Important Note: The following information is provided for your education. It should not be relied upon for personal diagnosis or treatment. If you believe that a particular therapy applies to you or someone you care about, be sure to consult a doctor before trying it.
   

Asthma Research: 2002-2006
     
Ann Allergy Asthma Immunol. 2006 Aug;97(2):149-57.
The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide.
Meltzer EO, Derendorf H.
Allergy and Asthma Medical Group and Research Center, San Diego, California 92123, USA. eomeltzer@aol.com

OBJECTIVE: To review the potential systemic activity of ciclesonide and its active metabolite, desisobutyryl-ciclesonide, by evaluation of the effects on hypothalamic-pituitary-adrenal (HPA) axis function. DATA SOURCES: EMBASE and MEDLINE searches using the keyword ciclesonide, without date restrictions, were conducted to identify published articles that related to clinical trials that included ciclesonide. STUDY SELECTION: The primary articles that reported systemic safety data for ciclesonide were reviewed. RESULTS: Ciclesonide (320-1,280 microg/d) demonstrated no detectable, clinically relevant effect on HPA axis function as evaluated by basal cortisol excretion measurements and dynamic stimulation tests. Furthermore, ciclesonide had no effect on the normal diurnal rhythm of endogenous cortisol secretion while simultaneously improving pulmonary function and reducing bronchial hyperresponsiveness. These results suggest that ciclesonide has a low systemic activity that may be attributable to unique pharmacologic properties, including a high degree of serum protein binding, a low oral bioavailability, and rapid systemic elimination, that reduce the level of systemically available pharmacologically active drug. CONCLUSIONS: Even at the higher doses used to treat more severe cases of asthma, ciclesonide was observed to have no effect on HPA axis function. These data, in conjunction with the observed clinical efficacy, suggest that ciclesonide may have an improved therapeutic margin compared with some other currently available inhaled corticosteroid treatments and, therefore, the potential to improve therapeutic outcomes.

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Lancet. 2006 Aug 26;368(9537):794-803.
Pharmacological management of mild or moderate persistent asthma.
O'Byrne PM, Parameswaran K.
Firestone Institute for Respiratory Health, St Joseph's Healthcare and Department of Medicine, McMaster University, Hamilton, Ontario, Canada. obyrnep@mcmaster.ca

Patients with mild persistent asthma rarely see their doctor with symptoms of the disease. Partly as a result of this situation, mild asthma is generally undertreated. Findings of several large randomised clinical trials have shown benefits for this population of regular treatment with low doses of inhaled corticosteroids. Additional drugs are rarely needed, and although leukotriene modifiers are effective, they are less so than inhaled corticosteroids. People with moderate persistent asthma are not well controlled on low doses of inhaled corticosteroids. A combination of this drug and long-acting inhaled beta2 agonists provides improved control compared with doubling of the maintenance dose of inhaled corticosteroids. The combination of budesonide and formoterol has been assessed as both maintenance and reliever treatment. This approach further reduces the risk for severe exacerbations. With these strategies, most individuals can achieve good control of their asthma. For patients who do not achieve asthma control despite taking drugs, measurement of the inflammatory response in the airway in induced sputum could provide further information to guide treatment.

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Lancet. 2006 Aug 26;368(9537):780-93.
The mechanisms, diagnosis, and management of severe asthma in adults.
Holgate ST, Polosa R.
AIR Division, Level D Centre Block, Southampton General Hospital, Southampton, UK. sth@soton.ac.uk

