The influence of antibodies on immunologic responses. I. The effect on the response to particulate antigen in the rabbit.

The influence of antibody on antibody formation to particulate antigen was examined in the rabbit with special reference to the importance of immunoglobulin type, the amount and relative proportion of antigen and antibody involved, and the specificity of this influence. 19S as well as 7S antibody was shown to be an effective inhibitor of antibody formation, although there was some evidence that 7S antibody was the more efficient of the two in doing so. The inhibitory effect of antibody was found to be specific for homologous antigenic determinants. Both 19S and 7S antibody were also able to enhance antibody formation. In contrast to the suppressive phenomenon, however, enhancement appeared to be nonspecific since antibody reactive with homologous (sheep red blood cell) determinants could enhance the response not only to homologous determinants but to heterologous (dinitrobenzene) determinants conjugated to the red blood cells as well. Smaller amounts of antibody were needed to enhance than to suppress antibody formation, and suppression and enhancement depended to some extent on the amount of antigen as well as to the amount of antibody used. The enhancing and suppressing influence of antibody on antibody formation appeared to be exerted concomitantly, for the response to some antigenic determinants was sometimes suppressed at the same time that the response to others was enhanced. It is suggested that enhancement or suppression of immunologic responses by antibody represents a different balance of at least two competing factors operating together: specific neutralization of appropriate determinants thus decreasing the total effective concentration of these determinants available to stimulate the formation of antibodies, and a nonspecific increase in the availability of antigen to immunologically competent cells.

The requirement of serine esterase function in complement-dependent erythrophagocytosis.

The p-nitrophenyl ethyl phosphonate esters have been shown to inhibit complement-dependent erythrophagocytosis when exposed to guinea pig polymorphonuclear leukocytes prior to the initiation of phagocytosis. Inhibition of phagocytosis occurred in a manner characteristic of the well-defined capacity of phosphonate esters to inactivate serine esterases: inhibition was irreversible, dependent upon the temperature of reaction and pH of the reaction medium, and proportional to the concentration of inhibitor used and the duration of exposure between leukocytes and inhibitor. Phosphonate inhibition was further shown to be independent of any general cell damaging effects of the compounds used. The phagocytic enzyme inhibited by phosphonate esters apparently exists in or on leukocytes in an already activated state prior to the initiation of the phagocytic process. The inhibitory profile of the activated phagocytic esterase was found to be essentially identical to the profile of inhibition previously obtained for the activated chemotactic esterase of rabbit polymorphonuclear leukocytes, suggesting that the same enzyme may function in both chemotaxis and phagocytosis. Various substrates including acetate esters reported to protect the activated chemotactic esterase from inhibition by phosphonate esters did not exhibit a clear protective effect in the phagocytic system and attempts to define the relationship between the two enzymes were unsuccessful. Suggestive evidence was also obtained for the requirement of the function of a second, activatable esterase in the phagocytic process.

An evaluation of levalbuterol HFA in the prevention of exercise-induced bronchospasm.

BACKGROUND: Exercise-induced bronchospasm (EIB) affects up to 90% of all patients with asthma. Objective. This study evaluated the ability of levalbuterol hydrofluoroalkane (HFA) 90 mug (two actuations of 45 microg) administered via metered dose inhaler (MDI) to protect against EIB in mild-to-moderate asthmatics. METHODS: This was a randomized, double-blind, placebo-controlled, two-way cross-over study. Patients with asthma (n = 15) were > or =18 years, had a > or =6-month history of EIB, > or = 70% baseline predicted forced expiratory volume in 1 second (FEV1), and a 20% to 50% decrease in FEV(1) after treadmill exercise challenge using single-blind placebo MDI. Levalbuterol or placebo was self-administered 30 minutes before exercise. Treatment sequences were separated by a 3-to 7-day washout period. Spirometry was performed predose, 20 minutes postdose/pre-exercise, and 5, 10, 15, 30, and 60 minutes post-exercise. The primary endpoint was the maximum percent decrease in FEV1 from baseline (postdose/pre-exercise). The percentage of protected (< or = 20% decrease in post-exercise FEV1) patients was also assessed. RESULTS: Levalbuterol had significantly smaller maximum percent post-exercise decrease in FEV1 compared with placebo (LS mean +/- SE; -4.8% +/- 2.8% versus -22.5% +/- 2.8%, respectively). For levalbuterol, 14/15 (93.3%) patients had < 20% decrease in post-exercise FEV1 compared with 8/15 (53.3%) for placebo (p = 0.0143). Treatment was well tolerated. CONCLUSION: Levalbuterol HFA MDI (90 microg) administered 30 minutes before exercise was significantly more effective than placebo in protecting against EIB after a single exercise challenge and was well tolerated. CLINICAL IMPLICATIONS: Levalbuterol HFA MDI when administered before exercise was effective in protecting adults with asthma from EIB.

