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Immunotherapy for cat asthma.

In 22 patients with cat asthma who were highly sensitive to cat, we compared, double-blind, the effects of immunotherapy with cat-hair and dander extract (11 patients) with effects of placebo (11 patients). Patients were matched by the dose of the cat extract expressed in Food and Drug Administration (FDA) units of Fel d I (previously called cat allergen 1) required for end point reaction in intradermal skin test end point titration (STEPT), for in vitro leukocyte histamine release (LHR), and for the dose of cat extract producing a 20% fall in FEV1 (cat-extract PD20) in bronchoprovocation test. Patients were matched also for bronchoprovocation dose of methacholine producing a 20% fall in FEV1 (methacholine PD20). Patients were randomly assigned to one of two treatment groups. During immunotherapy, doses were increased to maintenance dose of 4.56 FDA units of Fel d I, or, if this were less, to the highest tolerated dose. Systemic reactions to cat-extract immunotherapy were mild and infrequent. Before and during immunotherapy, we measured (in FDA units of Fel d I) cat-extract PD20, cat-extract intradermal STEPT, cat-extract in vitro LHR, serum levels of cat IgG and cat IgE, and methacholine PD20. After they had received 1 year of immunotherapy, patients receiving cat extract, in comparison to patients receiving placebo, had decreased cat-extract PD20 (p less than 0.01), diminished responses to cat-extract intradermal STEPT (p less than 0.025), increased IgE antibodies toward cat extract (p less than 0.01), increased IgG antibodies toward cat extract, Fel d I, and cat albumin (p less than 0.001), but no significant change in cat-extract in vitro LHR or in methacholine PD20. We conclude that cat-extract immunotherapy was well tolerated, significantly decreased skin and bronchial responses to cat extract, and significantly increased IgE antibodies to cat extract and IgG antibodies to cat extract, Fel d I, and cat albumin.

Adult↗

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.

Administration, Inhalation↗

An open study of auranofin in the treatment of steroid-dependent asthma.

To determine the efficacy of oral gold in asthma, 20 patients with steroid-dependent asthma received auranofin at a dose of 3 mg by mouth, twice daily, in a 24-week open clinical trial. Prospective evaluation of bronchial responsiveness to methacholine was determined before and 8 and 16 weeks after initiation of auranofin therapy. Serial spirometry (FEV1 and FVC), lung volumes, and diffusing capacities (single breath carbon monoxide diffusing capacity of the lungs) were measured before and at 10 and 20 weeks after treatment. All subjects were required to record concomitant medications, symptom scores, and morning and evening peak expiratory flow rates. In vitro immunologic studies performed before and after 8 and 20 weeks of auranofin therapy included leukocyte histamine release in response to antihuman IgE, lymphocyte blast transformation in response to concanavalin A and phytohemagglutinin, and leukocyte inhibitory factor activity in response to Candida albicans and tetanus toxoid antigens. In 18 patients evaluated, there were no significant differences between baseline and posttreatment spirometry, single breath carbon monoxide diffusing capacity of the lungs, and lung volumes. At week 16 of treatment, the steroid cumulative dose or the total prednisone dose administered from 7 days before through 10 days after each methacholine test day decreased from a mean of 293 +/- 125 mg at baseline to 192 +/- 115 mg. At week 16, nine of 18 patients (50%) exhibited decreased methacholine responsiveness as defined by a more than one-half log10 increase in the concentration of methacholine causing a 20% decrease in FEV1. A significant correlation (r = 0.60) was observed between the increase in the concentration of methacholine causing a 20% decrease in FEV1 and the decrease in steroid cumulative dose after 16 weeks of treatment. Leukocyte histamine release to anti-IgE exhibited significant reductions from baseline at week 20 to 10(-2) (p less than 0.002) and at 10(-3) (p less than 0.005) dilutions. At week 20, leukocyte inhibitory factor activity in response to Candida increased from baseline at the 0.1 mg per well (p = 0.025) and 1 mg per well (p = 0.05) concentrations; similarly, the responses to tetanus toxoid increased at the 1 mg per well (p less than 0.05) and 0.1 mg per well (p less than 0.01) concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Ketotifen inhibits the cutaneous but not the airway responses to platelet-activating factor in man.

