Protective effect of lodoxamide tromethamine on allergen inhalation challenge

Lodoxamide tromethamine (U-42,585E) is a new drug intended for prophylaxis of mast cell-mediated allergic disease. It is a water-soluble, cromolyn-like agent with demonstrated activity in rat peritoneal mast cell assay, rat percutaneous anaphylaxis (rat PCA) and sensitized rhesus monkey airway system. Ten allergen-sensitive asthmatics were pretreated with lodoxamide (0.01, 0.1, or 1.0 mg) or placebo, then challenged with serial dilutions of allergen extract. Analysis of allergen dose-response curve parameters shows that pretreatment with lodoxamide offers significant protection against experimental allergen-induced bronchoconstriction. At 0.01 mg, lodoxamide was effective in over half the subjects tested. Administration of lodoxamide by inhalation at doses of 0.1 and 1.0 mg uniformly allowed subjects to tolerate significantly larger doses of inhaled allergen. Side effects observed at these doses were minimal.     

A comparison of topical budesonide and oral montelukast in seasonal allergic rhinitis and asthma

BACKGROUND: Allergic rhinitis and asthma commonly coexist and are both mediated by similar inflammatory mechanisms. Leukotriene antagonists may therefore be an alternative to corticosteroid therapy. OBJECTIVE: To compare oral montelukast with inhaled plus intranasal budesonide in patients with seasonal allergic rhinitis and asthma. PATIENTS AND METHODS: A single-blind double-dummy placebo-controlled crossover study was performed comparing once daily 10 mg oral montelukast with 400 microg inhaled plus 200 microg intranasal budesonide in 12 patients with allergic rhinitis and asthma: mean (S.E.) age 34.0 years (2.7), forced expiratory volume in 1 s (FEV1) 91.2 (3.8)% predicted. Each treatment was for 2 weeks with a 1-week placebo run-in and washout. Measurements were made after each active treatment and placebo for: adenosine monophosphate bronchial challenge, exhaled and nasal nitric oxide. Patients also recorded their domiciliary peak expiratory flow, nasal peak inspiratory flow, asthma and seasonal allergic rhinitis symptoms. RESULTS: There were no significant differences between the placebos for any measurement. For adenosine monophosphate PC20, geometric mean fold differences (95% confidence interval (CI) for difference) were 6.4 (2.2-18.6) for placebo vs. budesonide, 2.9 (1.0-8.4) for placebo vs. montelukast, and 2.1 (1.1-4.5) for budesonide vs. montelukast. For exhaled nitric oxide (p.p.b.) there was significant (P < 0.05) suppression with both montelukast (10.9) and budesonide (10.1) compared with placebo (18.8). For nasal nitric oxide and nasal peak flow there were only significant differences with budesonide compared with placebo. Both treatments reduced total seasonal allergic rhinitis symptoms but only budesonide had a significant effect on nasal symptoms. CONCLUSION: Once-daily inhaled plus intranasal budesonide and once daily montelukast showed comparable efficacy on lower airway, but only the budesonide had significant efficacy on upper airway inflammatory markers. Both treatments significantly reduced allergic rhinitis symptoms.     

Effect of theophylline on gastroesophageal reflux in patients with asthma

A possible role of methylxanthines in the high incidence of gastroesophageal reflux (GER) in patients with asthma has been suggested. Therefore, we used a randomized, double-blind, crossover design to compare the effects of a 1-week conventional theophylline treatment and a 1-week placebo treatment in 16 adult patients with asthma. No oral or parenteral glucocorticoids were administered, but seven patients were taking inhaled corticoids. All patients needed inhaled adrenergic drugs. At the end of each period of theophylline or placebo treatment, the patients were carefully questioned with respect to respiratory and digestive symptoms, forced expiratory flows were measured, and GER was assessed by prolonged nocturnal intraesophageal pH monitoring. Peak expiratory flow was measured three times a day throughout the study. No significant increase in GER was found with theophylline compared to placebo, and forced expiratory flows improved with theophylline (p less than 0.05 for FEV1 and p less than 0.01 for peak expiratory flow rate). There was no correlation between GER, the duration of asthma, and forced expiratory flows. Thus, our study failed to demonstrate any adverse effect of a slow-release theophylline preparation on GER in patients with asthma. These results further suggest that the presence of GER is not a contraindication to the use of a slow-release theophylline in subjects with asthma.     

