Major classes of medication in asthma management include bronchodilating β2-agonists, anti-inflammatory inhaled corticosteroids, leukotriene modifiers and theophyllines. However, all asthmatics do not respond to the same extent to a given medication. Available data suggest that a substantial range of individual variability, as much as 70%, may be due to genetic characteristics of each patient. Pharmacogenomics offers the potential to optimize medications for individual asthmatics by using genetic information to improve efficacy or avoid adverse effects. The best-studied case of the potential contribution of pharmacogenomics to treatment response in asthma comes from studies on human β2 adrenergic receptors. In addition, genetic variation in β2-adrenergic receptor (Arg16Gly) may predict response to anticholinergics for the treatment of asthma. In case of inhaled corticosteroids, a recent investigation using a traditional SNP-based approach identified a gene for corticotropin releasing hormone receptor 1 as a potential marker of response. Another major pathway that has been investigated is the pathway underlying response to cysteinyl leukotriene receptor antagonist. It is likely that in the near future, pharmacogenomic approaches based on individual genetic information will be introduced into an asthma treatment guideline and this guideline will allow us to identify those who have the best chance to respond to a specific medication.
Asthma; pharmacogenomics; treatment response
Asthma is a complex genetic disease with multiple genetic and environmental determinants contributing to the observed variability in response to common anti-asthma therapies. Asthma pharmacogenetic research has focused on multiple candidate genes including the β2-adrenergic receptor gene (ADRβ2) and its effect on individual responses to beta agonist therapy. At present, knowledge about the effects of ADRβ2 variation on therapeutic responses is evolving and should not alter current Asthma Guideline approaches consisting of the use of short acting beta agonists for as-needed symptom based therapy and the use of a regular long-acting beta agonist in combination with inhaled corticosteroid therapy for optimal control of asthma symptoms in those asthmatics who are not controlled on inhaled corticosteroid alone. This approach is based upon studies showing a consistent pharmacogenetic response to regular use of short acting beta agonists (SABA) and less consistent findings in studies evaluating long acting beta agonist (LABA). While emerging pharmacogenetic studies are provocative and should lead to functional approaches, conflicting data with responses to LABA therapy may be caused by factors that include small sample sizes of study populations and differences in experimental design that may limit the conclusions that may be drawn from these clinical trials at the present time.
Purpose of review
Patient response to the asthma drug classes, bronchodilators, inhaled corticosteroids and leukotriene modifiers, are characterized by a large degree of heterogeneity, which is attributable in part to genetic variation. Herein, we review and update the pharmacogenetics and pharmaogenomics of common asthma drugs.
Early studies suggest that bronchodilator reversibility and asthma worsening in patients on continuous short-acting and long-acting β-agonists are related to the Gly16Arg genotype for the ADRB2. More recent studies including genome-wide association studies implicate variants in other genes contribute to bronchodilator response heterogeneity and fail to replicate asthma worsening associated with continuous β-agonist use. Genetic determinants of the safety of long-acting β-agonist require further study. Variants in CRHR1, TBX21, and FCER2 contribute to variability in response for lung function, airways responsiveness, and exacerbations in patients taking inhaled corticosteroids. Variants in ALOX5, LTA4H, LTC4S, ABCC1, CYSLTR2, and SLCO2B1 contribute to variability in response to leukotriene modifiers.
Identification of novel variants that contribute to response heterogeneity supports future studies of single nucleotide polymorphism discovery and include gene expression and genome-wide association studies. Statistical models that predict the genomics of response to asthma drugs will complement single nucleotide polymorphism discovery in moving toward personalized medicine.
asthma; genes; personalized medicine; polymorphisms; response heterogeneity
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.
asthma; genes; GWAS; network medicine; pharmacogenomics; SNP; systems biology
Rationale: To date, most studies aimed at discovering genetic factors influencing treatment response in asthma have focused on biologic candidate genes. Genome-wide association studies (GWAS) can rapidly identify novel pharmacogenetic loci.
Objectives: To investigate if GWAS can identify novel pharmacogenetic loci in asthma.
Methods: Using phenotypic and GWAS genotype data available through the NHLBI-funded Single-nucleotide polymorphism Health association-Asthma Resource Project, we analyzed differences in FEV1 in response to inhaled corticosteroids in 418 white subjects with asthma. Of the 444,088 single nucleotide polymorphisms (SNPs) analyzed, the lowest 50 SNPs by P value were genotyped in an independent clinical trial population of 407 subjects with asthma.
