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Background: Few studies have examined how developing obesity in early adulthood affects the course of asthma., Objective: We analyzed lung function and asthma impairment and risk among nonobese children with asthma, comparing those who were obese in young adulthood with those who remained nonobese., Methods: We carried out the post hoc analysis of 771 subjects with mild to moderate asthma who were not obese (pediatric definition, body mass index [BMI] < 95th percentile) when enrolled in the Childhood Asthma Management Program at ages 5-12 years. The subjects were then followed to age 20 years or more. For visits at ages 20 years or more, spirometry values as percent predicted and recent asthma symptom scores and prednisone exposure were compared between 579 subjects who were nonobese at all visits and 151 who were obese (adult definition of BMI ≥ 30 kg/m(2)) on at least 1 visit (median number of visits when obese = 4, IQR 2-7)., Results: Compared with participants who were nonobese (BMI 23.4 ± 2.6 kg/m(2)), those who became obese (BMI 31.5 ± 3.8 kg/m(2)) had significant decreases in forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) (P < .0003) and FEV1 (P = .001), without differences in FVC (P = .15) during visits at ages 20 years or more. For each unit increase of BMI, FEV1 percent predicted decreased by 0.29 (P = .0009). The relationship between BMI and lung function was not confounded by sex or BMI at baseline. Asthma impairment (symptom scores) and risk (prednisone use) did not differ between the 2 groups., Conclusion: Becoming obese in early adulthood was associated with increased airway obstruction, without impact on asthma impairment or risk., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Although recent studies have identified the presence of phenotypic clusters in asthmatic patients, the clinical significance and temporal stability of these clusters have not been explored., Objective: Our aim was to examine the clinical relevance and temporal stability of phenotypic clusters in children with asthma., Methods: We applied spectral clustering to clinical data from 1041 children with asthma participating in the Childhood Asthma Management Program. Posttreatment randomization follow-up data collected over 48 months were used to determine the effect of these clusters on pulmonary function and treatment response to inhaled anti-inflammatory medication., Results: We found 5 reproducible patient clusters that could be differentiated on the basis of 3 groups of features: atopic burden, degree of airway obstruction, and history of exacerbation. Cluster grouping predicted long-term asthma control, as measured by the need for oral prednisone (P < .0001) or additional controller medications (P = .001), as well as longitudinal differences in pulmonary function (P < .0001). We also found that the 2 clusters with the highest rates of exacerbation had different responses to inhaled corticosteroids when compared with the other clusters. One cluster demonstrated a positive response to both budesonide (P = .02) and nedocromil (P = .01) compared with placebo, whereas the other cluster demonstrated minimal responses to both budesonide (P = .12) and nedocromil (P = .56) compared with placebo., Conclusion: Phenotypic clustering can be used to identify longitudinally consistent and clinically relevant patient subgroups, with implications for targeted therapeutic strategies and clinical trials design.

Rationale: Low vitamin D levels are associated with asthma and decreased airway responsiveness. Treatment with inhaled corticosteroids improves airway responsiveness and asthma control., Objectives: To assess the effect of vitamin D levels on prebronchodilator FEV(1), bronchodilator response, and responsiveness to methacholine (PC(20), provocative concentration of methacholine producing a 20% decline in FEV(1)) in patients with asthma treated with inhaled corticosteroids., Methods: We measured 25-hydroxyvitamin D levels in the serum of children with persistent asthma at the time of enrollment in the Childhood Asthma Management Program. We divided subjects into the vitamin D sufficiency (>30 ng/ml), insufficiency (20-30 ng/ml), and deficiency (<20 ng/ml) groups. Covariates included age, treatment, sex, body mass index, race, history of emergency department visits, hospitalizations, and season that vitamin D specimen was drawn. Our main outcome measures were change in prebronchodilator FEV(1), bronchodilator response, and PC(20) from enrollment to 8-12 months., Measurements and Main Results: Of the 1,024 subjects, 663 (65%) were vitamin D sufficient, 260 (25%) were insufficient, and 101 (10%) were deficient. Vitamin D-deficient subjects were more likely to be older, African American, and have a higher body mass index compared with the vitamin D-sufficient and insufficient subjects. In the inhaled corticosteroid treatment group, prebronchodilator FEV(1) increased from randomization to 12 months by 140 ml in the vitamin D-deficient group and prebronchodilator FEV(1) increased by 330 ml in the vitamin D insufficiency group and by 290 ml in the vitamin D sufficiency group (P = 0.0072), in adjusted models., Conclusions: In children with asthma treated with inhaled corticosteroids, vitamin D deficiency is associated with poorer lung function than in children with vitamin D insufficiency or sufficiency.

Background: Asthma therapy is typically prescribed and titrated based on patient or parent self-report of symptoms. No longitudinal studies have assessed the relationship between symptoms and severe asthma exacerbations in children. The goal of our study was (1) to assess the association of asthma symptoms with severe asthma exacerbations and (2) to compare predictors of persistent asthma symptoms and predictors of severe asthma exacerbations., Methods: The Childhood Asthma Management Program was a multicenter clinical trial of 1,041 children randomized to receive budesonide, nedocromil, or placebo (as-needed β-agonist). We conducted a post hoc analysis of diary cards that were completed by subjects on a daily basis to categorize subjects as having persistent vs intermittent symptoms. We defined a severe asthma exacerbation as an episode requiring ≥ 3 days use of oral corticosteroids, hospitalization, or ED visit due to asthma based on self-report at study visits every 4 months., Results: While accounting for longitudinal measures, having persistent symptoms from asthma was significantly associated with having severe asthma exacerbations. Predictors of having persistent symptoms compared with intermittent symptoms included not being treated with inhaled corticosteroids, lower FEV(1)/FVC ratio, and a lower natural logarithm of provocative concentration of methacholine producing a 20% decline in FEV(1) (lnPC(20)). Predictors of having one or more severe asthma exacerbations included younger age, history of hospitalization or ED visit in the prior year, ≥ 3 days use of oral corticosteroids in the prior 3 months, lower FEV(1)/FVC ratio, lower lnPC(20), and higher logarithm to the base 10 eosinophil count; treatment with inhaled corticosteroids was predictive of having no severe asthma exacerbations., Conclusions: Patients with persistent symptoms from asthma were more likely to experience severe asthma exacerbations. Nevertheless, demographic and laboratory predictors of having persistent symptoms are different from predictors of severe asthma exacerbations. Although symptoms and exacerbations are closely related, their predictors are different. The current focus of the National Asthma Education and Prevention Program guidelines on the two separate domains of asthma control, impairment and risk, are supported by our analysis.

Vascular endothelial growth factor (VEGF) is an angiogenic factor implicated in asthma severity. The objective of the present study was to determine whether VEGF single nucleotide polymorphisms (SNPs) are associated with asthma, lung function and airway responsiveness. The present authors analysed 10 SNPs in 458 white families in the Childhood Asthma Management Program (CAMP). Tests of association with asthma, lung function and airway responsiveness were performed using PBAT software (Golden Helix, Inc. Bozeman, MT, USA; available at www.goldenhelix.com). Family and population-based, revpeated measures analysis of airflow obstruction were conducted. Replication studies were performed in 412 asthmatic children and their parents from Costa Rica. Associations with asthma, lung function and airway responsiveness were observed in both cohorts. SNP rs833058 was associated with asthma in both cohorts. This SNP was also associated with increased airway responsiveness in both populations. An association of rs4711750 and its haplotype with forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) ratio in both cohorts was observed. Longitudinal analysis in CAMP confirmed an association of rs4711750 with FEV(1)/FVC decline over approximately 4.5 yrs of observation. VEGF polymorphisms are associated with childhood asthma, lung function and airway responsiveness in two populations, suggesting that VEGF polymorphisms influence asthma susceptibility, airflow obstruction and airways responsiveness.