We studied the effect of ketotifen, an oral antiallergic and antihistaminic drug, on the airway and cutaneous responses to platelet-activating factor (PAF) in a double-blind, randomized, and crossover study in six normal subjects. Ketotifen (three doses of 2 mg taken during a 14-hour period before PAF) did not alter PAF-induced bronchoconstriction and did not prevent the accompanying flushing and coughing. The transient neutropenia (74.5 +/- 4.8% fall; p less than 0.001) and rebound neutrophilia (104 +/- 55% rise) induced by PAF were not affected by ketotifen. On the day placebo was received, airway responsiveness to methacholine increased after PAF exposure with the concentration needed to cause a 40% fall in baseline partial expiratory flow rate (PC40), decreasing from 69.2 mg/ml (geometric standard error of the mean, 2.69) to 23.3 mg/ml (2.34) on day 3 (p less than 0.001). Ketotifen had no effect, because on the day ketotifen was administered, mean PC40 also decreased from 52.7 mg/ml (2.5) to 21.5 mg/ml (2.14) (p less than 0.01). In the skin, ketotifen reduced the flare area (from 8.05 +/- 3.60 to 1.14 +/- 0.29 cm2; p less than 0.05) and the wheal volume (from 0.068 +/- 0.010 to 0.045 +/- 0.008 cc; p = 0.02) induced by intradermal PAF (200 ng). Cutaneous responses to histamine (1 microgram) were significantly inhibited. Thus, the bronchoconstriction and bronchial hyperresponsiveness induced by PAF are not inhibited by ketotifen. Ketotifen inhibits PAF-induced wheal and flare in the skin, which is probably histamine dependent. The airway effects of PAF are unlikely to be mediated by histamine release.

Adult↗

Dose response of inhaled gallopamil (D600), a calcium channel blocker, in attenuating airway reactivity to methacholine and exercise.

To determine if there is a dose-response relationship for calcium channel blockers in preventing experimentally induced bronchoconstriction, we evaluated the effects of inhaled gallopamil (D600), a potent methoxy derivative of verapamil, on airway reactivity to methacholine and exercise in volunteers with mild asthma. Methacholine challenges were completed by 11 subjects 2 hours before and 20 minutes after placebo, and 1, 2, 5, 10, and 20 mg of inhaled gallopamil administered in a single-blind, randomized manner on different days. Gallopamil did not significantly alter FVC, FEV1, or forced expiratory flow rate between 25% and 75% of FVC, but increased the dose of methacholine required to produce a 20% decrease in FEV1 from baseline (p less than 0.0001). The mean +/- SEM fold increase in the dose of methacholine required to produce a 20% decrease in FEV1 from baseline was 1.0 +/- 0.1 after placebo, 2.4 +/- 0.2 after 1 mg, 2.2 +/- 0.2 after 2 mg, 2.5 +/- 0.2 after 5 mg, 2.5 +/- 0.3 after 10 mg, and 2.3 +/- 0.2 after 20 mg. Thirty minutes before a standardized exercise challenge, 10 subjects inhaled 1 and 10 mg of gallopamil or placebo in a randomized, double-blind, crossover manner. The mean +/- SEM maximum decrease in FEV1 after exercise was 25.1 +/- 5% after 10 mg of gallopamil (p less than 0.01), 34.4 +/- 5% after 1 mg (p greater than 0.05), and 39.0 +/- 6% after placebo. We conclude that inhaled gallopamil only modestly alters airway reactivity to methacholine; increasing the dose greater than 1 mg did not provide greater benefit.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Expression of complement receptors type 1 (CR1) and type 3 (CR3) on circulating granulocytes in experimentally provoked asthma.

