Airway refractoriness to adenosine 5'-monophosphate after repeated inhalation

Adenosine-5'-monophosphate (AMP) is a bronchoconstrictor agonist in subjects with atopic and nonatopic asthma. In this study we have investigated the effect of repeated airway challenge with AMP in 10 atopic, subjects without asthma. At the first visit, subjects had repeated inhalation challenges with increasing doubling concentrations of AMP, and the provocation concentration required to reduce FEV1 by 20% of baseline was determined (PC20 AMP). When the FEV1 had returned to within 5% of the baseline, the AMP challenge test was repeated on a further one or two occasions. When the maximum concentration of AMP (400 mg/ml) failed to produce a PC20, a bronchial provocation test with histamine was performed and the PC20 was determined. On the second visit, the effect of three consecutive inhalation challenge tests with histamine on the airway response to this agonist was determined. On the third visit, the duration of induced refractoriness to AMP was assessed. With the first AMP challenge, all subjects demonstrated bronchoconstriction with a geometric mean (GM) PC20 of 332 mg/ml. With a second AMP challenge, five of the 10 subjects became refractory and failed to achieve a PC20. In the remaining five subjects, the GM PC20 increased from 110 to 583 mg/ml. With a third AMP challenge, these subjects also failed to achieve a PC20. The initial GM PC20 histamine for the group was 22.9 mg/ml, which did not change significantly with two further histamine challenges or when the airways were refractory to AMP, suggesting that loss of AMP effect was not related to loss of contractility of airway smooth muscle or down regulation of H1-histamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between nasal and bronchial responsiveness in perennial allergic rhinitic patients with asthma

BACKGROUND: The nasal and bronchial mucosa present similarities and most patients with asthma also have rhinitis, suggesting the concept of 'one airway one disease'. Although many studies may suggest the relationship between nasal and bronchial responsiveness in patients with allergic rhinitis and asthma, few studies have been published which address this question directly. The aim of this study is to investigate whether the relationship between nonspecific nasal and bronchial responsiveness exists in perennial allergic rhinitic patients with asthma. METHODS: Fifty-one perennial allergic rhinitic patients with the definitive or suspected asthma underwent methacholine bronchial provocation tests and nasal histamine challenge tests. A slope of the absolute changes in nasal symptoms score/log concentrations of histamine was calculated by linear regression analysis. A ratio of the final absolute change in nasal symptoms score to the sum of all the doses of histamine given to the subject was also calculated. The degree of bronchial responsiveness to methacholine was categorized as positive bronchial hyperresponsiveness (BHR) if PC(20) (provocative concentration of methacholine resulting in 20% fall in FEV(1)) was <4 mg/ml, borderline BHR if PC(20) was >or=4 but 16 mg/ml. Another index of bronchial responsiveness (BRindex) was calculated as the log [(% decline in FEV(1)/log final methacholine concentration as mg/dl) + 10]. RESULTS: The geometric means of the slope (4.47 vs. 2.95, p < 0.05) and the ratio (1.68 vs. 0.54, p < 0.01) were higher in patients with positive BHR (n = 23) than in patients with negative BHR (n = 19), respectively. The geometric means of the slope (3.50) and the ratio (1.13) in patients with borderline BHR (n = 9) were between the two groups, respectively. In all patients, the log-slope (r = 0.48, p < 0.001) and the log-ratio (r = 0.51, p < 0.001) were correlated well with the BRindex, respectively. Even in allergic rhinitic patients with definitive asthma, the log-slope was correlated with the BRindex (r = 0.39, p < 0.05) or log-PC(20) (r = -0.36, p < 0.05). CONCLUSIONS: The nonspecific nasal responsiveness may be related to the nonspecific bronchial responsiveness in patients with allergic rhinitis and asthma, which may support the viewpoint that allergic rhinitis and asthma represent a continuum of inflammation involving one common airway.     

Lack of tachyphylaxis to histamine in both moderate and mild asthmatic subjects

While some studies have clearly shown that tachyphylaxis occurs in asthmatic subjects when challenged consecutively with inhaled histamine, others were unable to demonstrate this phenomenon. There is reason to believe that these conflicting findings may be related to the different degrees of bronchial reactivity in the subjects studied. We selected 2 groups of 10 asthmatics on the basis of their degree of bronchial reactivity: a group with PC₂₀<1 mg/ml (moderate asthmatics); and a group with PC₂₀>2.5 mg/ml (mild asthmatics). Each subject underwent 3 successive histamine challenges, allowing recovery of FEV₁ after each to within 5% of the baseline value prior to the first challenge. Test results were recorded as the provoking concentration of histamine needed to produce a 20% fall in FEV₁ (PC₂₀). No significant change in histamine reactivity occurred in either group. However, one moderate and two mild asthmatics appeared to develop some tachyphylaxis. We conclude that tachyphylaxis to histamine is not a general phenomenon in asthma.     