There has been a recent increase in the prevalence of asthma worldwide; however, the 5-10% of patients with severe disease account for a substantial proportion of the health costs. Although most asthma cases can be satisfactorily managed with a combination of anti-inflammatory drugs and bronchodilators, patients who remain symptomatic despite maximum combination treatment represent a heterogeneous group consisting of those who are under-treated or non-adherent with their prescribed medication. After excluding under-treatment and poor compliance, corticosteroid refractory asthma can be identified as a subphenotype characterised by a heightened neutrophilic airway inflammatory response in the presence or absence of eosinophils, with evidence of increased tissue injury and remodelling. Although a wide range of environmental factors such as allergens, smoking, air pollution, infection, hormones, and specific drugs can contribute to this phenotype, other features associated with changes in the airway inflammatory response should be taken into account. Aberrant communication between an injured airway epithelium and underlying mesenchyme contributes to disease chronicity and refractoriness to corticosteroids. The importance of identifying underlying causative factors and the recent introduction of novel therapeutic approaches, including the targeting of immunoglobulin E and tumour necrosis factor alpha with biological agents, emphasise the need for careful phenotyping of patients with severe disease to target improved management of the individual patient's needs.

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Lancet. 2006 Aug 26;368(9537):754-62.
Secondary prevention of asthma by the use of Inhaled Fluticasone propionate in Wheezy INfants (IFWIN): double-blind, randomised, controlled study.
Murray CS, Woodcock A, Langley SJ, Morris J, Custovic A; IFWIN study team.
University of Manchester, North West Lung Centre, Wythenshawe Hospital, Manchester M23 9LT, UK. clare.murray@manchester.ac.uk

BACKGROUND: Wheezing and asthma often begins in early childhood, but it is difficult to predict whether or not a wheezy infant will develop asthma. Some researchers suggest that treatment with inhaled corticosteroids at the first signs of wheezing in childhood could prevent the development of asthma later in life. However, other investigators have reported that although such treatment could help control symptoms, the benefits can disappear within months of stopping treatment. We tested our hypothesis that to prevent loss of lung function and worsening asthma later in childhood, anti-inflammatory treatment needs to be started early in life. METHODS: We did a randomised, double-blind, controlled study of inhaled fluticasone propionate 100 mug twice daily in young children who were followed prospectively and randomised after either one prolonged (>1 month) or two medically confirmed wheezy episodes. The dose of study drug was reduced every 3 months to the minimum needed. If the symptoms were not under control by 3 months, open-label fluticasone propionate 100 mug twice daily was added to the treatment. Children were followed-up to 5 years of age, at which point we gave their parents or guardians questionnaires, and measured the children's lung function (specific airways resistance [sR(aw)], forced expiratory volume in 1s [FEV1]) and airway reactivity (eucapnic voluntary hyperventilation [EVH] challenge). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN86717853. FINDINGS: We followed 1073 children prospectively, of whom 333 were eligible, and 200 of these began treatment (130 male, median age 1.2 years [range 0.5-4.9]; 101 placebo, 99 treatment); 173 (85 treatment, 88 placebo) completed the follow-up at age five years. The groups did not differ significantly in the proportion of children with current wheeze, physician-diagnosed asthma or use of asthma medication, lung function, or airway reactivity (percentage change in FEV1, adjusted mean for placebo 5.5% [95% CI -2.5 to 13.4]) vs for treatment 5.0% [-2.2 to 12.2], p=0.87). There were no differences in the results after adjustment for open-label fluticasone propionate, nor between the two groups in the time before the open-label drug was added (estimated hazard ratio 1.12 [95% CI 0.73-1.73], p=0.60), or the proportion needing the open-label drug (43 [42.57%] placebo, 41 [41.41%] treatment). INTERPRETATION: The early use of inhaled fluticasone propionate for wheezing in preschool children had no effect on the natural history of asthma or wheeze later in childhood, and did not prevent lung function decline or reduce airway reactivity.

