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.     

Late asthmatic reaction decreased after pretreatment with salbutamol and formoterol, a new long-acting beta 2-agonist.

The inhibitory effect of salbutamol and formoterol, a new long-acting beta 2-agonist for inhalation, on the late asthmatic reaction (LAR), was studied in 12 patients with allergic asthma. After a single-blind, placebo-treatment control, equipotent bronchodilating doses of inhaled salbutamol (500 micrograms) and formoterol (30 micrograms) were administered 30 minutes before bronchial allergen challenge in a double-blind randomized design. The early asthmatic reaction was completely inhibited by both drugs (p less than 0.01) but not by placebo. The LAR was also significantly inhibited by both drugs (p less than 0.01); formoterol was only slightly, but significantly, more effective than salbutamol (p = 0.04). In contrast to some earlier studies, the present study indicates an inhibitory effect of beta 2-agonists on the LAR.     

The effect of repirinast on airway responsiveness to methacholine and allergen.

Repirinast, a novel ingested antiallergic asthma medication from Japan, was compared versus placebo on airway responsiveness to methacholine and was compared versus placebo and cromolyn on airway responses to allergen. In 14 patients with mild, stable, atopic asthma, we performed a double-blind, double-dummy, random-order trial with ingested repirinast 300 mg twice daily for 7 days, inhaled cromolyn 40 mg spincaps single dose, and double placebo on allergen-induced early (EAR) and late (LAR) asthmatic responses and increased airway responsiveness. In the 14 subjects, no difference occurred in methacholine PC20 after 6 days of repirinast or 6 days of placebo. In the 13 subjects who completed the allergen study, single-dose cromolyn significantly reduced the EAR by 63% and the LAR by 65% versus placebo (p < 0.02); repirinast was not significantly different from placebo, both the EAR and LAR being reduced by less than 10%. Allergen-induced increase in methacholine responsiveness was borderline (p = 0.052), and no significant drug effects occurred. In these models, a 1-week treatment period with repirinast, like other oral antiallergic asthma medications (e.g., ketotifen, fumarate), provides no protection against airway responses to methacholine or allergen.     

A comparison of the effects of oral cetirizine and inhaled beclomethasone on early and late asthmatic responses to allergen and the associated increase in airways hyperresponsiveness

Background Cetirizine is a non-sedating H₁ antihistamine which is effective in the treatment of allergic rhinitis and urticaria. It inhibits eosinophil and basophil chemotaxis in late cutaneous allergic reactions in skin windows. Its effect on early (EAR) and late asthmatic reactions (LAR) is less certain. Methods We examined the effect on EAR and LAR of 3 days treatment with oral cetirizine (15mg twice daily) compared with a single dose of inhaled beclomethasone 10min prior to allergen challenge in a placebo-controlled (oral and inhaled) doubleblind cross-over design with three treatment arms separated by 14 days. Results Cetirizine did not significantly inhibit either the EAR or LAR documented by maximum percentage fall in FEV₁ (0-3 and 6-9h) or as area under the curve (AUC between 0 and 3 and 6–9 h), Beclomethasone inhibited the LAR compared with placebo (P = 0.02) when expressed as AUC (6–9h). This did not quite reach statistical significance (P = 0.06) when expressed as maximal percentage late fall in FEV₁ between 6 and 9h. A greater than twofold increase in airways responsiveness to methacholine was observed 3h after challenge which was significantly reduced by beclomethasone compared with placebo (P < 0.02) and cetirizine (P < 0.05). The data suggest that oral cetirizine does not significantly inhibit either the EAR or LAR. Beclomethasone inhibited both the early increase in airways responsiveness and the subsequent LAR. Our study also confirms the view that early increases in airway responsiveness precede the late response and suggests that these associated events are not dissociable by the pharmacological treatments employed in this study.     

The superiority of combination beclomethasone and salbutamol over standard dosing of salbutamol in the treatment of chronic asthma

We studied the clinical effect of a combination aerosol containing salbutamol and beclomethasone dipropionate in comparison to doubling the standard dose of salbutamol from an inhaler. Fifty-seven patients completed the double-blind, crossover study. They were treated with either an aerosol of 100 micrograms beclomethasone dipropionate and 200 micrograms salbutamol or 400 micrograms salbutamol alone. Both regimens were administered four times a day for 4 weeks. The patients showed significant improvement in FEV1, PEFR, and symptom scores after treatment with beclomethasone dipropionate and salbutamol compared with pre-trial values and with treatment with double the dose of salbutamol. The patients demonstrated a clear preference for treatment with the combination of beclomethasone dipropionate and salbutamol. Regular treatment with beclomethasone dipropionate in addition to salbutamol as a combination inhaler provides much better control of asthma than merely increasing the dose of salbutamol in those patients poorly controlled on standard doses of inhaled bronchodilators.     

