Mechanism of ethanol-induced bronchoconstriction in Japanese asthmatic patients]

Acute ingestion of alcoholic beverages causes no changes in the expiratory airflow rates of most Occidental asthmatic patients. However, asthmatic symptoms are worsened after drinking small amounts of alcohol in Japanese asthmatic patients. Our laboratory results showed that the ingestion of pure ethanol caused a fall in FEV1.0 in about half of the Japanese asthmatic patients tested. The mechanism of ethanol-induced bronchoconstriction remains unclear. In order to investigate this mechanism, we performed oral-provocation tests with 10% ethanol in vivo, and leukocyte histamine release assay induced by ethanol and acetaldehyde in vitro. 55% of asthmatics showed a significant fall in FEV1.0 after ingestion of 10% ethanol (responder). There was no difference in the rise of blood ethanol concentration between the responder group and non-responder group. Acetaldehyde and histamine concentration in the responder group were significantly higher than in the non-responder group. Leukocyte histamine release assay showed that acetaldehyde (2 microM-100 microM) caused dose-dependent histamine release, whereas, ethanol (2 mM-100 mM) had no effect on histamine release. Our data indicate that histamine release from mast cells (or basophils) caused by acetaldehyde may play an important role in ethanol-induced bronchoconstriction. This is the first report on the mechanism of ethanol-induced bronchoconstriction in Japanese asthmatic patients.     

Eosinophil granule proteins in serum after allergen challenge of asthmatic patients and the effects of anti-asthmatic medication

Thirteen allergic asthmatic patients were challenged six times each and serum levels of ECP (eosinophil cationic protein), EPX (eosinophil protein-x) and blood counts of eosinophil granulocytes were measured in blood obtained before and at regular intervals after challenge. Three challenges were performed in a blinded and randomized fashion and included a one-dose pretreatment with the inhalant anti-asthmatic drugs disodium cromoglycate, terbutaline and budesonide. One challenge was performed after 4 weeks' pretreatment with the inhalant budesonide and one was a histamine challenge. Pre-challenge levels of ECP were significantly reduced both after 4 weeks and after a one-dose treatment with budesonide whereas the EPX levels were reduced only after the former. Blood eosinophil counts were unaffected by the challenge whereas the ECP levels were significantly reduced after the placebo challenge and when premedicated with disodium cromoglycate and terbutaline. The EPX levels stayed unaltered at the placebo challenge but were significantly reduced when the patients were premedicated with terbutaline. ECP and EPX levels as well as blood eosinophil counts before challenge were significantly related to the development of the late asthmatic reaction. The results again focus on a relation between the eosinophil granulocyte and asthma and suggest that an increased activity of the blood eosinophil, as suggested by the raised serum levels of the granule proteins ECP and EPX, is one prerequisite for the development of chronic asthma.     

Combined effect of nifedipine and diltiazem on methacholine-induced bronchoconstriction in asthmatic patients.

Calcium blockers alter airway hyperreactivity. We studied the effect of either 60 mg diltiazem or 20 mg nifedipine and their combination on the airway response to methacholine-induced bronchoconstriction. Compared with placebo or diltiazem, nifedipine significantly raised the PC20. When diltiazem was given alone, it had no effect on the airway but, when given with nifedipine, it significantly raised the PC20 to methacholine. The effect was superior to any of the other treatments given. This study supports the concept of combining two different calcium blockers in the treatment of bronchial asthma.     

Effect of nedocromil on antigen-induced bronchoconstriction in asthmatic subjects

Nedocromil sodium, a pyranoquinoline decarboxylic acid derivative, is a new antiasthma compound undergoing clinical investigation. It has been shown to be effective in the management of asthma and to attenuate exercise-induced bronchoconstriction. We performed a randomized, double-blind, placebo-controlled, crossover study in 12 ragweed-sensitive subjects known to respond to inhaled ragweed antigen. On two study days, four to ten days apart, ragweed challenges were performed using a standard protocol 30 minutes after a single dose (two puffs of 2 mg/puff) of either active drug or placebo. The PD20 (20% fall in FEV1) for each treatment day was compared by parametric and nonparametric 2-period crossover analyses. Baseline FEV1 pre-drug and post-drug administration did not differ significantly between study days. On the nedocromil day, the mean +/- SD for log PD20 was 2.25 +/- 0.561 and on the placebo day, 1.73 +/- 1.048 (P = 0.04). There were no side effects associated with either treatment. These results demonstrate that nedocromil is effective in shifting the stimulus response curve to inhaled antigen in some ragweed-sensitive subjects. Its wide spectrum of efficacy against bronchoprovocation suggests it is useful in the treatment of hyperreactive airway disorders.     