Measurements and Main Results: The lowest P value for the GWAS analysis was 2.09 × 10−6. Of the 47 SNPs successfully genotyped in the replication population, three were associated under the same genetic model in the same direction, including two of the top four SNPs ranked by P value. Combined P values for these SNPs were 1.06 × 10−5 for rs3127412 and 6.13 × 10−6 for rs6456042. Although these two were not located within a gene, they were tightly correlated with three variants mapping to potentially functional regions within the T gene. After genotyping, each T gene variant was also associated with lung function response to inhaled corticosteroids in each of the trials associated with rs3127412 and rs6456042 in the initial GWAS analysis. On average, there was a twofold to threefold difference in FEV1 response for those subjects homozygous for the wild-type versus mutant alleles for each T gene SNP.
Conclusions: Genome-wide association has identified the T gene as a novel pharmacogenetic locus for inhaled corticosteroid response in asthma.
polymorphism; genome; pharmacogenomics; glucocorticoid
Asthma is a complex disease with multiple genetic and environmental factors contributing to it. A component of this complexity is a highly variable response to pharmacological therapy. Pharmacogenomics is the study of the role of genetic determinants in the variable response to therapy. A number of examples of possible pharmacogenomic approaches that may prove of value in the management of asthma are discussed below.
A search of PubMed, Google scholar, E-Medicine, BMJ and Mbase was done using the key words “pharmacogenomics of asthma”, “pharmacogenomics of β-agonist, glucocorticoids, leukotriene modifiers, theophylline, muscarinic antagonists in asthma”.
Presently, there are limited examples of gene polymorphism that can influence response to asthma therapy. Polymorphisms that alter response to asthma therapy include Arg16Gly, Gln27Glu, Thr164Ile for β-agonist receptor, polymorphism of glucocorticoid receptor gene, CRHR1 variants and polymorphism of LTC4S, ALOX5. Polymorphic variants of muscarinic receptors, PDE4 and CYP450 gene variants.
It was concluded that genetic variation can improve the response to asthma therapy. However, no gene polymorphism has been associated with consistent results in different populations. Therefore, asthma pharmacogenomic studies in different populations with a large number of subjects are required to make possible tailoring the asthma therapy according to the genetic characteristic of individual patient.
Asthma; pharamacogenomics; polymorphism; variability in response
OBJECTIVE: To determine asthma patients' patterns of disease and knowledge of asthma. DESIGN: Telephone survey of patients with diagnosed asthma. SETTING: Residences in 10 Canadian provinces. PARTICIPANTS: Patients with asthma diagnosed by a doctor: 829 men and women with a mean age of 38 +/- 7 years. MAIN OUTCOME MEASURES: Classes of asthma medications, patterns of use, frequency and severity of asthma symptoms use of emergency departments and urgent medical services, participation in asthma education programs, presence of environmental triggers, and knowledge of asthma pathophysiology and treatment. RESULTS: Four hundred fifty-six patients (55%) reported daily symptoms of asthma; 431 patients (52%) used inhaled beta 2-agonists daily. Only 340 patients (41%) used inhaled corticosteroids (IC), and many used them irregularly. A total of 579 (72%) respondents reported no unscheduled visits to a family physician for worsening asthma, but one third of patients had been to an emergency department for uncontrolled asthma in the last 5 years, and most of these visits had occurred during the last year. As to knowledge, 406 patients (49%) disagreed with the statement that asthma is a lifelong condition that cannot be cured. Among IC users, only 101 (30%) knew that IC reduced airway inflammation; among beta 2-agonist users, only 33% agreed that beta 2-agonists opened the bronchial tubes. Two hundred forty patients (29%) reported being current cigarette smokers, and 381 (46%) reported having pets at home. CONCLUSIONS: Daily symptoms and daily use of beta 2-agonists are common among Canadian asthma patients, and this is in excess of what is considered acceptable by current asthma care guidelines. Underuse of IC, inadequate knowledge of asthma symptoms and treatments, and failure to avoid asthma triggers were common in the population studied.
