Azithromycin reduces pulmonary fibrosis in a bleomycin mouse model.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease without proper treatment. Despite intensive research, the exact underlying pathogenesis remains elusive. It is regarded as a continuous injury, resulting in inflammation, infiltration, and proliferation of fibroblasts and extracellular matrix deposition, leading to an irreversible restrictive lung function deterioration and death. In this study the effect of azithromycin, a macrolide antibiotic on bleomycin-induced pulmonary fibrosis was investigated. C57BL/6 mice were intratracheally instilled with bleomycin (0.5 mg/kg) or saline. In the bleomycin group, half of the animals received azithromycin every other day from day 1 on. Bronchoalveolar lavage and histology were performed at days 7 and 35, and pulmonary function tests on day 35. At day 35, fibrotic lesions (spindle cell proliferation/collagen I deposition) were paralleled by a restrictive lung function pattern. Alterations were found in neutrophils and macrophages (innate immunity) and in T(H)2, T(H)17, and Treg cytokines (adaptive immunity). Azithromycin significantly reduced both fibrosis and the restrictive lung function pattern. This study demonstrated a beneficial effect of azithromycin on bleomycin-induced pulmonary fibrosis. A possible mechanism could be a modulation of both innate immunity and adaptive immunity. These findings might suggest a potential role for azithromycin in the treatment of IPF.

Skeletal muscle weakness in patients with sarcoidosis and its relationship with exercise intolerance and reduced health status.

BACKGROUND: Skeletal muscle weakness is assumed to be present in patients with sarcoidosis but has never been reported in a consecutive group of patients. Moreover, its relationship with previously observed exercise intolerance and reduced health status has never been studied in these patients. METHODS: Pulmonary function, skeletal and respiratory muscle forces, peak and functional exercise capacity, health status, and the circulating levels of inflammatory and anabolic markers were determined in 25 patients with sarcoidosis who complained of fatigue (15 men) and in 21 healthy subjects (13 men). RESULTS: Patients with sarcoidosis had lower respiratory and skeletal muscle forces, reduced exercise capacity and health status, higher anxiety and depression scores, and higher circulating levels of tumour necrosis factor-alpha than healthy subjects (all p< or =0.01). Its soluble receptor p75 tended to be higher (p=0.04). Circulating levels of interleukin (IL)-6, IL-8, insulin-like growth factor I and its binding protein 3 were not significantly different between the two groups. Skeletal muscle weakness was related to exercise intolerance, depression, and reduced health status in patients with sarcoidosis, irrespective of age, sex, body weight and height (p< or =0.05). Quadriceps peak torque was inversely related to fatigue but not to the circulating levels of inflammatory or anabolic markers. The mean daily dose of corticosteroids received in the 6 month period before testing was related to quadriceps peak torque only in patients who received oral corticosteroids. CONCLUSION: Skeletal muscle weakness occurs in patients with sarcoidosis who complain of fatigue and is associated with reduced health status and exercise intolerance.

Modulation by cAMP of IL-1beta-induced eotaxin and MCP-1 expression and release in human airway smooth muscle cells.

Inflammatory cells, such as eosinophils, seem to be key players in the inflammatory process of asthma. These cells are attracted by chemokines, for example eotaxin and monocyte chemotactic protein (MCP-1). In this study, the authors investigated whether eotaxin and MCP-1 expression and release in human airway smooth muscle cells could be modulated by an increase in intracellular cyclic adenosine monophosphate (cAMP) concentration. The possible involvement of cAMP-dependent protein kinase A (PKA) was also studied. Forskolin, a direct stimulator of adenylyl cyclase, decreased the interleukin (IL)-1beta-induced eotaxin and MCP-1 release by 73+/-8 and 65+/-6%, respectively. 8Bromo-cAMP, a cAMP analogue, similarly decreased the chemokine production by 58+/-9 and 63+/-8% for eotaxin and MCP-1, respectively. Prostaglandin E2, known as an activator of the prostanoid receptors EP2 and EP4, which are positively coupled to adenylyl cyclase, also decreased the IL-1beta-induced eotaxin and MCP-1 production by 57+/-17 and 53+/-4%, respectively. H-89, an inhibitor of PKA, was able to inhibit the decrease in eotaxin and MCP-1 protein release induced by forskolin. Using Western-blot analysis, no effect of cAMP was found on the IL-1beta-induced p38 mitogen-activated protein kinase, extracellular signal-related kinase or cJun N-terminal kinase activation. This study shows that an increase in intracellular cyclic adenosine monophosphate concentration may decrease the interleukin-1beta-induced eotaxin and monocyte chemotactic protein-1 expression and production. This can be inhibited by addition of H-89, an inhibitor of cyclic adenosine monophosphate-dependent protein kinase. No decrease was observed in interleukin-1beta-induced p38 mitogen-activated protein kinase, extracellular signal-related kinase or cJun N-terminal kinase activation. These findings may be important for the further development of new anti-inflammatory drugs.