Inhibition of neutral endopeptidase potentiates bronchoconstriction induced by neurokinin A in asthmatic patients

The endogenous tachykinins exhibit a range of properties which may he relevant in the pathophysiology of asthma. Their effects on the airways seem to be modulated by a variety of lung peptidases, including neutral endopeptidase (NEP). In order to evaluate the potential role of endogenous NEP activity in modulating tachykinins-induced bronchconstriction in man in vivo, six atopic asthmatic patients, with a mean FEV₁ value of 3.38 ± 0.76 1, and a histamine PD20 mean value of 0.024 mg. were studied. The influence of inhaled phosphoramidon (a potent NEP inhibitor) was examined against the NKA-induced bronchospasm in a double-blind, placebo-controlled randomized study. Changes in airway calibre were followed as FEV₁ and agonists responsiveness expressed as PD20 and PD15 for histamine and NKA respectively. Patients received nebulized phospharamidon sodium salt (10^?5 M) or a control solution 10 min prior to the bronchoprovocation test with NKA. No significant difference was noticed between any of the study days and after inhaled phosphoramidon on baseline FEV₁ values (3.29 ± 0.90 1) in comparison with the control solution (3.31 ± 0.79 1). Inhaled NKA produced a dose-dependent fall in FEV₁ values in all the subjects studied with a mean PD15 value of 20.91 × 10^?9 mol. Phosphoramidon administered by inhalation elicited a significant (P < 0.0l vs baseline and control solution) potentiation in the airway responsiveness to inhaled NKA, the NKA PD15 value decreasing to 9.45 × 10^?9 mol. The present study confirms that inhaled NKA induces a dose-related bronchconstriction in asthmatic patients and demonstrates that inhaled phosphoramidon potentiates NKA-induced bronchoconstriction.     

Bronchial challenge to house dust can induce immediate bronchoconstriction in allergic asthmatic patients

The goal of the study was to evaluate whether natural exposure to house dust could elicit immediate bronchoconstriction. Two groups of asthmatic patients were studied: 12 asthmatics allergic to house dust mites and seven nonallergic asthmatics. The baseline FEV1 was similar in the two groups. Each subject was challenged through a nasal mask connected to nebulizer filled with house dust. Patients were randomly assigned to inhale dust with high or low Group I allergenic level. All allergic patients had an FEV1 drop larger than 20% of the baseline value. This drop was maximal at the 30th minute after challenge. FEV1 remained unchanged in nonallergic asthmatics. Allergic patients challenged with high Group I allergenic house dust (8.4 micrograms/g) had a mean FEV1 drop larger (P less than .01) than those challenged with the low Group I allergenic house dust (0.66 micrograms/g). Late asthmatic reactions were found in only two patients who were challenged with the high Group I allergenic house dust. These two patients had immediate FEV1 drops greater than 50% of the baseline value. Occurrence of symptoms during the test and the drop in FEV1 were correlated (r = .3; P less than .05). Natural exposure to house dust can induce immediate bronchial in allergic asthmatics in a dose-dependent manner.     

Comparative effects of various calcium entry blockers and anti-asthmatic compounds on antigen-induced bronchoconstriction in rat and histamine release from rat mast cells

The effects of four calcium entry blockers (diltiazem, nifedipine, mesudipine and verapamil) were studied on antigen-induced bronchoconstriction in sensitized rats and histamine release from rat mast cells, in comparison with compounds frequently used in atopic patients (theophylline, isoproterenol, disodium cromoglycate, ketotifen and clemastine). The four Ca2+ entry blockers produced a dose-related inhibition of the IgE-dependent bronchoconstriction in rat whereas the other drugs exhibited a weak effect or even were inactive. 48/80-induced histamine release was antagonized by nifedipine, verapamil and ketotifen. On the contrary, diltiazem, mesudipine, theophylline, isoproterenol, disodium cromoglycate and clemastine were not able to interfere with this release process. These data may suggest an important role of both extra- and intracellular calcium in such phenomena.     