Neutrophils demonstrate increased complement receptor activity, measured by rosetting of C3b-coated erythrocytes, after asthma that was provoked experimentally. However, it is not clear whether the increased rosetting is due simply to increase in receptor numbers or whether other factors, such as cell adhesiveness, are involved. We have therefore enumerated granulocyte complement receptors, after asthma provoked experimentally, with monoclonal antibodies against the receptors and flow cytometry. There was a maximal 28.2 +/- 7.5% and 33.4 +/- 9.5% (mean +/- SEM; n = 15) increase in granulocyte CR1 and CR3, respectively, at 3 hours after asthma induced by antigen. There was a maximal 32.0 +/- 7.3% (mean +/- SEM; n = 7) increase in granulocyte CR1, but no change in granulocyte CR3, at 1 hour after exercise-induced asthma. No significant changes in granulocyte CR1 or CR3 were observed up to 6 hours after methacholine challenge, or after exercise in subjects who did not develop exercise-induced asthma. There was a maximal 33 +/- 9% (mean +/- SEM; n = 8) increase in granulocyte CR1 at 30 minutes, but no increase in granulocyte CR3, after histamine challenge of subjects with asthma. Incubation of whole blood with histamine in vitro did not lead to any enhancement in expression of granulocyte CR1. This suggests that antigen- and exercise-induced release of histamine may augment granulocyte CR1 expression through an indirect mechanism. These data indicate that there is increase in the numerical expression of CR1 on granulocytes, after asthma provoked experimentally, which is accompanied by increases in granulocyte CR3 after bronchoprovocation with antigen, but not histamine or exercise.

Adolescent↗

Theophylline does not inhibit allergen-induced increase in airway responsiveness to methacholine.

Allergen-induced increase in airway hyperresponsiveness can be used as a model of airway inflammation for assessing antiasthma pharmacologic agents. Steroids and cromolyn, but not beta-agonists, inhibit this increase; theophylline, recently suggested as having anti-inflammatory effects, has not been evaluated in this model. Six atopic subjects with asthma and with late asthmatic responses (N = 5) and postallergen reduction in a provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) (N = 6) were studied. Sustained-release theophylline (Theo-Dur; Astra Pharmaceuticals Canada, Ltd., Mississauga, Canada), 300 mg, and placebo were administered single-blind twice daily for eight doses up to 1 hour before allergen inhalation; cromolyn sodium, 10 mg, was administered in a single dose 10 minutes before allergen inhalation on another day as a "positive control." Mean theophylline levels were in the low therapeutic range, 57 +/- 17 and 58 +/- 13 mumol/L 1 and 8 hours after the last tablet. The FEV1 was 7% and 9% greater after the seventh and eighth doses of theophylline versus placebo (p less than 0.05). Theophylline also produced a significant (p less than 0.05) twofold increase in methacholine PC20. There was a 40% (p = 0.06) reduction in early asthmatic fall in FEV1 and a 25% (not significant) reduction in late FEV1 fall when theophylline was compared to placebo. Theophylline did not influence the geometric mean allergen-induced fall in methacholine PC20 delta log PC20; this was true individually in five of the six subjects. By contrast, cromolyn sodium inhibited all aspects of the allergen response completely.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Superoxide generation and its modulation by adenosine in the neutrophils of subjects with asthma.

Airway inflammation with neutrophil infiltration may play a role in airway hyperreactivity. Neutrophils may exert their effects through the generation of superoxide O2- anion and other oxygen-derived free radicals. O2- generation by neutrophils has been demonstrated to be modulated by adenosine at physiologic concentrations. Therefore, we have investigated the function of peripheral blood neutrophils with respect to O2- anion generation and its regulation by adenosine in both subjects with asthma and normal subjects and also the relationship between O2- anion generation and airway hyperresponsiveness in subjects with asthma. Purified neutrophils were obtained from eight subjects with stable asthma and seven normal control subjects not taking chronic medications. O2- anion generation in subjects with asthma was significantly higher compared with that of normal subjects after stimulation with either N-formyl-methionyl-leucyl-phenylalanine (mean, 14.8 nmol/10(6) cells for subjects with asthma versus mean, 9.6 nmol/10(6) cells for normal subjects; p less than 0.01) or phorbol myristate acetate (mean, 13.6 nmol/10(6) cells versus mean, 8.1 nmol/10(6) cells; p less than 0.05). Adenosine inhibited N-formyl-methionyl-leucyl-phenylalanine-stimulated O2- anion generation in a dose-related fashion in subjects with asthma and normal subjects to a similar degree. Adenosine had no effect on O2- anion generation after phorbol myristate acetate stimulation. These results indicate that neutrophils from subjects with asthma produce more O2- anion when they are stimulated than do neutrophils from normal subjects and that this difference is not due to adenosine modulation. In subjects with asthma, O2- anion generation correlated with the degree of airway hyperresponsiveness to inhaled methacholine.