N-acetylcysteine reduces chemokine release via inhibition of p38 MAPK in human airway smooth muscle cells.

Reactive oxygen species are involved in the activation of several mitogen-activated protein kinases (MAPKs), key-players in the production of several cytokines. Therefore the current study investigated whether N-acetylcysteine (NAC), an antioxidative agent, inhibits the interleukin (IL)-1beta-induced expression and production of eotaxin and monocyte chemotactic protein (MCP)-1 in human airway smooth muscle cells (HASMC). NAC (10 mM) decreased the expression of eotaxin and MCP-1, by 46 +/- 11% (n=7) and 87 +/- 4% (n=6), respectively; the eotaxin release was inhibited by 75 +/- 5% (n=7), whereas the MCP-1 release was decreased by 69 +/- 41% (n=10). NAC (1 mM) also decreased the IL-1beta-induced activation of p38 MAPK. Compared with unstimulated cells, a four-fold increase in 8-isoprostane production in IL-1beta-stimulated HASMC was observed, which could be inhibited by NAC in a concentration-dependent way, with a maximum inhibition of 39 +/- 12%, with 1 mM NAC. The present study demonstrated that N-acetylcysteine inhibits the interleukin-1beta-induced eotaxin and monocyte chemotactic protein 1 expression and production due to a decreased activation of p38 mitogen-activated protein kinase. This study has also shown that N-acetylcysteine decreases the interleukin-1beta-induced production of reactive oxygen species, as suggested by a reduction in the 8-isoprostane production.

Practical approach to patients presenting with multiple synchronous suspect lung lesions: a reflection on the current TNM classification based on 54 cases with complete follow-up.

OBJECTIVES: To examine the survival after surgical treatment of patients presenting with two synchronous suspect lung lesions, and to reflect on the recent TNM classification, which has upgraded patients with two malignant lung lesions of the same histology into the T4 (both lesions in the same ipsilateral lobe) or M1 (different lobes or lungs) category. METHODS: Retrieval of all consecutive patients with a diagnosis of two synchronous suspect lung lesions in the prospective database of the Leuven Lung Cancer Group in the interval between 1990 and 1994. Analysis of characteristics and survival of all patients, who underwent surgical resection with intention to cure for both lesions. RESULTS: Forty-eight of 54 patients had surgical resection with curative intent. Thirty-five of these proved to have two malignant lesions, in 13 the second lesion was benign. The 5-year survival rate in the patients with two malignant lesions was 33% (95% CI: 17-49). The median survival time was 28 months. Although the number of patients in the subgroups was small, there were no obvious differences between patients with two lesions in the same or in different lobes, if a complete resection could be achieved. CONCLUSIONS: An aggressive surgical approach in carefully selected patients presenting with two suspect pulmonary lesions can be rewarding. Although some degree of upstaging is appropriate in patients with two malignant lung tumours of the same histology, their current stage IIIB or IV classification probably underestimates their prospects for long-term survival after radical resection.

Mechanisms of interleukin 1beta-induced human airway smooth muscle hyporesponsiveness to histamine. Involvement of p38 MAPK NF-kappaB.

