Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects

Previous studies have suggested that the endogenous release of inhibitory prostanoids limits the bronchoconstrictor response to repeated exercise. The aim of our study was to determine whether inhaled prostaglandin (PG)E2 attenuates exercise-induced bronchoconstriction or methacholine airway responsiveness in asthmatic subjects. Eight subjects with mild stable asthma and exercise bronchoconstriction were studied on 4 separate days, 48 h apart. Subjects inhaled PGE2 or placebo in a randomized, crossover, double-blind fashion, 30 min prior to an exercise challenge or a methacholine challenge. PGE2 inhalation significantly attenuated exercise bronchoconstriction. The mean maximal %fall in FEV1 after exercise was 26% (SEM 3.7%) after placebo, and was 9.7% (SEM 2.7%) after PGE2 (p < 0.001). PGE2 also significantly reduced the duration of exercise bronchoconstriction (p = 0.034). However, PGE2 did not significantly attenuate methacholine airway responsiveness. The geometric mean methacholine provocative concentration causing a 20% fall in FEV1 (PC20) was 0.77 (%SEM 1.48) after placebo day, and 1.41 (%SEM 2.20) after PGE2 (p = 0.30). These results demonstrate that inhaled PGE2 markedly attenuates exercise bronchoconstriction in asthmatic subjects and suggest that this effect is not occurring through functional antagonism of airway smooth muscle.     

Bronchial and cutaneous responses in atopic dermatitis patients after allergen inhalation challenge

BACKGROUND: Atopic dermatitis (AD) is often associated with allergic asthma (AA). Inhalation of allergens influences the activity of AA but the effect on the skin in AD is unclear. OBJECTIVES: We evaluated the degree of bronchial hyperresponsiveness to methacholine in eight AD patients with AA (AD+) and eight AD patients without AA (AD-) and studied bronchial and cutaneous responses after allergen inhalation challenge. METHODS: All patients were treated in hospital for their eczema with tar ointment (pix liquida) and orally administered antihistamines (mean hospital stay 37 days). After clearing of the skin lesions allergen inhalation challenge was performed. Cutaneous responses were studied by measuring the 'Costa' score before and 24 h after allergen inhalation challenge. RESULTS: The median value of the provocative concentration of methacholine causing a 20% fall (PC20 Mch) in forced expiratory volume in 1 second (FEV1) was significantly higher in the AD- group compared to the AD+ group with median values of 10.70 and 0.60 mg/mL, respectively. These values did not change significantly in both groups during hospital stay. After challenge all AD+ patients showed early and late asthmatic responses whereas only four AD patients showed early asthmatic responses (mean values of the maximal fall in FEV1 during the EAR 37%/16% and in PEF during the LAR 27%/4% for AD+ and AD-patients, respectively). The 'Costa' score increased in both groups (mean score before 19.1/24.4 and after challenge 26.8/26.9 for AD+ and AD- patients, respectively). The increase in the AD+ group was significantly higher compared with the AD- group (P=0.016). CONCLUSION: We conclude that allergen inhalation challenge causes a flare up of the skin lesions in atopic dermatitis patients. This was more prominent in atopic dermatitis patients who already suffered from an IgE-mediated allergic inflammation in the lung.     

Evaluation of the inhaled glucocorticosteroid effects on non specific bronchial reactivity with particular reference to the late inflammatory phase in atopic asthma patients. II. The effect of regular administration of budesonide R on specific and non-specific bronchial reactivity

The purpose of the study was to determine whether regular administration of budesonide R decreases inflammation, specific and non-specific bronchial hyperreactivity in allergic asthma patients. The studies were carried out on 16 patients suffering from mild to moderate allergic asthma, sensitive to D. pteronyssinus allergen. After performance of the specific and non-specific bronchial provocation tests, collection of blood samples for an ECP evaluation, the patients were regularly treated with budesonide R, 2 x 320 micrograms for a period of 8 weeks. At the end of the study the BPTs and blood collection were repeated. BPTs with methacholine and D. pteronyssinus were performed according to Ryan's method. After the allergen challenge, early (EAR) and late asthmatic reaction (LAR) were to be observed. After the therapy non-specific BHR to methacholine expressed as PC20FEV1 and specific BHR to allergen (PD20FEV1D. pteronyssinus) and serum ECP concentrations decreased significantly. Although after the treatment with budesonide R, the patients had to inhale much larger amounts of allergen, in order to induce EAR, the number of LAR did not change significantly. After treatment the LAR appeared about 1 hour later and the decrease in FEV1 was less than previously. We conclude that budesonide R decreases the intensity of the inflammation and BHR.     

