Multicentre, Randomised, Parallel-Group Study of the Efficacy and Tolerability of Flunisolide Administered Once Daily via AeroChamber?? in the Treatment of Mild to Moderate Asthma

Bielory, Leonard; Picone, Frank J.; Rabinowitz, Paul; Rossoff, Leonard J.; Winder, John; Incaudo, Gary A.; Wu, Jane; Newman, Ken

doi:10.2165/00044011-200019020-00002

Cited by 4 publications

(4 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The original study consisted of 515 moderate to severe asthmatic adults in ages 16-75, of which 58% were female, and 87% were self-reported as Caucasian (white) (7;26) . Inclusion criteria included a history of asthma and documentation within the previous year of at least 12% improvement in FEV 1 with administration of the short acting β-agonist, albuterol.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids

Hawkins

Lazarus

Smith

et al. 2009

Journal of Allergy and Clinical Immunology

109

View full text Add to dashboard Cite

Background Corticosteroids exert their anti-inflammatory action by binding and activating the intracellular the glucocorticoid receptor (GR) hetero-complex. Objective Evaluate the genes HSPCB, HSPCA, STIP1, HSPA8, DNAJB1, PTGES3, FKBP5, and FKBP4 on corticosteroid response. Methods Caucasian asthmatics (382) randomized to once daily flunisolide or conventional inhaled corticosteroid therapy were genotyped. Outcome measures were baseline FEV1, % predicted FEV1, and % change in FEV1 after corticosteroid treatment. Multivariable analyses adjusted for age, gender, and height, were performed fitting the most appropriate genetic model based on quantitative mean derived from ANOVA models to determine if there was an independent effect of polymorphisms on change in FEV1 independent of baseline level. Results Positive recessive model correlations for STIP1 SNPs were observed for baseline FEV1 [rs4980524, p=0.009; rs6591838, p=0.0045; rs2236647, p=0.002; and rs2236648; p=0.013], baseline % predicted FEV1 [rs4980524, p=0.002; rs6591838, p=0.017; rs2236647, p=0.003; and rs2236648; p=0.008] ; % change in FEV1 at 4 weeks [rs4980524, p=0.044; rs6591838, p=0.016; rs2236647; p=0.01] and 8 weeks therapy [rs4980524, p=0.044; rs6591838, p=0.016; rs2236647; p=0.01]. Haplotypic associations were observed for baseline FEV1 and % change in FEV1 at 4 weeks therapy [p=0.05 and p=0.01, respectively]. Significant trends towards association were observed for baseline % predicted FEV1 and % change in FEV1 at 8 weeks therapy. Positive correlations between haplotypes and % change in FEV1 were also observed. Conclusions STIP1 genetic variations may play a role in regulating corticosteroid response in asthmatics with reduced lung function. Replication in a second asthma population is required to confirm these observations. Clinical Implications Identifying genes that regulate corticosteroid responses could allow a priori determination of individual responses to corticosteroid therapy, leading to more effective dosing and/or selection of drug therapies for treating asthma.

show abstract

Section: Resultsmentioning

confidence: 99%

“…The adult corticosteroid response used in this study was a multi-center clinical trial comparing once-daily high dose inhaled flunisolide versus standard inhaled corticosteroid therapy (7;26) . DNA from 382 Caucasians who completed the study were genotyped.…”

Section: Methodsmentioning

confidence: 99%

The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids

Hawkins

Lazarus

Smith

et al. 2009

Journal of Allergy and Clinical Immunology

109

View full text Add to dashboard Cite

show abstract

“…To replicate our initial findings, we genotyped DNA obtained from subjects with asthma who were enrolled in three clinical trials: the 6-week common run-in period during which the subjects were using inhaled glucocorticoids in the Salmeterol or Corticosteroids (SOCS) trial 21 and the Salmeterol ± Inhaled Corticosteroids (SLIC) trial, 22 the Adult Study, 23 and the Leukotriene Modifier or Corticosteroid or Corticosteroid–Salmeterol (LOCCS) trial (ClinicalTrials.gov number, NCT00156819). 24 …”

Section: Methodsmentioning

confidence: 99%

Genomewide Association betweenGLCCI1and Response to Glucocorticoid Therapy in Asthma

Tantisira

Lasky‐Su

Harada³

et al. 2011

N Engl J Med

329

296

View full text Add to dashboard Cite

BACKGROUND The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. We hypothesized that a genomewide association study would reveal novel pharmacogenetic determinants of the response to inhaled glucocorticoids. METHODS We analyzed a small number of statistically powerful variants selected on the basis of a family-based screening algorithm from among 534,290 single-nucleotide polymorphisms (SNPs) to determine changes in lung function in response to inhaled glucocorticoids. A significant, replicated association was found, and we characterized its functional effects. RESULTS We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons (P = 0.0007), which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1) and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. In isolated cell systems, the rs37973 variant is associated with significantly decreased luciferase reporter activity. Pooled data from treatment trials indicate reduced lung function in response to inhaled glucocorticoids in subjects with the variant allele (P = 0.0007 for pooled data). Overall, the mean (± SE) increase in forced expiratory volume in 1 second in the treated subjects who were homozygous for the mutant rs37973 allele was only about one third of that seen in similarly treated subjects who were homozygous for the wild-type allele (3.2 ± 1.6% vs. 9.4 ± 1.1%), and their risk of a poor response was significantly higher (odds ratio, 2.36; 95% confidence interval, 1.27 to 4.41), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability. CONCLUSIONS A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00000575.)

show abstract

“…We genotyped 935 asthmatic participants from one asthma clinical trial: CAMP [39,40], and three replication cohorts, the SOCS [41] and SLIC [42] trials, the Adult Study [43] and the LOCCS [44] trial, with the goal of identifying novel variants associated with response to inhaled glucocorticoids (GCs). To identify markers with the greatest positive association with the primary-outcome phenotype of change in forced expiratory volume in 1 s (ΔFEV 1 ) from baseline during the first 16 months of budesonide therapy, 534,290 SNPs from an initial cohort of 403 CAMP trios (children and their parents) were first screened using a powerful family-based screening algorithm [45], which applies parental genotype information in order to rank the top 100 SNPs with the highest statistical associations [46].…”

Section: Progress In the Pharmacogenomics Of Asthmamentioning

confidence: 99%

Integrative Systems Biology Approaches in Asthma Pharmacogenomics

Dahlin

Tantisira

2012

Pharmacogenomics

View full text Add to dashboard Cite

In order to improve therapeutic outcomes, there is a tremendous need to identify patients who are likely to respond to a given asthma treatment. Pharmacogenomic studies have explained a portion of the variability in drug response and provided an increasing list of candidate genes and SNPs. However, as phenotypic variation arises from a network of complex interactions among genetic and environmental factors, rather than individual genes or SNPs, a multidisciplinary, systems-level approach is required in order to understand the inter-relationships among these factors. Systems biology, which seeks to capture interactions between genetic factors and other variables, offers a promising approach to improved therapeutic outcomes in asthma. This aritcle will review and update progress in the pharmacogenomics of asthma and then discuss the application of systems biology approaches to asthma pharmacogenomics.

show abstract

Multicentre, Randomised, Parallel-Group Study of the Efficacy and Tolerability of Flunisolide Administered Once Daily via AeroChamber?? in the Treatment of Mild to Moderate Asthma

Cited by 4 publications

References 16 publications

The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids

The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids

Genomewide Association betweenGLCCI1and Response to Glucocorticoid Therapy in Asthma

Integrative Systems Biology Approaches in Asthma Pharmacogenomics

Contact Info

Product

Resources

About