Asthma guidelines advocate inhaled corticosteroids as the cornerstone treatment of persistent asthma, yet several studies report underuse of inhaled corticosteroids in children with persistent asthma. Moreover, few studies use objective pharmacy data as a measure of drug availability of asthma medications. We examined factors associated with the use of inhaled corticosteroids in young underserved children with persistent asthma using pharmacy records as their source of asthma medications.
This was a cross-sectional analysis of questionnaire and pharmacy record data over a 12-month period from participants enrolled in a randomized clinical trial of a nebulizer educational intervention.
Although exposure to ≥1 inhaled corticosteroids refill was high at 72%, 1 of 5 children with persistent asthma had either no medication or only short-acting β agonist fills for 12 months. Only 20% of children obtained ≥6 inhaled corticosteroids fills over 12 months. Obtaining ≥3 inhaled corticosteroids fills over 12 months was significantly associated with an increase in short-acting β agonist fills and receiving specialty care in the regression models while controlling for child age, asthma severity, number of emergency department visits, having an asthma action plan, and seeking preventive care for the child’s asthma.
Overreliance on short-acting β agonist and underuse of inhaled corticosteroid medications was common in this group of young children with persistent asthma. Only one fifth of children obtained sufficient controller medication fills.
asthma; children; preventive care; antiinflammatory
Inhaled corticosteroids (ICS) are considered first-line treatment for persistent asthma; yet, there is significant variability in treatment response. Dual specificity phosphatase-1 (DUSP1) appears to mediate the anti-inflammatory action of corticosteroids.
To determine whether variants in the DUSP1 gene are associated with clinical response to ICS treatment.
Study participants with asthma were drawn from the following multi-ethnic cohorts: the Genetics of Asthma in Latino Americans (GALA) study, the Study of African Americans, Asthma, Genes & Environments (SAGE), and the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). We screened GALA participants for genetic variants that modified the relationship between ICS use and bronchodilator response. We then replicated our findings in SAGE and SAPPHIRE participants. In a group of SAPPHIRE participants treated with ICS for 6 weeks, we examined whether a DUSP1 polymorphism was associated with changes in forced expiratory volume at one second (FEV1) and self-reported asthma control.
DUSP1 polymorphisms, rs881152 and rs34507926, localized to different haplotype blocks and appeared to significantly modify the relationship between ICS use and bronchodilator response among GALA participants. This interaction was also seen for rs881152 among SAPPHIRE, but not SAGE participants. Among the group of SAPPHIRE patients prospectively treated with ICS for 6 weeks, rs881152 genotype was significantly associated with changes in self-reported asthma control but not FEV1.
DUSP1 polymorphisms were associated with clinical response to ICS therapy, and therefore, may be useful in the future to identify asthma patients more likely to respond to this controller treatment.
These findings further our understanding of ICS pharmacogenetics and will hopefully result in improved tailoring of this controller therapy among individuals with asthma and in better disease control.
We identified genetic variants in DUSP1 which appeared to mediate the clinical response to inhaled corticosteroid (ICS) medication. These findings may eventually assist in identifying individuals with asthma most likely to respond this controller therapy.
Asthma; inhaled corticosteroids; dual specificity phosphatase-1; DUSP1; corticosteroid responsiveness
Leukotrienes are now established contributors to the inflammatory process in asthma and leukotriene modifiers are mainstays in the therapy of asthma. This review focuses on published association studies implicating the role of leukotriene pathway genes in asthma pathogenesis and treatment response, specifically focusing on those genetic variants associated with asthma affection status, the development of aspirin exacerbated respiratory disease, and pharmacogenetic response. While published studies have been limited by small sample sizes and lack of independent replication, multiple loci within multiple leukotriene pathway genes have now been associated in more than one study related to asthma or asthma treatment response. Those specific variants include two variants in ALOX5 that are both associated with response to 5-LO inhibition and to leukotriene receptor antagonists, variants in the two established cysteinyl leukotriene receptor antagonists, CYSLTR1 and CYSLTR2 that are both associated with asthma susceptibility in at least two independent populations, and a LTC4S promoter polymorphism that has been associated with asthma affection status and with asthma exacerbated respiratory disease. Desite these successes, genetic investigations into this pathway remain in their formative stages. Future studies aimed at providing a broader scope of investigation through increased sample sizes and through genome-wide approaches are needed.
