Tolerance to the bronchoprotective effect of β2 -agonists: Comparison of the enantiomers of salbutamol with racemic salbutamol and placebo

Background: Regular use of racemic salbutamol results in the partial loss of its bronchoprotective effect. The 2 enantiomers of salbutamol, the bronchodilator R-salbutamol and nonbronchodilator S-salbutamol, are now available. Objective: We sought to compare the effect of regular use of S-salbutamol, R-salbutamol, racemic salbutamol, and placebo on the bronchoprotective effect of a single dose of racemic salbutamol against methacholine-induced bronchoconstriction. Methods: Eleven of 13 well-controlled β₂ -agonist–free asthmatic subjects completed a double-blind, randomized study comparing racemic salbutamol 2.5 mg, S-salbutamol 1.25 mg, R-salbutamol 1.25 mg, and diluent placebo nebulized and inhaled 3 times daily for 6 days (≥6-day washout period). Ten to 12 hours after the last dose, the subjects performed measurement of FEV₁ , methacholine PC₂₀ , and a repeat methacholine PC₂₀ done 1 hour after the first methacholine test and 10 minutes after 2 puffs (200 μg) of racemic salbutamol administered from a metered-dose inhaler. The primary endpoint was the methacholine PC₂₀ dose shift (Δlog PC₂₀ ÷ log 2) from before to after administration of 200 μg of racemic salbutamol. Results: The methacholine dose shift was 3.2 doubling doses (9-fold increase in methacholine PC₂₀ after 200 μg of racemic salbutamol) during the placebo treatment and was unaltered (3.2) after administration of S-salbutamol. The dose shift was significantly lower after both the R-salbutamol and racemic salbutamol treatments (2.2 and 2.6 doubling doses, respectively); there was no significant difference between R-salbutamol and racemic salbutamol. There was no treatment effect on baseline FEV₁ , baseline methacholine PC₂₀ , or bronchodilation. Conclusion: Regular treatment with racemic salbutamol or R-salbutamol, but not S-salbutamol, results in a partial loss of bronchoprotection, without loss of bronchodilation, compared with placebo. (J Allergy Clin Immunol 1999;103:1049-53.)     

The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients

BACKGROUND: Limited dose-response information is available for nebulized beta2 -agonists, especially in young children. OBJECTIVE: The purpose of this study was to determine the safety and efficacy of increasing doses of nebulized levalbuterol (Xopenex; the pure R-isomer of racemic albuterol) and racemic albuterol compared with placebo in the treatment of asthma in pediatric patients. METHODS: In this randomized, double-blind, crossover study, children (aged 3 to 11 years) with asthma (resting FEV1 50% to 80% of predicted normal [Polgar's] values) were treated with either levalbuterol, racemic albuterol, or placebo. Eligible subjects underwent a screening visit followed by 4 treatment visits. At each treatment visit, serial pulmonary function tests were completed before and after the treatment; plasma was collected to determine enantiomer levels, and safety was evaluated. RESULTS: Five 3- to 5-year-old patients and twenty-eight 6- to 11-year-old patients completed the study, and a total of 87 doses of levalbuterol were administered. In the 6- to 11-year-old group, all doses of levalbuterol were significantly greater than placebo in peak change and percent peak change in FEV1 and area under the FEV1 versus time curve (P <.05). The FEV1 values over the 8-hour study period were similar for levalbuterol 0.31 and 0.63 mg and racemic albuterol 2.5 mg and were greatest after levalbuterol 1.25 mg. Median plasma levels of R-albuterol depended on dose and were 0.4, 0.7, 1.2, and 1.0 after levalbuterol 0.31 mg, 0.63 mg, and 1.25 mg and racemic albuterol 2.5 mg, respectively. All patients in the 2.5-mg racemic albuterol arm had measurable plasma levels of S-albuterol, although S-albuterol levels were undetectable in most patients in the levalbuterol arms. In a few patients who received levalbuterol, S-albuterol levels were detected, which was likely because of the use of racemic albuterol as a concomitant medication. All active treatments were well tolerated. beta-Mediated changes in heart rate, potassium, and glucose were dose dependent for all active treatment groups. CONCLUSION: Levalbuterol caused a significantly greater increase in FEV1 than placebo, and FEV1 values were comparable with or better than those observed with racemic albuterol. beta-Mediated side effects were lower for an equipotent dose of levalbuterol when compared with racemic albuterol. Treatment with levalbuterol resulted in plasma levels that were dose dependent and had an approximate correlation with pharmacodynamic parameters.     