Prevention of exercise-induced bronchospasm in pediatric asthma patients: A comparison of two salmeterol powder delivery devices.

BACKGROUND: A powder formulation of salmeterol has been shown to prevent exercise-induced bronchospasm (EIB) in asthmatic children and adults; however, the delivery device (Diskhaler; Glaxo Wellcome Inc, Research Triangle Park, NC) must be reloaded after 4 doses. A new multidose powder inhaler (Diskus) provides 60 doses of salmeterol in a blister pack presentation with a dose counter. OBJECTIVE: To evaluate the safety and efficacy of 50-microg salmeterol powder via two different delivery systems (Diskhaler and Diskus) in preventing EIB in asthmatic children. STUDY DESIGN: A randomized, double-blind, double-dummy, single-dose, placebo-controlled, three-way crossover study was conducted in 24 children 4 to 11 years of age demonstrating EIB and mild to moderate asthma. Serial forced expiratory volume in 1 second (FEV(1)) was measured before and after treadmill exercise challenges conducted at 1, 6, and 12 hours after study drug administration. Adverse events were also assessed. RESULTS: During all exercise challenges, EIB-mediated reductions in FEV(1) were minimized or prevented in patients receiving single doses of salmeterol powder compared with placebo. Single doses of salmeterol powder delivered via either system were equally effective in preventing EIB. There were no drug-related adverse events, cardiovascular, or other clinically relevant safety concerns. CONCLUSIONS: Single doses of salmeterol powder delivered by either delivery system are safe and effective in preventing EIB for >/=12 hours in asthmatic children.

Antihistamines: pharmacology and clinical use.

Antihistamines are a diverse group of drugs which possess the ability to inhibit various histaminic actions. By and large, they bear a certain structural resemblance to histamine, and act principally to prevent histamine-receptor interaction through competition with histamine for histamine receptors. Consequently, they are helpful therapeutically in preventing, rather than reversing, histaminic actions. Individual antihistaminic drugs act to inhibit histaminic action at one or another histamine receptor (H1 or H2-receptor), but not at both receptors. The large number of antihistaminics which have been available for many years and employed chiefly as 'antiallergic' drugs are classified as H1-receptor inhibitors; they are most effective therapeutically in inhibiting manifestations of histamine-induced wheal and erythema formation and pruritus. H2-receptor inhibitors, agents which are able to inhibit histamine-induced gastric acid secretion, have been developed more recently. Antihistaminics in general and H1-receptor inhibitors in particular, exert a wide variety of pharmacological activities. Their use is frequently accompanied by undesirable side-effects, notably CNS depression, dryness of mucous membranes, and gastrointestinal effects. Used judiciously and in proper dosage, antihistaminic drugs are helpful in the control of allergic disorders, allergic rhinitis and urticaria in particular; newly developed H2-receptor inhibitors show therapeutic promise in the treatment of peptic ulceration.

Effectiveness and tolerability of zafirlukast for the treatment of asthma in children.

OBJECTIVE: This study was undertaken to examine the dose-response relationship of zafirlukast (5 to 40 mg BID) and to assess the efficacy and tolerability of the 10-mg BID dose in school-aged children with mild to moderate asthma. BACKGROUND: The efficacy and tolerability of zafirlukast, an oral leukotriene-receptor antagonist, has been demonstrated in adolescents and adults aged > or = 12 years. METHODS: Data from 2 placebo-controlled, parallel-group, multicenter trials (trial 1, 4-week double-blind; trial 2, 6-week double-blind) were integrated. Children aged 5 to 11 years were randomly assigned to receive zafirlukast 5 mg BID (n = 99), 10 mg BID (n = 205), 20 mg BID (n = 105), 40 mg BID (n = 99), or placebo (n = 206). The primary outcome was change from baseline in forced expiratory volume in 1 second (FEV1) expressed as percent of predicted normal. Secondary outcomes were FEV1 (L), morning and evening peak expiratory flow, peak flow variability, short-acting beta2-agonist use, asthma episode score, and nights awakened by asthma. RESULTS: Mean baseline FEV1 was 76.5% of predicted. The greatest improvements were generally seen with zafirlukast 5 mg BID or 10 mg BID, with no additional clinically significant benefits seen at higher doses. The pooled data analysis showed that 10 mg BID compared with placebo significantly improved (P < 0.045) all efficacy outcomes except asthma-episode score and nights awakened with asthma. However, in the subset of children who had > or = 1 night awakened per week at baseline (zafirlukast 10 mg BID = 78; placebo = 86), 10 mg BID significantly reduced nights awakened (P = 0.009) (mean difference from placebo at end point = -0.81 night/wk). All zafirlukast doses were well tolerated and had tolerability profiles that were clinically indistinguishable from placebo. CONCLUSION: These results support the effectiveness and tolerability of the 10-mg BID dose of zafirlukast for the prophylaxis and chronic treatment of mild to moderate asthma in children.