Changes in neurokinin A airway responsiveness with inhaled lysine-acetylsalicylate in asthma

Endogenously released cyclooxygenase products modulate the bronchoconstrictor response to various stimuli in asthma. Little is known of the change in airway responsiveness to neurokinin A (NKA) after cyclooxygenase blockade. In this randomized, double-blind, placebo-controlled study, we have investigated the effect of the potent cyclooxygenase inhibitor, lysine acetylsalicylate (L-ASA) administered by inhalation, on the bronchoconstrictor response both to neurokinin A (NKA) and methacholine in nine asthmatic subjects. Subjects attended the laboratory on four separate occasions to receive nebulized L-ASA (solution of 90 mg.mL-1) or matched placebo (glycine, solution of 30 mg.mL-1) 15 min prior to bronchial challenge with NKA or methacholine, in a randomized, double-blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and agonist responsiveness, expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). L-ASA elicited a significant fall in FEV1 from baseline. When compared with placebo, inhaled L-ASA reduced the airway responsiveness to NKA in 8 of the 9 subjects studied, the geometric mean (range) values for PC20 NKA increasing significantly from 153.2 (52.0-258.9) to 303.1 (83.4-668.5) micrograms.mL-1 after placebo and L-ASA, respectively. However, no significant change in airway responsiveness to methacholine was recorded after L-ASA, their geometric mean (range) PC20 values being 1.60 (0.17-9.59) and 1.53 (0.09-14.01) mg.mL-1 after placebo and L-ASA, respectively. The small decrease in airway responsiveness to neurokinin A after administration of lysine acetylsalicylate by inhalation suggests that endogenous prostaglandins may play a contributory protective role in the airway response to neurokinin A in human asthma.     

Bronchodilator response to salbutamol after spontaneous recovery from nonspecific bronchial provocation tests in asthma

Assessment of airway responsiveness by bronchoprovocation and bronchodilatation tests is important in the diagnostic work-up protocol of bronchial asthma and it would be convenient to undertake both tests on the same occasion. However, it is not known whether this can be done accurately. Therefore, this study evaluated the effect of a prior bronchial provocation test on the bronchodilator response to salbutamol after spontaneous recovery of the forced expiratory volume in one second (FEV1) in a group of asthmatic subjects. On two separate occasions at the same time of day, concentration-response studies with inhaled histamine or methacholine, or a sham challenge with normal saline were carried out in a blinded, randomized manner. Changes in airway calibre were followed as FEV1 and agonist responsiveness expressed as the provocative concentration causing a 20% fall in FEV1 (PC20). After either spontaneous recovery or a fixed-duration wait of 45 min (when appropriate), the subjects received 2x100 microg of salbutamol from a metered dose inhaler with a spacer. The bronchodilator response to salbutamol was expressed as a percentage of initial FEV1 (deltaFEV1% init). Bronchial challenge with both agonists failed to alter significantly the airway response to salbutamol, with the deltaFEV1% init mean value (range) being 16.9% (9.0-31.9) and 17.5% (11.6-31.2) on the sham and histamine/methacholine challenge day respectively. It was shown that the degree of bronchodilatation achieved after salbutamol 200 microg is not affected by prior bronchoprovocation testing when enough time is allowed for the airways to recover spontaneously to baseline forced expiratory volume in one second. Thus evaluation of airway responsiveness by both bronchial provocation tests and bronchodilator testing can be assessed reliably within a few hours in asthmatic patients.     