The magnitude of the spontaneous production of histamine-releasing factor (HRF) by lymphocytes in vitro correlates with the state of bronchial hyperreactivity in patients with asthma

In our previous studies we reported that lymphocytes from patients with asthma spontaneously produce histamine-releasing factor (HRF) in vitro. In an effort to examine whether spontaneous HRF production (SpHRF) by lymphocytes from patients with asthma is related to the state of bronchial hyperreactivity (BHR), 20 patients with mild to severe asthma were studied. Peripheral blood lymphocytes were cultured alone in a serum-free medium for 24 hours, and culture supernatant was assayed for HRF activity in two separate histamine-release tests with autologous basophils and normal basophils from known healthy donors. BHR was measured as bronchial reactivity to inhaled histamine and was expressed as a provocation concentration of histamine required to induce a 20% fall in FEV1 (PC20). The result of this study demonstrated that lymphocyte supernatant from all patients with asthma released significant amount of histamine from both autologous and normal basophils. Very high histamine release was usually induced by lymphocyte supernatant from severely ill patients who had PC20 less than 2 mg/ml. Statistical analysis demonstrated that the magnitude of the SpHRF significantly correlated (r = -0.86; p less than 0.001) with PC20. Since mast cell- and basophil-derived mediators have been implicated in the pathogenesis of BHR, high correlation between PC20 and SpHRF by lymphocytes suggests that the latter may contribute to the development of BHR. Further studies are required to disclose the exact relationship between SpHRF and BHR.     

Testing bronchial hyper-responsiveness: provocation or peak expiratory flow variability?

BACKGROUND: Assessing bronchial hyper-responsiveness (BHR) is a main diagnostic criterion of asthma. Provocation testing is not readily available in general practice, but peak expiratory flow (PEF) is. Several guidelines promote the use of PEF variability as a diagnostic tool for BHR. This study tested the agreement between histamine challenge testing and PEF variability, and the consequences for diagnosing asthma. AIM: To investigate the possibility of assessing BHR by PEF variability, using a histamine provocation test as a reference. METHOD: Subjects with signs of symptoms indicating asthma (persistent or recurrent respiratory symptoms or signs of reversible bronchial obstruction) (n = 323) were studied. They had been identified in a population screening for asthma. A histamine provocation test and PEF variability were assessed over a three-week period. Asthma was defined as signs or symptoms together with a reversible airflow obstruction or BHR to the histamine challenge test. BHR was defined as a PC20 histamine of < or = 8 mg/ml or a PEF variability of > or = 15%. Overall correlation between PC20 and PEF variability was calculated using Spearman's rho. Furthermore, a decision tree was constructed to clarify the role of BHR in diagnosing asthma. RESULTS: Thirty-two patients had a reversibility in forced expiratory volume in 1 second (FEV1) of > or = 9% predicted, 131 patients showed a PC20 of < or = 8 and 11 patients had a PEF variability of > or = 15%. Overall correlation was poor at only -0.27 (P < 0.0001). One hundred and fourteen of the 131 patients diagnosed as having asthma when the histamine challenge test was used were not diagnosed by PEF variability. CONCLUSION: PEF variability cannot replace bronchial provocation testing in assessing BHR. This indicates that PEF variability and bronchial provocation do not measure the same aspects of BHR. If BHR testing is required in diagnosing asthma, a bronchial provocation test has to be used in general practice as well.     

Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma

Bradykinin, a nonapeptide cleavage product of high molecular weight kininogen, is a potent bronchoconstrictor agonist in asthma; however, its mechanism of action is not known. Since bradykinin has been shown to stimulate mediator release from mast cells and augment the release of prostanoids, we have examined the effect of a selective histamine H1 receptor antagonist, terfenadine and a potent cyclooxygenase inhibitor, flurbiprofen on bronchoconstriction provoked by inhaled bradykinin in asthma. As a bronchial provocation procedure bradykinin challenge was repeatable to within 1 doubling dilution. In nine atopic asthmatic subjects, terfenadine 180 mg, when compared to placebo, increased the geometric mean provocation concentration of inhaled agonist required to reduce FEV1 by 20% of baseline (PC20) from 0.7 to greater than 22.9 mg/ml for histamine (P less than 0.01) and 0.3 to 0.5 mg/ml for bradykinin (P less than 0.01). In a further nine atopic asthmatics, flurbiprofen 150 mg when compared to placebo produced a small but significant protection of the airways against bradykinin, geometric mean PC20 increasing from 0.40 to 0.79 mg/ml (P less than 0.05). We conclude that bradykinin is a potent bronchoconstrictor agonist in asthma, being approximately 9.5 times more potent than histamine in molar terms. Pharmacological intervention with terfenadine and flurbiprofen led to a significant protection of the airways against the constrictor effect of bradykinin but the effect in each case was small. Thus, while histamine and prostanoids may contribute as mediators of bradykinin-induced bronchoconstriction, they are unlikely to account for the majority of the response.     

Dissimilarity between seasonal changes in airway responsiveness to adenosine-5'-monophosphate and methacholine in patients with grass pollen allergic rhinitis: relation to induced sputum

BACKGROUND: In patients with allergic rhinitis, bronchial hyperresponsiveness (BHR) and airway inflammation may increase during pollen exposure. BHR can be assessed by adenosine-5'-monophosphate (AMP) or methacholine challenge. It has been suggested that BHR to AMP is more closely related to airway inflammation than BHR to methacholine. Seasonal allergic rhinitis offers a dynamic model to study changes in BHR and airway inflammation during natural allergen exposure. METHODS: We measured BHR [provocative concentration causing a 20% fall (PC(20)) in forced expiratory volume in 1 s (FEV(1))] to AMP and methacholine, and induced sputum cells in 16 rhinitis patients before and during the 2001 grass pollen season. RESULTS: There was a decrease in PC(20) methacholine during pollen exposure (geometric mean PC(20) from 3.22 to 1.73 mg/ml, p = 0.0023), whereas no reduction was observed for PC(20) AMP (p = 0.11). There was no increase in sputum eosinophils [pre: 0.69% (95% confidence interval 0.22-2.07); during: 1.85 (0.55- 5.6), p = 0.31]. Although the correlation of log PC(20) methacholine and log PC(20) AMP at baseline was good (r = 0.76, p = 0.001), individual seasonal changes (doubling concentrations) in PC(20) methacholine were not correlated with changes in PC(20) AMP (rho = 0.21, p = 0.44). There was no correlation between baseline log PC(20) methacholine or seasonal changes in PC(20) methacholine and sputum eosinophils (p > 0.12, all correlations). In contrast, there was a significant correlation between seasonal changes in PC(20) AMP and changes in sputum eosinophils (rho = -0.59, p = 0.025). CONCLUSIONS: These data show dissimilarity between seasonal changes in PC(20) AMP and methacholine in patients with seasonal allergic rhinitis. Moreover, PC(20) AMP seems to be more closely related to sputum eosinophils than PC(20) methacholine. The clinical significance of this discrepancy is unclear.     

Increased responsiveness to histamine after propranolol in subjects with asthma nonresponsive to the bronchoconstrictive effect of propranolol

Eight nonsmoking subjects with asthma, nonresponsive to the bronchoconstrictive effect of oral propranolol, were studied. The airway response to increasing concentrations of histamine aerosol was assessed by measuring FEV1. The threshold provocative dose of histamine needed to cause a 20% fall in starting FEV1 (PD20) was measured by log dose-response curve. Histamine challenge was performed in duplicate after premedication with placebo or 40 mg of propranolol on separate days. The mean starting FEV1 did not change significantly after placebo and after propranolol administration. The mean PD20 values after propranolol (0.37 mg/ml and 0.32 mg/ml, respectively, for the first and the second challenge) were significantly lower (p less than 0.01) than mean control PD20 values (1.36 mg/ml and 1.48 mg/ml, respectively, for the first and the second challenge). These results indicate that propranolol increases airway responsiveness to histamine, even in those subjects with asthma in whom propranolol has little bronchoconstrictive effect.     