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Lancet. 2006 Aug 26;368(9537):744-53.
Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study.
Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG.
Department of Pulmonology, University of Leiden, Leiden, Netherlands. K.F.Rabe@lumc.nl

BACKGROUND: The contributions of as-needed inhaled corticosteroids and long-acting beta2 agonists (LABA) to asthma control have not been fully established. We compared the efficacy and safety of three reliever strategies: a traditional short-acting beta2 agonist; a rapid-onset LABA (formoterol); and a combination of LABA and an inhaled corticosteroid (budesonide-formoterol) in symptomatic patients receiving budesonide-formoterol maintenance therapy. METHODS: We did a 12-month, double-blind, parallel-group study in 3394 patients (aged 12 years or older), in 289 centres in 20 countries, who were using inhaled corticosteroids at study entry and symptomatic on budesonide-formoterol (160 microg and 4.5 microg, respectively), one inhalation twice daily, during a 2-week run-in. After run-in, patients were randomly assigned budesonide-formoterol maintenance therapy plus one of three alternative as-needed medications-terbutaline (0.4 mg), formoterol (4.5 microg), or budesonide-formoterol (160 microg and 4.5 microg). The primary outcome was time to first severe exacerbation, defined as an event resulting in hospitalisation, emergency room treatment, or both, or the need for oral steroids for 3 days or more. FINDINGS: Time to first severe exacerbation was longer with as-needed budesonide-formoterol versus formoterol (p=0.0048; log-rank test) and with as-needed formoterol versus terbutaline (p=0.0051). The rate of severe exacerbations was 37, 29, and 19 per 100 patients per year with as-needed terbutaline, formoterol, and budesonide-formoterol, respectively (rate ratios budesonide-formoterol versus formoterol 0.67 [95% CI 0.56-0.80; p<0.0001]; budesonide-formoterol versus terbutaline 0.52 [0.44-0.62; p<0.0001]; formoterol versus terbutaline 0.78 [0.67-0.91; p=0.0012]). Asthma control days increased to a similar extent in all treatment groups. As-needed formoterol did not significantly improve symptoms compared with as-needed terbutaline. All treatments were well tolerated. INTERPRETATION: Both monocomponents of budesonide-formoterol given as needed contribute to enhanced protection from severe exacerbations in patients receiving combination therapy for maintenance.

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Med J Aust. 2006 Aug 21;185(4):228-33.
Diagnosis, treatment and prevention of allergic disease: the basics.
Douglass JA, O'hehir RE.
Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Melbourne, VIC, Australia. j.douglass@alfred.org.au.

Allergy is defined as an immune-mediated inflammatory response to common environmental allergens that are otherwise harmless. The diagnosis of allergy is dependent on a history of symptoms on exposure to an allergen together with the detection of allergen-specific IgE. The detection of allergen-specfic IgE may be reliably performed by blood specific testing or skin prick testing. Skin prick testing is not without its attendant risks, and appropriate precautions need to be taken. A doctor should be present for safety and test interpretation. Accurate diagnosis of allergies opens up therapeutic options that are otherwise not appropriate, such as allergen immunotherapy and allergen avoidance. Allergen immunotherapy is an effective treatment for stinging insect allergy, allergic rhinitis and asthma. The most effective methods for primary prevention of allergic disease in children that can currently be recommended are breastfeeding and ceasing smoking. Emerging trends in allergen treatment include sublingual immunotherapy.

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Respir Res. 2006 Aug 18;7(1):110 [Epub ahead of print]
Inhaled steroid/long-acting beta-2 agonist combination products provide 24 hours improvement in lung function in adult asthmatic patients.
Lotvall J, Langley S Deceased, Woodcock A.