Low-dose levalbuterol in children with asthma: Safety and efficacy in comparison with placebo and racemic albuterol

BACKGROUND: Racemic albuterol (RAC) is an equal mixture of (R)-albuterol and (S)-albuterol. Only the (R)-isomer, levalbuterol (LEV), is therapeutically active. Lower doses of LEV, devoid of (S)-albuterol, have demonstrated efficacy comparable to that of higher doses of the (R)-isomer administered as a component of RAC. OBJECTIVE: The purpose of this study was to determine whether LEV results in improved safety and efficacy in children. METHODS: Asthmatic children aged 4 to 11 years (n = 338; FEV(1), 40% to 85% of predicted) participated in this multicenter, randomized, double-blinded study and received 21 days of 3-times-a-day treatment with nebulized LEV (0.31 or 0.63 mg), RAC (1.25 or 2.5 mg), or placebo. The primary endpoint was FEV(1) (peak percent change). Adverse events, clinical laboratory test results, vital signs, and electrocardiograms were evaluated for safety. RESULTS: All active treatments significantly improved the primary endpoint in comparison with placebo (P < .001). Significant differences in FEV(1) were noted immediately after nebulization (median change, 2.0%, 19.0%, 18.1%, 12.4%, and 15.6% for placebo, LEV 0.31 and 0.63, RAC 1.25 and 2.5 mg, respectively; P < .05 vs placebo; P < .05 for LEV 0.31 and 0.63 vs RAC 1.25 mg). LEV 0.31 mg was the only treatment not different from placebo for changes in ventricular heart rate, QT(c) interval, and glucose (P > .05). All active treatments decreased serum potassium (range, -0.3 to -0.6; P < .002 vs placebo), and RAC 2.5 mg caused the greatest change (P < .005 vs other actives). In a patient subset with severe asthma, a dose-response relationship was observed for levalbuterol, indicating that higher doses were more effective. CONCLUSION: LEV was clinically comparable to 4- to 8-fold higher doses of RAC, and it demonstrated a more favorable safety profile. LEV 0.31 mg should be used as the starting dose in 4-11 year old children with mild to moderate persistent asthma. Patients with severe disease might benefit from higher doses.     

Levalbuterol inhibits human airway smooth muscle cell proliferation: therapeutic implications in the management of asthma

BACKGROUND: Racemic albuterol is a mixture of (R)- and (S)-enantiomers of albuterol. Its pharmacological activity and clinical efficacy reside in the (R)-enantiomer (levalbuterol), but the (S)-enantiomer exacerbates airway reactivity in nonclinical models. The role of albuterols in airway smooth muscle cell (SMC) proliferation is not well understood. METHODS: The effect of levalbuterol on human bronchial SMC growth was compared with the effects of racemic albuterol and (S)-albuterol. Cells were fed albuterols and 3H-thymidine in 5% FBS and incubated for 24 h. The effect of (S)-albuterol on levalbuterol actions was also studied and so were the effects of cAMP/PKA, PI-3 kinase, NK-kappaB, and retinoblastoma (Rb) proteins on albuterols and human bronchial SMC proliferation. RESULTS: Levalbuterol inhibited cell proliferation at low concentrations. The growth-inhibitory effect of levalbuterol occurs via activation of the cAMP/PKA pathway. Addition of (S)-albuterol to levalbuterol decreased the growth-inhibitory effect of levalbuterol, and (S)-albuterol attenuated levalbuterol-induced cAMP release by 65%. Levalbuterol inhibited NF-kappaB and Rb protein expressions. ICI-118551 abrogated the inhibitory properties of levalbuterol. The PAF receptor antagonist CV-3988 inhibited (S)-albuterol-induced cell growth, with no effect on levalbuterol. CONCLUSIONS: Levalbuterol inhibits cell growth by activating the cAMP/PKA pathway and inhibiting PI-3 kinase, NF-kappaB and Rb protein expression, and (S)-albuterol induces cell growth by activating PAF-receptor-mediated cell signaling.     