The effect of R 15.7/HO, an anti-CD18 antibody, on the late airway response and airway hyperresponsiveness in an allergic rabbit model

1. The effects of a mouse (IgG1 fraction) anti-CD 18 neutralizing antibody (R15.7) on allergen-induced late airway response (LAR), airway hyperresponsiveness (AHR) and cellular recruitment were investigated in an allergic rabbit model. 2. Litter-matched NZW rabbits immunized within 24 h of birth with Alternaria tenuis (i.p.) and subsequently exposed to the allergen (i.p.) for the first 3 months of life were challenged with inhaled allergen as adult rabbits. Lung function in terms of dynamic compliance (Cdyn; ml cmH2O-1) and total lung resistance (RL; cmH2O-1 s-1) was monitored for 6 h following the allergen challenge. On day 16, separate groups of rabbits were pretreated with either control antibody (a non-binding mouse IgG1, 1 mg kg-1, i.v.) or R15.7 (1 mg kg-1, i.v.) and 1 h later all were challenged with Alternaria tenuis and lung function monitored thereafter. Airway responsiveness to inhaled histamine was assessed by measuring RL and Cdyn 24 h before and after allergen challenge and bronchoalveolar lavage (BAL) was also performed 24 h before and after allergen challenge. 3. Pretreatment of rabbits with the control antibody had no effect on the LAR as measured by AUC (Cdyn, 0-6 h). However, the magnitude of the LAR following treatment with R15.7 was significantly reduced when compared to LAR demonstrated on 1st challenge (P < 0.001) or to that of the control group on both challenges (P < 0.01). 4. In control antibody pretreated rabbits allergen induced a significant 3.4 fold reduction in the PC50 response to inhaled histamine in terms of RL changes (P < 0.05) and a significant 2.1 fold reduction in PC35 response to inhaled histamine in terms of Cdyn changes (P < 0.05). However, in anti-CD 18 antibody pretreated rabbits there was no significant change in responsiveness to histamine 24 h following allergen, as assessed by either RL PC50 or Cdyn PC35. 5. Allergen challenge induced a significant increase in eosinophil and neutrophil numbers (P < 0.05) in rabbits pre-treated with control antibody, whereas treatment with R15.7 significantly inhibited this increase in the numbers of both cell types. 6. This study demonstrates that the neutralization of CD-18 molecules reduces allergen-induced infiltration of both eosinophils and neutrophils into the airways and abolishes the accompanying LAR and AHR. These results provide evidence to support a role for CD-18 adhesion molecules in the transmigration of inflammatory cells into airways.     

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Tachyphylaxis to methacholine has been reported in nonasthmatic subjects. In a recent study on the prevalence of airway hyperresponsiveness (AHR) and atopy, we performed duplicate methacholine inhalation tests at a 60-min interval, in subjects with symptomatic asthma (n = 33), asymptomatic AHR (AAHR) (n = 72) and in a group of normal subjects (n = 130); 135/235 subjects were atopic. All subjects had a respiratory questionnaire, allergy skin prick tests, blood eosinophil counts and determination of total serum IgE level. In asthmatic subjects, PC20 just failed to be significantly higher on a second methacholine challenge (p = 0.09); when they were stratified according to severity of AHR and use of inhaled corticosteroids, we observed a significant increase in PC20 on the second test in asthmatic subjects with mild AHR not using corticosteroids (p < 0.01). In normal controls, PC20 methacholine was slightly increased on rechallenge (p < 0.01) as it was in those with AAHR (p < 0.01). There was no relationship between the magnitude of the change in PC20 and age, sex, baseline airway responsiveness, percent fall in FEV1 on the first challenge, atopic score, blood eosinophil counts and serum IgE levels. In conclusion, tachyphylaxis to methacholine is observed in normal or mild asthmatic subjects not using inhaled corticosteroids and in subjects with AAHR; however, in most subjects this change is of a small magnitude.     