ABSTRACT: BACKGROUND: The combination of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) is recommended by treatment guidelines for the treatment of persistent asthma. Two such combination products, salmeterol/fluticasone propionate (SFC, SeretideTM GSK, UK) and formoterol/budesonide (FBC, Symbicort, AstraZeneca, UK) are commercially available. Objectives: The purpose of these studies was to evaluate and compare the duration of bronchodilation of both combination products up to 24 hours after a single dose. METHODS: Two randomised, double blind, placebo-controlled, crossover studies were performed. Study A was conducted in 33 asthmatic adults receiving 400-1200mcg of budesonide or equivalent. Serial forced expiratory volume in one second (FEV1) was measured over 24 hours to determine the duration of effect of both SFC (50/100 mcg) and FBC (4.5/160mcg). Study B was conducted in 75 asthmatic adults receiving 800-1200mcg of budesonide or equivalent and comprised a 4 week run-in of 400mcg bd BecotideTM followed by 4 weeks treatment with either SFC 50/100mcg bd or FBC 4.5/160mcg bd taken in a cross-over manner. Serial 24-hour FEV1 was measured after the first dose and the last dose after each 4-weeks treatment period to determine the offset of action of each treatment. RESULTS: In study A, a single inhalation of SFC and FBC produced a sustained bronchodilation at 16 hours with an adjusted mean increase in FEV1 from pre-dose of 0.22L (95% CI 0.19, 0.35L) for SFC and 0.25L (95% CI 0.21, 0.37L) for FBC, which was significantly greater than placebo for both treatments (-0.05L; p<0.001). In study B, the slope of decline in FEV1 from 2 -24 hours post dose was -16.0ml/hr for SFC and -14.2ml/hr for FBC. The weighted mean AUC over 24 hours was 0.21Lxmin and 0.22Lxmin and mean change from pre-dose FEV1 at 12 hours was 0.21L for SFC and 0.20L for FBC respectively CONCLUSION: Both SFC and FBC produced a similar sustained bronchodilator effect which was prolonged beyond 12 hours post dose and was clearly measurable at 24h.

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J Sch Health. 2006 Aug;76(6):291-6.
Outcomes for a comprehensive school-based asthma management program.
Gerald LB, Redden D, Wittich AR, Hains C, Turner-Henson A, Hemstreet MP, Feinstein R, Erwin S, Bailey WC.

This article describes the evaluation of a comprehensive school-based asthma management program in an inner-city, largely African-American school system. All 54 elementary schools (combined enrollment 13,247 students) from a single urban school system participated in this study. Schools were randomly divided between immediate and delayed intervention programs. The intervention consisted of 3 separate educational programs (for school faculty/staff, students with asthma, and peers without asthma) and medical management for the children with asthma (including an Individual Asthma Action Plan, medications, and peakflow meters). Children with asthma were identified using a case detection program and 736 were enrolled into the intervention study. No significant differences were observed in school absences, grade point average, emergency room visits, or hospitalizations between the immediate and delayed intervention groups. Significant increases in knowledge were observed in the immediate intervention group. This study of a school-based asthma management education and medical intervention program did not show any differences between the intervention and control groups on morbidity outcomes. Our experience leads us to believe that such measures are difficult to impact and are not always reliable. Future researchers should be aware of the problems associated with using such measures. In addition, connecting children with a regular source of health care in this population was difficult. More intensive methods of medical management, such as school-based health centers or supervised asthma therapy, might prove more effective in inner-city schools. (J Sch Health. 2006;76(6):291-296).

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J Aerosol Med. 2006 Spring;19(1):100-9.
Hyperosmolar agents and clearance of mucus in the diseased airway.
Daviskas E, Anderson SD.
Department of Respiratory Medicine, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Clearance of mucus is an important function of the airways to maintain hygiene. In disease, persistent inflammation leads to excessive production of mucus, with high viscoelasticity and adhesivity, which is not easily transported by cilia or cough interactions. Accumulated mucus in the airways can lead to airway obstruction, bacterial colonisation, and recurrent infections, resulting in poor quality of life and increased morbidity and mortality. Hyperosmolar agents have the potential to alter the physical properties of mucus and facilitate its clearance by increasing the water in the airway lumen and by reducing the entanglements of the mucin network. Clinical studies using radioaerosols, and imaging with a gamma camera, have demonstrated that hypertonic saline (HS; 3-14.4%) and mannitol (300-400 mg) increase clearance of mucus acutely in patients with mild asthma, bronchiectasis, and cystic fibrosis (CF). Further, in sputum studies, a reduction in the viscoelastic properties, surface tension and spinnability and an increase in the hydration of mucus have been measured in response to HS, mannitol, and other sugars. Inhalation of mannitol (400 mg) twice daily over 2 weeks improved the quality of life significantly in patients with bronchiectasis. Inhalation of 7% HS, four times daily, over 2 weeks improved significantly the baseline mucus clearance rate and lung function in CF patients. In addition, inhalation of 7% HS twice daily over 12 months showed similar results to the short-term studies without a change in the bacterial load in CF patients. Further studies of the long-term clinical effect of hyperosmolar agents are needed.