A comparison of the effects of sodium cromoglycate and beclomethasone dipropionate on pulmonary function and bronchial hyperreactivity in subjects with asthma

After a run-in period of 2 weeks, receiving a regimen of inhaled beta 2-agonists and/or theophyllines, 38 atopic patients with asthma with perennial symptoms were randomly allocated to receive an 8-week treatment of additional inhalation treatment with either sodium cromoglycate (SCG), 2 mg four times daily, and placebo beclomethasone dipropionate (BDP), or BDP, 200 micrograms twice daily, and placebo SCG. After crossover, each group received the opposite treatment for the final 8 weeks. FEV1, FVC, and provocation concentration of histamine causing a 20% fall in FEV1 (PC20) were determined monthly and peak expiratory flow (PEF) daily throughout the study. A significant increase in FEV1, FVC, and PEF (p less than 0.01) was observed after BDP treatment was started, and likewise, in the second period, an increase in both FEV1 and PEF (p less than 0.05) was observed. The total effect on logarithm-natural (Ln) (PC20), i.e., the mean effects of the two periods, was also significant (p less than 0.01). SCG, however, was most effective when it was used as the first drug, indicated by a significant increase in FVC in the first period (p less than 0.05). Neither in the first nor in the second period did SCG treatment influence the Ln (PC20) value positively, and the SCG treatment administered in the second period could not maintain the improvement in the pulmonary function (i.e., FEV1, FVC, and PEF) obtained initially with the BDP treatment. When the effect of BDP on FEV1, FVC, PEF, and Ln (PC20) was compared to the effect of SCG in the first 8-week treatment period, no significant difference was observed (p greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of formoterol on the late asthmatic phenomena in guinea pigs.

We investigated the effects of formoterol, a new, long-acting, selective beta 2-adrenoceptor agonist, on the antigen-induced late asthmatic response (LAR) and airway inflammation in guinea pigs. Animals were sensitized by exposure to aerosolized ovalbumin (2% in saline). After antigen challenge, preceded by administration of an H1-receptor antagonist, specific airway conductance was measured with a two-chambered whole-body plethysmograph. An aerosolized solution of formoterol, isoproterenol, or saline was inhaled 15 minutes before challenge. Bronchoalveolar lavage (BAL) was performed 24 hours after challenge. The provocative concentrations of histamine required to decrease specific airway conductance by 50% were obtained before challenge, at 24 hours, and at 72 hours after challenge. The LAR (52.7% +/- 7.7% of the baseline; p less than 0.02) was observed 6 to 8 hours after antigen challenge. An increased cellular influx in BAL (mainly eosinophils and macrophages) and an increased bronchial responsiveness to histamine occurred 24 hours after antigen challenge. Formoterol completely inhibited the LAR and the cellular increase in BAL; however, isoproterenol failed to prevent either the cellular infiltration or the LAR. Formoterol also decreased the antigen-induced increase in bronchial reactivity. These findings suggest that formoterol has inhibitory effects on the underlying inflammatory processes in antigen-induced asthma in addition to prolonged bronchodilation.     

Effects of disodium cromoglycate and beclomethasone dipropionate on the asthmatic response to allergen challenge II. Late response (LAR)

The protective effects of disodium cromoglycate (DSCG; Lomudal, Intal) and beclomethasone dipropionate (BDA; Aldecin, Becotide, Beclovent) on the late asthmatic response to allergen challenge (LAR) were investigated in 61 patients with allergic bronchial asthma. The 61 patients developed a total of 83 late asthmatic responses, 35 isolated late responses (ILAR), and 48 dual late responses (DLAR), which is a combination of an immediate response (IDLAR) and a late response (LDLAR). Disodium cromoglycate demonstrated significant protective effects on the LAR (P less than .01), however, the LDLAR as part of the DLAR was decreased by DSCG to a slightly higher degree than the ILAR. The BDA also showed significant protective effects on the LAR (P less than .01), but the ILAR was protected by BDA to a slightly higher degree than the LDLAR as part of the DLAR. The immediate asthmatic response as part of the DLAR was prevented by DSCG significantly (P less than .01) while the BDA was ineffective (P greater than .05). It can be concluded that both DSCG and BDA demonstrated significant effects on the LAR. It is suggested that DSCG should be used as a drug of the first choice to control bronchial asthma with an allergy component where the LAR plays a role. The BDA should be added temporarily at the beginning of the treatment of patients in whom the isolated late asthmatic response plays the predominant role, or of patients in whom the DSCG does not provide full control of the LAR during a certain period, eg, during the peak of the pollen season.(ABSTRACT TRUNCATED AT 250 WORDS)     

Magnitude of late asthmatic response to allergen in relation to baseline and allergen-induced sputum eosinophilia in mild asthmatic patients.