Duration of the effect of astemizole on histamine-inhalation tests

The aim of the study was to investigate if astemizole, a new, long-acting antihistamine preparation, has an effect on histamine-inhalation tests and to assess the duration of action of this medication. The study included a group of 15 adult subjects with asthma in a clinically stable state. The subjects all demonstrated mild to severe bronchial hyperresponsiveness (geometric mean provocative concentration causing a 20% fall in FEV1 (PC20) histamine, 0.57; range, 0.20 to 4.7 mg/ml). The first part of the study was a double-blind, 7-day trial of astemizole (10 mg/day) or placebo, assigned in random order for the first eight subjects. The seven subjects entering the trial subsequently were administered active medication only. PC20 histamine was assessed on the 3 consecutive days before starting the trial, on the last day of medication, 3 days later, and once a week thereafter until PC20 returned to baseline. PC20 methacholine was also assessed before the trial and regularly thereafter to ensure functional stability. No significant changes in PC20 histamine were documented in the placebo-treated group, but the four subjects receiving active medication demonstrated marked changes in PC20 histamine (from a tenfold to a greater than 100-fold difference) (p = 0.001). There were no significant differences in changes in PC20 methacholine between the two treatment groups (p = 0.27). The duration of recovery of bronchial response to histamine in all 15 subjects ranged from 12 to 102 days (mean, 42 days) and was in some subjects, longer than the duration of the blocking effect of histamine reactivity found with skin testing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Histamine hyperresponsiveness of the extrathoracic airway in patients with asthmatic symptoms

Functional abnormalities of the extrathoracic airway (EA) may produce symptoms mimicking bronchial asthma. We assessed the bronchial (B) and EA responsiveness to inhaled histamine in 40 patients with asthmatic symptoms and in nine asymptomatic controls. FEV1 and maximal mid-inspiratory flow (MIF50) were used as index of bronchial and EA narrowing. Hyperresponsiveness of the intra-(BHR) or extra-(EA-HR) thoracic airway was diagnosed when the provocative concentrations of histamine (PC20FEV1 or PC25MIF50) were less than 8 mg/ml. Fiberoptic laryngoscopy was performed in nine patients and three controls. The glottal region was measured at mid-volume of maximal inspiration (AgMI) and expiration (AgME) before and after histamine. Predominant EA-HR was found in 13 patients, predominant BHR in 12, equivalent BHR and EA-HR in another 12; no significant airway narrowing was observed in three patients and in the nine controls. EA-HR was significantly associated with female sex, sinusitis, post-nasal drip, dysphonia; BHR with atopy, wheezing and lower MEF50. The percent change in AgMI after histamine was closely related to the PC25MIF50 (r = 0.87, P less than 0.001), that of AgME to the PC20FEV1 (r = 0.78, P less than 0.01). These findings suggest that the assessment of EA responsiveness may be useful in the evaluation of asthmatic symptoms, especially in patients with no BHR.     

The effect of inhaled ipratropium bromide alone and in combination with oral terfenadine on bronchoconstriction provoked by adenosine 5'-monophosphate and histamine in asthma.

The aim of this study was to investigate the effect of terfenadine, an antihistamine, 180 mg orally, the anticholinergic drug, ipratropium bromide (IB), 0.5 mg nebulized aerosol, the combination of these two drugs, and placebo tablets and aerosol on histamine- and adenosine 5'-monophosphate (AMP)-induced bronchoconstriction in a randomized, double-blind fashion. Airway response was evaluated as FEV1. After placebo, the geometric mean (GM) provocative concentration causing a 20% in FEV1 from the postsaline baseline value (PC20) for histamine and AMP was 0.63 and 5 mg/ml, respectively. Terfenadine displaced the FEV1 concentration-response curves obtained with both histamine (GM PC20 values increasing to 26.92 mg/ml) and AMP (GM PC20 values increasing to 26.7 mg/ml) to the right. IB had a small, but significant, protective effect against the fall in FEV1 produced by histamine and AMP, the GM PC20 values increasing to 1.69 and to 12.6 mg/ml, respectively. Terfenadine and IB in combination produced protection against histamine and AMP that was more than the production produced by either drug alone, the GM PC20 values increasing to 54.76 and 47.7 mg/ml, respectively. There was no correlation between degree of bronchodilatation induced by active treatments and concentration ratios for AMP or histamine. These data suggest that histamine release and vagal reflexes both contribute to AMP-induced bronchoconstriction in clinical asthma in man.     