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J Aerosol Med. 2006 Spring;19(1):61-6.
Recent advances in aerosol therapy for children with asthma.
Devadason SG.
School of Paediatrics and Child Health, University of Western Australia, Perth, Australia.

Inhalational drug delivery is the primary mode of asthma therapy in children and is the main focus of this article. Pressurized metered dose inhalers (pMDIs) are now the method of choice in infants and children under 5 years old, when used in combination with an appropriate valved holding chamber or spacer. Spacers are particularly important for steroid inhalation to maximize lung deposition and minimize unwanted oropharyngeal deposition. Optimal inhalation technique with a pMDI-spacer in infants is to inhale the drug by breathing tidally through the spacer. Drug delivery to the lungs using pMDIs can vary greatly, depending on the formulation used and the age of the child. Dry powder inhalers (DPIs) are driven by the peak inspiratory flow of the patient and are usually not appropriate for children under 5 or 6 years of age. Nebulizers continue to play a role in the treatment of acute asthma where high doses of bronchodilator are required, though multiple doses via pMDI spacer may suffice. Important drug delivery issues specific to children include compliance, use of mask versus mouthpiece, lower tidal volumes and inspiratory flows, determination of appropriate dosages, and minimization of adverse local and systemic effects.

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Clin Chest Med. 2006 Mar;27(1):133-47.
Biologic therapies for the treatment of asthma.
Wagelie-Steffen AL, Kavanaugh AF, Wasserman SI.
Division of Rheumatology, Allergy, and Immunology, Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0637, USA.

Asthma is a chronic disease of the airway whose pathogenesis involves the complex interplay between many cell types and inflammatory mediators. The mainstays of therapy, inhaled bronchodilators and corticosteroids, do not target the asthmatic airway specifically and therefore are associated with untoward side effects. Anti-IgE (omalizumab) is the only biologic therapy to have transitioned completely from bench to bedside. Other candidate therapies, such as those that alter the T-helper 1/T-helper 2 cytokine balance, interfere with inflammatory cell trafficking, or modify normal intracellular signaling cascades involved in inflammatory gene transcription, have had only limited success in human clinical trials. This article describes several potential novel biologic therapies that have been or could be investigated.

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Thorax. 2006 Mar 3; [Epub ahead of print]
A double-blind randomised controlled trial of two different breathing techniques in the management of asthma.
Slader CA, Reddel HK, Spencer LM, Belousova EG, Armour CL, Bosnic-Anticevich SZ, Thien FC, Jenkins CR.
Facutly of Pharmacy, University of Sydney, Australia.

Background: Previous studies have demonstrated that breathing techniques reduce short-acting beta-agonist use and improve quality of life in asthma. The primary aim of this double-blind study was to compare the effects of breathing exercises focussing on shallow nasal breathing with those of non-specific upper-body exercises, on asthma symptoms, quality of life (QoL), other measures of disease control, and inhaled corticosteroid (ICS) dose. This study also assessed the effect of peak flow monitoring on outcomes in patients using breathing techniques. Methods: After a two-week run-in, 57 subjects were randomised to one of two breathing techniques learned from instructional videos. During the following 30 weeks, subjects practised their exercises twice daily and as-needed for relief of symptoms. After Week 16, two successive ICS downtitration steps were attempted. The primary outcome variables were QoL score and daily symptom score at Week 12. Results: Overall, there were no clinically important differences between groups in primary or secondary outcomes at weeks 12 or 28. QoL score remained unchanged (baseline 0.7, Week 28 0.5, p=0.11 both groups combined) as did lung function and airway responsiveness. However, across both groups, reliever use decreased by 86% (p<0.0001) and ICS dose was reduced by 50% (p<0.0001), p>0.10 between groups. Peak flow monitoring did not have a detrimental impact on asthma outcomes. Conclusion: Breathing techniques may be useful in the management of patients with mild asthma symptoms who use reliever frequently, but at present there is no evidence to favour shallow nasal breathing over non-specific upper-body exercises.