BACKGROUND: Late asthmatic response (LAR) to allergen challenge is a validated method for studying the pathogenesis of and new treatments for asthma in the laboratory. OBJECTIVE: To evaluate the relationship between the magnitude of allergen-induced LAR and clinical and biological determinants, including sputum and blood eosinophil percentages and eosinophil cationic protein concentrations. METHODS: Thirty-eight untreated mild asthmatic patients (mean age, 21.2 years) were selected for the presence of allergen-induced early asthmatic response (EAR) and LAR. Each patient measured methacholine responsiveness (provocation dose that caused a decrease in forced expiratory volume in 1 second of 20% [PD20FEV1]) at baseline, differential blood cell counts and eosinophil cationic protein levels in blood and induced sputum, and serum neutrophil chemotactic activity at baseline and 24 hours after allergen challenge. RESULTS: A correlation was found between LAR (as area under the curve [AUC]) and sputum eosinophil percentages at baseline (r = 0.51; P = .001) and 24 hours after allergen challenge (r = 0.44; P < .007). Furthermore, we found significant correlations between AUC LAR and AUC EAR, baseline methacholine PD20FEV1, baseline blood eosinophil percentages, and baseline serum neutrophil chemotactic activity. A stepwise multiple regression analysis showed that the stronger determinants of AUC LAR were baseline sputum eosinophilia and AUC EAR. CONCLUSION: Baseline sputum eosinophilia and functional findings are determinants of the magnitude of allergen-induced LAR.     

The effect of inhaled thiorphan on allergen-induced airway responses in asthmatic subjects

Background Neuropeptides are likely to be implicated in the pathophysiology of allergen-induced airway responses. However, upon release in the airways, neuropeptides are potentially inactivated by neutral endopeptidase (NEP). Objective We hypothesized that NEP-inhibition by inhaled thiorphan (TH) would increase allergen-induced early (EAR) and late (LAR) asthmatic responses, and allergen-induced airway hyperresponsiveness to histamine in asthmatic subjects in vivo. The dose and dosing intervals of TH were derived from previous pharmacokinetic and dose-finding studies. Methods Nine non-smoking, atopic, asthmatic men with dual asthmatic responses to inhaled house-dust mite extract participated in a double-blind, placebo-controlled, cross-over study. During each study period PC₂₀ histamine was measured 24 h before, and 3 and 24 h post-allergen. TH (1.25 mg/mL, 0.5 mL) or placebo (P) were aerosolized pre-allergen, and three times at 2 h intervals post-allergen (total dose of TH: 2.5mg). Forced expiratory volume in one second (FEV₁) was recorded and expressed as percentage fall from baseline. The EAR (0–3 h) and the LAR (3–8 h) were defined as maximum percentage fall from the pre-allergen baseline and as corresponding areas under the time-response curves (AUC). Results As compared with P, TH failed to induce an acute effect on FEV₁ at any of the timepoints (P > 0.08). There was no significant difference between P and TH in the EAR and the LAR: neither in terms of maximum percentage fall from baseline (mean± SEM: EAR: 22.3 ±4.7% (P) and 20.4±4.1% (TH). P=0.75; LAR: 25.2 ± 4.7% (P) and 26.4±5.8% (TH), P= 0.77) nor in terms of AUC (P = 0.16). Correspondingly, the changes in PC₂₀ histamine were not different between the two treatments (F > 0.40). Conclusion We conclude that four adequate doses of the inhaled NEP-inhibitor, thiorphan. failed to potentiate allergen-induced airway responses in asthma. These results suggest that either neuropeptides do not play a predominant role in allergeninduced airway responses, or that allergen challenge induces NEP-dysfunction in humans in vivo.     

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.     