Rationale: Polymorphisms in the gene for transforming growth factor-beta1 (TGFB1) have been associated with asthma, but not with airway responsiveness or disease exacerbations in subjects with asthma., Objectives: To test for association between single nucleotide polymorphisms (SNPs) in TGFB1 and markers of asthma severity in childhood., Methods: We tested for the association between nine SNPs in TGFB1 and indicators of asthma severity (lung function, airway responsiveness, and disease exacerbations) in two cohorts: 416 Costa Rican parent-child trios and 465 families of non-Hispanic white children in the Childhood Asthma Management Program (CAMP). We also tested for the interaction between these polymorphisms and exposure to dust mite allergen on asthma severity., Measurements and Main Results: The A allele of promoter SNP rs2241712 was associated with increased airway responsiveness in Costa Rica (P = 0.0006) and CAMP (P = 0.005), and the C allele of an SNP in the promoter region (rs1800469) was associated with increased airway responsiveness in both cohorts (P

Background: Among asthmatic subjects, bronchodilator response (BDR) to inhaled beta(2)-adrenergic agonists is variable, and the significance of a consistent response over time is unknown., Objective: We assessed baseline clinical variables and determined the clinical outcomes associated with a consistently positive BDR over 4 years in children with mild-to-moderate persistent asthma., Methods: In the 1041 participants in the Childhood Asthma Management Program, subjects with a change in FEV(1) of 12% or greater (and 200 mL) after inhaled beta(2)-agonist administration at each of their yearly follow-up visits (consistent BDR) were compared with those who did not have a consistent BDR., Results: We identified 52 children with consistent BDRs over the 4-year trial. Multivariable logistic regression modeling demonstrated that lower baseline prebronchodilator FEV(1) values (odds ratio, 0.71; P < .0001), higher log10 IgE levels (odds ratio, 1.97; P = .002), and lack of treatment with inhaled corticosteroids (odds ratio, 0.31; P = .009) were associated with a consistent BDR. Individuals who had a consistent BDR had more hospital visits (P = .007), required more prednisone bursts (P = .0007), had increased nocturnal awakenings caused by asthma (P < .0001), and missed more days of school (P = .03) than nonresponders during the 4-year follow-up., Conclusions: We have identified predictors of consistent BDR and determined that this phenotype is associated with poor clinical outcomes.

Rationale: Airway responsiveness is a prognostic marker for asthma symptoms in later life., Objectives: To evaluate characteristics responsible for persistence of airway responsiveness in children with asthma., Methods: A total of 1,041 children, initially aged 5-12 years, with mild to moderate persistent asthma enrolled in the Childhood Asthma Management Program (CAMP) were studied prospectively for 8.6 +/- 1.8 years with methacholine challenges yearly., Measurements and Main Results: Least squares geometric mean models were fit to determine effects of sex and age on airway responsiveness (provocative concentration producing 20% decrease in FEV(1) [PC(20)]). Multiple linear regression analysis was performed to determine factors at baseline and over time, which were associated with PC(20) at end of follow-up. A total of 7,748 methacholine challenges were analyzed. PC(20) increased with age, with boys having greater increase after age 11 years than girls (P < 0.001). The divergence coincided with the mean age for Tanner stage 2. Postpubertal girls had greater airway responsiveness, even after adjustment for FEV(1) and other potential confounders. Although multivariable regression analyses noted a variety of factors that influenced airway responsivness in both sexes, a history of hay fever (beta= -0.30, P = 0.005), respiratory allergy (beta= -0.32, P = 0.006), or recent inhaled corticosteroid usage (beta= -0.18, P = 0.02) were associated with decrements in final log PC(20) only in girls., Conclusions: Airway responsiveness (PC(20)) is more severe in the postpubertal female with asthma than in males. Although there are factors associated with airway responsiveness in both males and females, sex-specific factors may contribute to new insights into asthma pathogenesis.

Background: The purpose of this study was to determine the effects of diphenhydramine HCl and Nedocromil sodium for the prevention of postsurgical adhesion formation in rat model., Methods: Sixty adult female rats were anesthetized by 5mg/kg ketamine hydrochloride. After opening the abdominal wall, a 2 cm(2) peritoneal layer was excised from the left abdominal wall and 10 longitudinal incisions of 2 to 3 cm in length were made on the right parietal peritoneum. The abdominal wall was closed with 4/0 atraumatic continuous nylon sutures. Group I was the control group, group II was given 10mg/kg diphenhydramine HCl, group III was given 100mg/kg Nedocromil sodium, and group IV was administered both drugs in the above doses. All the drugs were instilled into the peritoneal cavity after abdominal closure except Nedocromil sodium which was administered in two separate doses 30 min before surgery and just after abdominal closure. Relaparatomy was performed 2 weeks after the initial surgery and abdominal adhesions were scored. Kruskal-Wallis and Mann-Whitney U-test were used for the statistical evaluation., Results: The mean+/-S.D. (median) of adhesion scores were 2.5+/-0.90 (2.0), 1.58+/-0.99 (1.0), 0.92+/-0.86 (1.0) and 1.75+/-0.75 (2.0) in group I, II, III and IV, respectively. There were significant differences between the scores of groups I and II (P=0.033), groups I and III (P<0.001), and groups I and IV (P=0.033)., Conclusion: Both diphenhydramine HCl and Nedocromil sodium reduced postoperative abdominal adhesions separately and in combination with each other in our study. Average score of adhesion formation was lowest in the group that was administered Nedocromil sodium. More research is needed in order to discover any positive effect of these drugs as antiadhesive agents in humans.

The influence of processing on the performance of carrier material used in dry powder inhalers was investigated. alpha-Lactose monohydrate crystals were processed by ball milling for cumulative time durations and their properties evaluated. As expected, milling reduced the median particle diameter while increasing fine particulate (<10 microm) and amorphous levels. Recrystallization of these partially amorphous samples resulted in a reduction in fines, elimination of amorphous material with little change in median diameter. To study the effects of processing on aerosolization performance, blends of lactose monohydrate with a model drug (nedocromil sodium trihydrate), were evaluated using an in vitro multistage liquid impinger (MSLI) model. In general, milling and storage of the carriers at high humidity (prior to blending) had a significant (ANOVA, p < 0.05) effect on the fine particle fractions (FPF; <6.8 microm). These effects were attributed predominantly to the fines content, showing a strong correlation between increased fines and FPF (R(2) = 0.974 and 0.982 for milled and recrystallized samples, respectively). However, this relationship only existed up to 15% fines concentration, after which agglomerate-carrier segregation was observed and FPF decreased significantly. These results suggest that, after processing, high-dose drug formulation performance is dominated by the presence of fines., ((c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association.)

Accumulating evidence indicates that there are at least two phenotypes of wheezing in preschool years with distinct natural history. Frequent wheezing in the first 3 years of life with risk factors for asthma (e.g., eczema, maternal asthma) predicts symptoms in older age, while infrequent viral-associated wheezing without risk factors for asthma has a benign prognosis. This systematic review summarizes evidence on the use of anti-inflammatory medications in preschool children with wheezing. Literature search was performed using Medline and the Cochrane Library. Retrieved articles were critically appraised. Episodic use of high-dose inhaled corticosteroids (>1,600 mcg/day of beclomethasone) may ameliorate severity of intermittent viral-associated wheezing. Maintenance inhaled corticosteroids can control symptoms in children with frequent wheezing associated with risk factors for asthma. Inhaled corticosteroids do not alter the natural history of wheezing even when started early in life and could have a negative impact on linear growth rate. Short courses of oral corticosteroids have been proposed as an effective measure to control exacerbations of symptoms although there is little evidence supporting their use. Some studies support the administration of non-steroidal anti-inflammatory medications (leukotriene pathway modifiers, cromones, methylxanthines) for mild frequent wheezing. Maintenance inhaled corticosteroids is the most effective measure for controlling frequent wheezing in preschool children, especially when accompanied by risk factors for asthma. This treatment does not affect the natural history of wheezing, although deceleration of linear growth rate is the most commonly recognized systemic adverse effect., (Copyright 2007 Wiley-Liss, Inc.)

Stabilization of mast cells plays a key mechanism to protect gastrointestinal tract from injury. This study presents a comparative evaluation of mast cell stabilizers nedocromil sodium (NDS) and sodium cromoglycate (SCG) in experimental gastric and duodenal ulcers in rats. Wistar rats of either sex were used in this study. Both NDS and SCG, in the doses of 10, 30 and 100 mg/kg were given intraperitoneally for gastric secretion studies and by gavage for antiulcer studies. Acid secretion studies were undertaken in pylorus-ligated rats. Gastric lesions were induced by water immersion restraint stress (WIRS), indomethacin and ethanol whereas duodenal ulcers were produced by cysteamine. The level of glutathione (GSH) and gastric wall mucus were measured in glandular stomach of rats following ethanol-induced gastric lesions. SCG was more effective than NDS in preventing WIRS- and indomethacin-induced gastric lesions whereas reverse was true in ethanol- and cysteamine-induced ulcers. All the 3 doses of SCG offered almost equal protection against WIRS-induced gastric lesions whereas only medium and high dose of NDS provided significant protection in this model of ulcer. NDS significantly inhibited cysteamine-induced duodenal ulcers whereas SCG failed to do so. Pretreatment with NDS or SCG significantly and dose-dependently protected gastric mucosa against ethanol-induced injury, while the former drug appeared to be more effective. The cytoprotective effects of these two drugs were accompanied by the attenuation of ethanol-induced depletion of gastric wall mucus and GSH. The differential effects of NDS and SCG against various gastric lesions rationalize the possible benefits of a combined therapy (NDS+SCG) for the treatment of complex gastroduodenal ulcers.