Predictors of early- and late-phase reactions to bronchial allergen challenge

The influence of inhaled steroids and predictive factors on the response to bronchial allergen challenge (BCA) was evaluated in 80 asthmatics allergic to Dermatophagoides pteronyssinus (Der p). All underwent BCA with Der p and measurement of early (EAR) and late asthmatic reaction (LAR). The cumulative dose of allergen producing 20% fall in FEV1 in the EAR (PD20) was calculated. Bronchial histamine provocation, conjunctival provocation test (CPT), and skin prick test with Der p extract were performed. Specific IgE to Der p in serum (RAST), blood eosinophil (EOS) count, serum eosinophil cationic protein, and eosinophil protein X were measured. Thirty patients (38%) were treated with inhaled steroids. All patients had at least a 20% fall in FEV1 in EAR. Some 42% of nonsteroid- and 33% of steroid-treated patients had LAR with fall in peak flow of at least 20%. For patients not treated with steroid, 35% of variation in PD20 was explained by RAST and histamine reactivity, and 53% of variation of observed PD20 could be predicted. The baseline FEV1, EOS, and EAR explained 28% of variation in LAR, and 28% of variation in observed LAR could be predicted. For patients treated with steroids, 38% of variation in PD20 was explained by EOS and histamine reactivity, and only 18% of variation of observed PD20 could be predicted. For patients treated with steroids, it was impossible to predict LAR. We conclude that to achieve a quantitative estimation of allergen-specific EAR and LAR, BCA cannot be replaced by the tests used in this study. Treatment with inhaled steroids modifies the response to BCA, making quantitative prediction of EAR less accurate and prediction of the magnitude of LAR impossible.     

Beclomethasone given after the early asthmatic response inhibits the late response and the increased methacholine responsiveness and cromolyn does not

BACKGROUND: Single doses of inhaled beclomethasone or inhaled cromolyn, given before allergen inhalation, inhibit allergen-induced late asthmatic responses (LARs) and increased airway responsiveness (delta log methacholine PC20). We hypothesized that when given 2 hours after allergen, beclomethasone might work better than cromolyn. METHODS: In 10 patients with mild, stable, atopic asthma with LARs or delta log PC20 or both, we performed a double-blind, double-dummy, random-order trial comparing a single dose of inhaled beclomethasone (500 micrograms), cromolyn (20 mg), and placebo, administered 2 hours after allergen challenge on LAR and delta log PC20. RESULTS: The treatment effect on LAR was significant (p < 0.001). The LAR after beclomethasone (7.3% +/- 6.1%) was significantly less than after cromolyn (20.4% +/- 15.2%) or placebo (26.4% +/- 8.2%); cromolyn was not different from placebo. There was a borderline treatment effect on delta log PC20 (p = 0.056) with beclomethasone (0.12 +/- 0.31) less than placebo (0.37 +/- 0.39) but not less than cromolyn (0.34 +/- 0.18). CONCLUSION: Beclomethasone (500 micrograms) administered 2 hours after allergen challenge markedly inhibited the LAR and had a small effect on allergen-induced airway responsiveness. Cromolyn (20 mg) was not effective on maximal LAR; a small effect on the early part of the LAR was suggested.     

Differential expression of the p27Kip1 mRNA in IFN-sensitive and resistant cell lines

STUDY OBJECTIVES: In a previous study published by our group, six out of nine subjects with mild allergic asthma were shown to have an enhanced response to allergen challenge following a 1-h exposure in an 0.8-m3 exposure chamber (modified from a body plethysmograph) to an average of 120 parts per billion (ppb) ozone at rest. Other studies failed to confirm this effect. In the present study, using a similar design, we reexamined this effect using a larger group of asthmatics and a larger chamber allowing minimal fluctuations in ozone levels during exposures. DESIGN: Prospective, randomized single-blinded crossover study. SETTING: Pulmonary function laboratory equipped with an exposure chamber. SUBJECTS: Fifteen subjects had mild allergic asthma; 9 men and 6 women; the mean (SD) age was 32.5 (10) years; FEV1 was 3.4 (0.8) L; baseline methacholine provocation concentration causing a 20% fall in FEV1 was (PC20) 3.28 (4.1) mg/mL. INTERVENTIONS: Each participant was exposed, at rest, on 1 day to filtered air and on another day to ozone (mean level=120 ppb) in a larger exposure chamber than the one used in our first study with less variability in ozone level (110 to 130 vs 85 to 175 ppb) using a random, single-blinded design. After each exposure, the subject was challenged with allergen (nine with grass pollen extract and six with ragweed extract) and allergen PC15 was measured. RESULTS: Ozone preexposure did not affect allergen PC15 when compared with clean air preexposure (allergen PC15 dilution 1/114 vs 1/119, respectively). Ozone vs air preexposure resulted in an allergen PC15 that was lower in five subjects, higher in six, and unchanged (within one doubling dose) in four. CONCLUSIONS: At this low level with less variability and lower peaks than our previous study, ozone had no significant effect on airway allergen responsiveness.     