Effect of sodium cromoglycate on histamine inhalation tests

Sixteen adult asthmatic subjects in a clinical steady state were included in the study. On day 1, after baseline assessment of spirometry (FEV1, FEV1/FVC, FEF25-75), they underwent three to four consecutive inhalation tests using twofold increasing doses of histamine to measure the provocative concentration causing a fall in FEV1 of 20% (PC20). Baseline FEV1 was back to +/- 5% of the initial assessment before each histamine inhalation test (HIT). On days 2, 3, and 4, after baseline spirometry which confirmed that FEV1 was within 10% of initial day 1 assessment, placebo-lactose (P) or 40 mg of sodium cromoglycate (SCG) were nebulized in a double-blind randomized 4.3.1. two-treatment crossover study design. Ten minutes later, spirometry was repeated and followed by an HIT. Baseline spirometry was not significantly different on each day or after P and SCG. There was no statistical difference between the geometric means of the three or four PC20's done on day 1, indicating that there is no tachyphylaxis induced by repeated HIT. There was no statistical difference between mean PC20 after P (0.52 +/- 3.3 (SD) mg/ml), after SCG (0.50 +/- 3.2), and of the three to four HIT done on day 1 (0.40 +/- 3.6). We conclude that in asthmatic subjects SCG has no acute bronchodilator effect and does not alter the response to inhaled histamine.     

The in vivo potency and selectivity of azelastine as an H1 histamine-receptor antagonist in human airways and skin

Azelastine is a novel histamine H1 antagonist with putative antileukotriene activity in guinea pigs. With three different doses of oral azelastine, we have performed a dose-response study to determine its protective effect on the airways against histamine-induced bronchoconstriction in 12 patients with mild, atopic asthma. On 4 separate days, patients undertook standardized inhalation-challenge tests with increasing concentrations of histamine (0.03 to 32 mg/ml) 4 hours after placebo or azelastine, 4.4, 8.8, and 17.6 mg, administered double blind and in random order. On 2 additional days, patients underwent methacholine challenge tests after placebo or azelastine, 17.6 mg. Baseline FEV1 between treatment days and 4 hours after placebo and azelastine did not change significantly. The three doses of azelastine, 4.4, 8.8, and 17.6 mg, increased the concentration of histamine required to cause a 20% fall in FEV1 (PC20) from 0.16 mg/ml geometric mean (GM) after placebo to 1.98 (p less than 0.01), 8.8 (p less than 0.01), and 8.1 (p less than 0.01) mg/ml, respectively. GM potency ratios derived from the PC20 values obtained for each patient indicated that the three increasing doses of azelastine displaced the histamine dose-response curve to the right by factors of 12.8, 54.4, and 50.2. Azelastine had no effect on the airway response to methacholine with GM PC20 values of 0.16 and 0.19 after placebo and azelastine, 17.6 mg. Azelastine is a potent H1 histamine-receptor antagonist on human airways in vivo without demonstrable anticholinergic effect.     

The effect of histamine-H1 receptor antagonism with terfenadine on concentration-related AMP-induced bronchoconstriction in asthma

Selective histamine-H1 receptor antagonists inhibit adenosine 5'-monophosphate (AMP)-induced bronchoconstriction by greater than 80% when expressed as a percentage inhibition of the FEV1 time-response curve following inhalation of the provocation concentration of AMP required to produce a 20% decrease in FEV1 from baseline (PC20). To investigate this further we have determined that, in eight mild atopic asthmatic subjects, terfenadine (180 mg), administered 3 hr pre-challenge, increases the geometric mean PC20 for histamine from 0.4 (range 0.03-3) mg/ml after placebo, to 20.2 (range 0.6-64) mg/ml following active treatment (P less than 0.0001). For AMP, the PC20 increased from 9.3 (range 1.0-113.3) mg/ml after placebo, to 150.2 (range 32.1-1177.7) mg/ml with terfenadine (P less than 0.0001). This 16.2-fold (range, 5.5-47.9) displacement to the right of the AMP concentration-response curve by a selective histamine-H1 receptor antagonist emphasizes the central role of histamine in the airways response to this nucleotide.     