Background: The preventive use of medications has been proposed to be effective in the treatment of seasonal rhinitis., Objective: To evaluate the efficacy and safety of mometasone furoate and nedocromil sodium nasal sprays as prophylactic treatment for moderate to severe seasonal allergic rhinitis (SAR)., Patients: Sixty-one patients were recruited from 3 referral allergy centers. Inclusion criteria were history of SAR for 2 years or longer, sensitization to relevant local pollen (grasses, Parietaria, and olive), and age older than 12 years., Methods: An open-label, randomized, parallel-group, "real-life" study design was used. Patients received mometasone furoate nasal spray once daily or nedocromil sodium nasal spray 3 times daily starting 2 to 4 weeks before the pollen season and continuing for up to 4 months. Instructions regarding the use of additional medications were given. Diary cards recording symptoms, use of medication, and adverse events were kept by the patients., Results: All 61 patients completed the study. The prophylactic use of mometasone furoate vs nedocromil sodium led to significantly more days without symptoms (75.1% vs 54.5%; P < .001). The mometasone furoate group also had lower nasal symptom scores (mean, 1.4 vs 2.9; median, 0 vs 2; P < .001) and was more satisfied (93.1% vs 43.5%; P < .001). No serious adverse event was recorded, and there was no difference between the treatments in any adverse event., Conclusions: Prophylactic administration of mometasone furoate before the pollen season is safe and may lead to improved control of SAR compared with the use of nedocromil sodium.

Background: Left ventricular (LV) hypertrophy and dilation are important compensatory responses to chronic volume overload; however, the mechanisms responsible for this LV remodeling have not been well characterized. Previous observations that the number of myocardial mast cells are increased in congestive heart failure (CHF) suggested the hypothesis that mast cells might be involved in the ventricular remodeling induced by a chronic volume overload., Methods and Results: Accordingly, the intent of this study was to determine the contribution of mast cells to LV remodeling, dysfunction, and morbidity/mortality secondary to CHF in the infrarenal aortocaval fistula model of sustained volume overload. To this end, LV end-diastolic pressure, size, and function (ie, isovolumetric pressure-volume relations in the blood-perfused isolated heart) were assessed in both nedocromil sodium treated and untreated rats at 8 weeks after fistula and compared with age-matched controls. Nedocromil, a mast cell-stabilizing drug, effectively prevented the LV dilation and decreased contractility seen in the untreated fistula group in a dose-dependent fashion, resulting in a significant reduction in the incidence of morbidity/mortality from CHF., Conclusion: The ability of mast cell stabilization to prevent ventricular dilation induced by chronic volume overload identifies a key role for mast cells in the regulation of myocardial remodeling.

Over and beyond the avoidance of allergies, prophylactic measures can also prevent the development of lower airway disease from upper airway disease, for example, bronchial asthma from allergic rhinitis. A further protective effect can be achieved by reducing both prenatal and postnatal allergens. A major concept of prevention--not merely of pulmonary function changes and the development of allergies--is the avoidance of exposure to passive smoking. With regard to pharmacotherapeutic agents, both official approval for their use by the respective age group, and the dearth of study-based data need to be taken into account. To ensure the successful application of inhalative agents, the use of appropriate inhalation aids as also ensuring the correct inhalation technique are urgently recommended, particularly in the case of children and adolescents.

Background: The value of sputum induction in pediatric asthma lies in its potential to directly and noninvasively assess airway inflammation in children, because bronchoscopy and biopsy carry some risk. The Childhood Asthma Management Program (CAMP) study was designed to evaluate the long-term effects of budesonide and nedocromil compared with placebo in children with mild to moderate asthma across 8 centers., Objective: At the Denver CAMP site, we sought to evaluate the safety of sputum induction, to determine differences in airway inflammation between treatment groups by using induced sputum analysis, and to examine correlations between other biomarkers and sputum eosinophils., Methods: Sputum induction was performed, and exhaled nitric oxide, circulating eosinophil counts, and serum eosinophil cationic protein were obtained at treatment discontinuation and after washout. Spirometry and a methacholine challenge were also performed according to the CAMP protocol., Results: Ninety of 117 children provided an adequate sputum sample for analysis. In 9 subjects (3 nedocromil and 6 placebo), sputum induction resulted in bronchospasm. These subjects had greater disease severity, as measured by a lower median prebronchodilator FEV 1 percentage predicted (85.0% vs 96.0%; P =.024) and FEV 1 /FVC ratio (70.0% vs 79.0%; P =.0008); greater bronchodilator reversibility (16.5% vs 6.8%; P =.004); higher serum IgE (1390.0 vs 495.0 ng/mL; P =.017) and circulating eosinophil count (757.0 vs 282.0/mm 3; P =.04); greater use of prednisone (1.9 vs 0.9 courses per 100 person-years; P =.05); and greater supplemental inhaled steroid doses (85.3 vs 0 mg; P =.016). At treatment discontinuation, budesonide-treated patients had a lower median (1st, 3rd quartile) sputum percentage eosinophil (SPEos) (0.2% [0%, 1.2%] vs 0.8% [0.2%, 4.6%]; P =.03) compared with those treated with placebo; no significant difference was noted between nedocromil- and placebo-treated patients. Higher SPEos at the time of treatment discontinuation was associated with asthma worsening that required rescue prednisone (n = 23) during the washout period compared with patients who remained stable (3.6% [0.4%, 6.4%] vs 0.6% [0.2%, 3.2%] SPEos; P =.023). Finally, greater SPEos was associated with atopy, higher bronchodilator reversibility, lower FEV 1 /FVC ratio, higher exhaled nitric oxide levels, circulating eosinophils, sputum and serum eosinophil cationic protein, more prednisone courses during the treatment period, and greater asthma severity., Conclusions: Sputum induction is a relatively noninvasive and safe procedure that can provide information on eosinophilic inflammation and treatment response and is also associated with several measures of asthma control. However, this procedure still remains a research tool in asthma because of its requirements for technical expertise.

Asthma severity can be judged by measurements of symptoms, lung function, and medication requirements. The objective was to compare the effect of a 4-wk monotherapy with low-dose triamcinolone, montelukast and nedocromil on asthma control, lung function, eosinophil blood count, and bronchial hyper-reactivity in children with mild to moderate asthma allergic to dust mite. Two hundred fifty-six children, aged 6-18 yr, with mild to moderate asthma, participated in an 8-wk study. This was a three-arm, randomized no blinding or placebo pragmatic trial comparing the effect of triamcinolone acetonide (400 microg/day), inhaled nedocromil and montelukast sodium on clinical parameters of asthma [score, forced expiratory volume in 1 s (FEV(1))], PC20H, and eosinophil blood count. Two hundred forty-six children completed the study. After 4 wk of treatment with triamcinolone and montelukast, FEV(1) and PC20H significantly increased, and mean total symptoms score and mean number of eosinophil count in serum significantly decreased. Triamcinolone had a stronger effect on PC20H than montelukast. Nedocromil improved total asthma symptoms score and lung function. There was a reduction in the daytime and night-time symptom scores after treatment with all three drugs. Triamcinolone and montelukast had a stronger effect on asthma symptoms than nedocromil. There were statistically significant differences in reduction of nocturnal asthma symptoms between the triamcinolone and nedocromil groups (p < 0.001) and between montelukast and nedocromil (p = 0.001) groups, but not between the triamcinolone and montelukast groups. There was a reduction in beta-agonists use after treatment with all three drugs, with the strongest effect of triamcinolone. The study showed the strongest effect of low-dose inhaled steroids on clinical symptoms, lung function, bronchial hyper-reactivity and eosinophil blood count when compared to other asthma medications.