Comparison of bronchial reactivity to ultrasonically nebulized distilled water, exercise and methacholine challenge test in asthmatic children

We studied the responses to ultrasonically nebulized distilled water (UNDW) challenge, exercise challenge and methacholine challenge in asthmatic children. Fifty-four asthmatic and fourteen nonasthmatic control children participated in this study. The UNDW inhalation test was by the methodology described by Anderson. The average output of water was approximately 3.0 mL/min (SD = .1) and inhalation times were 30 seconds, one minute, two minutes and four minutes. Some subjects performed exercise challenge on a bicycle ergometer and methacholine challenge by an Astrograph technique. Twenty-three of 54 asthmatic patients (42.6%) and none of the controls showed a fall in FEV1 greater than 20% with UNDW challenge. The fall in FEV1 with UNDW correlated with that induced by exercise challenge (r = .89) and Log Dmin, which may reflect bronchial sensitivity (r = .70). Our method is not sensitive enough for detecting bronchial hyperresponsiveness in all asthmatic children. Bronchoconstriction induced by UNDW has a similar mechanism of action as exercise and methacholine.     

Non-specific airway hyperresponsiveness in mono-sensitive Sicilian patients with allergic rhinitis. Its relationship to total serum IgE levels and blood eosinophils during and out of the pollen season

BACKGROUND: Initial attempts to evaluate the association between allergic rhinitis and non-specific bronchial responsiveness has produced conflicting results. In fact, some studies showed a strong correlation and other failed to find an association. However, little is known about the effect of natural specific allergen exposure on the bronchial reactivity of mono-sensitive patients with rhinitis in the southern Mediterranean area, in relation to skin reactivity to allergens, total serum IgE levels and blood eosinophils. OBJECTIVES: The significance of the association between allergic rhinitis, and abnormal airway responsiveness with regard to the pathogenesis of asthma is unclear. For this reason, we have studied non-specific bronchial hyperreactivity, in patients with seasonal allergic rhinitis, with reference to the responsible allergen. The aim of the study was to correlate the responsiveness to bronchoprovocation with methacholine in subjects a with allergic rhinitis during and out of the pollen season with total serum IgE and blood eosinophils. METHODS: Fourty-nine non-smoking patients with clinical diagnosis of allergic rhinitis and mono-sensitive skin-prick tests to pollen allergens were enrolled in the study. Twenty patients suffered from seasonal rhinitis to Parietaria pollen, 15 patients to Gramineae pollen and 14 patients to Olea pollen. In all patients lung function measurements (assessed as response to methacholine), total serum IgE and blood eosinophil counts were measured during and out of the pollen season. RESULTS: During pollen season, 16 out of 49 rhinitis patients demonstrated values of bronchial responsiveness measured as response to inhaled methacholine in the asthmatic range whereas out of the pollen season only eight patients were in the asthmatic range. By analysing the results with reference to the responsible allergen, during the pollen season 15 out of 16 patients were Parietaria-sensitive and out of the pollen season seven out of eight patients. Finally, in Parietaria-sensitive rhinitis bronchial responsiveness significantly correlated, during and out of the pollen season, with total serum IgE and with blood eosinophil counts. CONCLUSIONS: Our results are consistent with the hypothesis that Parietaria is more important than Olea and Gramineae as a risk for developing non-specific bronchial hyperresponsiveness. On the whole, present observations provide further evidence that there is an interrelationship of allergen kind, total serum IgE, eosinophil and bronchial hyperresponsiveness suggesting that they may play a role in the development of bronchial asthma in rhinitis patients.     