The effect of salmeterol and salbutamol on mediator release and skin responses in immediate and late phase allergic cutaneous reactions

BACKGROUND: Salmeterol is a long-acting beta2-agonist which in animal studies has been shown to possess anti-inflammatory effects on early (EAR) and late (LPR) phase allergic responses. PURPOSE: To evaluate the anti-inflammatory effects of intradermally injected salmeterol and salbutamol on clinical and biochemical EAR and LPR in human skin. METHODS: Measurement of wheal and flare reactions to allergen, codeine, and histamine, and LPR (induration) to allergen. Assessment of histamine and prostaglandin D2 (PGD2) release by microdialysis technique in EAR, and measurement of mediators in LPR by suction blister technique. RESULTS: Both beta2-agonists inhibited allergen-induced histamine release and wheal and flare reactions with maximum inhibition of 40-50% at 10(-6) M, a concentration which reduced PGD2 synthesis by approximately 55%. Histamine release by codeine and skin reactions to codeine and histamine were not or only marginally reduced. Salmeterol and salbutamol (10(-6) M) inhibited clinical LPR at 6 h by 71% and 48%, Except for the clinical LPR, no statistical differences were found between the two drugs on any parameters. None of the drugs inhibited levels of histamine, tryptase, myeloperoxidase, or eosinophil cationic protein in LPR. CONCLUSIONS: Salmeterol and salbutamol inhibited allergen-induced skin responses, and reduced mediator release in EAR but not LPR. In general, the anti-inflammatory effects of salmeterol did not differ from those induced by salbutamol.     

The effect of inhaled fenoterol, administered during the late asthmatic reaction to house dust mite (Dermatophagoides pteronyssinus)

A double-blind, placebo-controlled crossover study was set up to investigate the effect of fenoterol (400 micrograms) during the late asthmatic reaction (LAR). Twenty young subjects with asthma (mean age, 11.8 years; range, 8.3 to 20.6 years) were selected on the basis that they developed an LAR after bronchial challenge with Dermatophagoides pteronyssinus. After the LAR occurred, a placebo and fenoterol were administered blindly by a metered-dose inhaler, with an interval of 15 minutes and in alternating, random sequence. At the start of the study, that is, a documented LAR, the two groups of subjects had the same severity of LAR, as expressed by the fall of the FEV1 (mean, -34.5% versus -33.5%). The mean FEV1 of the 10 patients who received placebo first changed only -1.1% (+/- 5.0), whereas after fenoterol, The FEV1 increased by 20.7% (+/- 10.8). In the 10 patients receiving fenoterol first, the mean FEV1 rose by 18.8% (+/- 8.0), whereas the placebo inhalation resulted in a supplementary increase of 3.1% (+/- 7.0). The paired Student's t test between these differences (placebo versus fenoterol) was highly significant (p less than 0.001). Although it was demonstrated in some studies that beta-agonists did not prevent the LAR, the present study demonstrates that the administration of fenoterol can reverse the FEV1 significantly, although it was not reversed completely, during an allergen-induced LAR.     

Role of tachykinin NK1 and NK2 receptors in allergen-induced early and late asthmatic reactions, airway hyperresponsiveness, and airway inflammation in conscious, unrestrained guinea pigs

Using a guinea pig model of allergic asthma, we investigated the effects of the inhaled, highly selective nonpeptide tachykinin NK₁ and NK₂ receptor antagonists SR 140333 and SR 48968, respectively, on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyperreactivity (AHR) after these reactions, and infiltration of inflammatory cells in the airways. Both SR 140333 (100 nM, 3 min) and SR 48968 (100 nM, 3 min) had no effect on the severity of the EAR, while the NK₂ receptor antagonist SR 48968, but not the NK₁ receptor antagonist SR 140333, caused significant inhibition of the LAR. SR 140333 significantly reduced the allergen-induced AHR to histamine, both after the EAR and the LAR. By contrast, SR 48968 did not affect the AHR after the EAR, but significantly attenuated the AHR after the LAR. Bronchoalveolar lavage studies performed after the LAR indicated that SR 140333 caused significant inhibition of allergen-induced infiltration of eosinophils, neutrophils and lymphocytes, while SR 48968 attenuated the infiltration of neutrophils and lymphocytes, but not of eosinophils. Both NK receptor antagonists tended to reduce the accumulation of ciliated epithelial cells in the airways. These results indicate that NK₁ and NK₂ receptors are importantly, but differentially, involved in the development of allergen-induced airways obstruction, AHR and infiltration of inflammatory cells in the airways. Therefore, both NK₁ and NK₂ receptor antagonists, or dual NK₁ and NK₂ antagonists, could be useful in the treatment of allergic asthma.     