Comparative effects of desloratadine versus montelukast on asthma symptoms and use of beta 2-agonists in patients with seasonal allergic rhinitis and asthma

BACKGROUND: Asthma and seasonal allergic rhinitis (SAR) are recognized as manifestations of a single airway disease. Desloratadine has demonstrated efficacy in treating SAR symptoms, including nasal obstruction. METHODS: Safety and efficacy of desloratadine and montelukast each were assessed in a double-blind, placebo-controlled trial of patients with SAR and symptoms of asthma, who were assigned randomly to once-daily treatment with desloratadine 5 mg, montelukast 10 mg, or placebo for 4 weeks. Change from baseline of AM/PM reflective total asthma symptom severity scores (TASS), FEV(1), individual asthma symptom scores, and beta(2)-agonist usage were assessed. RESULTS: Desloratadine and montelukast each were associated with statistically significant reductions from baseline in the mean TASS averaged over the 4-week period (p < or =0.022 vs. placebo). Individual asthma symptom scores also improved significantly for both therapies (p < or = 0.05). Patients treated with desloratadine or montelukast demonstrated improvement from baseline in FEV(1) versus placebo; significant improvement was seen in a subset of patients with baseline FEV(1) <80% of predicted normal (both p < 0.05). Both active therapies significantly reduced beta(2)-agonist use (both p < 0.01). Improvements for both therapies were comparable for all efficacy parameters; they were tolerated well with adverse event profiles similar to placebo. CONCLUSIONS: Asthma symptoms and beta(2)-agonist were improved significantly in patients with concomitant SAR and asthma treated with desloratadine 5 mg as well as montelukast 10 mg once daily. Both therapies significantly improved FEV(1) in a subset of patients with FEV(1) <80% of predicted normal at entry. Improvements in asthma symptoms were comparable for both active treatment groups.     

Omalizumab improves asthma-related quality of life in patients with severe allergic asthma

BACKGROUND: We have previously shown that omalizumab, a recombinant humanized monoclonal anti-IgE antibody, reduces asthma exacerbations and decreases inhaled corticosteroid (ICS) requirement in patients with severe allergic asthma who were symptomatic despite moderate-to-high doses of ICSs. OBJECTIVE: The aim of the present study was to assess the effects of omalizumab on asthma-related quality of life (QOL). METHODS: These analyses were part of a multicenter, 52-week, randomized, double-blind, placebo-controlled study assessing the efficacy, safety, and tolerability of subcutaneous omalizumab (> or =0.016 mg/kg of IgE [in international unit per milliliter] per 4 weeks) in 525 adults with severe allergic asthma. A 16-week steroid-stable phase was followed by a 12-week steroid-reduction phase and a 24-week double-blind extension phase. The effect of treatment on asthma-related QOL was evaluated by using the Asthma Quality of Life Questionnaire (AQLQ) administered at baseline and at weeks 16, 28, and 52. RESULTS: The 2 treatment groups were comparable in terms of baseline AQLQ scores. At weeks 16, 28, and 52, omalizumab-treated patients demonstrated statistically significant improvements across all AQLQ domains, as well as in overall score. Moreover, a greater proportion of patients receiving omalizumab achieved a clinically meaningful improvement in asthma-related QOL during each phase of the study. Greater than 50% of both patients and investigators rated treatment similarly with omalizumab as excellent or good compared with less than 40% of placebo recipients. CONCLUSION: In patients requiring moderate-to-high doses of ICSs for severe allergic asthma, the measurably improved disease control afforded by add-on omalizumab therapy is paralleled by clinically meaningful improvements in asthma-related QOL.     