Long-term safety of triamcinolone acetonide nasal aerosol for the treatment of perennial allergic rhinitis.

A 1-year, open-label extension of a 12-week, double-blind clinical trial was conducted to evaluate the long-term safety and efficacy of once-daily therapy with triamcinolone acetonide nasal aerosol (110, 220, or 440 micrograms) in 93 patients with perennial allergic rhinitis. All three doses of triamcinolone acetonide were associated with sustained improvement in allergic rhinitis symptoms over the course of 1 year, as evidenced by physicians' and patients' global evaluations, ratings of the nasal environment (appearance and color of the nasal mucosa, as well as the quality of nasal secretions), nasal eosinophil counts, and requirement for escape medication. Among patients who reported adverse clinical experiences, most were considered unrelated or remotely related to therapy. Few patients experienced nasal irritation or throat discomfort, and no serious adverse experiences were attributed to treatment. Among 6 patients who withdrew from the study because of adverse experiences, a possible drug relationship was cited in 2 individuals (1 with headache and 1 with nasal blood) and a remote relationship in 1 (with acne). No clinically meaningful changes in vital signs, physical examinations, or laboratory values were noted, and mean serum cortisol levels were not suppressed during long-term treatment. These findings demonstrate that both safety and efficacy are maintained during long-term once-daily therapy with triamcinolone acetonide nasal aerosol in patients with perennial allergic rhinitis.

Once-daily cetirizine effective in the treatment of seasonal allergic rhinitis in children aged 6 to 11 years: a randomized, double-blind, placebo-controlled study.

Cetirizine (once daily), a highly selective H1-antagonist, is efficacious for treating seasonal allergic rhinitis (SAR), perennial allergic rhinitis, and chronic idiopathic urticaria. A 4-week, randomized, double-blind, placebo-controlled trial investigated the safety and efficacy of cetirizine syrup (5 or 10 mg daily) in 209 children ages 6 to 11 years with SAR. Parents assisted patients in recording symptom severity (sneezing, nasal discharge, itchy eyes, itchy nose or mouth, conjunctivitis, nasal congestion) daily. A total symptom severity (TSS) score was derived from all symptoms, excluding nasal congestion. At baseline, TSS was comparable for all groups (range 6.8-7.0). Cetirizine 10 mg produced a significantly greater mean TSS reduction (3.2) than placebo (P < 0.05) over the treatment period. Cetirizine 5 mg once daily produced mean reductions in weekly symptom scores of 2.4; this did not differ statistically from placebo. Furthermore, cetirizine 10 mg significantly improved symptoms of itchy eyes, nose, or mouth. The most commonly reported adverse reactions to both cetirizine and placebo were headache, pharyngitis, and abdominal pain, which did not occur with an incidence statistically different from that of placebo. Once-daily cetirizine is safe for treating SAR in children ages 6-11 years. Once-daily cetirizine 10 mg provides effective improvement in symptoms and is well tolerated.

Effectiveness of azelastine nasal solution in seasonal allergic rhinitis.

Azelastine is a novel antiallergy medication currently under investigation for the treatment of allergic rhinitis and asthma. Pharmacologic studies in laboratory animals and in vitro model systems indicate that azelastine exerts multiple actions including modulation of airways smooth muscle response, interference with inflammatory processes, and inhibition of allergic reactions. In a previous controlled clinical trial, azelastine nasal solution (ASTELIN N.S.) demonstrated effectiveness in controlling symptoms of seasonal allergic rhinitis (SAR). The objective of this 2-week double-blind, parallel-group study was to further assess the effectiveness of azelastine nasal solution in improving allergic rhinitis symptoms. Two hundred forty-seven patients (> or = 12 years) with symptomatic SAR who satisfied a minimum symptoms score during a 1-week, single-blind, baseline evaluation period were randomized to receive azelastine 2 sprays per nostril bid, azelastine 2 sprays per nostril qd, chlorpheniramine 12 mg bid, or placebo using a double-dummy technique to insure blinding. The primary efficacy variables were changes in Major Symptom Complex (nose blows, sneezes, runny nose/sniffles, itch nose, and watery eyes) and Total Symptom Complex (Major plus itchy eyes/ears/throat/palate, cough, and postnasal drip) severity scores. Patients treated with azelastine nasal solution qd and bid had mean percent improvements in the Total and Major Symptom Complex severity scores that were clinically significant (> or = 50% improvement over placebo) after both weeks, at endpoint, and overall. The improvements for the azelastine bid group were statistically significant (P < or = .05) at all evaluation points. Adverse experiences occurred infrequently, and none was considered serious or potentially limiting to the clinical utility of the nasal solution.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic rhinitis in children.

