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Development of small molecules to target the IgE:FcεRI protein-protein interaction in allergies.

Development of small molecules to target the IgE:FcεRI protein-protein interaction in allergies.

Future Med Chem. 2013 Aug;5(12):1423-35

Authors: Smith LD, Leatherbarrow RJ, Spivey AC

Abstract
The protein-protein interaction (PPI) between IgE and its high-affinity receptor (FcεRI) is a key component of the allergic response. Inhibiting the IgE:FcεRI PPI is an attractive strategy for therapeutic intervention and the development of allergy treatments. This PPI has been validated as a viable target by the monoclonal anti-IgE antibody omalizumab (Xolair(®)), which has demonstrated clinical efficacy when prescribed to treat moderate-to-severe asthma and hay fever, but small molecules would be a more convenient form of treatment. Cyclic peptides, small proteins and a natural product have all been developed to target the IgE:FcεRI PPI, and these will be discussed in this review. Targeting the IgE:FcεRI complex with small molecules presents various challenges, some of which are inherent in all PPI targets but some of which are unique to this system, which presents great opportunities for the development of new therapeutics for the treatment of allergies.

PMID: 23919552 [PubMed - in process]

Risk Factors for Persistence of Asthma in Children: 10 Year Follow-up.

Risk Factors for Persistence of Asthma in Children: 10 Year Follow-up.

J Asthma. 2013 Aug 6;

Authors: Aydogan M, Ozen A, Akkoc T, Eifan A, Aktas E, Deniz G, Gocmen I, Bahceciler NN, Barlan I

Abstract
Abstract Objective: Risk factors related to the outcome of childhood asthma are not yet well established. We aimed to investigate the long-term outcome for children with asthma to determine the risk factors in predicting persistence of disease. Methods: Sixty-two children with asthma were evaluated retrospectively at the end of a 10 year follow-up. Patients were asked to complete a questionnaire requesting clinical information, and underwent physical examination, skin prick testing, a pulmonary function test, and bronchial provocation testing. Immunologic parameters evaluated were allergen-specific IgE and IgG4 levels, and allergen-induced generation of CD4(+)CD25(+) cells. Results: Mean age at final assessment was 15.9±3.6 years, and duration of follow-up was 10.30±1.27 years. Fifty percent of patients outgrew their asthma during the 10 year follow-up period. All the non-atopic patients outgrew their disease during the study period, whereas 67% of atopic patients did not. We identified two risk factors independently related to the persistence of symptoms: presence of bronchial hyper-responsiveness, and presence of rhinitis. Atopic children who were in remission demonstrated significantly higher allergen-induced CD4(+)CD25(+) T cells compared to healthy controls. Conclusions: Atopy, presence of rhinitis, positive and presence of bronchial hyper-reactivity are important risk factors for the persistence of asthma in children. Allergen-induced CD4(+)CD25(+) T cells were higher in the atopic children who outgrew their disease, implicating an immunological mechanism of asthma remission in children.

PMID: 23919566 [PubMed - as supplied by publisher]

Long acting β2 agonists in adult asthma.

A 30 year old man with asthma, previously well controlled with inhaled beclometasone 100 μg (two puffs twice daily) and salbutamol (as required), presented to his general practitioner with a three month history of increasing breathlessness and wheeze, primarily overnight and in the mornings. He was a non-smoker with no obvious trigger factors. He reported using his inhaler as prescribed, and his technique was satisfactory. He had no other medical history and no symptoms of allergic rhinitis. His general practitioner suggested a further inhaler containing a long acting β2 agonist (LABA), but the patient expressed concerns as he had read that these inhalers were linked to an increased risk of fatal asthma.

What are long acting β2 agonists ?

LABAs have become an increasingly popular treatment over the past two decades as a supplement to inhaled corticosteroids in the management of persistent asthma.1 They have a bronchodilator effect when bronchomotor tone (the state of airway smooth muscle contraction or relaxation regulating airway calibre) is low, and a protective (or “airway stabilising”) effect with increased bronchomotor tone ...

Prevalence of Atopy and Respiratory Allergic Diseases in the Elderly SAPALDIA Population.