Leukotrienes; SNP; asthma, 5-lipoxygenase; zileuton; montelukast; pharmacogenetics
Pharmacogenetics/pharmacogenomics is the study of how genetic variation affects pharmacology, the use of drugs to treat disease. When drug responses are predicted in advance, it is easier to tailor medications to different diseases and individuals. Pharmacogenetics provides the tools required to identify genetic predictors of probable drug response, drug efficacy, and drug-induced adverse events—identifications that would ideally precede treatment decisions. Drug abuse and addiction genetic data have advanced the field of pharmacogenetics in general. Although major findings have emerged, pharmacotherapy remains hindered by issues such as adverse events, time lag to drug efficacy, and heterogeneity of the disorders being treated. The sequencing of the human genome and high-throughput technologies are enabling pharmacogenetics to have greater influence on treatment approaches. This review highlights key studies and identifies important genes in drug abuse pharmacogenetics that provide a basis for better diagnosis and treatment of drug abuse disorders.
Pharmacogenomics; addiction; treatment; psychiatric disease; SNP
OBJECTIVE: To comprehensively evaluate clinical, economic, and patient-reported outcomes associated with various therapeutic classes of asthma controller medications.
PATIENTS AND METHODS: This observational study, which used administrative claims data from US commercial health plans, included patients with asthma aged 18 through 64 years who filled a prescription for at least 1 asthma controller medication from September 1, 2003, through August 31, 2005. Outcome metrics included the use of short-acting β-agonists (SABAs), the use of oral corticosteroids, inpatient (INP)/emergency department (ED) visits, and asthma-related health care costs. A subset of 5000 patients was randomly selected for a survey using the Mini-Asthma Quality of Life Questionnaire, the Work Productivity and Activity Impairment questionnaire, and the Asthma Therapy Assessment Questionnaire.
RESULTS: Of 56,168 eligible patients, 823 returned completed questionnaires. Compared with inhaled corticosteroids (ICSs), leukotriene modifiers (LMs) were associated with lower odds of INP/ED visits (odds ratio [OR], 0.80; P<.001), lower odds of using 6 or more SABA canisters (OR, 0.81; P<.001), and higher annual cost ($193; P<.001). In the subgroup analysis of adherent patients, LMs were associated with higher odds of INP/ED visits (OR, 1.74; P=.04), lower odds of using 6 or more SABA canisters (OR, 0.46; P<.001), and higher annual cost ($235; P<.001). Inhaled corticosteroids and LMs had a comparable impact on all patient-reported outcomes. For combination therapy, ICS plus a long-acting β-agonist consistently showed at least equivalent or better outcomes in the use of SABAs and oral corticosteroids, the risk of INP/ED visits, cost, asthma control level, quality of life, and impairment in productivity and activity.
CONCLUSION: Inhaled corticosteroids were associated with a lower risk of INP/ED visits, and a lower cost if adherence was achieved. When adherence cannot be achieved, LMs may be a reasonable alternative. Combination therapy with ICS plus a long-acting β-agonist was associated with better or equivalent clinical, economic, and patient-reported outcomes.
Inhaled corticosteroids were associated with a lower risk of inpatient/emergency department visits, and a lower cost if adherence was achieved. When adherence cannot be achieved, leukotriene modifiers may be a reasonable alternative. Combination therapy with inhaled corticosteroids plus a long-acting β-agonist was associated with better or equivalent clinical, economic, and patient-reported outcomes.
Clinical response to therapeutic treatments often varies among individual patients, ranging from beneficial effect to even fatal adverse reaction. Pharmacogenomics holds the promise of personalized medicine through elucidating genetic determinants responsible for pharmacological outcomes (e.g., cytotoxicities to anti-cancer drugs) and therefore guide the prescription decision prior to drug treatment. Besides traditional candidate gene-based approaches, technical advances have begun to allow application of whole-genome approaches to pharmacogenomic discovery. In particular, comprehensive understanding of human genetic variation provides the basis for applying GWAS (genome-wide association studies) in pharmacogenomic research to identify genomic loci associated with pharmacological phenotypes (e.g., individual dose requirement for warfarin). We therefore briefly reviewed the background for pharmacogenetic/pharmacogenomic research, with statins and warfarin as examples for the GWAS discovery and their clinical implementation. In conclusion, with some challenges, whole-genome approaches such as GWAS have allowed unprecedented progress in identifying genetic variants associated with pharmacological phenotypes, as well as provided foundation for the next wave of pharmacogenomic discovery utilizing sequencing-based approaches. Furthermore, investigation of the complex interactions among genetic, and epigenetic factors on the whole-genome scale will become the post-GWAS research focus for pharmacologic complex traits.