Levalbuterol: pharmacologic properties and use in the treatment of pediatric and adult asthma.

LEARNING OBJECTIVES: To review the rationale supporting the use of levalbuterol [(R)-albuterol] for the treatment of pediatric and adult asthma. DATA SOURCES: Peer-reviewed articles, selected abstracts from studies presented at recent professional meetings, and the Xopenex [levalbuterol, (R)-albuterol; Sepracor, Marlborough, MA] Summary Basis of Approval and package insert. STUDY SELECTION: Institutional review board-approved clinical study protocols. RESULTS: Levalbuterol is a single isomer beta2-agonist that differs from racemic albuterol by elimination of (S)-albuterol. Levalbuterol is an effective bronchodilator whose primary mechanism of action is unimpeded by (S)-albuterol. Thus, when compared with racemic albuterol, clinically comparable bronchodilation can be achieved with doses that substantially lessen beta-mediated side effects. In chronic or acute treatment of asthma, this favorable therapeutic profile cannot apparently be duplicated by increasing or decreasing the dose of racemic albuterol or by the addition of anticholinergic agents such as ipratropium bromide. CONCLUSIONS: Levalbuterol seems to provide efficacy and safety advantages in pediatric and adult patients suffering from asthma. Its use may afford a cost benefit as well. More clinical studies are required to extend these observations for use in the treatment of other pulmonary diseases in both adults and children and to determine levalbuterol's impact on long-term therapy of respiratory diseases.     

Long-term safety study of levalbuterol administered via metered-dose inhaler in patients with asthma.

BACKGROUND: Previous studies have raised concerns regarding the safety of regular use of beta2-agonists for treating asthma. Few studies have explored the safety of at least 1 year of use of racemic albuterol, and none have examined long-term dosing of levalbuterol. OBJECTIVE: To examine the long-term safety of levalbuterol hydrofluoroalkane (HFA) vs racemic albuterol HFA administered via metered-dose inhaler (MDI) in patients with stable asthma. METHODS: Patients with mild to moderate asthma (mean forced expiratory volume in 1 second [FEVI], 68.3% of predicted) 12 years or older participated in a multicenter, parallel-group, open-label study. Patients were randomized to levalbuterol HFA MDI (90 microg; 2 actuations of 45 microg; n = 496) or racemic albuterol HFA MDI (180 microg; 2 actuations of 90 microg; n = 250) for 52 weeks of 4 times daily dosing. The primary end point was the incidence of postrandomization adverse events. Asthma exacerbations and pulmonary parameters were also assessed. RESULTS: The overall incidence of adverse events was similar for levalbuterol (72.0%) and racemic albuterol (76.8%). Rates of beta-mediated adverse events, serious adverse events, and discontinuations because of adverse events were low (<15%) and were comparable between groups. Rates of asthma adverse events for levalbuterol and racemic albuterol were 18.3% and 19.6%, respectively. Mean percentage of predicted FEV1 improved after dosing and was stable for both groups. CONCLUSION: In this trial, up to 52 weeks of regular use of levalbuterol HFA MDI or racemic albuterol HFA MDI was well tolerated, and no deterioration of lung function was detected during the study period.     