Exercise-induced asthma (EIA) refers to the transient narrowing of the airways that occurs after vigorous exercise in 50-60% of patients with asthma. The need to condition the air inspired during exercise causes water to be lost from the airway surface, and this is thought to cause the release of inflammatory mediators (histamine, leukotrienes, and prostaglandins) from mast cells. EIA is associated with airway inflammation and its severity is markedly reduced following treatment with inhaled corticosteroids. Drugs that inhibit the release of mediators and drugs that inhibit their contractile effects are the most successful in inhibiting EIA. Single doses of short-acting beta(2)-adrenoceptor agonists, given as aerosols immediately before exercise, are very effective in the majority of patients with asthma, providing about 80% protection for up to 2 hours. Long-acting beta(2)-adrenoceptor agonists (LABAs) given in single doses can be effective for up to 12 hours when used intermittently, but tolerance to the protective effect occurs if they are taken daily. Drugs such as cromolyn sodium (sodium cromoglicate) and nedocromil given as aerosols are less effective than beta(2)-adrenoceptor agonists (beta(2)-agonists), providing 50-60% protection for only 1-2 hours, but they have some advantages. They do not induce tolerance, the aerosol dosage can be easily titrated for the individual, and the protective effect is immediate. Because they cause no significant adverse effects, multiple doses can be used in a day. Leukotriene receptor antagonists, such as montelukast and zafirlukast, are also used for the prevention of EIA and provide 50-60% protection for up to 24 hours when given as tablets. Tolerance to the protective effect does not develop with regular use. If breakthrough EIA occurs, a beta(2)-agonist can be used effectively for rescue medication. For those patients with more persistent symptoms, the use of a LABA in combination with an inhaled corticosteroid has raised a number of issues with respect to the choice of prophylactic treatment for EIA. The most important issue is the development of tolerance to the protective effect of a LABA such that extra treatment may be needed in the middle of a treatment period. Recommending extra doses of a beta(2)-agonist to control EIA is not advisable on the basis that multiple doses can enhance the severity of EIA, delay spontaneous recovery from bronchoconstriction, and enhance responses to other contractile stimuli. It is time to take into account the advantages and disadvantages of the different drugs available to prevent EIA and to recognize that there are some myths related to their use in EIA.

Purpose: To investigate preoperative and postoperative prophylactic treatment with different pharmacological agents before flap cutting and exposure to a diffuse lamellar keratitis (DLK) causative agent., Setting: Magill Research Center for Vision Correction, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA., Methods: The study comprised 48 eyes of 24 Dutch-belted rabbits. Three days before a corneal flap was cut and the corneal interface was exposed to Pseudomonas aeruginosa lipopolysaccharide endotoxin, a DLK causative agent, the eyes were randomly assigned to treatment with a mast-cell stabilizer, a nonsteroidal antiinflammatory drug (NSAID), or a corticosteroid or left without treatment as controls. The treatment was maintained throughout the 1-week follow-up. Slitlamp examinations and photographs were performed at 1, 3, 5, and 7 days; DLK was graded by a masked observer from 0 (no DLK) to IV. Corneal interface scrapings were performed in selected eyes on day 7., Results: At the end of the follow-up, 36 eyes were available for evaluation. At 1 week, 100% of the control eyes and the eyes treated with the mast-cell stabilizer developed DLK; in the NSAID-treated and corticosteroid-treated eyes, the DLK rate was 86% and 70%, respectively. At 1 day, the severity of DLK was significantly lower in eyes treated with the mast-cell stabilizer (0.44) and at 7 days, it was significantly lower in corticosteroid-treated eyes (0.3) than in the control group (1.5 and 1.4, respectively) (P<.05, Wilcoxon test). Corneal interface scraping from an eye with grade III DLK showed numerous inflammatory cells., Conclusions: Preoperative and postoperative treatment with corticosteroids significantly reduced the severity of DLK compared to the untreated control eyes in this animal model. Treatment with a mast-cell stabilizer and an NSAID had less effect on the postoperative course of DLK.

Asthma is a disease that demonstrates chronic Th2 lymphocyte-mediated pulmonary inflammation. We hypothesized that cytokines produced by asthmatic lung inflammation bias the immune response to antigens administered systemically toward a Th2 response, as assessed by serum IgE antibody and lymphocyte-secreted IL-4 and IL-5. We also hypothesized that treatment of asthmatic children with local anti-inflammatory agents reduces this cytokine-mediated Th2 influence. We systemically immunized groups of asthmatic children (n=29) who were participating in a long-term, randomized, placebo-controlled clinical trial of inhaled anti-inflammatory therapy (Childhood Asthma Management Program) and nonasthmatic children (n=12) with hepatitis B (Hep B) antigen, and examined their antigen-specific antibody and lymphocyte cytokine secretion profiles. The asthmatic population demonstrated an increased amount of Th2-mediated serum IgE anti-Hep B antibody, as compared to nonasthmatic children; but comparable amounts of IgG1, IgG2, IgG3, IgA, and IgM anti-Hep B antibody and lymphocyte IFNgamma, IL4, and IL5. There was no significant difference of antibody isotype or cytokine production between asthmatic subjects receiving treatment with budesonide or nedocromil, as compared to placebo. In conclusion, there is a subtle bias in responses to systemic immunization in children with asthma, but anti-inflammatory therapy does not affect this bias. The findings support the concept that the Th2 bias may be largely genetic. Importantly, we confirmed that children with asthma, including even those on inhaled corticosteroids, responded to Hep B immunization as well as did nonasthmatic children with the major isotypes of anti-Hep B antibody, suggesting that vaccine protection against hepatitis B is not influenced by inhaled steroid therapy., (Copyright 2003 Wiley-Liss, Inc.)

Background: Despite increased attention focused on the need to prevent patient attrition in long-term clinical trials, high dropout rates have threatened the success of numerous studies., Objective: To evaluate the disease, demographic, and psychological factors associated with missed visits and study dropout to help improve patient management in long-term clinical trials., Methods: Predictors of attrition were examined within the Childhood Asthma Management Program (CAMP), a large, multicenter clinical trial that followed up 1,041 children with asthma for 4 to 6 years., Results: Eighty-two percent of patients attended all study visits. The tendency to miss visits was increased among older children with milder asthma, lower intellectual and social competence, and more symptoms of behavioral problems and emotional distress. Forty-two patients who missed 3 or more visits in a row and did not attend the final visit were considered study dropouts; these patients at baseline had milder asthma; lower cognitive, academic, and social competence skills; and more family conflict and distress than found among participants who remained in the study. The 49 children who had erratic attendance but did not drop out also had lower intellectual and academic skills and less family social support., Conclusions: The 4% dropout rate in CAMP was lower than reported in any previous long-term asthma trial. The findings of milder disease, decreased psychological resources, and increased distress in problem-attendance patients can assist in identifying patients who are at risk for missed visits or dropout during the trial either to block their entry into the trial or to focus efforts at maintaining their attendance once enrolled in the trial.

Background: Allergic rhinitis is a common disease altering quality of life. Its treatment is well established and guidelines have been proposed. However, their efficacy has never been tested. The aim of the study was to validate the guidelines of the International Consensus on Rhinitis in the treatment of seasonal allergic rhinitis., Methods: A multicenter, multinational, open label, parallel, randomized study compared two therapeutic strategies in seasonal allergic rhinitis during a 3-week treatment. General practitioners were randomized into two groups. In the first group of 224 patients, doctors followed guidelines from the International Consensus on Rhinitis. Depending on the severity of nasal and ocular symptoms defined using visual analogue scales, patients received ebastine (an oral antihistamine), triamcinolone acetonide (a topical corticosteroid) and/or ophthalmic nedocromil sodium (a topical ocular cromone). In the second group of 241 patients, general practitioners had a free choice of treatment. The primary efficacy end points were quality of life measured using the standardized rhinoconjunctivitis quality of life questionnaire (RQLQ) and the symptom-medication scores assessed daily with an electronic dairy system., Results: Adjusted mean total symptom scores over 21 days were 4.93 in the guidelines strategy group compared with 7.48 in the free-choice treatment group (P = 0.0001). Mean total scores in the RQLQ decreased by 2.19 in the guidelines group compared with a decrease of 1.79 in the free-choice treatment group (P = 0.0001). At 21 days, the least square mean difference in improvement in overall scores for RQLQ in the guidelines group compared with the free-choice treatment group was 0.53, which was greater than the minimal important difference., Conclusions: Patients with seasonal allergic rhinitis often present severe symptoms which are not well recognized or controlled by physicians using their own criteria of severity and treatment. Using a simple method for the evaluation of the severity and a simple therapeutic scheme based on International Guidelines, patients with seasonal allergic rhinitis presented a significant improvement by comparison with those receiving a non-standardized treatment.

