Ten patients with exercise induced asthma, in whom inhaled nedocromil sodium 4 mg by metered dose inhaler attenuated the exercise fall in forced expiratory volume in one second (FEV1) by at least 40%, participated in a double blind dose response study to compare the protective effect of nedocromil sodium given 15 minutes before exercise challenge via a nebuliser (Wright) in concentrations of0 5, 5, 10, and 20 mg/ml with that ofplacebo (saline). Response was assessed as the maximum fall in FEV, after the patient had run on a treadmill for six to eight minutes. Plasma concentrations ofnedocromil sodium were measured at the time ofchallenge. After exercise challenge the mean (SEM) maximum percentage falls in FEV, were 30 3 (1 6) for the control run and 28-0 (4-1) after placebo. The percentage fall was attenuated by pretreatment with all concentrations of nedocromil sodium to 12-8 (2-8), 112 (2-1), 12-8 (2 1), and 14-1 (3-5) for the 0 5, 5, 10, and 20 mg/ml concentrations respectively (p < 0 001). There were no significant differences between the different nedocromil concentrations. Mean plasma concentrations of nedocromil were proportional to dose. Thus concentrations ofnebulised nedocromil sodium that ranged from 0 5 to 20 mg/ml gave a similar degree of protection (50-60%) against exercise induced asthma. This appears to be the maximum protection that can be achieved with nedocromil sodium and is similar to the protection obtained with 4 mg nedocromil administered by metered dose aerosol.

Respiratory heat loss has been proposed as a mechanism of exercise induced asthma. Whether the predominant stimulus is airway drying or cooling remains unclear. We have measured changes in FEV, after isocapnic cold air hyperventilation (CAH) (-23.40 (SD 0.430) C) and dry ambient air hyperventilation (AAH) (18.7 (0 52°)C) in seven asthmatic patients (mean age 31 (SD 9) years and baseline FEV, 3-2 (0-9) 1) and in seven normal subjects (age 28 (6) years and FEV, 3-6 (0-7) 1). osmolarity of the airway epithelium. It was calculated that ambient air hyperventilation required a greater mass of water to humidify the inspirate than was available from a stationary boundary of water lining the airway down to the seventh generation bronchi. Hahn et al exercised subjects breathing air at different temperatures and matched water vapour content. No significant variation in the airway response that followed was reported despite differences in the imposed airway cooling stress.To examine the contribution of airway drying and cooling in hyperventilation induced bronchoconstriction we have studied the effect ofcold air hyperventilation and ambient air hyperventilation using air with the same water content. MethodsAirway drying and cooling has been measured as a single variable-the rate of respiratory heat exchange (RHE). This is a power index (expressed in watts) and relates to the net work done by the airway in conditioning the inspirate to expiration temperature and water vapour content, at a rate determined by the level of ventilation. The respiratory heat exchange comprises sensible (cooling based) and latent (drying based)

Bacterial infections of the respiratory tract are a major cause of morbidity and mortality in elderly people. The inflammatory response to such infection is an important protective process and has been suggested to be less effective in elderly patients. To investigate the inflammatory response in respiratory infections acquired in the community by elderly people we studied 52 consecutive patients who met the criteria for either a non-pneumonic chest infection or pneumonia. After exclusion, 41 patients were available for evaluation, with 25 fulfilling the criteria of pneumonia and 16 the criteria of chest infection. Pyrexia was a feature of the patients with pneumonia. Circulating levels of neutrophil elastase-alpha-1-antitrypsin complex and C-reactive protein were greater in the patients with pneumonia than in those with a chest infection and were reduced following antibiotic treatment. No changes occurred in the chest infection group for these markers of inflammation. In both groups, a further neutrophil granule protein, lactoferrin, was unaffected by antibiotic treatment. This study indicates that elderly patients with pneumonia can initiate an appropriate inflammatory response as demonstrated by clinical indicators and circulating mediators of the inflammatory response.