Adenosine↗

Relationship between deposition of and responsiveness to inhaled methacholine in normal and asymptomatic subjects.

The purpose of this study was to determine if the intersubject variability in airway responsiveness to methacholine is a function of the methacholine mass deposited in the airways and if methacholine hyperresponsiveness in asymptomatic subjects with asthma is related to increased methacholine deposition. Ten normal and 10 age-matched asymptomatic subjects with asthma inhaled, with a standardized single breath maneuver, a dry aerosol (mass median aerodynamic diameter, 1.5 micron; geometric SD, 2.1) generated from solutions of methacholine at concentrations ranging from 0.078 mg/ml to 80 mg/ml in buffered saline, mixed with a fixed concentration of the fluorescent tracer quinine. The mass of methacholine deposited was calculated from the fluorescence of the inspired and expired aerosol trapped on an absolute filter before inspiration and during expiration. Specific airway conductance (SGaw) was measured before and after the inhalation of increasing concentration of methacholine, and the provocative deposited mass corresponding to a 35% decrease in SGaw was calculated. Baseline aerosol deposition (quinine-labeled buffered saline) ranged from 63% to 94% and was similar in normal subjects (mean 85%) and asymptomatic subjects with asthma (mean 84%). There was a correlation between the decrease in SGaw and methacholine mass deposited at first dose in the normal subjects (p less than 0.001) but not in asymptomatic subjects with asthma. Mean provocative methacholine mass corresponding to a 35% decrease in SGaw was 86 micrograms (range 2 to 157 micrograms) in asymptomatic subjects with asthma and 1361 micrograms (range 157 to 3434 micrograms) in normal subjects (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

Airway responsiveness to methacholine after inhalation of nebulized hypertonic saline in bronchial asthma.

To assess whether the changes in airway methacholine (Meth) responsiveness induced by an initial hypertonic challenge determine the response to a subsequent hypertonic provocation, 11 subjects with asthma had bronchial challenges with 3.6% hypertonic saline (HS) and Meth in a dose-dependent manner and in random order. Challenges consisted of (1) an HS challenge (HS1) followed 1 hour later by a second HS challenge (HS2), (2) a Meth challenge alone (Meth1), and (3) an HS challenge followed 1 hour later by a Meth challenge (Meth2). The dose of HS that produced a 35% fall in SGaw (PD35) in HS1 was 69 L (geometric mean), and the PD35 in HS2 was 107 L (p = 0.02). Refractory index (PD35 HS2/PD35 HS1) ranged from 0.7 to 5.0. After HS challenge, airway responsiveness to Meth increased, and the Meth PD35 fell from 0.26 mumol to 0.11 mumol (geometric mean, p = 0.004). There was an inverse linear correlation between the refractory index and increases in Meth sensitivity (PD35 Meth1/PD35 Meth2) (r = -0.66; p = 0.027). After an initial HS challenge, the ratio of PD35 HS to PD35 Meth increased in all subjects, indicating that all subjects had become less responsive to HS compared to Meth, irrespective of their refractory index. We suggest that an initial HS challenge induces protective mechanisms toward a subsequent HS challenge in all individuals. The degree of increase in Meth responsiveness elicited by the initial provocation is a major factor in determining the airway response to a subsequent HS challenge.

Administration, Inhalation↗

Transdermal scopolamine attenuates methacholine-induced bronchospasm.