We have investigated the effect of IL-1beta on histamine H(1)-receptor (H(1)R)-mediated inositol phosphate (IP) accumulation in human airway smooth muscle cells (HASMC) and on histamine-induced contraction of human bronchial rings. Stimulation of HASMC for 24 h with IL-1beta resulted in significant loss of histamine-induced IP formation, which was associated with a reduction of histamine- induced contraction of IL-1beta-treated human bronchial rings. An inhibitor of NF-kappaB activation, pyrrolidine dithiocarbamate, and a p38 MAPK inhibitor, blocked the IL-1beta-induced H(1)R desensitization, whereas anisomycin, an SAPK/JNK and p38 MAPK activator, mimicked the effect of IL-1beta. IL-1beta has been demonstrated to induce cox-2 expression and PGE(2) synthesis. In our study, indomethacin a cox antagonist, completely inhibited the effect of IL-1beta on H(1)R, whereas exogenously added PGE(2) was able to desensitize H(1)R. Furthermore, H-89, a selective PKA inhibitor, antagonized the effect of IL-1beta. Here, we have demonstrated that IL-1beta desensitizes H(1)R, which involves the activation of p38 MAPK and NF-kappaB, leading to the expression of cox-2 and the synthesis of PGE(2). PGE(2) increases intracellular cAMP resulting in PKA activation, which phosphorylates and functionally uncouples H(1)R. Our results suggest that IL-1beta protects airway smooth muscle against histamine-induced contractile responses and that bronchial hyperreactivity to histamine is not associated with proinflammatory cytokine-induced enhancement in H(1)R signaling.

Epinastine (WAL 801CL) inhibits the electrical field stimulation-induced cholinergic contraction in guinea pig and human airways in vitro.

Epinastine is an antihistamine drug with binding affinities at 5-hydroxytryptamine (5-HT) receptors. The current study was performed to investigate whether epinastine could modulate the cholinergic contraction in guinea pig and human airways in vitro. Isolated guinea pig and human airway preparations were suspended in organ baths containing modified Krebs-Henseleit solution. Electrical field stimulation was applied to elicit cholinergic contractions. Epinastine produced a concentration-dependent inhibition of the cholinergic contraction in guinea pig airways and pretreatment with methysergide (5-HT1/2/7 antagonist) significantly attenuated these inhibitory effects of epinastine. Pretreatment with tropisetron (5-HT3/4 antagonist), ketanserin (5-HT2 antagonist), SDZ216-525 (5-HT1A antagonist) or phentolamine (alpha-adrenergic antagonist) had no effect. Epinastine did not displace the concentration-response curve to acetylcholine. These results suggest that epinastine inhibits the cholinergic contraction in guinea pig airways through stimulation of prejunctional 5-hydroxytryptamine receptors, located to postganglionic cholinergic nerves. Inhibitory effects of epinastine on the cholinergic contraction in human airways in vitro were also demonstrated, which suggests that a similar mechanism might be present in human airways. The pharmacological profile of epinastine, which shows binding affinity at the 5-hydroxytryptamine7 receptor but not at the 5-hydroxytryptamine1 receptor subtypes corroborates the hypothesis that the inhibitory prejunctional 5-hydroxytryptamine receptor on cholinergic nerves is of the 5-hydroxytryptamine7 subtype.

Prognostic importance of the standardized uptake value on (18)F-fluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: An analysis of 125 cases. Leuven Lung Cancer Group.