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J Allergy Clin Immunol. 2006 Mar;117(3):563-70. Epub 2006 Jan 27.
Asthma control can be maintained when fluticasone propionate/salmeterol in a single inhaler is stepped down.
Bateman ED, Jacques L, Goldfrad C, Atienza T, Mihaescu T, Duggan M.
University of Cape Town, South Africa.

BACKGROUND: Asthma control is the goal of treatment, but little data exist to support treatment strategies for stepping down treatment once control has been achieved. OBJECTIVE: We assessed whether either the long-acting beta2-agonist or corticosteroid could be reduced without loss of asthma control once control had been attained with fluticasone propionate/salmeterol (FSC). METHODS: After 12 weeks of open-label treatment with FSC 250/50 microg twice daily, patients whose asthma was well controlled were randomized to FSC 100/50 microg twice daily or fluticasone propionate (FP) 250 microg twice daily. for 12 weeks. The primary endpoint was mean morning peak expiratory flow over the randomized study period. Secondary endpoints included symptom scores, rescue albuterol use, and asthma control. RESULTS: During open-label treatment, improvements from baseline were seen, and 435 of 641 patients (68%) achieved well controlled status during each of the last 4 weeks of this period. A total of 246 patients received FSC 100/50 microg twice daily and 238 FP 250 microg twice daily. The adjusted mean change in morning peak expiratory flow from the end of open-label treatment was -0.3 L/min for FSC and -13.2 L/min for FP (treatment difference, 12.9 L/min; 95% CI, 8.1-17.6; P<.001). Secondary efficacy endpoints also showed FSC 100/50 microg twice daily to be more effective than FP 250 microg twice daily alone. The majority of patients remained well controlled, but the proportion was higher with FSC. CONCLUSION: In patients achieving asthma control with FSC 250/50 microg twice daily, stepping treatment down to a lower dose of FSC 100/50 microg twice daily is more effective than switching to an inhaled corticosteroid alone.

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Pharmazie. 2006 Feb;61(2):122-4.
Can corticosteroids be beaten in future asthma therapy?
Amon A, Pahl A, Szelenyi I.
Department of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuernberg, Erlangen, Germany.

Despite the enormous therapeutic advance, there is a general trend towards increasing morbidity and mortality due to asthma, which suggests that there is a need for new and improved treatments. The past decade was determined by the so-called "new biology" that identified and cloned almost all receptors and ion channels. This scientific revolution should lead to a more rapid identification of novel targets for major diseases and processes like high throughput screening and combinatorial chemistry should have improved and fastened the development of new drugs. Interestingly, exactly the opposite has happened. With the exception of leukotriene receptor antagonists and some monoclonal antibodies, no new developments have been introduced into asthma therapy during the last decade. The most promising approach is still to find drugs like corticosteroids with multiple functions. However, there is no evidence at the very moment that corticosteroids can be beaten in the next ten years. Therefore, our task is to improve the corticosteroids and make therapy with them even safer. The so-called soft-steroids such as loteprednol and etiprednol belong to the future promising therapeutically effective and safe treatments of allergic disorders.