Reduction of histamine-induced bronchoconstriction by magnesium in asthmatic subjects

The effects of inhaled MgSO4 on histamine bronchoprovocation test (BPT) were studied in nine asthmatics in clinical remission (FEV1 greater than 80% of predicted). Patients performed histamine BPT on 2 separate days, one day after saline and the other after MgSO4 inhalation, in a randomized double-blind design. Spirometry and flow/volume curve were recorded on each test day before and 5 min after NaCl or MgSO4. No significant difference was observed in lung function measurements 2 days before and after either NaCl or MgSO4. The dose of histamine which produced a 20% decrease in control FEV1 (PD20FEV1) was significantly increased by aerosolized MgSO4 (from 0.177 +/- 0.036 mg after NaCl to 0.350 +/- 0.085 after MgSO4, P less than 0.05. After MgSO4 the dose-steps of histamine concentration increased two-fold in two subjects and one-fold in five.     

Protection of nedocromil sodium on bronchoconstriction induced by inhaled neurokinin A (NKA) in asthmatic patients

Neurokinin A (NKA) has been shown to exert a potent contractile action on bronchial smooth muscles both in vitro and in vivo. Although this effect seems to be due either to a direct action of this peptide on specific muscular receptors or to an indirect effect on mast cells and/or nerves, its mechanism of action in bronchial asthma is still unknown. In the present study we have investigated the airway response to inhaled NKA in 10 asthmatic subjects and the activity of the novel pyranoquinoline dicarboxylic acid drug, nedocromil sodium, on this response. Ten asthmatic patients with stable asthma took part in the study consisting of four separate visits. On the first two occasions we derived histamine and NKA PD15 values in absence of any drug treatment. On the following two visits the inhalation challenge with NKA was performed after administration of either nedocromil sodium or matched placebo administered as pressurized aerosols via metered dose inhalers in a randomized double-blind order. Inhaled NKA produced a dose-related fall in FEV1 in all the subjects studied. Inhaled nedocromil sodium had a significant effect on the FEV1 response to NKA inhalation, the geometric mean PD15 value increasing from 16.6 to 32.2 x 10(-9) mol. We conclude that nedocromil sodium attenuates subsequent responsiveness to inhaled NKA in asthmatic subjects.     

The inhibitory effect of azelastine hydrochloride on histamine- and allergen-induced bronchoconstriction in atopic asthma

We have examined the effect of azelastine, a new H1 histamine receptor antagonist, against bronchoconstriction induced by histamine and allergen. Twelve mild, atopic asthmatics each underwent two histamine and two allergen concentration-response inhalation challenges 4 hr after treatment with either 8.8 mg of azelastine or a matched placebo. Following azelastine the dose of histamine required to provoke a 20% fall in FEV1 (PD20 histamine) rose, from a geometric mean of 0.31 mg/ml to greater than 13.2 mg/ml. Azelastine also significantly inhibited allergen-induced bronchoconstriction, the PD20 allergen rising from 9.3 cumulative breath units (c.b.u.) to greater than 47.9 c.b.u., a greater than 5-fold increase. We conclude that azelastine effectively inhibits both histamine and allergen-induced bronchoconstriction, with considerably greater potency against histamine.     

Effects of pranlukast on aspirin-induced bronchoconstriction: differences in chemical mediators between aspirin-intolerant and tolerant asthmatic patients.