PURPOSE: The amount of radio-labeled (18)F-fluoro-2-deoxy-glucose (FDG) uptake, a measurement of the increased glucose metabolism of non-small-cell lung cancer (NSCLC) cells, has recently been correlated with proliferation capacity. The Standardized Uptake Value (SUV), a semi-quantitative measurement of FDG uptake on positron emission tomography (PET) scan, could thus be of prognostic significance. PATIENTS AND METHODS: We analyzed the follow-up of 125 potentially operable NSCLC patients, previously included in three of our prospective PET protocols. Performance status, maximal tumor diameter, tumor-cell type, SUV, and final staging were analyzed for their possible association with survival. RESULTS: Sixty-five patients had stage I or II NSCLC, 37 had stage IIIA, and 23 had stage IIIB. Treatment was complete resection in 91 cases. In a univariate analysis, performance status (P =.002), stage (P =.001), tumor diameter (P =.06), tumor-cell type (P =.03), and SUV greater than 7 (P =.001) were correlated with survival. For SUV, group dichotomy with a cut-off SUV of 7 had the best discriminative value for prognosis, both in the total and surgical cohort. A multivariate Cox analysis identified performance status (P =.02), stage (P =.01), and SUV (P =.007) as important for the prognosis. In the surgical group, patients with a resected tumor less than 3 cm had an expected 2-year survival of 86%, if the SUV was below 7, and 60%, if above 7. Nearly all resected tumors larger than 3 cm had SUV's greater than 7 and an expected 2-year survival of 43%. CONCLUSION: We conclude that the FDG uptake in primary NSCLC on PET has an important prognostic value and could be complementary to other well-known factors in the decision on adjuvant treatment protocols.

The effects of 5-HT on cholinergic contraction in human airways in vitro.

Inhaled 5-hydroxytryptamine (5-HT) causes bronchoconstriction in asthmatics, and 5-HT plasma levels are elevated in asthma. Electrical field stimulation (EFS) of human airways, in vitro, evokes cholinergic contraction mediated by the release of acetylcholine (Ach) from postganglionic cholinergic nerves. The present study investigates whether selective 5-HT agonists and antagonists can modulate EFS-induced cholinergic contraction in human airways in vitro. Human airways, obtained from resections for bronchial carcinoma or organ transplant donors, were suspended under 2-g tension, between two platinum wire electrodes, in carbogenated Krebs solution at 37 degrees C and EFS was applied (1-32 Hz, 50 V, 0.5 ms, 15 s every 4 min) to elicit cholinergic contractions. 5-HT (10 microM-0.3 mM) produced frequency- and concentration-dependent facilitation of cholinergic contraction, but did not displace the concentration/response curve to Ach. Tropisetron (1 microM), a 5-HT3 and 5-HT4 antagonist, completely blocked the facilitatory effect of 5-HT (100 microM), whereas both ondansetron (1 microM) and GR 125478D (1 microM), a selective 5-HT3 and 5-HT4 antagonist, respectively, also attenuated the 5-HT-induced enhancement of cholinergic contraction. This facilitatory effect of 5-HT was partially mimicked by both selective 5-HT3 (2-methyl-5-HT) and 5-HT4 (RS 67333 and 5-methoxytryptamine) agonists. Fluoxetine (10 microM), a 5-HT uptake inhibitor, had no effect on the 5-HT (10-100 microm) induced potentiation of cholinergic contraction. These findings suggest that 5-HT facilitates cholinergic contraction in human airways in vitro through stimulation of both prejunctional 5-HT3 and 5-HT4 receptors. This may implicate a role of 5-HT in asthma.

Expression of monocyte chemotactic protein (MCP)-1, MCP-2, and MCP-3 by human airway smooth-muscle cells. Modulation by corticosteroids and T-helper 2 cytokines.

We have demonstrated that, in addition to their contractile function, human airway smooth-muscle cells (HASMC) are able to express and to secrete chemokines of the monocyte chemotactic protein (MCP)/ eotaxin subfamily. This group of chemokines is believed to play a fundamental role in the development of allergic airway diseases such as asthma. The expression levels of MCP (MCP-1, -2, and -3) messenger RNA (mRNA) were compared with those of regulated on activation, normal T cells expressed and secreted (RANTES) mRNA in HASMC in culture. HASMC express MCP and RANTES mRNA after stimulation with interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma. MCP mRNA was maximal at 8 h, whereas RANTES mRNA expression was delayed to 24 h after stimulation. Further, significant differences were observed in the induction patterns of MCP and RANTES mRNA expression after stimulation with the individual cytokines. Dexamethasone (DEX) significantly inhibited cytokine-induced accumulation of MCP and RANTES mRNA, in contrast to IL-4, IL-10, and IL-13, which had no inhibitory effect on cytokine-induced chemokine expression. The cytokine-induced MCP mRNA expression in HASMC was associated with MCP release, which was inhibited by DEX and post-translationally by IL-4. HASMC can actively participate in the pathogenesis of asthma by the expression and release of chemokines, which are likely to play a critical role in the generation and regulation of the inflammatory response characteristic of allergic airway diseases.