Effects of albuterol isomers on the contraction and Ca2+ signaling of small airways in mouse lung slices

The beta(2)-adrenergic agonist, albuterol, is used as a bronchodilator by patients with asthma and consists of a racemic mixture of (R)- and (S)-albuterol. However, the action of the individual enantiomers is poorly understood. Consequently, we investigated the effects of (R)-, (S)- and racemic-albuterol on airway smooth muscle cell (SMC) contraction and Ca(2+) signaling in mouse lung slices with phase-contrast and confocal microscopy. (R)-albuterol relaxed airways contracted with methacholine (MCh) in a dose-dependent manner. By contrast, (S)-albuterol had no effect on airways. (R)-albuterol had a greater relaxant effect than a double concentration of racemic albuterol. Because MCh-induced contraction of airway SMCs is mediated by Ca(2+) oscillations and an increase in Ca(2+) sensitivity, the effects of albuterol on these responses were examined. Both (R)- and racemic albuterol decreased the frequency of the MCh-induced Ca(2+) oscillations by a similar amount. However, (R)-albuterol was more effective than racemic albuterol in decreasing the Ca(2+) sensitivity of the airway SMCs in "model" lung slices with a clamped [Ca(2+)](i). In contrast, (S)-albuterol had no effect on the Ca(2+) oscillations or the Ca(2+) sensitivity. In conclusion, (R)-albuterol consistently induced a greater airway relaxation than racemic albuterol, and (S)-albuterol appears to be responsible for this reduced efficacy.     

Inhalation challenge testing of latex-sensitive health care workers and the effectiveness of laminar flow HEPA–filtered helmets in reducing rhinoconjunctival and asthmatic reactions

Background: There are few data relating latex aeroallergen concentrations to biologic responses in latex-sensitized persons. Objectives: We sought to investigate acceptable latex aeroallergen concentrations below which latex-sensitive health care workers do not experience symptoms and to study the effect of high-efficiency particle arrest (HEPA)–filtered laminar flow helmets in preventing latex-induced symptoms. Methods: Under challenge chamber conditions, latex-sensitive health care workers underwent 7 sequential inhalation challenge tests by donning and discarding either vinyl gloves (challenge 1), low latex–allergen powder-free gloves (challenge 2), or high latex–allergen powdered gloves (challenges 3 to 7) for up to 1 hour. Volunteers wore a laminar flow helmet during all challenges; HEPA filters in the helmet were in place only during challenges 3 and 4. Flow-volume loops, symptom scores, and latex aeroallergen concentrations were measured before and during each test. Results: At 60 minutes, latex aeroallergen concentrations during challenges 3 to 7 (mean, 7600 ng/m³ ; range, 93 to 54,000 ng/m³ ) were significantly higher than during challenges 1 or 2 (mean, 65 ng/m³ ; range, nondetectable to 100 ng/m³ ) (P < .001). During challenges 5 and 6, mean maximum percent falls in FEV₁ (–16% and –11%, respectively) were significantly greater compared with those measured during challenges 3 and 4 (–3% and –1%, respectively) (P = .03). Mean maximum change from baseline symptom scores during challenges 5 and 6 was significantly higher than that during challenges 3 and 4 (P = .006). During challenges with high latex–allergen gloves, 4 volunteers had reproducible FEV₁ falls of 20% or greater at cumulative inhaled latex aeroallergen doses ranging from less than 100 ng to 1500 ng. Conclusion: The laminar flow helmets were effective in reducing latex-induced symptoms. Only 1 volunteer exhibited a fall in FEV₁ of 20% or greater after a cumulative inhaled latex aeroallergen dose of less than 100 ng, and no volunteer showed a decline in FEV₁ after exposure to powder-free low allergen gloves. (J Allergy Clin Immunol 1998;102:998-1004.)     

Effect of AA-2414, a thromboxane A2 receptor antagonist, on airway inflammation in subjects with asthma