The role of asthma controller medication adherence and the level of asthma control in children is poorly defined.
To assess the association between asthma controller medication adherence and asthma control in children using routinely acquired prescribing data.
A retrospective observational study of children aged 0–18 years prescribed inhaled corticosteroids only (ICS), leukotriene receptors antagonists (LTRA), or long-acting β2 agonists (LABA) and ICS prescribed as separate or combined inhalers, between 01/09/2001 and 31/08/2006, registered with primary care practices contributing to the Practice Team Information database. The medication possession ratio (MPR) was calculated and associations with asthma control explored. Poor asthma control was defined as the issue of prescriptions for ≥1 course of oral corticosteroids (OCS) and/or ≥6 short-acting β2 agonists (SABA) canisters annually.
A total of 3172 children prescribed asthma controller medication were identified. Of these, 15–39% (depending on controller medication) demonstrated adequate MPR. Adequate MPR was associated with male gender, good socio-economic status, and oral LTRA therapy. Adequate MPR was more likely to be associated with increased use of rescue medication. However logistic regression only identified a significant relationship for ICS only (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.35–2.48; p<0.001), LTRA (OR, 2.11; 95% CI, 1.27–3.48; p = 0.004) and LABA/ICS (OR, 2.85; 95% CI, 1.62–5.02; p<0.001).
Poor adherence was observed for all asthma controller medications, although was significantly better for oral LRTA. In this study adequate adherence was not associated with the use of less rescue medication, suggesting that adherence is a complex issue.
It is increasingly recognized that large proportions of patients with asthma remain poorly controlled with daily symptoms, limitation in activities, or severe exacerbations despite traditional treatment with inhaled corticosteroids and other agents. This suggests that there is considerable scope for the refinement of traditional guidelines on the use of inhaled therapies in asthma and also a need for the development of novel therapeutic agents, particularly for the treatment of severe asthma. This review aims to discuss a range of emerging treatment approaches in asthma. Firstly, we will set the scene by highlighting the importance of achieving good asthma control in a patient-focused manner and discussing recent work that has furthered our understanding of asthma phenotypes and paved the way for patient-specific treatments. Secondly, we will review new strategies to better use the existing therapies such as inhaled corticosteroids and long-acting β2-agonists that remain the mainstay of treatment for most patients. Finally, we will review the novel therapies that are becoming available, both pharmacological and interventional, and discuss their likely place in the management of this complex disease.
asthma; treatments; classification; phenotypes; management
Pharmacogenetic research aims to study how genetic variation may influence drug efficacy and/or toxicity; pharmacogenomics expands this quest to the entire genome. Pharmacogenetic findings may help to uncover new drug targets, illuminate pathophysiology, clarify disease heterogeneity, aid in the fine-mapping of genetic associations, and contribute to personalized treatment. In diabetes, there is precedent for the successful application of pharmacogenetic concepts to monogenic forms of the disease, such as maturity onset diabetes of the young or neonatal diabetes. Whether similar insights will be produced for the common form of type 2 diabetes remains to be seen. With recent advances in genetic approaches, the successive application of candidate gene studies, large-scale genotyping studies and genome-wide association studies has begun to generate suggestive results that may lead to changes in clinical practice. However, many potential barriers to the translation of pharmacogenetic discoveries to the clinical management of diabetes still remain. Here, we offer a contemporary overview of the field in its current state, identify potential obstacles, and highlight future directions.
Type 2 diabetes; pharmacogenetics; genome-wide association studies; single nucleotide polymorphisms; sulfonylureas; metformin; thiazolidinediones
There is evidence that humanized monoclonal antibody against IgE (Omalizumab) is effective in severe allergic asthma. In this study, we examined the effectiveness of omalizumab on asthma and nasal symptoms in Japanese patients with severe allergic asthma and rhinitis.
An open-label study that enrolled 7 patients with both severe allergic asthma and rhinitis who visited Allergy Center, Saitama Medical University was performed. All patients presented uncontrolled asthma despite medication including high-dose inhalational corticosteroids, long-acting beta2-agonist, leukotriene receptor antagonist, theophylline, and oral predonisolone. Omalizumab was added on their treatments and symptoms score using Asthma Contol Test (ACT), peak expiratory flow rate (PEFR), exhaled nitric oxide (eNO), sputum eosinophils and nasal symptoms were evaluated before and 12 to 16 weeks after omalizumab.