The effect of cigarette smoking on exhaled nitric oxide in mild steroid-naive asthmatics.

STUDY OBJECTIVES: It has been demonstrated previously that exhaled nitric oxide (eNO) is increased in steroid-naive asthmatics and that inhaled steroids reduce eNO in these patients. Cigarette smoking has also been reported to reduce the eNO in healthy volunteers. Recently a correlation has been demonstrated between eNO and airway hyperresponsiveness in steroid-naive, mild asthmatics. We hypothesized that cigarette smoking would reduce the eNO level in steroid-naive asthmatics and might, therefore, affect the correlation between eNO and airway hyperresponsiveness. DESIGN: Comparison of eNO in healthy smoking and nonsmoking volunteers with the level of eNO in steroid-naive and steroid-treated asthmatics. Correlate the eNO level with the provocative concentration of histamine causing a 20% fall in FEV1 (PC20hist) in the asthmatic smoking and nonsmoking patients. SETTING: University outpatient asthma clinic. PATIENTS AND METHODS: eNO levels and PC20hist were measured in three different asthmatic patient groups (group A = 29 steroid-naive, nonsmoking asthmatics; group B = 19 steroid-treated, nonsmoking asthmatics; and group C = 13 smoking, steroid-naive asthmatics) and in two healthy volunteer groups (group D = 18 nonsmoking; and group E = 16 smoking). RESULTS: eNO in group A was significantly increased compared with the values in groups B and D (21.8+/-12.7, 12.8+/-4.9, and 10.6+/-2.2 parts per billion [ppb], respectively). Cigarette smoking decreased eNO in healthy volunteers (7.4+/-1.8 ppb, group E) as well as in steroid-naive asthmatics (12.7+/-5.1 ppb, group C). There was a significant correlation between eNO and PC20hist in group A (r = -0.45, p < 0.05); this correlation was, however, lost in both groups B and C. CONCLUSION: Cigarette smoking and inhaled steroids reduce the eNO in patients with mild asthma to a comparable extent. Because the correlation between eNO and airway hyperresponsiveness was lost in steroid-treated and smoking, steroid-naive asthmatics, we question the value of eNO as a marker of airway inflammation, at least in mild asthmatics who are already being treated with inhaled steroids or who are currently smoking.

The effects of 8-hydroxy-2-(di-n-propylamino)tetralin on the cholinergic contraction in guinea pig and human airways in vitro.

Electrical field stimulation of guinea pig tracheal strips and human bronchial rings, in vitro, evokes a cholinergic contraction mediated by the release of acetylcholine. 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is a 5-HT1A and 5-HT7 agonist. In this study, we have investigated whether 8-OH-DPAT could modulate the cholinergic contraction in guinea pig and human airways in vitro. 8-OH-DPAT (1 to 30 microM) produced a concentration-dependent inhibition of the cholinergic contraction in guinea pig tracheal strips with a maximal inhibition of 75.8% +/- 4. 7% (30 microM, 0.5 Hz). Pretreatment of the tissues with the 5- HT1/2/7 antagonist methysergide (10 to 30 microM) significantly attenuated the inhibitory effects of 8-OH-DPAT (10 to 30 microM) on the cholinergic contraction. Pretreatment with ketanserin (10 microM), a 5-HT2 antagonist, tropisetron (1 microM), a 5-HT3/4 antagonist, SDZ 216-525 (1 to 10 microM) and pindobind (10 microM), both selective 5-HT1A antagonists, or capsaicin (10 microM), which depletes sensory nerves from neuropeptides, had no effect on the inhibition of the cholinergic contraction by 8-OH-DPAT (10 to 30 microM). 5-carboxamidotryptamine (5-CT) (10 to 100 microM), a 5-HT1/2/7 agonist, partially mimicked the inhibitory effects of 8-OH-DPAT on the cholinergic contraction. 8-OH-DPAT (10 to 30 microM) also inhibited the cholinergic contraction in human bronchial rings in vitro with a maximal inhibition of 46.2% +/- 7.2% (30 microM, 1 Hz). SDZ 216-525 (10 microM) had no effect, whereas methysergide (30 microM) partially prevented the effect of 8-OH-DPAT in human airways. 8-OH-DPAT (30 microM) did not displace the concentration-response curve to acetylcholine (10 nM-30 mM) in guinea pig and human airways in vitro. These results suggest that 8-OH-DPAT inhibits the cholinergic contraction in guinea pig and human airways in vitro through stimulation of prejunctional atypical 5-HT receptors, possibly of the 5-HT7 subtype, located on postganglionic cholinergic nerves.