The late asthmatic response is associated with baseline allergen-specific proliferative responsiveness of peripheral T lymphocytes in vitro and serum interleukin-5

BACKGROUND: Increasing insights into the mechanism underlying the allergen-induced late asthmatic response (LAR) have been gained with implication of activated eosinophils and CD4+ T lymphocytes. However, the patient characteristics that indicate the individual capacity to develop a LAR are not well-defined. METHODS: In 22 subjects with mild to moderate house dust mite-allergic asthma, we investigated the relationship between the LAR and two other models of late-phase allergic inflammation, i.e. the allergen-specific proliferative response of peripheral blood T lymphocytes in vitro and the late cutaneous response. Non-specific bronchial responsiveness (PC20histamine), lung function (FEV1), peripheral blood eosinophil count, early phase allergic skin sensitivity, and levels of total and specific immunoglobulin E (IgE) were determined prior to bronchial allergen challenge. Serum levels of interleukin-5 (IL-5) were measured before and at several time points after allergen inhalation. RESULTS: A significant correlation was found between the magnitude of the LAR and the allergen-specific proliferative response of peripheral T lymphocytes (r = 0.44, P = 0.04) but not the late cutaneous response. Stepwise-multiple linear regression of the magnitude of the LAR on the parameters analysed at baseline, resulted in a model combining PC20 histamine, early phase allergic skin sensitivity, and the allergen-specific proliferative response of peripheral T lymphocytes (R2 = 0.84, P<0.001). No contribution of the late cutaneous response to the prediction of the LAR was found. Serum levels of IL-5 increased significantly at 6 h (P = 0.01) and 24 h (P = 0.003) after bronchial allergen challenge and correlated with the allergen-specific proliferative response of peripheral T lymphocytes in vitro (rho = 0.48, P = 0.02). CONCLUSIONS: The findings in this study point to a role of TH2-lymphocyte responses in the development of the allergen-induced LAR. In allergic asthmatic patients, allergen-specific responsiveness of peripheral T-lymphocytes in vitro may serve as a model to determine the individual capacity to develop a LAR after allergen inhalation.     

Differential effects of fluticasone and montelukast on allergen-induced asthma

Early asthmatic responses (EAR) and late asthmatic responses (LAR) to allergen are induced by the local release of a series of bronchoconstrictor mediators, including leukotrienes and histamine. Both anti-leukotrienes and other anti-asthma drugs, such as inhaled glucocorticoids, have been shown to reduce both EAR and LAR. The aim of the present study was to directly compare the effects of regular treatment with an oral anti-leukotriene, montelukast (Mont; 10 mg once daily, for 8 days), and an inhaled glucocorticoid [fluticasone propionate (FP) 250 microg twice daily for 8 days] on the EAR and LAR to an inhaled allergen challenge. Patients with a documented EAR and LAR at a screening visit were randomized to these treatments, or placebo, in a double-blind, double-dummy, crossover fashion. Allergen challenge at a dose causing both an EAR and LAR was given on the eighth day of treatment. The maximum fall in FEV1 during the EAR was 17.8% during placebo treatment, 8.3% during Mont and 16.3% during FP (P <0.05 for Mont vs placebo). The maximum fall during the EAR was 13.8% during placebo treatment, 11.8% during Mont and 2% during FP treatment (P <0.05 for FP vs placebo and FP vs Mont). PC20 methacholine was significantly higher 24 h after allergen challenge during FP-treatment compared with Mont (P <0.05). Both montelukast and fluticasone reduced the relative amount of sputum eosinophils after allergen compared with placebo treatment. This study shows that anti-leukotrienes are effective to attenuate the EAR, whereas inhaled glucocorticoids are more effective than anti-leukotrienes in attenuating the EARs and improves bronchial hyperresponsiveness to a greater extent. In conclusion, inhaled glucocorticoids have overall greater efficacy than oral anti-leukotrienes to attenuate allergen-induced airway responses in mild asthmatic patients.     