Effect of inhaled lodoxamide tromethamine in prevention of antigen-induced bronchospasm

Lodoxamide tromethamine, a new cromolyn-like drug, was studied to determine its effectiveness and duration of action in preventing antigen-induced bronchospasm in 15 subjects with clinically stable extrinsic asthma. All subjects underwent antigen inhalation challenge 15 min after inhalation of an aerosolized solution of 0.1 mg of lodoxamide in saline or of saline solution alone (placebo) administered on separate days according to a double-blind, random-allocation protocol. Those subjects demonstrating a protective effect of lodoxamide subsequently underwent antigen inhalation challenges at various time intervals (2 to 8 hr) after lodoxamide treatment. Thirteen of 15 subjects (87%) showed a protective effect of lodoxamide administered 15 min prior to antigen challenge. Six of the 13 subjects who were protected initially remained protected 4 hr after lodoxamide treatment and one of these six subjects was also protected at 6 to 8 hr. One additional subject not protected at 4 hr was protected at 3 hr. Lodoxamide exhibited no bronchodilator activity and was not associated with any significant side effects. Further studies are warranted to compare the effectiveness of lodoxamide with that of cromolyn sodium in protection against antigen-induced bronchospasm and to evaluate the relative efficacy and safety of lodoxamide in long-term clinical trials.     

Allergen injection therapy with glutaraldehyde-modified--ragweed pollen-tyrosine adsorbate. A double-blind trial.

The effect of a preseasonal course of four injections of glutaraldehyde-modified—ragweed pollen-tyrosine adsorbate (MRTA), in a total dose of 7,000 Noon pollen units, was compared with a tyrosine base placebo in a double-blind trial in 43 matched patients with ragweed pollen-induced allergic rhinitis. During the pollen season, troublesome symptoms were treated with a standardized therapeutic regimen. The minimum medication requirement that adequately controlled symptoms was used as the main indicator of severity of the allergic rhinitis. Consequently, the symptom scores were similar in both treatment groups; however, the MRTA-treated group required approximately 50% less medication than the placebo group (p < 0.05). Subjective improvement was reported by 67% of the MRTA group and 38% of the placebo group (0.05 < p < 0.1). Serum concentrations of IgE and IgG antibodies to ragweed increased in response to MRTA (p < 0.02) but not in response to placebo. Side effects of MRTA included generalized urticaria in 2, mild asthma in 1, and large late swellings at the injection site which necessitated stopping the injections in 6 patients. MRTA was superior to placebo in reducing the severity of ragweed pollen-induced allergic rhinitis and was associated with a modest incidence of side effects.     

Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma

BACKGROUND: Patients with severe asthma are often inadequately controlled on existing anti-asthma therapy, constituting an unmet clinical need. OBJECTIVE: This randomized, double-blind, placebo-controlled trial evaluated the ability of omalizumab, a humanized monoclonal anti-IgE antibody, to improve disease control sufficiently to enable inhaled corticosteroid reduction in patients with severe allergic asthma. METHODS: After a run-in period when an optimized fluticasone dose (> or =1000 microg/day) was received for 4 weeks, patients were randomized to receive subcutaneous omalizumab [minimum 0.016 mg/kg/IgE (IU/mL) per 4 weeks; n=126] or matching placebo (n=120) at intervals of 2 or 4 weeks. The study comprised a 16-week add-on phase of treatment followed by a 16-week fluticasone-reduction phase. Short-/long-acting beta(2)-agonists were allowed as needed. RESULTS: Median reductions in fluticasone dose were significantly greater with omalizumab than placebo: 60% vs. 50% (P=0.003). Some 73.8% and 50.8% of patients, respectively, achieved a > or =50% dose reduction (P=0.001). Fluticasone dose reduction to < or =500 microg/day occurred in 60.3% of omalizumab recipients vs. 45.8% of placebo-treated patients (P=0.026). Through both phases, omalizumab reduced rescue medication requirements, improved asthma symptoms and asthma-related quality of life compared to placebo. CONCLUSION: Omalizumab treatment improves asthma control in severely allergic asthmatics, reducing inhaled corticosteroid requirements without worsening of symptom control or increase in rescue medication use.     

Omalizumab is effective in the long-term control of severe allergic asthma.