Significant changes in nonspecific bronchial responsiveness after isolated immediate bronchospecific reactions caused by isocyanates but not after a late reaction caused by plicatic acid

Although late bronchospastic reactions after exposure to antigenic and sensitizing agents usually significantly alter bronchial responsiveness to histamine or methacholine, presumably by causing bronchial inflammation, isolated immediate bronchospastic reactions do not induce such changes. We studied three subjects who demonstrated different patterns of reaction. The first individual was diagnosed as having occupational asthma to red cedar. This was confirmed by specific inhalation challenges that resulted in late bronchospastic reaction. No significant changes in the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) were found 1 day after this reaction. Two weeks later, serial assessments (five and six, respectively) of PC20 histamine were recorded on control days and up to 48 hours after exposure to plicatic acid, which caused a late bronchospastic reaction with a maximum fall of 37% in FEV1. No significant changes in PC20 were found; the maximum variations on control days were 0.36 to 0.74 mg/ml, and on active days, from 0.37 to 0.59 mg/ml. By contrast, two other subjects, who demonstrated isolated immediate reactions after exposure to diphenylmethane diisocyanate, had significant changes in PC20 histamine and methacholine, in one subject from 3.1 mg/ml to 0.6 mg/ml 8 hours after exposure, and in the other subject, from 61.0 to 7.4 mg/ml 7 hours after exposure, with recovery during the next few days. These examples demonstrate that the pattern of nonspecific bronchial responsiveness after immediate and late bronchospastic reactions can be different from what has previously been described. Immediate bronchospastic reactions may lead to bronchial hyperresponsiveness, whereas late asthmatic reactions do not always induce changes in bronchial responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)     

Grading severity and treatment requirements to control symptoms in asthmatic children and their relationship with airway hyperreactivity to methacholine

Airway hyperreactivity has been proposed to be an important determinant of severity of asthma and medication needs to control symptoms in adults. In this study we tried to determine if this relationship existed in childhood asthma. One hundred and forty-five asthmatic children aged 6 to 19 years with a positive methacholine (MCH) challenge test and a baseline forced expiratory volume in one second (FEV1) of 56% to 118% predicted were studied. The MCH concentration required to decrease the FEV1 from baseline by 20% (PC20) ranged from 0.1 to 20 mg/mL (geometric mean = 1.85 mg/mL). Asthma symptoms in this population before the study ranged from 2 months to 14 years. They were followed for a mean of 10 months after the MCH challenge and then grouped into four groups according to overall severity of symptoms and treatment needed to control symptoms. The first grade was comprised of patients with intermittent symptoms only, with a respiratory tract infection (URTI), and no medication; grade 2 symptoms were severe enough to require intermittent bronchodilators (BD); grade 3 symptoms were severe enough to require daily BD; and grade 4 symptoms were severe enough to require daily BD and steroids. Geometric means PC20 were significantly different among the four groups when they were analyzed by ANOVA P less than .01. There was, however, marked overlap between the individual levels of PC20 among the four groups. There was no significant difference in mean FEV1, age, sex, or duration of symptoms among the four groups. There was no significant correlation between baseline FEV1 and the degree of airway hyperreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of nedocromil sodium on the early and late reaction and allergen-induced bronchial hyperresponsiveness.

Bronchial hyperresponsiveness (BHR) to methacholine was studied in 14 patients with asthma and five healthy control subjects, with and without pretreatment with nedocromil sodium, 3 and 24 hours after allergen challenge. Eleven patients demonstrated a dual asthmatic response. A significant decrease in the provocative concentration causing a 20% fall in FEV1 was found from a geometric mean starting value of 1.18 mg/ml on the control day to 0.24 mg/ml (p less than 0.001) and to 0.17 mg/ml (p less than 0.001) 3 and 24 hours after allergen challenge. A significant correlation was observed between the increased BHR at 3 hours and the magnitude of the late response (r = -0.57; p less than 0.05). Nedocromil sodium (6 mg) significantly inhibited the increase in BHR, 1 mg/ml (p less than 0.001) at 3 hours and 0.50 mg/ml (p less than 0.001) at 24 hours. Nedocromil sodium shifted the severity of the early allergic reaction (EAR) from mean -34.8% to -6.9% and inhibited the later allergic reaction (LAR) from -30.5% to +0.4% (p less than 0.005). From the study can be concluded that nedocromil sodium inhibits the EAR and LAR and the allergen-induced increase in BHR. The inhibitory effect of nedocromil sodium on the LAR may be related to its ability to inhibit the increased BHR before the development of the LAR.     