Background: Asthma is a chronic inflammatory disease of the airways. The chemokines are potent chemoattractants for eosinophils and other types of cells associated with allergic inflammation. AA-2414, a new thromboxane A₂ receptor antagonist, reduces bronchial hyperresponsiveness in asthmatic subjects, but its mechanism of action is unclear. Objective: We tested the hypothesis that the beneficial effects of AA-2414 in asthma result from reduction in the number of inflammatory cells infiltrating the airway associated with inhibition of chemokine release. Methods: We studied bronchial biopsy specimens from 31 asthmatic subjects before and after oral treatment with AA-2414 (80 mg/day) or matched placebo for 4 months in a double-blind manner. Biopsy specimens were examined by immunohistochemistry. Each subject recorded symptom score and peak expiratory flow (PEF). Lung function and bronchial responsiveness to methacholine were measured before and after treatment. Results: After treatment, significant improvements in symptom score (P < .05), PEF (P < .01), diurnal variation of PEF (P < .01), and bronchial responsiveness (P < .01) were observed in the AA-2414 group compared with the placebo group. These improvements were accompanied by a significant decrease in the number of submucosal EG2⁺ eosinophils (P < .05). There was also a reduction in the number of cells expressing RANTES (P < .05) and macrophage inflammatory protein (MIP)-1α (P < .05) in the epithelium and of cells expressing monocyte chemotactic protein-3 (P < .01), RANTES (P < .05), MIP-1α (P < .01), and eotaxin (P < .01) in the submucosa in the AA-2414 treatment group. A significant correlation was found between the number of EG2⁺ eosinophils and numbers of monocyte chemotactic protein-3⁺ (r_s = 0.52, P < .005), MIP-1α⁺ (r_s = 0.34, P < .05), and eotaxin⁺ cells (r_s = 0.47, P < .01) in the submucosa. There was a significant negative correlation between the increase in bronchial responsiveness and the change in number of submucosal EG2⁺ cells (r_s = –0.65, P < .001). Conclusions: These findings suggest that AA-2414 treatment of patients with asthma may inhibit activated eosinophil infiltration in part by modulating the expression of chemokines in bronchial tissues. (J Allergy Clin Immunol 1999;103:1054-61.)     

Oral administration of a dominant T-cell determinant peptide inhibits allergen-specific TH1 and TH2 cell responses in Cry j 2–primed mice

Background: Oral immunotherapy with a peptide for allergic immune responses is theoretically a promising therapy but has not been established yet. Objective: To evaluate immune suppressive efficacy of oral administration of an immunodominant peptide, we investigated changes in T-cell proliferation, T_H1 - and T_H2 -cytokine production, and T_H1 - and T_H2 -mediated antibody production in mice after oral administration of a peptide. Methods: Peptide p246-259, containing a dominant T-cell determinant of Cry j 2, which is the major allergen in Japanese cedar pollen, was used in this study. Groups of mice received p246-259 or PBS alone before or after they were primed intranasally with Cry j 2 and cholera toxin. In another experiment mice were primed intraperitoneally with Cry j 2 and alum. Proliferative response and cytokine production by nasal-associated lymph node cells against Cry j 2 were investigated. Amounts of systemic anti-Cry j 2 IgE and IgG antibodies were also measured. Results: Oral administration of the peptide to mice before, or even after, the sensitization induced oral tolerance in T-cell responses against the allergen; the tolerance was associated with decreased production of T_H1 (IFN-γ and IL-2) and T_H2 (IL-4) cytokines. Allergen-specific T_H1 -mediated (IgG2a and IgG2b) and T_H2 -mediated (IgG1 and IgE) antibody responses were also inhibited. Conclusions: Oral administration of a dominant T-cell determinant peptide induces immunologic tolerance in both T_H1 and T_H2 cell responses against the whole protein allergen. Our study is the first, to our knowledge, to demonstrate the potential for peptide-based oral immunotherapy in order to treat allergic immune responses. (J Allergy Clin Immunol 1998;102:961-7.)     