BACKGROUND: Previous reports show that addition of omalizumab to standard therapy reduces asthma exacerbations and simultaneously decreases use of inhaled corticosteroids (ICSs) and rescue medication in patients with allergic asthma. OBJECTIVE: To determine the effect of omalizumab on long-term disease control in patients with severe allergic asthma. METHODS: The present study concerns the 24-week, double-blind extension phase to a previous 28-week core study in which patients received subcutaneous omalizumab or matching placebo (at least 0.016 mg/kg/IgE [IU/mL] every 4 weeks) for 16 weeks in addition to their existing ICS therapy (beclomethasone dipropionate [BDP]; steroid-stable phase), followed by a 12-week phase in which controlled attempts were made to gradually reduce ICS therapy (steroid-reduction phase). During the extension phase patients were maintained on randomized treatment (omalizumab or placebo) and the lowest sustainable dose of BDP. The use of other asthma medications was permitted during the extension phase. Investigators were also allowed to switch patients from BDP to other ICS medications if considered necessary. RESULTS: A total of 460 patients (omalizumab, n = 245; placebo, n = 215) entered the extension phase. Overall, omalizumab-treated patients experienced significantly fewer exacerbations vs placebo during the extension phase (0.60 and 0.83 exacerbations per patient, respectively; P = 0.023), despite a sustained significant reduction in their use of ICS (mean BDP equivalent dose: omalizumab, 227 microg/d; placebo, 335 microg/d; P < 0.001). Treatment with omalizumab was well tolerated and the incidence of adverse events was similar in both treatment groups. CONCLUSIONS: These results indicate that omalizumab is effective in the long-term control of severe allergic asthma.     

Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma.

Experimental studies have demonstrated that induction of a nasal allergic reaction can lead to an increase in bronchial responsiveness (BR). To assess the clinical relevance of these experimental changes to chronic asthma, we sought to determine the effect of nasal beclomethasone dipropionate (Bdp) on BR in patients with seasonal allergic rhinitis and asthma. Eighteen subjects with histories of seasonal allergic rhinitis and asthma during the fall pollen season with positive skin tests to short ragweed and bronchial hyperresponsiveness to inhaled methacholine were assigned to receive either nasal Bdp (336 micrograms/day) or placebo for the entire ragweed season. Patients recorded daily nasal and chest symptoms, nasal blockage index, oral peak expiratory flow rates, and supplemental medication use. BR to methacholine was measured during the baseline period and 6 weeks into the ragweed season. Although the Bdp group did have a significant improvement in nasal blockage index, there was no improvement in daily asthma symptom scores, oral peak expiratory flow, or asthma medication use. However, subjects treated with Bdp were protected from the increase in BR seen in the placebo group (geometric mean PC20 placebo group: baseline = 0.70, week 6 = 0.29; Bdp group: baseline = 0.80, week 6 = 0.93; intergroup difference, p = 0.022). We conclude that nasal corticosteroid therapy can prevent the increase in BR associated with seasonal pollen exposure in patients with allergic rhinitis and asthma.     

Immunological and clinical changes in allergic asthmatics following treatment with omalizumab

IgE plays a key role in allergic asthma. We investigated whether omalizumab treatment of patients with moderate to severe allergic asthma leads to changes in inflammatory mediators and clinical symptoms. This sub-study was conducted on 35 patients with a positive skin prick test (SPT) requiring daily administration of beclomethasone dipropionate (500-1,000 microg), who participated in a multicentre, randomised, double-blind, placebo-controlled study. Omalizumab or placebo was administered at 0.016 mg/kg/IgE every 4 weeks. Patients recorded peak expiratory flow, asthma symptom score and beta(2)-agonist use in daily diaries and spirometry was performed at each visit. beta(2)-Agonist use and SPT wheal reaction decreased significantly (p < 0.05). Circulating levels of IL-5, IL-6, IL-8, IL-10, IL-13 and s-ICAM were measured before and after 16 weeks of treatment. IL-13 and s-ICAM were measured before and after 16 weeks of treatment. IL-13 decreased significantly (p < 0.01). IL-5 and IL-8 decreased in the omalizumab group compared to baseline. The other circulating mediators did not demonstrate any changes. Histamine release was significantly reduced (p < 0.01). Airway resistance (p < 0.05) and the provocative concentration inducing a 20% decrease in FEV(1) (p < 0.05) were measured before, after 16 weeks, and 3 months after completion of treatment. Both parameters decreased significantly (p < 0.05). Peripheral eosinophil count decreased significantly compared to placebo (p < 0.01). These findings suggest that omalizumab has potential as a novel treatment for allergic asthma.     

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)     

Preseasonal IgE ragweed antibody level as a predictor of response to therapy of ragweed hay fever with intranasal cromolyn sodium solution.