Omalizumab significantly improved ACT scores especially dose of rescue use of short-acting beta2-agonist (P < 0.05) and PEFR (P < 0.05). Furthermore, omalizumab significantly decreased exhaled both eNO (P < 0.05) and the percentage of eosinophils in induced sputum. On the other hand, nasal symptoms were not change following induction of omalizumab.
Clinical effectiveness of omalizumab was confirmed in Japanese population of severe allergic asthma, but not rhinitis. The therapeutic potency of omalizumab on asthma likely involves anti-inflammatory properties such as decreasing eNO or airway eosinophilia.
Asthma affects nearly 300 million people worldwide. The majority respond to inhaled corticosteroid treatment with or without beta-adrenergic agonists. However, a subset of 5 to 10% with severe asthma do not respond optimally to these medications. Different phenotypes of asthma may explain why current therapies show limited benefits in subgroups of patients. Interleukin-13 is implicated as a central regulator in IgE synthesis, mucus hypersecretion, airway hyperresponsiveness, and fibrosis. Promising research suggests that the interleukin-13 pathway may be an important target in the treatment of the different asthma phenotypes.
interleukin-13; asthma; airway hyper-reactivity; fibrosis; single nucleotide polymorphism
Recent asthma recommendations advocate the use of long-acting beta-agonists (LABAs) in uncontrolled asthma, but also stress the importance of stepping down this therapy once asthma control has been achieved. The objective of this study was to evaluate downtitration of LABA therapy in pediatric patients who are well-controlled on combination-inhaled corticosteroid (ICS)/LABA therapy. Clinical and physiologic outcomes were studied in children with moderate-to-severe persistent asthma after switching from combination (ICS/LABA) to monotherapy with ICS. Of the 54 patients, 34 (63%) were determined to have stable asthma after the switch, with a mean followup of 10.7 weeks. Twenty (37%) had loss of asthma control leading to addition of leukotriene receptor antagonists, increased ICS, or restarting LABA. There were 2 exacerbations requiring treatment with systemic steroids. In patients with loss of control, there was a statistically significant decline in FEV1 (−8% versus −1.9%, P = 0.03) and asthma control test (−3.2 versus −0.5, P = 0.03). This did not approach significance for FEF25-75%, exhaled nitric oxide, lung volumes or airway reactivity. No demographic, asthma control measures, or lung function variables predicted loss of control. Pediatric patients with moderate-to-severe persistent asthma who discontinue LABA therapy have a 37% chance of losing asthma control resulting in augmented maintenance therapies. Recent recommendations of discontinuing LABA therapy as soon as control is achieved should be evaluated in a prospective long-term study.
Pharmacogenetics and pharmacogenomics have been widely recognized as fundamental steps toward personalized medicine. They deal with genetically determined variants in how individuals respond to drugs, and hold the promise to revolutionize drug therapy by tailoring it according to individual genotypes.
The clinical need for novel approaches to improve drug therapy derives from the high rate of adverse reactions to drugs and their lack of efficacy in many individuals that may be predicted by pharmacogenetic testing.
Significant advances in pharmacogenetic research have been made since inherited differences in response to drugs such as isoniazid and succinylcholine were explored in the 1950s. The clinical utility and applications of pharmacogenetics and pharmacogenomics are at present particularly evident in some therapeutic areas (anticancer, psycotrophic, and anticoagulant drugs).
Recent evidence derived from several studies includes screening for thiopurine methyl transferase or uridine 5'-diphosphoglucuronosyl-transferase 1A1 gene polymorphisms to prevent mercaptopurine and azathioprine or irinotecan induced myelosuppression, respectively. Also there is a large body of information concerning cytochrome P450 gene polymorphisms and their relationship to drug toxicity and response. Further examples include screening the presence of the HLA-B*5701 allele to prevent the hypersensitivity reactions to abacavir and the assessment of the human epidermal growth factor receptor (HER-2) expression for trastuzumab therapy of breast cancer or that of KRAS mutation status for cetuximab or panitumumab therapy in colorectal cancer.