Objective: Inhaled corticosteroids are recommended as first-line therapy for pediatric asthma. However, few controlled long-term studies have investigated their effect on bone mineral density (BMD) and growth., Methods: Children who were aged 6 to 14 years and had persistent asthma were randomized to 24 months' treatment with fluticasone propionate (FP) 200 micro g/d or nedocromil sodium (NS) 8 mg/d (if uncontrolled, maximum doses of 400 micro g/d and 16 mg/d, respectively). BMD was assessed blind and analyzed at a central facility on the basis of dual-energy x-ray absorptiometry measurements of the lumbar spine and femoral neck at months 0, 6, 12, and 24. Height was measured at months 0, 12, and 24. Efficacy parameters (lung function, asthma control, occurrence of exacerbations) were measured every 3 months., Results: In total, 174 children were randomized to treatment (87 received FP, and 87 received NS). At month 24, the adjusted mean percentage increase in lumbar spine BMD was 11.6% in the FP group compared with 10.4% in NS-treated children (95% confidence interval for treatment difference: -0.7% to 3.1%). The corresponding increases in femoral neck BMD were 8.9% and 8.5%, respectively. There was no significant difference in growth between the 2 groups: adjusted mean growth rates were 6.1 cm/y with FP and 5.8 cm/y with NS. FP was significantly superior for every efficacy parameter investigated and was similarly well tolerated as NS., Conclusions: The long-term effects of FP and NS on BMD accrual and growth are similar among children with asthma. The benefit:risk ratio of FP may be considered superior to that of NS.

Purpose: Ocular symptoms are often under-treated in patients with allergic rhinoconjunctivitis. The efficacy of fexofenadine hydrochloride 60 mg capsules supplemented with nedocromil sodium 2% ophthalmic solution was evaluated to determine the optimal drug regimen for control of ocular allergic symptoms., Methods: In this 5-week, open-label, randomized, multicentre comparative study, 89 patients with documented ragweed pollen allergy received fexofenadine b.i.d. with nedocromil rescue, fexofenadine q.d. with nedocromil b.i.d., or fexofenadine rescue with nedocromil b.i.d. during the ragweed pollen season., Results: For all regimens, mean symptom severity scores for itching, burning, tearing, redness, grittiness, discharge, light sensitivity and swelling improved significantly (P < 0.003). Similarly, all groups experienced significant (P < 0.02) improvement in all clinical signs: erythema, oedema, discharge, conjunctival injection and conjunctivitis, as well as quality-of-life scores (P < 0.0001). All regimens reduced overall symptom severity scores after 5 min (P < 0.05) with relief persisting over 12 h (P < 0.03). Improvements in mean symptoms, signs and quality-of-life scores were similar among the treatment groups as were onset and duration of action even though patients in two of the three study arms were taking one-half or less of the recommended fexofenadine dosage. Patients and physicians judged the regimens containing lower fexofenadine dosages (with nedocromil b.i.d.) to be more effective overall than the regimen containing the highest fexo-fenadine dosage (with nedocromil as rescue only)., Conclusions: Supplementation of oral fexofenadine therapy with nedocromil sodium 2% ophthalmic solution relieves ocular symptoms of seasonal allergic rhinoconjunctivitis, allowing control of rhinal symptoms with half the recommended dosage of fexofenadine.

Purpose: To induce diffuse lamellar keratitis (DLK) and investigate a prophylactic treatment with pharmacological agents., Setting: Magill Research Center for Vision Correction, Storm Eye Institute, Charleston, South Carolina, USA., Methods: In 100 eyes of 50 Dutch Belted rabbits, a nasal corneal flap was cut and the interface inoculated with Pseudomonas aeruginosa lipopolysaccharide endotoxin (n = 50) or Palmolive Ultra soap (n = 50). The eyes were randomly assigned to treatment with a mast-cell stabilizer, a nonsteroidal antiinflammatory drug (NSAID), a fluoroquinolone antibiotic agent, a corticosteroid, or left without treatment as a control. Slitlamp examinations and photographs were performed 1, 3, 5, and 7 days postoperatively, and DLK was graded by a masked observer from 0 (no DLK) to stage 4., Results: At the end of the study, 80 eyes were available for evaluation. Ninety-four percent of the untreated eyes developed DLK compared to 56% of eyes treated with NSAIDs and 63% of eyes treated with steroids (P<.05, Fisher exact test). The DLK rates with the mast-cell stabilizer and fluoroquinolone antibiotic agent were 86% and 76%, respectively. The DLK incidence in the latter 2 groups was not significantly different from that in the control eyes (P>.05, Fisher exact test)., Conclusions: Postoperative prophylactic treatment with NSAIDs and corticosteroids led to a statistically significantly lower incidence of postoperative DLK. The study demonstrated that corticosteroids and NSAIDs can be used to treat DLK after LASIK. While steroids are a generally accepted treatment for DLK, NSAIDS may offer an additional potent modality.

It has been reported that pulmonary injury (i.e. capillary stress failure) evoked histamine release from airway inflammatory/mast cells contributes to exercise-induced arterial hypoxemia (EIAH) and that pre-exercise inhalation of nedocromil sodium mitigated EIAH in human subjects 'Med. Sci. Sports Exercise 29, (1997) 10-16'. Because exercise-induced pulmonary hemorrhage due to capillary stress failure is routinely observed in racehorses, we examined whether nedocromil inhalation would similarly benefit EIAH and desaturation of hemoglobin in horses. Two sets of experiments, namely, placebo studies followed in 7 days by pre-exercise nedocromil sodium (30 puffs=60 mg) inhalation experiments were carried out on 7 healthy, sound, exercise-trained thoroughbred horses. In both treatments, arterial and mixed-venous blood-gas/pH measurements were made at rest pre- and post-placebo/drug inhalation, as well as during incremental exercise leading to galloping at 14 m/sec on a 3.5% uphill grade-a workload that elicited maximal heart rate and caused pulmonary hemorrhage in all horses in both treatments, thereby indicating capillary stress failure had occurred. In both treatments, significant (P<0.0001) EIAH of a similar magnitude had developed by 30 sec of maximal exertion, and further significant changes in arterial O(2) tension did not occur as exercise duration progressed to 120 sec. Thus, pre-exercise inhalation of nedocromil sodium was ineffective in modifying the development and/or severity of EIAH in the present study. These findings argue against the airway inflammatory mediator(s) release hypothesis for causing arterial hypoxemia in racehorses.

This randomized, double-masked, active-control, parallel-group trial compared the mast cell stabilizers pemirolast potassium 0.1% and nedocromil sodium 2% in the treatment of seasonal allergic conjunctivitis. Pemirolast is currently indicated for four-times-daily administration, nedocromil, for twice-daily dosing. Both ophthalmic solutions were instilled bilaterally twice a day for 8 weeks. The study involved four office visits and two telephone contacts. Participants evaluated their symptoms daily in take-home diaries (itching was the primary efficacy variable) and completed questionnaires to assess comfort. Of a total enrollment of 80, 78 patients completed the study. No significant differences were found between pemirolast and nedocromil on any signs or symptoms of allergic conjunctivitis (redness, chemosis, itching, eyelid swelling). At each visit, pemirolast was rated significantly more comfortable than nedocromil. A significantly higher percentage of the pemirolast group experienced no signs or symptoms at work or school (58% vs 28%; P = .005). The number of adverse events did not differ significantly between groups. Twice-daily administration of pemirolast potassium was as efficacious and safe as twice-daily nedocromil sodium in the 8-week treatment of ragweed allergic conjunctivitis and was superior to nedocromil in comfort. Increased comfort with pemirolast may increase patient satisfaction and compliance with therapy.