Lymph node staging in non-small-cell lung cancer with FDG-PET scan: a prospective study on 690 lymph node stations from 68 patients.

PURPOSE: To compare the accuracy of computed tomography-(CT) scan and the radiolabeled glucose analog 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) visually correlated with CT (PET + CT) in the locoregional lymph node (LN) staging of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Sixty-eight patients with potentially operable NSCLC underwent thoracic CT, PET, and invasive surgical staging (ISS). Imaging studies were read prospectively and blinded to the surgical and pathologic data. A five-point visual scale was used for the interpretation of LNs on PET. Afterwards, with knowledge of the pathology, the relationship between standardized uptake values (SUVs) and the presence of metastasis in LNs was explored in a receiver operating characteristic (ROC) analysis, and the likelihood ratios (LRs) for SUVs of LNs were determined. RESULTS: ISS was available for 690 LN stations. CT correctly identified the nodal stage in 40 of 68 patients (59%), with understaging in 12 patients and overstaging in 16 patients. PET + CT was accurate in 59 patients (87%), with understaging in five patients and overstaging in four patients. In the detection of locally advanced disease (N2/N3), the sensitivity, specificity, and accuracy of CT were 75%, 63%, and 68%, respectively. For PET + CT, this was 93%, 95%, and 94% (P = .0004). In the ROC curve, the best SUV threshold to distinguish benign from malignant LNs was 4.40. The analysis with this SUV threshold was not superior to the use of a five-point visual scale. The LR of a SUV less than 3.5 in an LN was 0.152; for a SUV between 3.5 and 4.5, it was 3.157; and for a SUV greater than 4.5, it was 253.096. CONCLUSION: PET + CT is significantly more accurate than CT alone in LN staging of NSCLC. A five-point visual scale is as accurate as the use of an SUV threshold for LNs in the distinction between benign and malignant nodes. The very high negative predictive value of mediastinal PET could reduce the need for mediastinal ISS in NSCLC substantially.

Vindesine-ifosfamide-platinum (VIP) induction chemotherapy in surgically staged IIIA-N2 non-small-cell lung cancer: a prospective study. Leuven Lung Cancer Group.

PURPOSE: In the pioneer data from the Memorial-Sloan-Kettering group, preoperative mitomycin-C-vindesine-platinum (MVP) induction chemotherapy in N2-NSCLC was accompanied with substantial pulmonary toxicity. In this study, the efficacy and toxicity of three-drug VIP induction chemotherapy, the pathologic response in resection specimens, the early survival and relapse patterns are examined. PATIENTS AND METHODS: Between June 1995 and March 1997, 39 consecutive patients with pathology proven N2-NSCLC were treated with three cycles of VIP induction, followed by definitive locoregional treatment (resection and mediastinal dissection or radical radiotherapy). Several patients had unfavorable prognostic characteristics with respect to clinical and biological findings, tumor location and bulk of disease. RESULTS: The response rate to chemotherapy was 59% (95% Confidence Interval 34-75). Twenty-three responding patients had radical locoregional treatment: radical radiotherapy in four, resection in 19. Downstaging was present in nine of the 19 resection specimens, with two pathologic complete responses. The median survival time (MST) of all patients is 19 months, with a projected two-year survival of 49%. In patients responsive to chemotherapy who received definitive local treatment, the MST is not yet reached, and the projected two-year survival is 57%. Relapses were mainly distant, with isolated brain relapse as a disturbing finding. The main toxicity's were leukopenia and vomiting, but they were manageable. In contrast with MVP, no severe pulmonary toxicity occurred. CONCLUSIONS: VIP is a suitable induction regimen for N2-NSCLC, demonstrating a good activity and very acceptable toxicity.