Effects of topical corticosteroids on inflammatory mediator–induced eicosanoid release by human airway epithelial cells

Background: Airway epithelial cells are among the first cells to come in contact with aerosolized corticosteroids. However, the relative potencies and time course of action of the several commonly used aerosolized corticosteroids on eicosanoid production by airway epithelial cells are unknown. Objectives: This study compared the effects of fluticasone, budesonide, and triamcinolone on eicosanoid output by human airway epithelial cells in vitro. We also determined the spectrum of eicosanoids affected and the mechanism for corticosteroid action. Methods: Cultured BEAS-2B airway epithelial cells (a transformed cell line) were exposed to corticosteroids (1 nmol/L to 1 μmol/L) for 2 to 48 hours and then assayed for basal- and bradykinin (BK)-stimulated eicosanoid output. The eicosanoid profile was identified by HPLC in tritiated arachidonic acid prelabelled cells, and PGE₂, the major eicosanoid product, was quantitated by RIA. The effect of corticosteroids on the immunoreactivity of key proteins involved in eicosanoid metabolism (ie, cyclooxygenase [COX], phospholipase A2 [PLA₂], and Clara cell protein, a PLA₂ inhibitor) was determined by Western blotting. Results: Eicosanoid output was largely confined to prostaglandins with values of 5 ± 2 and 82 ± 35 ng PGE₂/10⁶ cells for basal- and BK stimulation, respectively (n = 8). All 3 corticosteroids inhibited basal- and BK-induced PGE₂ output in a dose- and time-dependent manner. Fluticasone and budesonide completely eliminated PGE₂ output in nanomolar concentrations in contrast to triamcinolone, which required micromolar concentration. The rank order of potency was: fluticasone = budesonide > triamcinolone. The time course of action for PGE₂ inhibition also differed, with budesonide acting more slowly than the other 2 corticosteroids (P = .04). All 3 corticosteroids markedly reduced COX2 with little effect on COX1, cPLA₂ (Type IV), or iPLA₂ (Type VI) immunoreactivity or their relative distribution in cytosol versus membrane fractions. Clara cell protein immunoreactivity was undetectable in control and corticosteroid-treated cell lysates. Conclusion: These results show that in a human airway epithelial cell line, the 3 inhaled corticosteroids commonly used to treat asthma differ in onsets of action as inhibitors of prostaglandin synthesis and vary considerably in potency. All 3 corticosteroids act mechanistically in similar fashion by inhibiting COX2 synthesis. (J Allergy Clin Immunol 1999;103:1081-91.)     

Reversibility of inspiratory lung function parameters after short-term bronchodilators in COPD

Background

The responsiveness of short-term bronchodilator use on inspiratory lung function parameters (ILPs), including Forced Inspiratory Volume in one second (FIV₁), Inspiratory Capacity (IC), Forced Inspiratory Flow at 50% of the vital capacity (FIF₅₀), Peak Inspiratory Flow (PIF) and on the relationship between these values and dyspnea in COPD subjects has been examined only sparsely in past studies. The aim of this study was to assess the effects of inhaled salbutamol 400 mcg, ipratropium 80 mcg and a placebo on ILP and FEV₁ and their relationship to dyspnea, as measured with a Visual Analogue Scale (VAS).

Methods

A total of 85 subjects with stable COPD participated in a crossover, randomized, double-blind, placebo-controlled study. Spirometry was performed before and after inhalation of salbutamol, ipratropium or a placebo. The primary analysis was performed using 63 participants with absent reversibility.

Results

All ILP and FEV₁ values improved significantly after bronchodilator administration except for FIF₅₀ after ipratropium administration. After administration of both bronchodilators, the mean percent changes from initial values did not significantly differ between the various ILPs and FEV₁. The mean VAS score showed significant improvements after bronchodilator and placebo inhalation but did not significantly correlate with changes in lung function parameters. For each lung function parameter, patients were further classified as responders if the amount of change was greater than the coefficient of repeatability of the test. Response rates did not differ significantly between the various ILPs. Moreover, no significant differences were found between responders and non-responders with respect to dyspnea after bronchodilator inhalation. This finding applied to all ILP and FEV₁ values.

Conclusions

In subjects with COPD, all ILP, FEV₁ values and VAS scores showed significant improvements after bronchodilator use as well as with placebo. However, ILPs were not more sensitive than FEV₁ for detecting responders after bronchodilator use or changes in the VAS score.     