Moreover, the application of pharmacogenetics and pharmacogenomics to therapies used in the treatment of osteoarticular diseases (e.g. rheumatoid arthritis, osteoporosis) holds great promise for tailoring therapy with clinically relevant drugs (e.g. disease-modifying antirheumatic drugs, vitamin D, and estrogens).
Although the classical candidate gene approach has helped unravel genetic variants that influence clinical drug responsiveness, gene-wide association studies have recently gained attention as they enable to associate specific genetic variants or quantitative differences in gene expression with drug response.
Although research findings are accumulating, most of the potential of pharmacogenetics and pharmacogenomics remains to be explored and must be validated in prospective randomized clinical trials.
The genetic and molecular foundations of personalized medicine appear solid and evidence indicates its growing importance in healthcare.
pharmacogenetics, drug effects, drug metabolism, drug therapy, antineoplastic agents.
There is considerable controversy about the regular use of short- acting β-agonists for the treatment of asthma. Although case–control studies have suggested that excessive use of these drugs may worsen asthma control and increase the risk of fatal or near-fatal asthma, the controversy remains unresolved because of the confounding that exists among disease control, disease severity and the use of short-acting β-agonists. Whatever the cause-and-effect relation between the use of short-acting β-agonists and disease severity, we hypothesized that their excessive use, in conjunction with underuse of inhaled corticosteroids, would be a marker for poorly controlled asthma and excessive use of health care resources.
To characterize the pattern of health services utilization among asthmatic patients taking various doses of inhaled β-agonists and corticosteroids in British Columbia, we linked the relevant health administrative databases. All patients between 5 and 50 years of age for whom a prescription for a short-acting β-agonist was filled in 1995 and whose prescription data were captured through the provincial drug plan were included in a retrospective analysis of prescriptions for asthma drugs, physician prescribing patterns and health services utilization. Patients' use of asthma medication was classified as appropriate (low doses of short-acting β-agonist and high doses of inhaled corticosteroid) or inappropriate (high doses of short-acting β-agonist and low doses of inhaled corticosteroid), and the 2 resulting groups were compared, by means of logistic, Poisson and gamma regression, for differences in prescribing patterns, physician visits and use of hospital resources.
A total of 23 986 patients were identified as having filled a prescription for a short-acting β-agonist (for inhalation) in 1995. Of these, 3069 (12.8%) filled prescriptions for 9 or more canisters of β-agonist, and of this group of high-dose β-agonist users, 763 (24.9%) used no more than 100 μg/day of inhaled beclomethasone. On average, those with inappropriate use of β-agonists visited significantly more physicians for their prescriptions (1.8 v. 1.4), and each of these physicians on average wrote significantly more prescriptions for asthma medications per patient than the physicians who prescribed to appropriate users (5.2 v. 2.5 prescriptions). Patients with inappropriate use were more likely to be admitted to hospital (adjusted relative risk [RR] 1.68, 95% confidence interval [CI] 1.25–2.26), were admitted to hospital more frequently (adjusted RR 1.81, 95% CI 1.41–2.32) and were more likely to require emergency admission (adjusted RR 1.93, 95% CI 1.35–2.77).
Despite the widespread distribution of guidelines for asthma pharmacotherapy, inappropriate use of asthma medications persists (specifically excessive use of inhaled short-acting β-agonists combined with underuse of inhaled corticosteroids). Not only are patients who use medication inappropriately at higher risk for fatal or near-fatal asthma attacks, but, as shown in this study, they use significantly more health care resources than patients with appropriate medication use.
Rationale: Long-acting β-agonists (LABAs) and inhaled corticosteroids administered together appear to be complementary in terms of effects on asthma control. The elements of asthma control achieved by LABAs (improved lung function) and leukotriene receptor antagonists (LTRAs; protection against exacerbations) may be complementary as well.
Objective: We sought to determine whether the combination of the LTRA montelukast and the LABA salmeterol could provide an effective therapeutic strategy for asthma.
Methods and Measurements: In a randomized, placebo-controlled, crossover study of 192 subjects with moderate asthma, we compared the clinical efficacy of regular treatment over 14 weeks with the combination of montelukast and salmeterol to that with the combination of beclomethasone and salmeterol in moderate asthma. The primary efficacy outcome was time to treatment failure.
