred in the beclomethasone aerosol treated patients. It is concluded that beclomethasone dipropionate in aerosol form is not only a safe and effective method for symptomatic control of adult bronchial asthma but is also economically worthwhile as a means of reducing hospital admissions in this vulnerable group of patients.     

Leukotriene receptor antagonist, montelukast, can reduce the need for inhaled steroid while maintaining the clinical stability of asthmatic patients

BACKGROUND: Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma. OBJECTIVE: To determine whether the addition of montelukast could lead to a reduction in inhaled corticosteroid dose without a significant decrease in peak expiratory flow rate (PEFR). METHODS: After a 4-week run-in period, 191 moderate-to-severe asthmatic patients whose asthma had been well controlled with daily inhaled corticosteroid therapy (beclometasone dipropionate 800 to 1600 micro g/day), were randomly assigned to one of two treatments - placebo (n = 98) or montelukast 10 mg once daily (n = 93) - for a 24-week, multicentre, double-blind, treatment period. At the beginning of the active treatment period, the daily dose of inhaled corticosteroid was halved in all of the patients. In addition, the inhaled corticosteroid dose was subsequently titrated every 8 weeks, based on PEFR, asthma symptoms and beta-agonist use. RESULTS: After 8 weeks of a 50% reduction in inhaled corticosteroid use, morning PEFR increased by 5.3 +/- 32.3 L/min from baseline in patients receiving montelukast and significantly decreased by 6.9 +/- 29.0 L/min in those receiving placebo (P = 0.035). In addition, evening PEFR significantly decreased by 9.8 +/- 28.5 L/min (P = 0.003) in the placebo group, but was maintained in the montelukast group. In spite of a subsequent 50% reduction in the inhaled corticosteroid dose every 8 weeks, morning and evening PEFRs were maintained over the 24-week treatment period in the montelukast group; PEFR significantly decreased in the placebo group. There was a significant difference between the two groups with regard to morning PEFR, therapy score and asthmatic score at weeks 8, 16 and 24, as well as evening PEFR at week 8. However, the symptom scores were not significantly different between the two groups or within each group. CONCLUSION: These data suggest that montelukast reduces the need for inhaled corticosteroids while maintaining asthma control over a 24-week period. Therefore, montelukast may be useful for long-term treatment in patients with asthma who require high doses of inhaled corticosteroids.     

Clinical and physiological assessment of asthmatic children treated with beclomethasone dipropionate

Forty-two perennial asthmatic children were selected for a 12-wk study using beclomethasone dipropionate. The groups included 21 steroid-dependent children (Group I and 21 patients (Group II) whose disease was of sufficient severity that corticosteropd therapy was contemplated. All children received the drug in a dose of 100 μg 4 times daily. During the study, oral prednisone was withdrawn from the steroid-dependent children while other therapy was essentially unchanged. Group II children underwent a double-blind trial, receiving beclomethasone for 6 wk and placebo for 6 wk. Objective assessment of adrenal and pulmonary function was obtained at regular intervals. For the latter, total lung capacity and its subdivisions, airways resistance, maximum expiratory flow volume, and oxygen tension, were measured in both groups. In Group II static elastic recoil was measured also. For most tests the results were statistically significant. In both groups, 18 of 21 patients demonstrated an excellent clinical response, no evidence of adrenal suppression, and improvement in pulmonary function. Forty of 42 patients were followed for another 12 wk, and 19 of each group did well. After 20–24 wk of therapy, 16% of patients harbored monilia in their oropharynx, and 1 patient had clinical monilial stomatitis. Within the limits of the time of the study, beclomethasone dipropionate appeared to provide adequate clinical control in many chronic, severe, steroid-dependent and nonsteroid-dependent asthmatic children.     

Plasma basic fibroblast growth factor levels in colorectal cancer: a clinically useful assay?

Angiogenic cytokines in the plasma and serum of cancer patients may serve as `surrogate' markers of tumour neoangiogenesis. Serum VEGF correlates with disease stage in colorectal cancer (CRC), but the role of bFGF in CRC is uncertain. This study aimed to assess plasma bFGF levels in CRC patients before treatment, during chemoradiotherapy and at one-year follow-up. Plasma samples were taken from 124 CRC patients, 26 polyp patients and 55 controls, and bFGF levels were measured by ELISA. 19 patients underwent pre-operative chemoradiotherapy. One-year follow-up samples were available from 48 disease-free patients and 18 patients with progressive disease. There were no detectable differences between plasma bFGF levels in polyp, Dukes' A or B patients (4.55, 5.77, 4.25 pg/ml, respectively), but there was a significant increase in metastatic CRC patients [Dukes' C and D (7.42 and 6.6 pg/ml; P=0.004 and 0.048, respectively)], relative to median control levels of 4.14 pg/ml. At follow-up, there was a significant fall in plasma bFGF levels in disease-free patients (pre-op 6.09 and follow-up 3.45 pg/ml, P=0.0004), but a non-significant rise in 18 patients with progressive disease (pre-treatment 5.90 and follow-up 9.99 pg/ml, P=0.33). Pre-treatment plasma bFGF in patients receiving chemo-radiotherapy was similar in those with responsive and non-responsive tumours. There were no detectable changes in plasma bFGF through the adenoma-carcinoma sequence or patient groups with non-metastatic cancers. Elevated plasma bFGF was, however, associated with metastatic spread. The significant fall in bFGF in disease-free patients following therapy suggests that bFGF may be useful in clinical practice. This revised version was published online in July 2006 with corrections to the Cover Date.     