We examined whether the acute protective effect of nedocromil sodium aerosol could be enhanced by increasing the deposition uniformity of the drug in the lungs of adult patients with allergic asthma. Ten patients with mild-to-moderate asthma were challenged with the same doses of allergen on two occasions in a randomized manner. Thirty minutes before these challenges, patients inhaled 4 mg nedocromil sodium, admixed with the radioisotope (99m)technetium. Radiolabeled drug was inhaled during slow (25.4 +/- 4.6 L/min) and faster (58.0 +/- 7.3 L/min) inhalations from a 700 ml holding chamber. Percent changes in FEV(1) at the same top dose of allergen on the two treatment visits were compared. Lung deposition fraction (LDF) and indices of distribution uniformity, quantified from gamma camera images, were also compared. Acute protection against allergen challenge was similar and complete after slow or faster inspiration of nedocromil sodium. Mean (+/- SD) allergen-induced changes in FEV(1) were -1.05 +/- 2.78% and -0.39 +/- 2.80%, respectively, compared to -26.30 +/- 8.49% on a screening challenge (no drug). Mean LDF was also similar on the two visits, averaging 16.4 +/- 4.6% and 16.1 +/- 7.2% of administered drug, respectively. Distribution of nedocromil sodium was most uniform after slow inspiration, but increased uniformity was not related to enhanced protection. Complete protection against acute bronchoconstriction induced by inhaled allergen can be obtained with 4 mg of nedocromil sodium aerosol, inhaled from a large volume holding chamber, 30 min before the exposure, and at inspiratory flow rates between approximately 20-60 L/min. Protection does not appear to be enhanced by increased uniformity of drug distribution within the lungs.

Purpose: To assess the efficacy of nedocromil sodium 2% eye drops and emedastine difumarate 0.05% eye drops in controlling the ocular allergic reaction induced by conjunctival allergen challenge (CAC)., Methods: Thirty subjects with a personal history of allergic conjunctivitis were enrolled (first visit). At the second visit each subject randomly received emedastine 0.05% or nedocromil 2% in one eye and placebo in the other eye. Five minutes after the medication the offending allergen was instilled in both eyes. Ocular redness and itching were evaluated according to a standardized scoring system at 3, 10 and 20-minute intervals after instillation of the allergen. After one week (third visit) the whole procedure was repeated using the placebo in the eye used as control during second visit and one of the trial drug that was not used at second visit in the other eye (either emedastine or nedocromil)., Results: Emedastine 0.05% and nedocromil 2% eye drops were more effective than placebo in controlling ocular redness and itching (p<0.01). Emedastine was more effective (p<0.01) than nedocromil in alleviating redness and itching 3 and 10 minutes after application of the allergen., Conclusions: Emedastine 0.05% appeared superior to nedocromil 2% in producing immediate relief when subjects with allergic conjunctivitis were exposed to the offending allergen.

Levels of pro-allergic cytokine IL-4 are increased in asthmatic airways, contributing to allergic inflammation. IL-4 and IL-13 are the most important factors in production of class E immunoglobulin, playing major role in childhood atopic asthma. The mechanism of effect of nedocromil, often prescribed in children, has been discussed. Our previous study on the effect of nedocromil on different inflammatory markers, showed decreased levels of IL-4 and IgE after monotherapy in 15 asthmatic children. The purpose of this study was to define the effect of treatment with nedocromil on serum level of IL-4 and IgE, clinical symptoms and bronchial hyperreactivity (BHR) in children with moderate atopic asthma. It was 8 week, placebo-controlled and randomized, double blind trial of 81 children with moderate atopic asthma allergic to dust mite. Patients were randomly allocated to receive nedocromil sodium two puffs four times daily (0.002 g/puff) (n = 34) or placebo (n = 47). 69 children completed the study. After treatment with nedocromil the levels of IL-4 and IgE in blood serum in study group significantly decreased, and all clinical parameters improved. Mean levels of IL-4 in serum before and after treatment with nedocromil were 0.13 pg/ml +/- 0.01 and 0.12 pg/ml +/- 0.02 respectively (p < 0.01). Mean serum levels of IgE before and after treatment with nedocromil were 556.83 IU/ml +/- 201.3 and 485 IU/ml +/- 200.5 respectively (p < 0.02). This study demonstrate that one possible way by which nedocromil contribute to inhibition of allergic inflammation is by decreasing IL-4 and IgE levels.

Eosinophil-mediated damage to the respiratory epithelium is a major pathogenetic mechanism in asthma. Glucocorticoids have confirmed antiinflammatory properties and effect of formoterol, montelukast and nedocromil on markers of inflammation has been studied. Eosinophil blood counts and eosinophil cation protein (ECP) serum level are often use as markers of clinical monitoring of the disease activity. To evaluate the effect of treatment on allergic inflammation, we measured eosinophil blood counts and ECP serum level, and clinical parameters before and after 4 weeks treatment with triamcinolon, montelukast, nedocromil, formoterol. It was 8 week, placebo-controlled and randomized, double blind trial of 154 children with moderate atopic asthma. Patients were randomly allocated to receive 400 mg triamcinolon (n = 28), 5 or 10 mg (according to age) montelukast (n = 27), 16 mg nedocromil (n = 26), 24 micrograms formoterol (n = 28) or placebo (n = 45). 140 children completed the study. After treatment with triamcinolon and montelukast eosinophil blood counts significantly decreased, after treatment with triamcinolon, montelukast and nedocromil ECP serum level significantly decreased; all clinical parameters improved after treatment with each drug; treatment with triamcinolon had the strongest effect on most parameters (except of FEV1). Mean eosinophil blood counts before and after treatment with triamcinolon were 277.4 and 187.2 cells/mm3 respectively (p < 0.001); with montelukast were 279.6 and 250.7 cells/mm3 respectively (p = 0.002); with nedocromil were 181.7 and 170.1 cells/mm3 respectively (p < 0.183); with formoterol were 276.4 and 264.1 cells/mm3 respectively (p = 0.2). Mean ECP serum levels before and after treatment with triamcinolon were 94.3 and 63.5 micrograms/l respectively (p < 0.001); with montelukast were 85.1 micrograms/l and 71.2 micrograms/l respectively (p < 0.001); with nedocromil were 92.6 and 80.1 micrograms/l respectively (p < 0.001); with formoterol were 95.9 micrograms/l and 87.8 micrograms/l (p = 0.05). We found significant correlation between ECP and hyperresponsiveness after treatment with triamcinolon, montelukast. This study shows that triamcinolon, montelukast contribute to inhibition of allergic inflammation by decreasing eosinophil blood counts and ECP. The serum level of ECP seems to be a good clinical marker of monitoring the disease.

In a multicenter, open-label evaluation, 1098 patients with ocular itching and a history of perennial or seasonal allergic conjunctivitis instilled one drop of nedocromil sodium 2% twice daily in each eye. Ocular symptoms, signs, and global improvement were assessed at baseline and 1 month; satisfaction scores, quality-of-life variables, and adverse events were also recorded. Significant improvements from baseline (P<.012) occurred in mean severity scores for itching, burning, stinging, watering, swelling, tired eyes, dryness, gritty sensation, eye pain, foreign-body sensation, and light sensitivity. Physicians reported significant reductions (P<.0001) in bulbar conjunctival redness and swelling. Two thirds of patients (634/954) and three fourths of physicians (710/954) reported at least 75% improvement in overall condition after 1 month. The most common adverse events were burning (2.7%) and unpleasant taste (1.4%); headache (1.2%) and adverse events leading to discontinuation (1.3%) were rare. Patients reported significant improvement (P<.001) in their ability to perform daily activities; 65% were more satisfied with nedocromil than with their typical medication. Physicians would prescribe nedocromil again to 80% of the patients. Nedocromil sodium 2% twice daily was effective and safe for the treatment of symptoms of allergic conjunctivitis, significantly improving quality of life and producing high rates of user and physician satisfaction.

Levels of an interleukin 10 (IL-10) are reduced in asthmatic patients in comparison to healthy subjects. Fact, that IL-10 is produced by Th1 and that inhibits cytokine production by Th2 lymphocytes has led to the concept that IL-10 might be beneficial in mitigating allergic inflammation. The purpose of this study was to define the effect of 4 week monotherapy with triamcinolone acetonide or nedocromil sodium on the serum level of IL-10, bronchial hyperresponsiveness and clinical parameters in atopic asthma children. It was an 8 week, randomised, double-blind trial of 37 children with moderate asthma allergic to house dust mite. Patients were randomly allocated to receive 200 mcg triamcinolone twice daily (n = 18), or 0.004 g nedocromil four times daily (n = 19). Thirty children completed the study. After treatment with triamcinolone the level of IL-10 in blood serum significantly increased, bronchial hyperreactivity significantly decreased, and all clinical parameters improved. Mean IL-10 levels in serum before and after treatment with triamcinolone were 7.5 pg/ml with 95%CI 6.79%-8.22% and 14.21 pg/ml with 95%CI 11.33%-17.09% respectively (p < 0.001). After treatment with nedocromil, clinical symptoms improved significantly, IL-10 serum levels and bronchial hyperreactivity did not change significantly (p = 0.094 and p = 0.09 respectively). This study demonstrates that one possible way by which triamcinolone contribute to inhibition of inflammation is by effect on IL-10.