Anticholinergic agents have been widely used in the management of asthma. The use of scopolamine has been limited by significant side effects. Transdermal delivery of scopolamine (TS) has, however, been used successfully for the prevention of motion sickness. The purpose of this study was to determine if TS would decrease methacholine-induced bronchospasm in a group of subjects with mild asthma. Bronchoprovocational challenges with inhaled methacholine were performed on three separate occasions in 10 male subjects who each had a past history of asthma. After a baseline challenge, each subject received, in a double-blinded fashion, either a placebo patch or TS patch. The challenge was then repeated after at least 36 hours, and the alternate patch was then dispensed. The provocative dose producing a fall in FEV1 by 20% from baseline was then calculated by linear regression analysis. No significant change in baseline pulmonary function was noted with placebo patch or TS. With the use of TS, there was a small but significant increase in the provocative dose producing a fall in FEV1 by 20% from baseline for the group (p less than 0.05). In conclusion, we were able to demonstrate that a TS patch worn for a short period of time, can significantly decrease airway reactivity to methacholine in some patients with hyperactive airways.

Administration, Cutaneous↗

The relationship between plasma histamine concentrations and bronchial obstruction to antigen challenge in allergic rhinitis.

Antigen activation of pulmonary mast cells causes mediator release and airway obstruction in allergic patients with asthma. Concomitant measurements of airway mediators and pulmonary function are technically difficult, even with bronchoalveolar lavage. Thus, a procedure was developed to evaluate further the relationship between mediator release, as measured by plasma histamine concentrations, and airway obstruction in patients with allergic rhinitis challenged with inhaled ragweed antigen. At an initial challenge, the cumulative antigen dose to decrease the FEV1 by approximately 20% was determined. Approximately 4 weeks later, the entire predetermined cumulative antigen dose to decrease the FEV1 by approximately 20% was administered in five consecutive inhalations with simultaneous monitoring of plasma histamine. We found the percent fall in FEV1 (24.3 +/- 2.3 versus 30.4 +/- 4.0; p greater than 0.05; n = 7) was similar whether antigen was administered by a cumulative or single-dose challenge. With the single-dose antigen challenge and monitoring blood samples frequently, we found plasma histamine (picograms per milliliter) values to increase from 73 +/- 17 to 1071 +/- 377 (p = 0.022) with peak value 5 minutes after challenge. Furthermore, we found that the intensity of airway obstruction to antigen corresponded to both the patient's baseline airway responsiveness to histamine and the absolute changes in plasma histamine after antigen challenge. Thus, the degree of airway obstruction to inhaled antigen is determined by both the intensity of the allergic reaction (as reflected by the plasma histamine value) and bronchial responsiveness.

Adult↗

Bronchoprovocation studies in basidiospore-sensitive allergic subjects with asthma.

Bronchoprovocation challenge with basidiospore extracts was performed in eight subjects with asthma and with positive wheal-and-flare skin reactivity and RAST to basidiospore allergens. Five of the eight patients demonstrated a significant decrease in FEV1 ranging from 20% to 47% after basidiospore-extract challenge. Both immediate and late-phase reactivity was observed. Six atopic control subjects with asthma and with negative skin reactivity to basidiospore extracts did not exhibit significant bronchospasm after basidiospore challenge. These results demonstrate that basidiospore extracts can induce bronchospasm in subjects with asthma who demonstrate IgE antibodies to basidiospore allergens.

Allergens↗

The pathophysiology of rhinitis. III. The control of IgG secretion.

To examine the sources of IgG in nasal secretions, nasal provocation tests with histamine (H) and methacholine (MC) were performed on 22 subjects. Nasal lavages were assayed for IgG, total protein, albumin (Alb), nonsecretory IgA (nonsIgA), and secretory IgA (sIgA). H stimulation dramatically increased the secretion of IgG, nonsIgA, and Alb and also increased the proportion of these proteins compared to total protein. H-induced protein secretion was significantly inhibited by nasal pretreatment with chlorpheniramine maleate but was unaffected by atropine sulfate. sIgA was also stimulated by H challenge, but unlike IgG and other vascular proteins, the proportion of sIgA to total protein (sIgA percent) decreased after H challenges. MC stimulation also increased secretion of IgG, Alb, nonsIgA, and sIgA but did not alter their proportions, compared to total protein. Topical atropine significantly inhibited secretion of all proteins, suggesting a mode of transportation mediated by glandular muscarinic receptor stimulation. Thus, MC can increase the amount of IgG secretion, whereas H increases both the amount and relative proportion of IgG in nasal secretions. These data suggest that pharmacologic stimulation of IgG into nasal secretions may be used as a total to modulate mucosal immunity.