Main Results: Three months after the randomization of the last subject, the Data and Safety Monitoring Board determined that the primary research question had been answered and terminated the trial. The combination of montelukast and salmeterol was inferior to the combination of beclomethasone and salmeterol as judged by protection against asthma treatment failures (p = 0.0008), lung function (26 L/min difference in a.m. peak expiratory flow rate, p = 0.011), asthma control score (0.22 difference in Asthma Control Questionnaire score, p = 0.038), and markers of inflammation and airway reactivity.
Conclusions: Patients with moderate asthma similar to those we studied should not substitute the combination of an LTRA and an LABA for the combination of inhaled corticosteroid and an LABA.
combination therapy; leukotriene; beta-agonists; inhaled corticosteroids
Purpose of the review
Children with severe asthma have a high degree of respiratory morbidity despite treatment with high doses of inhaled corticosteroids and are therefore very difficult to treat. This review will discuss phenotypic and pathogenic aspects of severe asthma in childhood, as well as remaining knowledge gaps.
As a group, children with severe asthma have a number of distinct phenotypic features compared to children with mild-to-moderate asthma. Clinically, children with severe asthma are differentiated by greater allergic sensitization, increased exhaled nitric oxide, and significant airflow limitation and air trapping that worsens as a function of age. These findings are accompanied by structural airway changes and increased and dysregulated airway inflammation and oxidant stress which may explain the differential nature of corticosteroid responsiveness in this population. Because children with severe asthma themselves are a heterogeneous group, current efforts are focused on improved definition and sub-phenotyping of the disorder. While the clinical relevance of phenotyping approaches in severe asthma is not yet clear, they may provide important insight into the mechanisms underlying the disorder.
Improved classification of severe asthma through unified definitions, careful phenotypic analyses, and mechanism-focused endotyping approaches may ultimately advance knowledge and personalized treatment.
Severe asthma; difficult asthma; children; phenotype; endotype
Background: Inhaled corticosteroids (ICS) affect many inflammatory pathways in asthma but have little impact on cysteinyl leukotrienes. This may partly explain persistent airway inflammation during chronic ICS treatment and failure to achieve adequate asthma control in some patients. This double blind, randomised, parallel group, non-inferiority, multicentre 16 week study compared the clinical benefits of adding montelukast to budesonide with doubling the budesonide dose in adults with asthma.
Methods: After a 1 month single blind run in period, patients inadequately controlled on inhaled budesonide (800 µg/day) were randomised to receive montelukast 10 mg + inhaled budesonide 800 µg/day (n=448) or budesonide 1600 µg/day (n=441) for 12 weeks.
Results: Both groups showed progressive improvement in several measures of asthma control compared with baseline. Mean morning peak expiratory flow (AM PEF) improved similarly in the last 10 weeks of treatment compared with baseline in both the montelukast + budesonide group and in the double dose budesonide group (33.5 v 30.1 l/min). During days 1–3 after start of treatment, the change in AM PEF from baseline was significantly greater in the montelukast + budesonide group than in the double dose budesonide group (20.1 v 9.6 l/min, p<0.001), indicating faster onset of action in the montelukast group. Both groups showed similar improvements with respect to "as needed" ß agonist use, mean daytime symptom score, nocturnal awakenings, exacerbations, asthma free days, peripheral eosinophil counts, and asthma specific quality of life. Both montelukast + budesonide and double dose budesonide were generally well tolerated.
Conclusion: The addition of montelukast to inhaled budesonide is an effective and well tolerated alternative to doubling the dose of inhaled budesonide in adult asthma patients experiencing symptoms and inadequate control on budesonide alone.
As the overall prevalence of asthma has escalated in the past decades, so has the population of patients with severe asthma. This condition is often difficult to manage due to the relative limitation of effective therapeutic options for the physician and the social and economic burden of the disease on the patient. Management should include an evaluation and elimination of modifiable risk factors such as smoking, allergen exposure, obesity and non-adherence, as well as therapy for co-morbidities like gastro-esophageal reflux disease and obstructive sleep apnea. Current treatment options include conventional agents such as inhalational corticosteroids, long acting β2 agonists, leukotriene antagonists, and oral corticosteroids. Less conventional treatment options include immunotherapy with methotrexate, cyclosporine and tacrolimus, biological drugs like monoclonal antibodies, tumor necrosis factor-α blockers and oligonucleotides, phosphodiesterase inhibitors, antimicrobials and bronchial thermoplasty.
severe asthma; treatment