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Azelastine, a new oral agent with antiallergic and antihistamine properties, has been shown to inhibit the effect ofhistamine and leukotriene (LT) in vitro, though not a specific leukotriene receptor antagonist. The effect of both a single dose (8-8 mg) and 14 days' treatment (8 8 mg twice daily) with azelastine on bronchoconstriction induced by LTC4 and histamine has been examined in 10 patients with mild asthma in a placebo controlled, double blind, crossover study. LTC4 and histamine were inhaled in doubling concentrations from a dosimeter and the results expressed as the cumulative dose (PD) producing a 20% fall in FEVY (PD20FEV,) and 35% fall in specific airways conductance (PD35sGaw). The single dose of azelastine produced a significantly greater FEVy and sGaw values than placebo at 3 hours, but this bronchodilator effect was not present after 14 days of treatment. Azelastine was an effective H, antagonist; after a single dose and 14 days' treatment with placebo the geometric mean PD20FEV, histamine values (umol) were 0 52 (95% confidence interval 0 14-1 83) and 054 (0 12-2-38), compared with 22-9 (11 5-38 3) and 15 2 (6 47-35 6) after azelastine (p < 0 01 for both). LTC4 was on average 1000 times more potent than histamine in inducing bronchoconstriction. Azelastine did not inhibit the effect of inhaled LTC4; the geometric mean PD20FEV, LTC4 (nmol) after a single dose and 14 days' treatment was 0 60 and 0-59 with placebo compared with 0 65 and 0 75 with azelastine. The PD35sGaw LTC4 was also unchanged at 0-66 and 0 73 for placebo compared with 0 83 and 0 74 for azelastine. Thus prolonged blockade of H, receptors did not attenuate the response to LTC4, suggesting that histamine and LTC4 act on bronchial smooth muscle through different receptors. Four patients complained of drowsiness while taking azelastine but only one who was taking placebo and three patients complained of a bitter, metallic taste while taking azelastine.Airway hyperresponsiveness to specific and nonspecific stimuli is characteristic of bronchial asthma, though the mechanisms are unclear. It has been suggested that the sulphidopeptide leukotrienes (LT), derived from membrane arachidonic acid, may play a part in airway hyperresponsiveness in asthmatic patients.' 5LTC4 and LTD4 are released in vitro and in vivo after allergen challenge67 and both are extremely potent bronchoconstrictors in man. Inhaled LTE4 has been reported to enhance airway responsiveness to inhaled histamine in patients with asthma.8

The changes in transcutaneous oxygen saturation (SaO2%) and airway responses to inhaled histamine and leukotriene C4 (LTC4) were examined in 10 asthmatic patients, and the effect of inhaled LTC4 (16 nmol) on cardiopulmonary hemodynamics was examined in seven nonasthmatic patients undergoing diagnostic cardiac catheterization. In asthmatic patients, LTC4 produced oxygen desaturation on two occasions. At a lower dose (2.0 nmol) LTC4 produced a marked fall in SaO2% that lasted less than 15 min and occurred in the absence of significant bronchoconstriction as measured by changes in FEV1, FEF25-75, and SGaw. At a higher cumulative dose (7 nmol), LTC4 caused prolonged oxygen desaturation with slow recovery and this was associated with significant bronchoconstriction. In contrast, histamine inhalation produced a single response with a fall in both FEV1 and SaO2% of short duration. The dose-response characteristics of LTC4 and histamine on oxygen desaturation in asthmatic patients appear to differ significantly and probably are dependent on relative sensitivities of pulmonary vascular and bronchial smooth muscle to these agonists. A single inhaled dose of LTC4 in nonasthmatic subjects produced a marked drop in PaO2 with significant increase in AaPO2, and this was associated with a mean (SEM) decrease in FEV1 of 14% (2.5) from the baseline. The mean cardiac output fell by 15% (3.4) without significant changes in blood pressure and heart rate. There was no electrocardiographic evidence of myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

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The dose-duration effect of nebulized nedocromil sodium was studied in ten patients with exercise-induced asthma (7 males mean (SEM) age 30.1 (3.5) yrs and predicted forced expiratory volume in one second (FEV1) 102%). All of these patients showed > 40% protection of their exercise asthma with 4 mg of nedocromil sodium delivered via metered dose inhaler. Three concentrations of nedocromil sodium (0.5, 2.5 and 10 mg.ml-1) and placebo were administered in double-blind, randomized manner. One ml of each solution was nebulized via a Wright nebulizer. Effects were assessed from the mean maximal percentage fall in FEV1 after 6-8 min treadmill exercise at 15, 135 and 255 min following each treatment and expressed as percentage protection. The mean baseline FEV1 values before and after treatments were comparable on four days of testing. Nedocromil sodium inhibited exercise-induced fall in FEV1 at all concentrations (p < 0.001) and the inhibitory effect was still present at 255 min. No differences were observed between active treatments.