An evaluation of the efficacy and safety of azelastine in patients with chronic asthma

BACKGROUND: Azelastine, an oral nonsteroidal, antiinflammatory drug with a good safety profile, has demonstrated relief of symptoms in patients with asthma. OBJECTIVE: The study was designed to evaluate the efficacy and safety of azelastine, a novel antiallergy compound, in patients with asthma who required maintenance therapy. METHODS: During this 16-week, double-blind, randomized, parallel-group study, patients received orally administered azelastine (4 mg twice daily), albuterol sulfate (4 mg twice daily), or placebo. RESULTS: Overall, patients in the azelastine group used 2.5 times less backup medication (p = 0.024) for relief of their asthma symptoms than patients in the placebo group. Reductions in asthma symptoms in the azelastine group were also noted throughout the double-blind treatment period. Moreover, the azelastine group had statistically significant improvements in FEV₁ after the first dose of medication. The only notable adverse experiences in the azelastine group were alterations in taste perception and a small mean increase in body weight. CONCLUSION: Oral administration of azelastine to patients with asthma resulted in overall improvement in airway function while reducing the requirement for adjunctive antiasthma medications. (J ALLERGY CLIN IMMUNOL 1996;97:1218-24.)     

Effects of (R)- and (S)-isomers of β-adrenergic agonists on eosinophil response to interleukin-5

BACKGROUND: Racemic beta2-adrenergic receptor agonists (beta2-agonists) are used frequently to treat patients with asthma. Potential differences in the biological activities and clinical efficacies among racemic beta2-agonists and their isomers are controversial, and research into these possible differences is limited. OBJECTIVE: We hypothesized that the (S)- and the (R)-isomers of beta2-agonists have opposing effects on the activation of inflammatory cells. METHODS: Isolated human eosinophils were pretreated with 1:1 racemic (R,S)-, (R)- or (S)-albuterol, isobutyl methylxanthine (IBMX), and stimulated with IL-5. The kinetics of superoxide production were examined by reduction of cytochrome c, and the effects of pharmacological agents on superoxide production were monitored for 180 min. RESULTS: (R,S)-albuterol inhibited IL-5-induced superoxide production. This inhibition was enhanced by a cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor, IBMX, and was reversed by the selective beta2-adrenergic receptor antagonist, ICI 118, 551, verifying the involvement of both cAMP and the beta2-adrenergic receptor. In addition, (R)-albuterol alone, similarly to (R,S)-albuterol, significantly inhibited IL-5-induced superoxide production up to 60 min (P<0.05, n=4), but the inhibition was lost with longer incubation. In contrast, (S)-albuterol with IBMX did not inhibit IL-5-induced superoxide production before 60 min, but it significantly enhanced IL-5-mediated superoxide production after 60 min (P<0.05, n=4). When both were present as racemic (R,S)-albuterol, the inhibitory effect of (R)-albuterol was not affected by (S)-albuterol. CONCLUSION: When incubated with IL-5-activated eosinophils, (R)-albuterol shows anti-inflammatory effects and (S)-albuterol shows pro-inflammatory effects in the presence of IBMX. The kinetics of these effects are different, and when used simultaneously, (R)-albuterol predominates. When marked usage of the (S)-isomer is anticipated, racemic (R,S)-albuterol should be used clinically with caution.     

Differential effects of (S)- and (R)-enantiomers of albuterol in a mouse asthma model