Nasal eosinophilic inflammation contributes to bronchial hyperresponsiveness in patients with allergic rhinitis

There are increasing evidences that allergic rhinitis (AR) may influence the clinical course of asthma. We conducted methacholine challenge test and nasal eosinophils on nasal smear to patients with allergic rhinitis in order to investigate the mechanism of connecting upper and lower airway inflammation in 35 patients with AR during exacerbation. The methacholine concentration causing a 20% fall in FEV1 (PC20) was used as thresholds of bronchial hyperresponsiveness (BHR). Thresholds of 25 mg/dL or less were assumed to indicate BHR. All patients had normal pulmonary function. Significant differences in BHR were detected in the comparison of patients with cough or postnasal drip and without cough or postnasal drip. There were significant differences of PC20 between patients with cough or postnasal drip and those without cough or postnasal drip (3.41+/-3.59 mg/mL vs 10.2+/-1.2 mg/mL, p=0.001). The levels of total IgE were higher in patients with seasonal AR than in patients with perennial AR with exacerbation (472.5+/-132.5 IU/L vs. 389.0+/-70.9 IU/L, p<0.05). Nasal eosinophils were closely related to log PC20 (r=-0.65, p<0.01). These findings demonstrated that nasal eosinophilic inflammation might contribute to BHR in patients with AR.     

Changes in bronchial hyperresponsiveness following high- and low-sulphite wine challenges in wine-sensitive asthmatic patients

BACKGROUND: Previous studies suggest that challenge of most wine-sensitive asthmatic patients may not result in a reduction in forced expiratory volume in 1 s (FEV(1)). OBJECTIVE: The aim of this study was to assess whether changes in bronchial hyperresponsiveness (BHR) occur following wine challenge of asthmatic patients who report sensitivity to wine, and whether such changes could help clarify the role of sulphite additives in wine-induced asthmatic responses. METHODS: Eight self-reporting wine-sensitive asthmatic patients completed double-blind challenges with high- and low-sulphite wines on separate days. FEV(1) and histamine PC(20) were measured before and after consumption of 150 mL of wine. RESULTS: None of the eight subjects demonstrated a clinically significant >or=15%) reduction in FEV(1) following challenge with either high- or low-sulphite wine. In contrast, one patient demonstrated clinically significant increase in BHR following challenge with both high- and low-sulphite wines, and a smaller increase in BHR following placebo challenge. A second patient showed a significant increase, while another showed a significant decrease in BHR following challenge with low-sulphite wine. A fourth patient showed borderline increases in BHR following challenge with both high- and low-sulphite wines. CONCLUSIONS: Although changes in BHR, in the absence of reductions in FEV(1), were observed in some asthmatic patients following wine challenge, these changes were not consistent with a single aetiology. Consequently, this study did not support a major role for the sulphite additives in wine-induced asthmatic responses in the patients studied. The aetiology of wine-induced asthma is likely to be complex and appears to vary among individuals who are sensitive to these drinks.     

Passive cigarette smoke-challenge studies: increase in bronchial hyperreactivity.

Degree and duration of bronchial hyperreactivity (BHR) after environmental tobacco smoke (ETS) inhalation was assessed in 31 smoke-sensitive subjects with asthma who exhibited lower airway symptoms on ETS exposure (group I) and 39 smoke-sensitive subjects without asthma who manifested only upper airway symptoms on cigarette-smoke exposure (group II). Subjects were challenged with ETS for 4 hours in a static-test chamber. The atmosphere was continuously monitored for airborne particulate levels (800 cpm), total suspended particulates (1266 +/- 283 micrograms/m3), and airborne nicotine levels (226 +/- 49 micrograms/m2). Methacholine challenges were performed before and serially after cigarette-smoke exposure, and the provocative dose causing a 20% fall in FEV1 was determined. Five of the 31 smoke-sensitive subjects with asthma and none of the smoke-sensitive subjects without asthma reacted to cigarette-smoke challenge (greater than or equal to 20% fall from baseline FEV1). Thirty-two percent (10/31) of the subjects with asthma demonstrated increased BHR at 6 hours, 29% (9/31) at 24 hours, and 13% (4/31) up to day 14 after ETS challenge. Of the subjects without asthma, 18% (7/39) demonstrated increased BHR at 6 hours, 10% (4/39) at 24 hours, and 8% (3/39) at 3 weeks. These studies demonstrated an increase in BHR after cigarette-smoke challenge in a number of study subjects (although they were clinically asymptomatic) and suggest that prolonged subclinical airway inflammation can occur in the absence of demonstrable change in airway caliber on exposure to ETS.