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Early asthmatic responses (EAR) of similar severity were produced by allergen inhalation challenges in nine asthmatic subjects. The severity of the airways allergic reaction was estimated by measuring the skin test weal size produced by the same dilution of allergen which caused the EAR. The non-specific bronchial reactivity was assessed by inhalation of incresing concentrations of histamine acid phosphate. Possible relationships between the severtiy of the airways allergic reaction, the level of non-specific bronchial hyper-reactivity and the pattern of asthmatic response were examined. There was a marked inverse correlation between the required severity of the airways allergic reaction and the non-specific bronchial reactivity (log10) of the individual (r = -0-96, P less than 0-001). The EAR was followed by a late asthmatic response (LAR) in five subjects. There was no evident correlation between the magnitude of the EAR and that of the LAR. In addition, no correlation was obtained between the pattern of response interms of EAR or LAR and the severity of the allergic reaction, or the level of non-specific bronchial reactivity. These results indicate that the allergic reaction and the non-specific bronchial reactivity are interrelated in the production of allergen-induced asthma. Thus a mild allergic reaction will induce and EAR in patients with markedly increased non-specific bronchial reactivity, whereas a severe allergic reaction is required to produce an EAR in those with only slightly increased non-specific reactivity. The lack of correlation between the occurrence of the LAR and the intensity of the airways allergic reaction, the non-specific bronchial reactivity and the intensity of the EAR indicates that other factors are involved in the development of LAR.     

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Airway responsiveness assessed using histamine and methacholine is safe, reproducible and relatively easily undertaken in adults and children. Results are similar for methacholine and histamine although methacholine is better tolerated. Responsiveness is increased in children and the elderly, and in women compared to men, possibly due to body size effects. Baseline lung function confounds the interpretation of airway responsiveness and may explain the effect of smoking in most studies. Results are most usefully expressed as the provocative dose producing a 20% fall in FEV1 (PD20FEV1) or the dose-response slope (DRS). When technical factors are controlled the reproducibility of the test is from one to two doubling doses. Measurements of airway responsiveness have been widely used in clinical and research practice. However, assessing their value in diagnosing asthma is limited by the lack of a gold standard for the definition of asthma. Using a cut-off value of 8 mg/mL or 8 mumol for PD20, the tests will discriminate asthmatic from non-asthmatic subjects (based on questionnaire definitions of asthma) with a sensitivity of around 60% and a specificity of around 90%. These properties of the test result in positive and negative predictive values of 86% and 69% when the prevalence of asthma is high (50%-as in the clinical setting) and 40% and 95% when the prevalence of asthma is low (10%, as in general population studies). In the usual clinical setting, assessing the significance of atypical or non-specific symptoms, the tests are of intermediate value in predicting the presence of asthma and less useful in excluding asthma. The additional benefit of testing airway responsiveness to measuring peak flows or to a trial of therapy has yet to be fully assessed. Testing of airway responsiveness may be of value in assessing occupational asthma, asthma severity and the effects of potential sensitizers or treatments. In research, tests of airway responsiveness are more useful for excluding cases of asthma. In population studies, they serve as an objective marker of abnormal airway function which may be genetically determined and, like allergy, are strongly associated with asthma. The predictive value of airway hyperresponsiveness for the development of airway disease is yet to be clearly established. In epidemiology the benefits of measuring airway responses must be weighed against the added inconvenience and cost that is incurred.     

Inhaled steroids modify bronchial responses to hyperosmolar saline

We investigated the effects of inhaled beclomethasone dipropionate (BDP) on airway sensitivity (provocative dose producing a 20% fall in forced expiratory volume in one second (FEV1) from baseline (PD20)) and reactivity (slope of the dose-response curve) to inhaled aerosols of hyperosmolar (4.5%) saline, and histamine or methacholine. This was an open study on 13 patients referred to the laboratory by their respiratory physician for investigation of their asthma. These challenges were performed on separate days before (initial visit) and 8.8 +/- 0.8 (SD) weeks (range 5.6-12.4 weeks) after (visit 1) a treatment period with BDP (dose range 600-1,500 micrograms.day-1). At visit 1 there was a significant reduction in sensitivity to 4.5% NaCl and histamine/methacholine and in reactivity. The PD20 increased 5.6 fold for 4.5% NaCl and 4.1 fold for histamine/methacholine. All patients remained responsive to histamine/methacholine and a fall in FEV1 > 20% to 4.5% saline was documented in 10 of the 13 patients. We conclude that treatment with BDP reduces sensitivity and reactivity to both osmotic and pharmacological challenge.     