Intranasal administration of a 4% solution of cromolyn sodium for the treatment of ragweed hay fever was tested in an 8-week double-blind matched-pair study involving 66 patients. Patients on active drug received 5.2 mg into each nostril 6 times daily; control patients received a placebo spray. The treated group showed a significant reduction in mouth breathing (p less than 0.001), stuffy nose (p less than 0.002), runny nose (p less than 0.003), and postnasal drip (p less than 0.035). Patients receiving the active drug also reported fewer sneezing episodes (p less than 0.003) and nose blowing episodes (p less than 0.015). One patient using cromolyn solution developed nasal ulceration, tongue swelling, coughing, and wheezing. Other side effects were minimal and occurred with equal frequency in both groups. In the treated group relief of symptoms was most marked in patients with high preseasonal levels of IgE ragweed antibody. Intranasal 4% cromolyn solution appears to be an effective drug for the treatment of ragweed hay fever; measurement of the preseasonal level of IgE ragweed antibody is a useful screening test to identify patients most likely to achieve a maximal beneficial response to treatment.     

Efficacy of once-a-day intranasal administration of triamcinolone acetonide in patients with seasonal allergic rhinitis.

A 4-week, double-blind, parallel group study compared the safety and efficacy of once-a-day intranasal administration of triamcinolone acetonide (Nasacort) versus placebo in 304 patients (155 adult and 149 adolescent) with seasonal allergic rhinitis. Patients were randomized to receive triamcinolone acetonide (110, 220, or 440 microgram) or placebo once daily each morning. Daily rhinitis symptoms scores, weekly patient and physician global assessments, and weekly nasal eosinophil smears were obtained. In each triamcinolone acetonide group, significant (P less than .05) improvement over placebo was noted in the nasal index (sum of ratings for stuffiness, discharge, and sneezing) by week 1, the first point of analysis, and maintained throughout the study. Triamcinolone acetonide groups also demonstrated significant (P less than .05) improvement over placebo in all individual rhinitis symptoms evaluated. The greatest improvement in symptoms was observed at the 440 microgram dose. A significant decrease in eosinophil counts paralleled clinical improvement in all triamcinolone acetonide groups. Physicians and patients rated triamcinolone acetonide significantly (P less than .05) more effective than placebo. Responses of adult and adolescent patients were comparable. Adverse experiences, clinical laboratory values, and results of physical examinations were unremarkable and comparable between the triamcinolone acetonide and placebo groups. We conclude that triamcinolone acetonide is safe, well tolerated, and superior to placebo as a once-a-day treatment for seasonal allergic rhinitis.     

Effect of montelukast on symptoms and exhaled nitric oxide levels in 7- to 14-year-old children with seasonal allergic rhinitis.

BACKGROUND: Cysteinyl leukotrienes have been found to exert potent inflammatory effects in the upper airways and play a fundamental role in the pathogenesis of allergic rhinitis. Previous studies have reported increased levels of exhaled nitric oxide (eNO) in patients with allergic rhinitis without asthma symptoms. OBJECTIVE: To investigate the role of treatment with montelukast on symptoms, eNO levels, and peripheral eosinophil counts of children with seasonal allergic rhinitis during pollen season. METHODS: A randomized, double-blind, parallel-group study performed between April and June 2005 in 57 children aged 7 to 14 years with seasonal allergic rhinitis was performed. The study comprised a 1-week screening period, a 1-week run-in period, and a 2-week treatment period with once daily montelukast, 5 mg, or matching placebo. RESULTS: No significant difference at baseline was found in symptom scores, eNO levels, and blood eosinophil counts between the treatment and placebo groups. After 2 weeks of montelukast treatment, improvements from the baseline in the daytime nasal, composite, and daytime eye symptoms scores were significantly greater in the montelukast group compared with the placebo group (P < .001, P < .001, and P < .01, respectively). A significant decrease was also found in eosinophil counts (P < .001) in the montelukast group compared with the placebo group after treatment. Montelukast treatment did not produce a significant effect on eNO levels compared with placebo (P = .96). CONCLUSION: Montelukast treatment provided significant improvement in symptoms and peripheral eosinophil counts of school-age children with seasonal allergic rhinitis; however, it did not show a significant effect on eNO levels.     