BACKGROUND: Aspirin inhibits cyclooxygenase activity and modifies production of the arachidonate cascade in aspirin-induced asthma. The aim of the present study was to examine the effects of leukotriene (LT) receptor antagonist on aspirin challenge on eosinophil activity and chemical mediators released into the airway of asthmatic patients. METHODS: Aspirin oral provocation test was performed in aspirin-intolerant asthmatic patients (AIA; N = 7) and aspirin-tolerant asthmatic patients (ATA; N = 7). In AIA, LT receptor antagonist (pranlukast) was administered orally 2 hours before the test, and its inhibitory effects on sputum LTC4+C4, eosinophil cationic protein (ECP), eosinophil count, urinary LTE4/creatinine (Cr), 11-dehydrothromboxane (11-dhTX) B2/Cr, serum LTC4+D4, ECP, and peripheral blood eosinophil count were compared with the findings in ATA subjects. RESULTS: In AIA, aspirin induced an immediate reaction associated with increased urinary LTE4/Cr and sputum ECP and a fall in urinary 11-dhTXB2/Cr. Pranlukast inhibited the bronchial reaction and an increase in sputum ECP after threshold dosed of ASA, but failed to change aspirin-induced LT production in sputum and urine. In ATA, aspirin challenge was only associated with a fall in urinary 11-dhTXB2. CONCLUSIONS: Our results indicated that aspirin-induced asthma is associated with overproduction of LT with a shift to the 5-lipoxygenase series of the arachidonate cascade and that leukotriene receptor antagonist are useful for AIA through inhibition of production of LT and eosinophilic inflammation in the airway.     

Clinical study on the inhibitory effect of AA-2414 on platelet function in asthmatic patients

We studied the effect of AA-2414, a TXA2 receptor antagonist, on platelet function in 12 asthmatic patients, 6 males and 6 females, whose mean age was 43.6 years. AA-2414 was orally administered to each patient at 20 mg/day for two weeks and then at 40 mg/day for the following two weeks. Platelet aggregation, plasma concentration of TXB2, and serum concentrations of AA-2414 and its metabolites were measured before and after the administration of each dose. Platelet aggregation induced by U-46619 (an analogue of PGH2), STA2 (a stable analogue of TXA2) and arachidonic acid with the administration of AA-2414 was significantly inhibited. The degree of this inhibition was proportional to the serum level of the drug. Plasma concentration of TXA2 tended to be lowered by administration of AA-2414, but it was not statistically significant. Eight (75.0%) of the 12 patients showed clinical improvement. In the cases where the drug was ineffective, the inhibition of platelet aggregation after administration of AA-2414 was less than in those cases where it was effective. We conclude that AA-2414 might exert its antiplatelet and antiasthmatic effects through antagonism of the TXA2 receptor. Investigation of the response to AA-2414 may be useful in assessing the clinical effect of this compound.     

The expression of IgE Fc receptors on peripheral blood monocytes in asthmatic patients]

We measured the expression of the IgE Fc receptor, Fc epsilon RII, on peripheral blood monocytes isolated from asthmatic patients and normal subjects by laser flow cytometry. After peripheral blood mononuclear cells were incubated with monoclonal antibodies, H107, which recognize Fc epsilon RII, FITC-labeled second antibodies were reacted with them. The cells were then incubated with PE-labeled Leu M3 monoclonal antibodies and the ratios of H107 positive monocytes were measured by two color analysis. The ratio of H107 positive monocytes in atopic asthmatic patients was significantly greater than the ratio in normal subjects. But the ratio was not higher in 9 out of the 14 atopic asthmatic patients. This indicated that atopic asthmatic patients are divided into two groups by the expression of Fc epsilon RII on monocytes. Total serum IgE level was not related to the ratio of H107 positive monocytes.     

The effects of albuterol on sulfur dioxide-induced bronchoconstriction in allergic adolescents

Ten allergic subjects with exercise-induced bronchospasm were studied to determine whether albuterol could prevent sulfur dioxide (SO2)-induced bronchoconstriction. Albuterol or placebo (180 micrograms) were administered by metered-dose inhaler 20 minutes before a 10-minute exposure to SO2 or clean air during moderate exercise on a treadmill at an exercise level that by itself did not produce exercise-induced bronchospasm. Pulmonary functions (FEV1 and total respiratory resistance [RT]) were measured before the drug, after the drug, and after exposure to SO2 or clean air. Albuterol treatment produced significant bronchodilation and also prevented SO2-induced bronchoconstriction. Following SO2 inhalation after placebo, FEV1 decreased 15% (p less than 0.02) and RT increased 50% (p less than 0.03). Following SO2 inhalation after albuterol treatment, neither FEV1 or RT changed significantly. We conclude that albuterol, a beta 2-agonist, inhibits SO2-induced bronchoconstriction. This result suggests that the adrenergic nervous system or mast cell degranulation are involved in SO2-induced bronchoconstriction.     