Administration, Topical↗

Allergic respiratory disease in grain workers: the role of storage mites.

One hundred thirty-three grain-store workers employed at a regional grain store in Essex, U.K., participated in a survey of respiratory symptoms, lung function, bronchial responsiveness to methacholine and skin tests, and specific IgE to occupational allergens, including extracts of five storage-mite (SM) species and grain extracts. Previously reported associations between occupational respiratory symptoms and cigarette smoking, and symptoms of bronchial hyperresponsiveness to methacholine were confirmed. This study also disclosed significant associations between work-related symptoms (WRS) and positive skin tests and/or specific IgE to SMs, but not between WRSs and positive skin tests or specific IgE to Dermatophagoides pteronyssinus, or between WRSs and positive skin tests to grain. These findings suggest that in United Kingdom grain workers, allergic responses to SMs may be another factor responsible for WRSs in grain-store workers.

Adolescent↗

Gustatory rhinitis: a syndrome of food-induced rhinorrhea.

The consumption of certain foods causes watery rhinorrhea (gustatory rhinitis) in many individuals. To examine the underlying mechanisms responsible for this common phenomenon, 12 subjects ingested control foods and positive foods (foods that cause rhinorrhea). Nasal lavages performed 10 minutes after each food challenge were analyzed for albumin and total protein. Positive food challenge, but not control food challenge, induced rhinorrhea in all subjects. Positive food challenge increased albumin (7.8 +/- 1.9 to 24.5 +/- 7.6 mg/L; p less than 0.025) and total protein (79 +/- 9 to 258 +/- 41 mg/L; p less than 0.001) without altering the ratio of albumin to total protein (albumin percent). Nasal pretreatment with atropine clinically blocked the positive food-induced rhinorrhea and significantly inhibited secretion of both albumin and total protein, again without affecting the albumin percent. Thus, gustatory rhinitis is produced by spicy foods that stimulate atropine-inhibitable muscarinic receptors (probably on submucosal glands), and the syndrome can be treated prophylactically by use of topical atropine.

Administration, Topical↗

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)

Adult↗

The effect of an inhaled leukotriene antagonist, L-648,051, on early and late asthmatic reactions and subsequent increase in airway responsiveness in man.

We have investigated the protective effects of the inhaled cysteinyl leukotriene antagonist, L-648,051, on allergen-induced early asthmatic response (EAR) and late asthmatic response (LAR) and the subsequent changes in bronchial responsiveness to methacholine. Ten atopic men with asthma participated in a double-blind, crossover, placebo-controlled trial. All subjects had documented EAR and LAR to house dust-mite extract. Responsiveness to methacholine was measured the day before and the day after a standardized allergen-challenge test. L-648,051 was inhaled in two doses of 12 mg 20 minutes before and 3 hours after the allergen challenge. The response was obtained from FEV1 and flows from maximal (V40m) and partial (V40p) expiratory flow-volume curves. All subjects had an EAR and LAR during placebo therapy, but only a minority demonstrated an increase in methacholine responsiveness of more than one doubling dose. The ratio of V40m to V40p during methacholine challenge was higher than during both EAR and LAR (p less than 0.05). There was no difference between drug- and placebo-therapy periods in baseline function, EAR, LAR, ratio of V40m to V40p, and the allergen-induced hyperresponsiveness (p greater than 0.1). These results indicate that an effective aerosolized leukotriene antagonist in man does not protect against allergen-induced airflow obstruction, despite the evidence of an inflammatory response to allergen challenge. This suggests that either the potency or duration of activity of L-648,051 is limited or that leukotrienes C4 and D4 do not play a causative role in human allergic asthma.

Administration, Inhalation↗