Efficacy and safety of dry powder fluticasone propionate in children with persistent asthma.

BACKGROUND: Flovent Diskus is a powder formulation of the inhaled corticosteroid fluticasone propionate (FP) delivered via a breath-actuated, multidose inhaler. OBJECTIVE: To determine the efficacy and safety of dry powder FP administered once or twice daily (200 microg per day) to children with persistent asthma. METHODS: Twelve-week, randomized, double-blind, placebo-controlled, multicenter trial with a 52-week, open-label extension. Children aged 4 to 11 were required to have pulmonary function 50% to 85% of predicted values. The population was stratified for baseline therapy (inhaled corticosteroid/cromolyn or bronchodilators only). After a 2-week placebo run-in, 242 patients received dry powder FP 200 microg each morning, dry powder FP 100 microg BID, or placebo for 12 weeks; 192 were rerandomized to the QD or BID regimen for an additional 52 weeks of open-label treatment. Primary endpoints were mean changes in FEV1 and morning PEF recorded at clinic visits. RESULTS: Both dry powder FP regimens significantly improved FEV1, evening PEF, and asthma symptoms at the double-blind phase endpoint (P < or = .017 compared with placebo). The BID regimen also significantly improved morning PEF and nighttime awakenings due to asthma (P < or = .005). Among patients previously treated with inhaled corticosteroids/cromolyn, improvements observed with the QD and BID regimens were similar. Patients switched from BID to open-label QD treatment showed additional improvements at week 52 generally comparable to patients who received the BID regimen during both phases. Fluticasone propionate was well tolerated for up to 64 weeks with few reports of drug-related adverse events or morning plasma cortisol abnormalities. CONCLUSIONS: Once daily dosing of dry powder FP 200 microg is an effective and convenient alternative for children whose asthma is controlled with a more frequent dosing regimen of inhaled corticosteroids.     

Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma.

OBJECTIVE: To evaluate the long-term effects of the anti-IgE antibody omalizumab in children with asthma. METHODS: This was a 28-week, double-blind, randomized, placebo-controlled trial with a 24-week open-label extension. In the core trial 225 children (ages 6 to 12 years) with moderate-to-severe allergic asthma requiring inhaled beclomethasone dipropionate (BDP) received omalizumab every 2 or 4 weeks, and 109 received placebo. BDP dosage was stable for weeks 1 to 16, then reduced during weeks 17 to 24 using strict safety criteria. The lowest dose for optimal asthma control was maintained for 4 more weeks. During the 24-week extension, all patients (n = 309) received open-label omalizumab in addition to other asthma medications. One-year safety data were analyzed. RESULTS: The incidence of adverse events in patients treated with omalizumab for 52 weeks was similar to those treated for 28 weeks in the core trial, which was generally comparable with placebo. In the 52-week omalizumab group, upper respiratory tract infection and headache were the most frequently reported adverse events (47.1% and 42.7%, respectively). Eleven patients (4.9%) reported urticaria, which resolved spontaneously or with antihistamine, except for 1 patient who was discontinued because of severe urticaria. No anaphylactic reactions or adverse events suggestive of serum sickness or immune complex formation occurred. No anti-omalizumab antibodies were detected in any of the children. There is no evidence that new or more serious adverse events occur with long-term omalizumab treatment. CONCLUSIONS: Long-term treatment with omalizumab is safe and well tolerated in children with allergic asthma.     

Leukotriene receptor antagonist, montelukast, can reduce the need for inhaled steroid while maintaining the clinical stability of asthmatic patients