BACKGROUND: (R)- and (S)-Enantiomers of albuterol likely exert differential effects in patients with asthma. The (R)-enantiomer binds to the beta2-adrenergic receptor with greater affinity than the (S)-enantiomer and is responsible for albuterol's bronchodilating activity. (S)-Albuterol augments bronchospasm and has proinflammatory actions. OBJECTIVE: The study aim was to determine whether the (S)-enantiomer, in contrast to the (R)-enantiomer, has adverse effects on allergic airway inflammation and hyperresponsiveness in a mouse asthma model. METHODS: Mice sensitized to ovalbumin (OVA) intraperitoneally on days 0 and 14 were challenged with OVA intranasally on days 14, 25, and 35. On day 36, 24 hours after the final allergen challenge, the effect of the (R)- and (S)-enantiomers of albuterol (1 mg x kg(-1) x d(-1) administered by means of a miniosmotic pump from days 13-36) on airway inflammation and hyperreactivity was determined. RESULTS: In OVA-sensitized/OVA-challenged mice, (R)-albuterol significantly reduced the influx of eosinophils into the bronchoalveolar lavage fluid and airway tissue. (R)-Albuterol also significantly decreased airway goblet cell hyperplasia and mucus occlusion and levels of IL-4 in bronchoalveolar lavage fluid and OVA-specific IgE in plasma. Although (S)-albuterol significantly reduced airway eosinophil infiltration, goblet cell hyperplasia, and mucus occlusion, it increased airway edema and responsiveness to methacholine in OVA-sensitized/OVA-challenged mice. Allergen-induced airway edema and pulmonary mechanics were unaffected by (R)-albuterol. CONCLUSION: Both (R)- and (S)-enantiomers of albuterol reduce airway eosinophil trafficking and mucus hypersecretion in a mouse model of asthma. However, (S)-albuterol increases allergen-induced airway edema and hyperresponsiveness. These adverse effects of the (S)-enantiomer on lung function might limit the clinical efficacy of racemic albuterol.     

Gelatin-induced T-cell activation in children with nonanaphylactic-type reactions to vaccines containing gelatin

Background: Many cases of anaphylactic or nonanaphylactic reactions have been reported to measles-mumps-rubella vaccine or its component vaccines that contain gelatin as a stabilizer. Increased levels of specific IgE antibodies to gelatin have been reported in children with anaphylactic reactions. However, IgE is not increased in cases of nonanaphylactic reaction, and the mechanisms of the reaction are still controversial. Objective: The study was aimed to elucidate the relationship between nonanaphylactic reaction and gelatin. Methods: We investigated in vitro induction of activated memory helper T cells (CD4⁺ CD25⁺ CD45RO⁺ cells) in response to gelatin in children with nonanaphylactic reactions to vaccines containing gelatin. Results: In patients with delayed-type sensitivity to gelatin confirmed with a positive skin test response, CD4⁺ CD25⁺ CD45RO⁺ cells were significantly more strongly induced in culture containing gelatin than in control cultures. However, there was no significant difference between cultures with gelatin and those with control solvent in patients without reactions after vaccination. Of 76 patients with nonanaphylactic reactions after immunization with vaccine containing gelatin, 61 had an increased lymphocyte stimulation index to gelatin versus control children. Conclusion: These results suggest the possibility that nonanaphylactic reactions to gelatin-containing vaccine in Japan might be mediated by delayed hypersensitivity reactions against gelatin. (J Allergy Clin Immunol 1998;102:1028-32.)     

Lipopolysaccharide augments IgG and IgE responses of mice to the latex allergen Hev b 5

Background: LPS is a common contaminant in the health care environment and in latex examination gloves. Objective: We sought to investigate the role of LPS in enhancing the immune responses of mice to inhaled latex allergen. Methods: As our model allergen, we used a fusion protein containing the potent latex allergen Hev b 5. BALB/c mice were lightly anesthetized and given repeated intranasal doses of saline, LPS, and/or Hev b 5. The doses were given in 2 courses separated by a 6-week period, with the first course consisting of 6 doses and the second consisting of 3 doses. Results: After the first set of immunizations, mice given Hev b 5 alone had no detectable IgG1 or IgE responses to Hev b 5, whereas mice given the antigen along with LPS had significant responses (IgG1, 0.73 U ± 0.05; IgE, 0.88 U ± 0.2). No enhancement of specific IgG2a was observed. A stimulatory effect of LPS on all 3 immunoglobulin types was apparent after the second course. Lymphocytes from mice immunized with LPS and Hev b 5 had increased proliferation to Hev b 5 and its fusion partner. Conclusions: LPS may be an important immunoadjuvant for the development of allergic reactions to latex protein allergens. (J Allergy Clin Immunol 199;102:977-83.)