Because of changing world demographics, the elderly population is steadily increasing. Few studies have assessed the prevalence of atopy and allergic diseases in elderly persons with objective measures.

The aim of this paper is to describe the prevalence of atopy, self-reported allergic rhinitis and doctor's diagnosed asthma in persons over the age of 60 in Switzerland.

Methods: The cross-sectional examination of the Swiss Study on Air Pollution and Health in Adults (SAPALDIA 1), performed in 1991, included 9,651 adults aged 18-60 years. In 2001-2002 the same subjects were invited for a follow-up examination (SAPALDIA 2). Serum samples collected at baseline and follow-up were tested for specific IgE sensitization with the Phadiatop® (Phadia, Uppsala, Sweden, now Thermo Fisher Scientific) assay containing a mixture of common respiratory allergens (grass, birch, mugwort, Parietaria and olive pollen, dog, cat, horse, Cladosporium herbarum, house dust mite and flour mite). Atopy was defined as a positive result in the Phadiatop test according to guidelines by the manufacturer. The prevalence rates of atopy, self-reported allergic rhinitis and doctor's diagnosed asthma were evaluated by sex and age group (≤60 or >60 years).

Results: 7,667 subjects (men = 3,692/women = 3,975) participated in the follow-up by responding to a detailed questionnaire (80% of SAPALDIA 1 participants). Phadiatop results were available for 5,835 participants (men = 2,839/women = 2,996). Prevalence rates of atopy (Phadiatop positive) were 36.4% in men aged ≤60 years versus 26.2% in men aged >60 years and 30.6 and 18.1% in women, respectively (both p < 0.001). Prevalence rates of self-reported allergic rhinitis in subjects >60 years old were 13.0% for men and 15.4% for women (p = 0.12), and for doctor's diagnosed asthma 6.6% versus 7.6%, respectively (p = 0.40). Both rhinitis and asthma prevalences were higher in persons <60 years. The results were not sensitive to potential bias from nonparticipation at follow-up as demonstrated by imputation of sex- and age-specific allergic rhinitis and asthma among nonparticipants.

Conclusions: According to our estimates, the prevalence of allergic rhinitis among persons aged between 60 and 70 years in Switzerland in the present cohort is of the order of 13-15% and should not be underestimated, although it is lower than in age groups ≤60 years.

The Effect of Obesity on the Level of Fractional Exhaled Nitric Oxide in Children with Asthma.

Several studies have demonstrated a relationship between asthma and obesity. However, the results have been conflicting with regard to the relationship between fractional exhaled nitric oxide (FeNO), used as a marker of airway inflammation in asthmatic patients, and obesity.

We aimed to evaluate the association of FeNO with obesity and obesity-related metabolic complications in asthmatic and nonasthmatic children.

Methods: The study population included children aged between 6 and 17 years and consisted of 4 groups: obese asthmatics (n = 52), normal-weight asthmatics (n = 49), obese nonasthmatics (n = 51) and normal-weight nonasthmatics (n = 42). FeNO measurement and spirometry were performed for all patients. To evaluate the metabolic complications, serum lipids, glucose and insulin levels were measured. Insulin resistance (IR) was estimated by the homeostasis model assessment, HOMA-IR. All participants were evaluated for the presence of metabolic syndrome (MS).

Results: The mean age for the 194 subjects participating in the study was 11.6 ± 2.5 years. The FeNO level of asthma patients with MS was not different from those without MS (14.5 ± 8.0 and 16.7 ± 8.7, respectively, p = 0.449). In the nonasthmatic group, subjects with MS had a higher FeNO level than subjects without MS (12.5 ± 5.1 and 17.3 ± 8.3, respectively, p = 0.014). Spearman's rank correlation coefficients revealed a positive correlation between FeNO and body mass index (BMI; p = 0.049, r(2): 0.204) in the nonasthmatic group and after multivariate regression analysis, BMI still persisted as an independent risk factor for FeNO.

Conclusion: We found a positive correlation between BMI and FeNO level which suggests a link between obesity and increased airway inflammation in nonasthmatic children.

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