BACKGROUND: Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma. OBJECTIVE: To determine whether the addition of montelukast could lead to a reduction in inhaled corticosteroid dose without a significant decrease in peak expiratory flow rate (PEFR). METHODS: After a 4-week run-in period, 191 moderate-to-severe asthmatic patients whose asthma had been well controlled with daily inhaled corticosteroid therapy (beclometasone dipropionate 800 to 1600 micro g/day), were randomly assigned to one of two treatments - placebo (n = 98) or montelukast 10 mg once daily (n = 93) - for a 24-week, multicentre, double-blind, treatment period. At the beginning of the active treatment period, the daily dose of inhaled corticosteroid was halved in all of the patients. In addition, the inhaled corticosteroid dose was subsequently titrated every 8 weeks, based on PEFR, asthma symptoms and beta-agonist use. RESULTS: After 8 weeks of a 50% reduction in inhaled corticosteroid use, morning PEFR increased by 5.3 +/- 32.3 L/min from baseline in patients receiving montelukast and significantly decreased by 6.9 +/- 29.0 L/min in those receiving placebo (P = 0.035). In addition, evening PEFR significantly decreased by 9.8 +/- 28.5 L/min (P = 0.003) in the placebo group, but was maintained in the montelukast group. In spite of a subsequent 50% reduction in the inhaled corticosteroid dose every 8 weeks, morning and evening PEFRs were maintained over the 24-week treatment period in the montelukast group; PEFR significantly decreased in the placebo group. There was a significant difference between the two groups with regard to morning PEFR, therapy score and asthmatic score at weeks 8, 16 and 24, as well as evening PEFR at week 8. However, the symptom scores were not significantly different between the two groups or within each group. CONCLUSION: These data suggest that montelukast reduces the need for inhaled corticosteroids while maintaining asthma control over a 24-week period. Therefore, montelukast may be useful for long-term treatment in patients with asthma who require high doses of inhaled corticosteroids.     

Antiallergic activity of topical lodoxamide on in vivo and in vitro models

Lodoxamide is an antiallergic drug acting as a mast-cell stabilizer, which is effective in the treatment of allergic conjunctivitis. The study aimed to evaluate the effect of lodoxamide eye-drops on the inflammatory early-phase reaction (EPR) changes induced by allergen-specific conjunctival challenge (ASCC). This was a cross-over, double-blind, placebo-controlled, randomized study, including 10 outpatients suffering from allergic rhinoconjunctivitis due to Parietaria judaica. Patients received one drop of lodoxamide tromethamine 0.1% or placebo 30 min before each ASCC. Clinical evaluation and cytologic assessment were done at baseline and 30 min after each ASCC. Lodoxamide induced a reduction in total symptom score and hyperemia during the EPR ( P <0.05). Lacrimation, itching/burning, and eyelid swelling were only slightly (nonsignificantly) reduced. Lodoxamide induced a reduction in the total number of inflammatory cells and neutrophils during the EPR ( P <0.02). Eosinophil and lymphocyte number and ICAM-1 expression showed only a slight, not statistically significant decrease. Placebo did not affect the studied parameters. Lodoxamide reduced early clinical events and cellular changes after ASCC consistently with its activity as mast-cell stabilizer. Moreover, lodoxamide was able to downregulate in vitro ICAM-1 expression on the continuously cultured, differentiated conjunctival cell line WK. This was shown both in basal conditions ( P <0.05) and upon interferon—gamma stimulation ( P <0.03), although at high concentration.     

The characterization of lodoxamide,a very active inhibitor of mediator release,in animal and human models of asthma

A most active biologue of disodium cromoglycate (DSCG) available, lodoxamide tromethamine (LT), has been studied and characterized pharmacologically, in animal and human models of asthma. It has self-tachyphylaxis, but has oral activity (lodoxamide ethyl) in rats, primates, and man. In rats (LT) was 2,500× more active than DSCG (ID₅₀=0.001 mg/kg), in primates the drug was also active by several routes (inhalation 1 g/kg, IV 0.001 mg/kg, and oral 10 mg/kg). In isolated rat peritoneal mast cells, the compound displayed a biphasic dose response inhibition to histamine release initiated by (48/80, anti-IgE, and the calcium ionophore A23,187) with IC₅₀ values of 0.1–50 M. The consistent finding relating to its mode of action was its ability to inhibit⁴⁵calcium flux into the mast cell in response to antigen or A23,187.Clinical evaluations of lodoxamide tromethamine showed that at aerosol doses of 1.0 mg or less, it demonstrated significant inhibitory activity against antigen or exercise induced bronchospasm. However, in pilot evaluation studies in clinical asthma settings, the compound could not be shown to spare bronchodilator usage, relative to placebo, or be shown to be more effective than placebo treated patients based on other clinical endpoints. The reason for rat and primate models not being predictive for human long-term clinical asthma in the characterization of anti-release compounds is not known.