Linear growth in prepubertal asthmatic children treated with montelukast, beclomethasone, or placebo: a 56-week randomized double-blind study.

BACKGROUND: Antileukotrienes and inhaled corticosteroids are asthma controller agents widely used in the treatment of pediatric asthma. OBJECTIVE: To evaluate the effects of montelukast and beclomethasone on linear growth in prepubertal asthmatic children for 1 year. METHODS: This was a 30-center study of boys (6.4-9.4 years old) and girls (6.4-8.4 years old) at Tanner stage I with mild, persistent asthma. After a placebo run-in period, 360 patients were randomized in equal ratios to double-blind, double-dummy treatment with 5 mg of montelukast, 200 microg of beclomethasone twice daily (positive control), or placebo for 56 weeks; 90% of the patients completed the study. The primary end point was linear growth velocity, measured using a stadiometer. RESULTS: Linear growth rates were similar between the montelukast and placebo groups; the mean difference for the year was 0.03 cm. The mean growth rate with beclomethasone was significantly less than with placebo (-0.78 cm) or montelukast (0.81 cm) (P < .001 for both). Median percentage of days with beta-agonist use was greater with placebo (14.58%) vs montelukast (10.55%) or beclomethasone (6.65%) (P < .05 for all). More patients used oral corticosteroid rescue with placebo (34.7%) than with montelukast (25.0%) or beclomethasone (23.5%). An imbalance in bone marker levels was seen with beclomethasone but not with montelukast. CONCLUSION: In prepubertal asthmatic children, montelukast did not affect linear growth, whereas the growth rate with beclomethasone was significantly decreased during 1 year of treatment.     

A comparison of 2 extrafine hydrofluoroalkane-134a-beclomethasone formulations on methacholine hyperresponsiveness.

BACKGROUND: Small airways inflammation is a recognized pathologic component of asthma, and it is postulated that the observed airway-wall remodeling in small airways could be due to uncontrolled inflammation in airways that are not penetrated by conventional inhaled corticosteroids. Thus, extrafine particle formulations of inhaled corticosteroids are of clinical interest. OBJECTIVE: To compare 2 extrafine solution hydrofluoroalkane-134a formulations of beclomethasone dipropionate (Beclate and Qvar). METHODS: Fifteen asthmatic patients (mean +/- SEM forced expiratory volume in 1 second [FEV1], 2.62 +/- 0.21 L; provocative concentration of methacholine causing a 20% decrease in FEV1 [PC20], 1.06 +/- 0.58) were randomized to completion in a placebo-controlled, double-blind, crossover manner to receive Beclate or Qvar at doses of 100 or 400 microg/d for 2 weeks, with a 1-week washout period before each randomized treatment. Methacholine hyperresponsiveness was the primary outcome measure. RESULTS: The 2 formulations were equivalent in terms of predefined equivalence limits of +/- 1 doubling dilution for PC20 at both doses: -0.25 (95% confidence interval [CI], -0.77 to 0.27) doubling dilution difference between the 100-microg doses and a 0.26 (95% CI, -0.29 to 0.82) doubling dilution difference between the 400-microg doses for the difference between Beclate and Qvar, respectively. Both formulations, at either dose, produced a statistically significant (P < .05) reduction in mean exhaled nitric oxide levels: 400 microg/d of Beclate, 14.1 ppb (95% CI, 5.6 to 22.6 ppb); and 400 microg/d of Qvar, 14.2 ppb (95% CI, 6.0 to 22.4 ppb). The higher doses produced a statistically significant (P < .05) reduction in early morning urinary cortisol-creatinine ratio (geometric mean fold suppression: Beclate, 1.48 [95% CI, 1.16 to 1.89]; and Qvar, 1.42 [95% CI, 1.12 to 1.79]). Both formulations significantly improved peak expiratory flow, FEV1, and forced expiratory flow between 25% and 75% of forced vital capacity at the higher doses (P < .05). CONCLUSIONS: Beclate and Qvar were equivalent for all primary and secondary outcome measures.