Children are not small adults, and although many features of chronic rhinitis in children are similar to those in adults, there are significant differences in etiologic factors, manner of presentation, and therapy. The fact that children are growing and developing also has special therapeutic implications in the management of rhinitis.

The relationship between allergy and croup.

The relationship between allergy and croup is examined addressing possible associations between croup and IgE antibody production, and between croup and atopic allergic disorders irrespective of the presence or absence of IgE antibody. A case can be made for an increased association between allergy and recurrent croup. Children with croup are more likely to produce IgE antibodies than normal children without croup and there is an association between the production of IgE antibody to certain respiratory viral infections and the development of croup. There also is an increased association between croup, asthma and nonspecific bronchial hyperresponsiveness associated with asthma.

Long-acting beta 2-agonist salmeterol compared with albuterol in maintenance asthma therapy.

BACKGROUND: Salmeterol is the first long-acting inhaled bronchodilator available in the United States. This paper summarizes the combined results of the two pivotal US studies evaluating the efficacy of this beta 2-agonist in the maintenance treatment of asthma. METHODS: Salmeterol (42 micrograms twice daily) was compared with the short-acting beta 2-agonist albuterol (180 micrograms four times daily) in two double-blind, randomized studies involving 556 patients with mild-to-moderate asthma. All patients could use supplemental inhaled albuterol as needed for breakthrough symptoms, and patients were allowed to continue to use inhaled corticosteroids during the study. RESULTS: Salmeterol, 42 micrograms bid, was more effective than albuterol, 180 micrograms qid, or placebo in maintaining bronchodilation, as measured by FEV1 over 12-hour periods and morning and evening peak expiratory flow rates. Patients who received salmeterol also experienced significantly greater increases in the number of days without asthma symptoms and the percentage of nights without awakenings compared with either the albuterol or placebo group. There was no difference between patients who received concomitant inhaled corticosteroids and those who did not with respect to pulmonary-function measurements or improvements in symptoms. There was no loss of asthma control with salmeterol over the 12-week period. CONCLUSIONS: Salmeterol, 42 micrograms twice daily, was more effective than albuterol, 180 micrograms four times daily, or placebo (plus as-needed albuterol) in improving pulmonary function and controlling asthma symptoms.

Bronchial asthma. A perspective from childhood to adulthood.

Asthma is a greatly underdiagnosed disorder in childhood. Even when recognized, its severity generally is underestimated. It is responsible for much physical, social, and economic hardship due to poor control and inadequate treatment from poor understanding of the disease. Nonallergic factors alone may be of prime importance in the disorder or may act in conjunction with "allergy." Asthma commonly is not "outgrown," although it may become less conspicuous, often to surface overtly in adulthood. It is important to recognize and treat asthma in childhood, not only because of acute disease morbidity and potential mortality but also because of its possible prolonged morbidity in later childhood and in adulthood.

Pathophysiology of the inflammatory response.

Airway allergic reactions enlist diverse cells and a multitude of chemical mediators that are responsible for the clinical symptoms of allergic rhinitis and asthma. Experiments in vitro and in animal models, as well as increasingly numerous studies in atopic human subjects, are revealing that an orchestrated continuum of cellular activities leading to airway allergic inflammation is set in motion in genetically predisposed individuals at the first exposure to a novel antigen. This sensitization step likely depends on differentiation of and cytokine release by T(H)2 lymphocytes. Among T(H)2-derived cytokines, IL-4 potently enhances B-lymphocyte generation of immunoglobulin E antibodies. The attachment of these antibodies to specific receptors on airway mast cells sets the stage for an acute inflammatory response on subsequent antigen exposure because IgE cross-linking by a bound antigen activates mast cells to release numerous inflammatory mediators. These mast cell-derived mediators collectively produce acute-phase clinical symptoms by enhancing vascular leak, bronchospasm, and activation of nociceptive neurons linked to parasympathetic reflexes. Simultaneously, some mast cell mediators up-regulate expression on endothelial cells of adhesion molecules for leukocytes (eosinophils, but also basophils and lymphocytes), which are key elements in the late-phase allergic response. Chemoattractant molecules released during the acute phase draw these leukocytes to airways during a relatively symptom-free recruitment phase, where they later release a plethora of cytokines and tissue-damaging proteases that herald a second wave of airway inflammatory trauma (late-phase response). The repetition of these processes, with the possible establishment in airway mucosa of memory T lymphocytes and eosinophils that are maintained by paracrine and autocrine cytokine stimulation, may account for airway hypersensitivity and chronic airway symptoms.