The effect of IVX-0142, a heparin-derived hypersulfated disaccharide, on the allergic airway responses in asthma

Background:  IVX-0142 is a heparin-derived hypersulfated disaccharide devoid of anticoagulant activity while possessing anti-allergic and anti-inflammatory activity in preclinical studies. In a proof-of-concept study, the allergen inhalation challenge model was used to investigate the effect of IVX-0142 in mild atopic asthma.
Methods:  Nineteen subjects, not on controller medications, were randomized to an evaluator-blind, placebo-controlled, cross-over study. The effect of a single nebulized dose of IVX-0142 (80 mg) or placebo administered 30 min prior to allergen inhalation was evaluated on the allergic airway responses, airway responsiveness, and airway inflammation.
Results:  When compared with placebo, 14 and 13 subjects experienced a relatively smaller maximum fall in forced expiratory volume in 1 s (maxFEV₁%) for the early airway response (EAR) and late airway response (LAR) with IVX-0142, respectively ( P  < 0.01). The degree of attenuation in the EAR [maxFEV₁% (mean ± SE) 26.5 ± 2.8% vs placebo 31.0 ± 2.8%, P  = 0.059] and LAR (15.6 ± 2.9% vs placebo 19.0 ± 2.9%, P  = 0.24) with IVX-0142, however, was small and did not reach statistical significance compared with placebo. Similarly, a trend in the attenuation of allergen-induced increase in the absolute sputum cell counts was also observed. No difference in the allergen-induced increase in airway hyper-responsiveness and exhaled nitric oxide was noticed.
Conclusions:  The majority of mild atopic asthmatics demonstrated a reduction in the EAR and LAR to IVX-0142. However, the treatment effect observed with a single prechallenge dose of IVX-0142 was small and heterogeneous. The potential anti-allergic and anti-inflammatory effects using multiple higher doses need to be evaluated.     

Factors in allergen-induced asthma: relevance of the intensity of the airways allergic reaction and non-specific bronchial reactivity

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

Inhibitory effect of FK-506 on the development of late asthmatic response and on the increased bronchial responsiveness]

We examined the effects of FK-506, a potent immunosuppressive agent, on the development of late asthmatic response (LAR) and on the increased bronchial responsiveness to acetylcholine following LAR in guinea pig model of asthma. Guinea pigs sensitized by repeated inhalation of ovalbumin (OA) were intravenously given metopiron 24 hours before and 30 minutes before antigen challenge and to prevent death from immediate severe bronchoconstriction, chlorpheniramine maleate was also injected. When we defined LAR as the responses with a two-fold increase in respiratory resistance during the late phase of antigen challenge, twelve out of fifteen control animals demonstrated apparent LAR. However, when guinea pigs were treated with FK-506 from the beginning of immunization period, the development of LAR was completely inhibited, although similar magnitude of immediate bronchoconstriction was observed, and a subsequent increase in bronchial responsiveness was significantly blocked. We also measured bronchial responsiveness to acetylcholine before, 24 and 72 hours after antigen challenge. FK-506-treated animals inhibited an increase in bronchial responsiveness to acetylcholine. These results suggest that the involvement of cell-mediated immunity may be important in the development of LAR and an increase in bronchial responsiveness.     

Effect of a single dose of the selectin inhibitor TBC1269 on early and late asthmatic responses

BACKGROUND : Selectins participate in the initial phase of leucocyte migration from circulation to inflamed tissues and may play a role in inflammatory cellular influx into airways in asthma. In the sheep asthma model, TBC1269, a pan-selectin antagonist, reduced late allergen response by 74%. OBJECTIVE : To determine whether a single dose of TBC1269 inhibits early (EAR) and late (LAR) asthmatic responses, and whether it inhibits sputum leucocyte influx after inhalation allergen challenge in atopic asthmatic subjects treated with bronchodilators only. METHODS : Twenty-one asthmatic subjects (mean+/-SD, age=32.5+/-6.7 years, 8 males, FEV1 percent predicted=84+/-15%) with known late asthmatic response based on a screening inhalation allergen challenge were randomly assigned to receive intravenous treatment with either placebo (n=11) or TBC1269 (n=10, 30 mg/kg) infused over 15 min immediately prior to a second (post-treatment) allergen challenge at least 4 weeks after the screening challenge. After each challenge, EAR and LAR were monitored for 7 h. In addition, sputum was induced 1 day before and 1 day after each allergen challenge. RESULTS : TBC1269 did not attenuate the EAR compared with placebo (largest fall in FEV1 within 1 h of 34.1+/-13.9% vs. 31.8+/-12.2% for TBC1269 and placebo groups respectively, P=0.61) or the LAR (largest fall in FEV1 between 3 and 7 h of 39.3+/-15.3% vs. 32.6+/-13.8%, P=0.24). TBC1269 had only minor effects on allergen-induced sputum eosinophilia. CONCLUSION : We conclude that TBC1269 administered before allergen challenge as a single intravenous dose does not attenuate early or late asthmatic responses to allergen in asthmatic subjects.