Role of neutral endopeptidase in exercise-induced bronchoconstriction in asthmatic subjects

The membrane-bound metalloproteinase, neutral endopeptidase (NEP), is a degrading enzyme of both bronchoconstrictor and bronchodilator peptides within the airways. To examine the role of NEP in exercise-induced bronchoconstriction (EIB) in asthmatic subjects, we used inhaled thiorphan, a NEP inhibitor, as pretreatment to a 6-min standardized exercise challenge. Thirteen clinically stable asthmatic subjects participated in this double-blind, placebo-controlled, crossover study that was performed on 2 days separated by 48 h. Thiorphan was administered by two inhalations of 0.5 ml containing 1.25 mg/ml. Subsequently, exercise was performed on a bicycle ergometer at 40-50% of predicted maximal voluntary ventilation while inhaling dry air (20 degrees C, relative humidity 6%). The airway response to exercise was measured by forced expiratory volume in 1 s (FEV1) every 3 min, up to 30 min postexercise challenge, and was expressed both as the maximal percent fall in FEV1 from baseline and as the area under the time-response curve (AUC) (0-30 min). The acute effects of both pretreatments on baseline FEV1 were not different (P > 0.2), neither was there any difference in maximal percent fall in FEV1 between thiorphan and placebo (P > 0.7). However, compared with placebo, thiorphan reduced the AUC by, on average, 26% [AUC (0-30 min, +/-SE): 213.6 +/- 47.7 (thiorphan) and 288.6 +/- 46.0%fall.h (placebo); P = 0.047]. These data indicate that NEP inhibition by thiorphan reduces EIB during the recovery period. This suggests that bronchodilator NEP substrates, such as vasoactive intestinal polypeptide or atrial natriuretic peptide, modulate EIB in patients with asthma.     

Airway responsiveness to hyperosmolar saline challenge in cystic fibrosis: a pilot study

Hyperosmolar aerosols are used to assess airway responsiveness in subjects with asthma. Using a 10% NaCl aerosol, we investigated airway responsiveness in 23 cystic fibrosis (CF) subjects (12 females, 11 males; 19.1 +/- 3.3 years) who had asthma-like symptoms. The pre-challenge predicted forced expiratory volume in 1 second (FEV1) was 74.7 +/- 21.5. The aerosol was generated by a MistO2gen 143A ultrasonic nebulizer and inhaled for 0.5, 1, 2, 4, 8, 8, and 8 minutes or part thereof. Spirometry was performed before and 1 minute after each inhalation period. The challenge was stopped when a > or = 20% fall from the baseline FEV1 was recorded, after the last inhalation period, or when requested by the subject. We recorded different responses to 10% NaCl among subjects. In 7, the FEV1 fell progressively throughout the challenge in a manner similar to asthmatics. By contrast, in 15 subjects the FEV1 was higher at the completion of challenge compared to during challenge, i.e., the fall in FEV1 was transient. In 7 of these subjects, the final FEV1 at the end of the challenge was higher than the pre-challenge FEV1. We conclude that inhaled 10% hyperosmolar saline causes either progressive and sustained or transient airway narrowing during challenge in the majority of CF subjects. The cause of the transient airway narrowing requires further investigation.     

Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response

Inhaled allergens, acting through IgE-dependent mechanisms, are important triggers of asthma symptoms and inducers of airway hyperresponsiveness and airway inflammation. The effect of anti-IgE recombinant humanized monoclonal antibody-E25 (rhuMAb-E25) on the provocation concentration of allergen causing a 15% fall in FEV1 (allergen PC15) during the allergen-induced early asthmatic response (EAR) was assessed in a multicenter, randomized, double-blind, parallel group study. Ten of 11 allergic asthmatic subjects randomized to receive intravenous rhuMAb-E25, 2 mg/kg on study day 0 and 1 mg/kg on Days 7, 14, 28, 42, 56, and 70 completed the study; nine received intravenous placebo. The allergen PC15 was measured on Days -1, 27, 55, and 77 and methacholine PC20 on Days -2, 42, and 76. rhuMAb-25 was well tolerated and only one patient (active group) was withdrawn because of a generalized urticarial rash after the first dose. Compared with baseline values (Day -1), the median allergen PC15 on Days 27, 55, and 77 were increased by 2.3, 2.2, and 2.7 doubling doses (delta log PC15/0.3) respectively with rhuMAb-E25 and -0.3, +0.1, and -0.8 doubling doses with placebo (p < or = 0.002). Methacholine PC20 improved slightly after rhuMAb-E25, this change becoming statistically significant on Day 76 (p < 0.05); no change was observed in the placebo group. Mean serum-free IgE fell by 89% after rhuMAb-E25 while there was no significant change after placebo. The inhibitory effects of rhuMAb-E25 on allergen-induced EAR suggest that it may be an effective, novel antiallergic treatment for asthma.     