Bivalent effects of MK-801 on ethanol-induced sensitization do not parallel its effects on ethanol-induced tolerance

The relationship between the effects of the N-methyl-D-aspartate (NMDA) antagonist MK-801 on acute responses to ethanol and its ability to block ethanol sensitization and tolerance was examined in DBA/2J mice. Cross-sensitization between these drugs was also studied. Repeated administration of 0.1 mg/kg MK-801 with ethanol potentiated, whereas 0.25 mg/kg attenuated, sensitization to ethanol's locomotor stimulant effects; rearing was similarly affected. There was evidence for cross-sensitization between ethanol and 0.25 mg/kg MK-801. MK-801 potentiated ethanol's ataxic effects in the grid test, but had no effect on tolerance to this effect. MK-801's effects on ethanol sensitization appeared to be related to its own behavioral effects, rather than NMDA receptor blockade per se. Further, these studies demonstrate dissociation between ethanol sensitization and tolerance.     

Effects of various anti-asthmatic agents on mite allergen-pulsed murine bone marrow-derived dendritic cells

Background Dendritic cells (DCs) play an important role in the immune response and are critically involved in asthma. β₂‐agonists could potentially exacerbate type 2 T helper (Th2) cell‐mediated immune response. Objectives To determine the effects of various anti‐asthmatic agents on DCs function both in vitro and in vivo. Methods Murine bone marrow‐derived DCs were pulsed with mite allergen in the presence of pranlukast, salbutamol, salmeterol or fluticasone. These DCs were then inoculated intranasally into naïve mice to induce allergic airway inflammation in vivo. Results Pranlukast reduced IL‐10 and increased IL‐12, while fluticasone reduced both IL‐10 and IL‐12 production by mite allergen‐pulsed DCs. Allergic airway inflammation in pranlukast‐ and fluticasone‐treated and mite allergen pulsed DCs‐harbouring mice was attenuated and such response was associated with inhibition of Th2 response in the airway. Salbutamol did not alter cytokine production, while salmeterol reduced IL‐12 production by mite allergen‐pulsed DCs. Lung pathology in β₂‐agonist‐harbouring mice was comparable with those of mite allergen‐pulsed DCs‐harbouring mice. Conclusions Our results indicate that leukotriene receptor antagonists and corticosteroids inhibit DCs‐induced Th2 skewed immune response, and that short‐ and long‐acting β₂‐agonists do not modify DCs‐induced allergic airway inflammation.     

Bronchodilatation and inhibition of allergen-induced bronchoconstriction by circulating epinephrine in asthmatic subjects

The influence of circulating epinephrine on basal bronchial tone and its ability to counteract the bronchial response to specific allergen challenge was investigated in eight patients with extrinsic seasonal asthma. A pretrial bronchial allergen challenge was positive for birch or timothy pollen. The patients were free from all medication at least 1 wk before experiments. On two separate occasions placebo (saline) or epinephrine (0.25 and 0.50 nmol X kg-1 X min-1) were infused. Epinephrine caused dose-dependent increases in end expiratory flow rates but did not influence peak expiratory flow rates or specific airway conductance, indicating dilatation of predominantly smaller airways. During placebo infusions allergen provocation induced clear-cut bronchoconstriction but no increase in circulating epinephrine levels. Elevation of circulating epinephrine (to 5 to 6 nmol/L in venous plasma) counteracted the allergen-induced bronchoconstriction. During epinephrine infusions all patients tolerated higher allergen doses than during placebo infusions. When the allergen dose was increased sufficiently to cause bronchoconstriction also during epinephrine infusions, the bronchoconstriction observed was similar in terms of changes in lung function parameters but less responsive to treatment with a high dose of the beta-2-agonist, salbutamol. This may have therapeutic implications since protection offered by treatment with, e.g. beta 2-agonists, may lead to exposure to higher allergen doses and similarly aggravated asthmatic reactions when they do occur despite this treatment.