Observations on the histamine forming capacity of mouse tissues and of its potentiation after adrenaline.

1. The histamine forming capacity (h.f.c.) was determined in minced or homogenized skin, lung, skeletal muscle or stomach of mice weighing 18-20 g using radioactive (14)C histidine as substrate and determining the radioactive (14)C histamine formed by conversion to its dibenzenesulphonyl derivative.2. The optimal pH for the formation of histamine was 7.0-7.5 for lung and skin, 6.5-7.5 for skeletal muscle. For stomach a more acid pH was optimal and depended on substrate concentration.3. The formation of histamine increased with an increase of the substrate histidine.4. The formation of histamine was not affected by the presence in the incubation mixture of chlorpromazine, pyridoxal-5-phosphate, non-radioactive histamine or benzene. The addition of aminoguanidine slightly increased the formation in skin, lung and skeletal muscle but not in stomach. The formation was unchanged when incubation was in an atmosphere of nitrogen instead of air.5. H.f.c. for stomach of normally fed mice varied 170-fold. For stomachs of mice unfed for 16 hr, h.f.c. was much lower and it varied only sevenfold.6. Injection of adrenaline into mice increased h.f.c. of the skin, lung and skeletal muscle. With skin tissue a linear log. dose log. response relation was demonstrated. The injection of adrenaline caused however either no or only a slight increase in the h.f.c. of stomach tissue.7. The effect of adrenaline on h.f.c. in skin, lung and skeletal muscle was not abolished by alpha- or beta-adrenergic blocking agents either injected separately or together before the injection of adrenaline.

Once-daily budesonide inhalation powder (Pulmicort Turbuhaler) maintains pulmonary function and symptoms of asthmatic children previously receiving inhaled corticosteroids.

BACKGROUND: The incidence of pediatric asthma has increased dramatically over the past few decades, with approximately 5% of American children affected by the disease. OBJECTIVES: To compare the efficacy and safety of once-daily budesonide Turbuhaler with placebo in asthmatic children previously treated with orally inhaled corticosteroids. METHODS: This randomized, double-blind, placebo-controlled, multicenter (17 centers) study included 274 male and female children (aged 6 to 17 years) with a history of asthma for at least the previous 6 months. Patients received placebo or budesonide Turbuhaler (200 microg or 400 microg) once daily for 12 weeks. Efficacy variables included mean changes from baseline in forced expiratory volume in 1 second (FEV1), AM and PM peak expiratory flow rates (PEFRs), nighttime and daytime asthma symptom severity scores, patient discontinuations, use of beta2-agonists as breakthrough medication, forced vital capacity (FVC), and midexpiratory flow rate between 25% and 75% of FVC (FEF25%-75%). Safety was evaluated by adverse events, physical examinations, vital signs, and laboratory tests. RESULTS: Baseline characteristics were comparable among treatment groups. Percentage of predicted FEV1 at baseline was 76.6 +/- 6.9 for placebo, 77.5 +/- 7.1, and 77.0 +/- 7.8 for the budesonide Turbuhaler 200 microg and 400 microg groups, respectively. Significantly (P < or = 0.024) more placebo patients (24%) discontinued treatment because of disease deterioration or no improvement than budesonide Turbuhaler 200 microg (11%) or 400 microg patients (10%). Patients receiving budesonide Turbuhaler experienced significant improvements in FEV1 compared with patients receiving placebo (P < or = 0.015). Significant (P < or = 0.041) improvements over placebo also were observed in AM and PM PEFRs, FVC, FEF25%-75%, nighttime and daytime asthma symptoms, and amount of beta2-agonist used in both budesonide Turbuhaler groups. Adverse events were generally mild or moderate in intensity and similar among treatment groups. CONCLUSIONS: Once-daily budesonide Turbuhaler is effective and safe in children with persistent asthma previously maintained on at least twice-daily dosing regimens of inhaled corticosteroids.