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Pflege. 2006 Feb;19(1):4-10.
[Coping strategies of children with asthma. Testing the applicability of the German version of the Schoolagers' Coping Strategies Inventory (SCSI)]
[Article in German]
Fley G, Beier J.
Charite - Universitatsmedizin Berlin, Zentrum fur Human- und Gesundheitswissenschaften Institut fur Medizin-Pflegepadagogik und Pflegewissenschaft. G.Fley@t-online.de

Little is known about how children suffering from bronchial asthma assess their own capabilities to cope with the asthmatic symptoms. This descriptive study is designed to record how frequently and effectively children with bronchial asthma (n = 29) make use of coping strategies. An American self-assessment instrument, the Schoolagers' Coping Strategies Inventor, (SCSI), was used in its German translation to test whether or not it is appropriate for use with German children. The German Inventory is appropriate for use (alpha-coeffizient Frequency 0.72, Effectiveness 0.71). There are only two strategies that should be changed in the German translation in order to help German children understand it better: Our study shows that the five strategies "Watch TV or listen to music", "Draw, write or read something", "Do something about it", "Play a game or something" and "Talk to someone" that are used most frequently are also considered to be the most effective ones. In addition, we observed that there are strategies that are rarely used by the children but which are still considered to be effective. A comparison of the studies performed in the USA and in Germany reveals that good strategies to take the minds of both American and German children off things are watching TV and listening to music. Aggressive behaviors do not play any major role.

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Chem Immunol Allergy. 2006;91:16-29.
Should asthma management include sojourns at high altitude?
Schultze-Werninghaus G.
Berufsgenossenschaftliche Kliniken Bergmannsheil, Bochum, Germany.

Sojourns in the high mountains have been recommended by specialists for patients with asthma since many decades. An inquiry among physicians of the 'Davoser arzteverein' revealed as early as 1906 that 133/143 patients with bronchial asthma had no or only few asthma attacks during their stay in Davos, and that 81% had a persistent improvement of their disease. These early observations about effects of the alpine climate were, of course, reported at a time, when the spectrum of pharmacotherapy was very limited. However, these observations were consistent and were therefore regarded as proof for the therapeutic value of sojourns under alpine conditions in bronchial asthma. In recent years, however, the indication for asthma treatment in high mountains is increasingly questioned, in particular by health insurance systems. Therefore it is the aim of this contribution to summarize the available data about the effects of a stay of asthmatic patients at 1,500-1,800m above sea level. It is concluded that the available evidence suggests a significant beneficial effect of high altitude in bronchial asthma, in particular in steroid-dependent patients.

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Allergy. 2006 Jan;61(1):72-8.
Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma.
Bousquet J, Aubier M, Sastre J, Izquierdo JL, Adler LM, Hofbauer P, Rost KD, Harnest U, Kroemer B, Albrecht A, Bredenbroker D.
Hopital Arnaud de Villeneuve, Montpellier, France.

Background: Roflumilast is an oral, once-daily phosphodiesterase 4 inhibitor with anti-inflammatory activity in development for the treatment of asthma. Roflumilast was compared with inhaled beclomethasone dipropionate (BDP) in patients with asthma. Methods: In a double blind, double-dummy, randomized, noninferiority study, 499 patients (forced expiratory volume in 1 s [FEV(1)] = 50-85% predicted) received roflumilast 500 mug once daily or BDP 200 mug twice daily (400 mug/day) for 12 weeks. Lung function and adverse events were monitored. Results: Roflumilast and BDP significantly improved FEV(1) by 12% (270 +/- 30 ml) and 14% (320 +/- 30 ml), respectively (P < 0.0001 vs baseline). Roflumilast and BDP also significantly improved forced vital capacity (FVC) (P < 0.0001 vs baseline). There were no significant differences between roflumilast and BDP with regard to improvement in FEV(1) and FVC. Roflumilast and BDP showed small improvements in median asthma symptom scores (-0.82 and -1.00, respectively) and reduced rescue medication use (-1.00 and -1.15 median puffs/day, respectively; P < 0.0001 vs baseline). These small differences between roflumilast and BDP were not considered clinically relevant. Both agents were well tolerated. Conclusions: Once daily, oral roflumilast 500 mug was comparable with inhaled twice-daily BDP (400 mug/day) in improving pulmonary function and asthma symptoms, and reducing rescue medication use in patients with asthma.