Safety and efficacy of fluticasone and beclomethasone in moderate to severe asthma. Belgian Multicenter Study Group.

There are still some concerns about the safety of high doses of inhaled glucocorticosteroids (ICS). We compared the safety and efficacy of fluticasone propionate (FP) and beclomethasone dipropionate (BDP) in 306 patients with moderate to severe asthma in a double-blind, multicenter, cross-over study of 12 mo duration. During the 1-mo run-in period, bronchodilators were replaced by salmeterol 50 microg twice daily, increasing morning peak expiratory flow rate (PEFR) by 28 L/min (p < 0.001) and FEV1 by 6.2% predicted (p < 0.001). At randomization the current ICS was replaced by 500 microg BDP or 250 microg FP in accordance with previously taken 500 microg BDP or 400 microg budesonide (BUD). No significant differences between the two treatments regarding morning plasma cortisol, urinary excretion of calcium and hydroxyproline, FEV1, and PEFR were observed at any time point during the study. Osteocalcin and bone mineral density (BMD) were improved over baseline in the FP group, resulting in higher serum osteocalcin levels (mean difference 0.28 ng/ml; p < 0.001) and higher BMD in the spine (1.0%; p = 0.05), femoral neck (1.6; p < 0.01), and Ward's triangle (3.6%; p = 0.01) as compared with BDP. We conclude that chronic treatment with FP, at half the dose of BDP, results in a similar antiasthma effect but a more favorable safety profile with respect to bone metabolism and mineral density.

Exhaled nitric oxide correlates with airway hyperresponsiveness in steroid-naive patients with mild asthma.

Endogenously released nitric oxide (NO) has been detected in the exhaled air of humans. Exhaled NO (NOexh) levels have been significantly increased in patients with inflammatory airways disorders such as asthma, and NOexh has been suggested to be a usable marker of airway inflammation. In the present study, NOexh levels were measured both in steroid-treated and untreated subjects with mild asthma, and were correlated with the degree of airway hyperresponsiveness (AHR), measured as the dose of histamine that produced a 20% decrease in FEV1 (PC20histamine). NOexh levels, which were significantly increased in steroid-naive patients (Group A1: NOexh = 21 +/- 11 ppb; n = 56) in comparison with levels in control subjects (Group B: NOexh = 10 +/- 2 ppb; n = 20; p < 0.001), correlated significantly with the PC20histamine (r = -0.65; p < 0.0001). The NOexh level was significantly lower in patients with chronic cough of other causes than bronchial asthma (Group A2: NOexh = 11 +/- 3 ppb; n = 18) when compared with the level in subjects with mild asthma (Group A1: p < 0.001). Therefore, the noninvasive measurement of NOexh allowed us to discriminate, among patients with respiratory complaints, between those with and without AHR. In asthmatic subjects treated with inhaled steroids, the NOexh levels were significantly lower (Group A3: NOexh = 13 +/- 5 ppb; n = 25) than in untreated subjects (Group A1; p < 0.01), and there was no relationship with the PC20histamine (r = -0.18, p = NS). These findings confirm that NOexh reflects AHR in patients with mild asthma who have not already been treated with inhaled steroids. Patients treated with inhaled steroids had an NOexh level comparable to levels in control subjects, although AHR could still be demonstrated.