Neutral endopeptidase inhibition with inhaled phosphoramidon: no effect on bronchial responsiveness to adenosine 5'-monophosphate (AMP) in asthma

Part of the contractile response of adenosine in the asthmatic airways may be due to the activation of peptidergic pathways with subsequent local release of spasmogenic neuropeptides. At present, little is known about the potential role of lung peptidases in modulating adenosine-induced airway dysfunction in humans in vivo. We have, therefore, investigated the change in bronchial reactivity to adenosine 5'-monophosphate (AMP), after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double-blind, placebo-controlled, randomized study of 12 asthmatic subjects. Subjects attended on six separate occasions, during which concentration response studies with inhaled AMP and methacholine were carried out, initially in the absence of treatment and then after nebulized phosphoramidon sodium salt (10[-5] M) or matched placebo 5 min prior to a bronchoprovocation test with AMP or methacholine. Agonist responsiveness was expressed as the provocative concentration of AMP or methacholine producing a 20% fall in FEV1 from baseline (PC[20,AMP] or PC[20,meth], respectively). When compared to placebo, phosphoramidon failed to potentiate the airway response to AMP. The geometric mean (range) PC20 AMP value of 23.4 (4.4-190.6) mg x mL(-1) after placebo was not significantly different from that of 20.7 (45-100.9) mg x mL(-1) obtained after phosphoramidon. The lack of change in bronchial reactivity to adenosine 5'-monophosphate after phosphoramidon indicates that endogenous airway neutral endopeptidase may not be of physiological importance in modulating the contractile response of adenosine in the airways. Thus, the present data do not support the view that activation of peptidergic pathways with subsequent local release of spasmogenic neuropeptides is important in the airway response to adenosine     

Evaluation of the Brusini glaucoma staging system for follow-up in glaucoma

There is evidence that bronchial responsiveness to allergen is quantitatively correlated with bronchial responsiveness to nonspecific stimuli in subjects with allergic asthma. This association has been questioned in occupational asthma due to low molecular weight substances. It was the aim of this study to assess the quantitative association of bronchial responsiveness to methacholine (MCH) and platinum salts (Pt), in the form of hexachloroplatinic acid, in workers with occupational asthma due to Pt salts. Fifty-seven subjects with exposure to Pt, work-related asthma, and a positive bronchial challenge with Pt underwent skin prick test with Pt and bronchial challenge with MCH. Using the provocation concentration causing a > or = 50% fall in specific airway conductance (PC50sGaw(Pt)) as a dependent variable, anamnestic data (period from first symptoms to removal, period between removal from exposure and diagnosis, and smoking), season of the investigation, skin prick tests with environmental allergens, total immunoglobulin E (IgE), skin reactivity to Pt (Pt concentration causing a 2 mm wheal), and PC50sGaw(MCH) were included as independent variables for regression analysis. Fifty-two subjects (91%) showed a PC50sGaw(MCH) < 8 mg.mL-1 (geometric mean for all subjects 1.6 mg.mL-1). Responsiveness to Pt varied widely between subjects (geometric mean of PC50sGaw(Pt) 9 x 10(-5) mol.L-1, range 2 x 10(-7) to 10(-2) mol.L-1). There was no univariate correlation between bronchial responsiveness to MCH and Pt, but there was a correlation between skin reactivity to Pt and PC50sGaw(Pt) (r = 0.6). This association could not be improved by considering PC50sGaw(MCH), the period from first symptoms to removal, or the period between removal from exposure and diagnosis. The parameters that showed the highest (negative) associations with PC50sGaw(Pt) were skin reactivity to Pt and the period between removal from exposure and diagnosis (r = 0.65). We conclude that there is a moderate association between bronchial responsiveness to platinum salts and skin reactivity to platinum salts. However, there is no association between methacholine responsiveness and bronchial responsiveness to allergen in occupational asthma due to platinum salts.