In this 8-week open-label, prospective study, 30 patients with grass pollen allergy and ocular itching instilled nedocromil sodium 2% ophthalmic solution twice daily for a 5-day baseline period, followed by once-daily dosing thereafter. Physicians assessed clinical signs after the twice-daily period and after weeks 1 and 3 of the once-daily period; patients rated ocular symptoms daily. Use of specified rescue medication was permitted. Symptom scores for ocular itching, stinging, redness, swelling, burning, tearing, and light sensitivity did not differ significantly between the dosage periods. Scores for erythema, edema, conjunctival injection, and the entire conjunctiva decreased slightly during once-daily administration; discharge scores were unchanged. Of the 20 patients who used rescue medication, only 5 increased their usage by more than two doses per week during the once-daily period. Eighty-three percent of patients were willing to continue the once-daily regimen during the next allergy season. Physicians rated overall control of seasonal allergic conjunctivitis with once-daily administration as "good" or "moderate" in 100% of the patients; 93% of patients applied those ratings themselves. Nedocromil sodium 2% ophthalmic solution instilled once daily maintains control of symptoms in patients who are established on a twice-daily regimen.

The efficacy of inhaled nedocromil sodium (NS) for children with a persistent cough was studied. Children aged 4-12 years with a persistent cough for >1 month were recruited and entered a 2-week baseline period during which an asthma diary was kept. Children with a cough score of >20 received inhaled NS via a spacer, 4mg qid for 2 weeks followed by 4mg bd for another 4 weeks. Twenty-two (42%) of 52 children recruited fulfilled treatment criteria. Four children were withdrawn from the study (2 developed wheezing and 2 were not compliant). The baseline cough score (29.1 +/- 13.6) improved after 2 weeks of treatment (15.2 +/- 9.3, p < 0.01) and improvement was sustained after 6 weeks (14.2 +/- 13.0, p = 0.01). Parents and patients had a more favourable perception of its efficacy compared to physicians (72% vs 50%, p = 0.01) Inhaled NS may be considered for treatment of persistent cough in children.

Background: Asthma is a major cause of morbidity that disproportionately affects inner-city children. For children with persistent asthma, defined as having asthma symptoms 3 or more days per week or 3 or more nights per month, national guidelines recommend the use of daily antiinflammatory agents. Despite these recommendations, antiinflammatory agents remain underused, particularly in inner-city children with high asthma morbidity., Objectives: The objectives of our study were to determine: 1) whether persistent asthma symptoms in inner-city children are related to acute care utilization and to the frequency of acute exacerbations; 2) whether children with persistent asthma are receiving recommended daily antiinflammatory agents; and 3) whether antiinflammatory medication use relates to sociodemographic factors, caretaker self-efficacy, the frequency of primary care visits, and/or measures of quality asthma care., Design and Methods: A 64-item telephone survey was administered between July 1996 and June 1997 to 219 parental caretakers of 2- to 12-year-old children who had been hospitalized with asthma at an inner-city medical center between January 1995 and February 1996. Persistent asthma symptoms were assessed by inquiring about the frequency of daily and nocturnal asthma symptoms over the last 4 weeks. Children's asthma severity was classified by applying the 1997 National Asthma Education and Prevention Program (NAEPP) Asthma Guidelines' severity classification scheme based on the frequency of asthma symptoms. Asthma morbidity was defined as the frequency of acute asthma exacerbations, emergency department visits and hospitalizations. Daily antiinflammatory medication use was compared by sociodemographic factors, caretaker self-efficacy, frequency of primary care visits, and measures of quality asthma home management., Results: In this sample, quantifying persistent asthma symptoms and applying the NAEPP symptom criteria identified 17% of the children with mild intermittent asthma, 27% with mild persistent asthma and 56% with moderate to severe persistent asthma. There were no differences in the age of the children in the 3 groups (mean age: 6 years). Asthma morbidity, as measured by the number of asthma exacerbations in the last 6 months, was significantly higher in the children with moderate to severe persistent asthma compared with children with mild intermittent asthma (9.8 vs 3.5) or mild persistent asthma (9.8 vs 4.5). In addition, there were significantly more emergency department visits in the moderate to severe group than in the mild persistent (3.05 vs 1.69) or mild intermittent group (3.05 vs 1.76). Lastly, as asthma symptom frequency increased, there were trends toward more hospitalizations and more days hospitalized. Overall, 35% of the 219 families reported giving daily antiinflammatory medications to their child (mostly cromolyn sodium). Of the 181 children (83%) who met NAEPP symptom criteria for persistent asthma, only 39% were receiving daily antiinflammatory treatment. Of the children with symptoms of moderate to severe asthma, only 15% were receiving inhaled steroids in contrast to the guidelines' recommendations. Use of antiinflammatory agents was not related to caretaker sociodemographic factors or self-efficacy scores. Measures of quality asthma home management, which included use of mattress covers, written plans, and peak flow meters, correlated positively with use of antiinflammatory agents. Children whose families reported using daily antiinflammatory medications had more primary care visits in the last 6 months than those children not receiving antiinflammatory medications., Conclusion: Questioning parents about the frequency of their child's asthma symptoms is an important, inexpensive, and readily accessible bedside and office tool that may aid in the detection of persistent symptoms and help direct therapy. Our study suggests that classifying asthma severity by quantifying persistent asthma symptoms, as defined in the NAEPP Guidelines, is a clinically useful tool that relates to asthma morbidity. In our sample of previously hospitalized children with asthma, 83% met 1997 NAEPP symptom criteria for persistent asthma, and yet only 35% were receiving daily antiinflammatory agents. Use of antiinflammatory agents correlated positively with other indicators of quality asthma home management. Additional work is necessary to increase appropriate use of antiinflammatory agents in this population, and in particular, to increase inhaled steroid use for children with moderate or severe symptoms.

Nedocromil sodium trihydrate is not amenable to conventional methods of dry powder inhaler formulation, including the preparation of coarse carrier systems and aggregation of the pure drug powder. It is considered that the in vitro aerosol performance of such systems is governed by the cohesive drug-drug interactions. Therefore, alternative powder formulation strategies (novel to nedocromil sodium) were developed. By decreasing the particle size of the lactose carrier, the deaggregation and subsequent fine particle drug deposition were significantly improved. Further improvements were made by selecting and then optimizing high-shear mixing procedures. It was concluded, based on these findings and supportive microscopic studies (low-temperature and environmental scanning electron microscopy together with energy-dispersive X-ray analysis), that the FPL are producing their functional effects by intercalating within the drug self-agglomerates and physically disrupting the cohesive drug-drug interactions. The use of a smaller-sized lactose fraction in conjunction with a blending procedure capable of optimally disrupting the drug self-agglomerates allowed maximal intercalation of the excipient material within the drug self-agglomerates. The adhesive drug-FPL interactions are considered to be weak compared with the cohesive drug-drug particle interactions, cohesive interactions that would normally govern the aerosol performance of powder systems containing a high mass of nedocromil sodium trihydrate.

Aim: To analyse informative value of monitoring of NO metabolites concentration in condensate of expired air vapor (EAVC) for definition of bronchial asthma (BA) severity and antiinflammatory effect of basic therapy., Material and Methods: NO metabolites concentration in EAVC was measured with Grace's reagent in 76 adults and 180 children in the course of basic therapy with flixotide, tailed, ketotiphen with intal., Results: NO metabolites occurred in high concentrations in EAVC of both children and adults. These concentrations were the highest in attacks and in severe BA and were reduced by basic therapy. This effect differed with the drug and its dose, e.g. flixotide and tailed given to children for a month reduced NO metabolites close to concentrations observed in healthy subjects. Ketotiphen and intal for 6 months failed to low NO metabolites significantly., Conclusion: NO secretion monitoring is sensitive in assessment of respiratory inflammation in BA and is informative in assessment of effectiveness of the basic therapy. In moderate BA children on flixotide and tailed were the first to achieve normal NO secretion in the airways.

The objective of this review was to compare the effects of prophylactic doses of nedocromil sodium (NCS) and sodium cromoglycate (SCG) on postexercise lung function, in persons diagnosed with exercise-induced bronchoconstriction. Randomized controlled trials were identified from the Cochrane Airways Review Group Asthma Register, plus hand searching for trials in journals, bibliographies of relevant studies and review articles. Randomized controlled trials comparing NCS to SCG in prophylactic treatment of exercise-induced bronchoconstriction were eligible. Studies were pooled using odds ratios (OR) for dichotomous outcomes or weighted mean differences (WMD) with 95% confidence intervals (95% CI) for continuous outcomes. No significant differences were noted between NCS and SCG with respect to the maximum per cent decrease in forced expiratory volume in one second (WMD=-0.88; 95% CI -4.50-2.74), complete protection (OR=0.95; 95% CI 0.50-1.81), clinical protection (OR=0.71; 95% CI 0.36-1.39), unpleasant taste (OR=6.85; 95% CI 0.77-60.73), or sore throat (OR=3.46; 95% CI 0.32-37.48). Subgroup analyses based on age, dosages of medications and timing of exercise postinhalation were consistent with the overall pooled analyses. No significant differences were evident between the effects of nedocromil sodium and sodium cromoglycate during the immediate postexercise period in adults and children with exercise-induced bronchoconstriction, with regards to maximum per cent decrease in forced expiratory volume in one second, complete protection, or clinical protection. Side-effect profiles were similar.

Previous investigations have found that the in vitro aerosol performance of nedocromil sodium is poor. A study has been undertaken to gain a better understanding of the physicochemical properties of the drug particles together with the factors governing the aerosol performance of inhalation systems containing this drug. Material previously passed through a hammer mill only and particles subsequently passed through a micronizer were characterized, and the information gathered was correlated with the in vitro aerosol performance of the pure drug systems. Optimization of particle sizing procedures revealed that both sets of materials were ultrafine powders with a volume median diameter of approximately 1 microm. It is concluded that the processing stages, employed in the manufacture of these batches of fine particle nedocromil sodium trihydrate, may not in fact be primary particle size reduction stages but instead deaggregation stages and that these govern the aerosol performance. The in vitro aerosol performance of samples of the "micronized" nedocromil sodium stored over a range of relative humidities (RHs) was characterized. Storage RHs in the range 12-76% (where nedocromil sodium is stable as the trihydrate) did not have a dramatic effect on the in vitro aerosol performance of the drug. However, conversion to the heptahemihydrate (following storage of the drug at 86% RH) significantly decreased the deaggregation performance in an in vitro model.

Objective: To compare the expected costs of treating patients with asthma with versus without inhaled anti-inflammatory medications, adjusting for other factors that also influence medical care expenditures., Design: Nonlinear exponential regression analyses were used to estimate relationships between medical care expenditures and treatment with inhaled corticosteroids, sodium cromoglycate (cromolyn) or nedocromil. The regressions adjusted for differences in patients' demographics, location, plan type and severity of illness., Setting: Large, self-insured, corporate-sponsored medical plans represented in MarketScan database., Patients and Participants: 7466 continuously enrolled patients with asthma., Interventions: Treatment with inhaled corticosteroids, sodium cromoglycate or nedocromil., Main Outcome Measures: (i) Total inpatient, outpatient and pharmaceutical expenditures; and (ii) asthma-related expenditures in the 1996 calendar year., Results: If all patients had been treated with inhaled anti-inflammatory drugs, total expenditures would be expected to be about $US944.82 per patient lower, on average, than would be the case if no patients received these drugs. Asthma-related expenditures would be about $US498.74 per patient higher, on average, if all patients were treated with these drugs., Conclusions: Using inhaled anti-inflammatory agents would be associated with higher asthma-related expenditures but lower total expenditures. Treatment with inhaled anti-inflammatory drugs may represent an investment in better care that pays off with better health and lower total medical care expenditures.

Purpose: To determine the efficacy and safety of nedocromil sodium 2% ophthalmic solution in the treatment of seasonal allergic conjunctivitis., Methods: A combined analysis of two multicenter, randomized, comparative, double-masked, placebo-controlled clinical trials involving 261 patients diagnosed with seasonal allergic conjunctivitis was used. Patients were randomly assigned to receive either topical 2% nedocromil sodium or placebo twice daily for eight weeks. Diary card scores and clinician assessments of allergic symptoms were recorded throughout the study; efficacy was determined by comparing symptom severity at the peak pollen period with symptom severity at baseline. Clinician and patient evaluations of treatment effectiveness were used as secondary measurements of efficacy., Results: Patients treated with nedocromil sodium experienced improvement in allergy symptoms, with reductions in the summary symptom score, itch, redness, conjunctival injection, and conjunctival edema significantly (p<0.05) greater than those observed in the patients treated with placebo. Clinicians' and patients' opinions of nedocromil sodium treatment effectiveness were significantly (p<0.02) superior to those of placebo treatment effectiveness., Conclusion: Nedocromil sodium is effective in the management of seasonal allergic conjunctivitis.

The efficacy and safety of twice-daily nedocromil sodium 2% ophthalmic solution and vehicle were compared in the treatment of ragweed seasonal allergic conjunctivitis. Two separate multicenter, randomized, double-masked, placebo-controlled studies were subjected to a combined analysis. Following a one-week baseline period during the beginning of the ragweed pollen season, 189 patients with seasonal allergic conjunctivitis received either nedocromil sodium or vehicle b.i.d. for eight weeks. Efficacy was evaluated by patient diary cards and clinical eye examinations. Safety was assessed by reports of adverse events. Compared with vehicle, nedocromil sodium produced significantly greater decreases in summary symptom score (p = 0.005), itch (p = 0.005), tearing (p = 0.004), overall eye condition (p = 0.001), and clinician-evaluated conjunctival edema (p = 0.018), and significantly better (p = 0.001), and patient (p = 0.001) opinions of treatment effectiveness at the peak pollen period. Additionally, the superiority of nedocromil sodium compared to vehicle approached statistical significance in redness reduction (p = 0.087) and clinician-evaluated conjunctival injection (p = 0.087). There were no serious treatment-related adverse events in either treatment group. In summary, nedocromil sodium 2% ophthalmic solution b.i.d. was found to be effective and to have a favorable safety profile in the treatment of seasonal allergic conjunctivitis.

Nedocromil sodium inhibits the response to exercise-induced asthma (EIA). Mannitol given as a powder by inhalation is an osmotic stimulus that identifies EIA. We studied the acute effect of nedocromil on airway responsiveness to mannitol in 24 asthmatic subjects. After a control day, nedocromil (8 mg) or its placebo was administered randomized, double blind, 10 min before a challenge with progressively increasing doses of mannitol. Nedocromil inhibited the response to mannitol and there was a significant increase in the dose of mannitol required to cause a 15% reduction in FEV(1) (PD(15)) after nedocromil 409 (316,503) mg compared with placebo 156 (106,229) mg (p < 0.001). In the presence of nedocromil 12 subjects no longer recorded a 15% decrease in FEV(1) in response to mannitol. The remaining 12 required a significantly greater dose of mannitol to achieve a 15% decrease in FEV(1) after nedocromil. Following nedocromil, a plateau in responsiveness to mannitol was observed in 14 subjects. Nedocromil significantly inhibits the responsiveness to inhaled mannitol in asthmatic subjects.

In this 2-week, randomized, crossover study, ophthalmic solutions of nedocromil sodium 2% and olopatadine hydrochloride 0.1% were compared for effectiveness and acceptability in 28 patients with perennial allergic conjunctivitis and previous olopatadine experience. Patients received nedocromil twice daily or olopatadine twice daily for 1 week, then were crossed over to the alternate medication for 1 week. Outcome measures were patient satisfaction (questionnaire), severity of ocular symptoms (daily diary scores), clinical signs (physician assessments), quality of life (questionnaire), and global assessments of effectiveness. Both medications were well accepted. Of the 28 patients, 16 (57.1%) would request a nedocromil prescription, 10 (35.7%) an olopatadine prescription (P = .157); 22 patients (78.6%) would recommend nedocromil to other allergy sufferers, while 18 (64.3%) would recommend olopatadine (P = .480). Light sensitivity scores were significantly lower with nedocromil (P = .0125); other symptom scores were comparable between medications. Both drugs significantly (P < .01) and comparably decreased erythema, conjunctival injection, and overall conjunctival signs from baseline. Comparable improvement also occurred in quality-of-life scores. Both physicians and patients judged nedocromil and olopatadine to be similarly effective in preventing signs and symptoms. Nedocromil sodium 2% is an effective treatment for perennial allergic conjunctivitis. Patients receiving olopatadine can be switched to nedocromil with no loss in efficacy or satisfaction, but with a reduction in cost.