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Curr Opin Pulm Med. 2006 Jan;12(1):48-53.
Initial corticosteroid therapy for asthma.
Gibson PG, Powell H.
aHunter Medical Research Institute, Department of Respiratory and Sleep Medicine, John Hunter Hospital, New South Wales, Australia bUniversity of Newcastle, Australia.

PURPOSE OF REVIEW: This review examines the commencement of maintenance pharmacotherapy for asthma: inhaled corticosteroids alone or in combination with long-acting beta2 agonists. RECENT FINDINGS: A systematic review of randomized controlled trials has examined the starting dose of inhaled corticosteroids (high, moderate, low) and the dose regimen (step down versus constant) in asthma. There was no significant difference in key asthma outcomes for step down compared with a constant inhaled corticosteroid dose. There was no significant difference between high or moderate dose inhaled corticosteroid groups (n = 11) for morning peak expiratory flow, symptoms and rescue medication use. There may be a benefit from high-dose inhaled corticosteroids for airway hyperresponsiveness. There was a significant improvement in peak expiratory flow and nocturnal symptoms in favour of a moderate inhaled corticosteroid dose compared with low-dose treatment. Long-acting beta2 agonists combined with inhaled corticosteroids as initial asthma therapy has been examined in a systematic review of nine randomized controlled trials. Inhaled corticosteroids combined with long-acting beta2 agonists led to significant improvements in forced expiratory volume in 1 s, morning peak expiratory flow, symptom score and symptom-free days but no difference in exacerbations requiring oral corticosteroids. A randomized controlled trial of patients with uncontrolled asthma found a benefit of escalating doses of salmeterol/fluticasone compared with fluticasone on asthma control. SUMMARY: Initial inhaled corticosteroid therapy should begin with a constant, moderate dose. Initial therapy with long-acting beta2 agonist and inhaled corticosteroids achieves superior improvement in symptoms and lung function, and at a quicker rate than inhaled corticosteroids alone. There is no benefit in terms of reduced exacerbations unless an escalating inhaled corticosteroid dose strategy is used.

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Pulm Pharmacol Ther. 2005 Dec 12; [Epub ahead of print]
The treatment of asthma in children: Inhaled corticosteroids.
Ricciardolo FL.
Unit of Pulmonary Disease, IRCCS G. Gaslini Institute, Largo G. Gaslini, 5, 16147 Genoa, Italy.

The evidence that asthma is characterized by extensive inflammation of the airways has warranted the use of inhaled corticosteroid (ICS) in asthma maintenance therapy. Corticosteroid treatment, especially if high or frequent doses are required, is associated with a range of adverse effects including adrenal suppression and impairment in growth and bone metabolism. New corticosteroids are in development, including mometasone furoate, and some of these are predicted to have reduced adverse effects such as the soft steroid ciclesonide. Soft steroids are designed for delivery near to their site of action, to exert their effect and then to undergo controlled and predictable metabolism to inactive metabolites. This review points out the anti-inflammatory effects of corticosteroid in asthmatic airways and the clinical efficacy and safety of ICS in asthmatic children. The development of a soft steroid should help to achieve the aim of improving the therapeutic profile of ICS in asthma and thus alleviate the ongoing problem of poor patient compliance especially in childhood.

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Pulm Pharmacol Ther. 2005 Dec 13; [Epub ahead of print]
Safety of inhaled corticosteroids: Room for improvement.
Rossi GA, Cerasoli F, Cazzola M.
Pulmonary Diseases Unit, G. Gaslini Research Institute, Genoa, Italy.

Inhaled corticosteroids (ICS) are the standard of care in asthma and are widely used in the treatment of patients with chronic obstructive pulmonary disease. High-dose regimens and long-term use of ICS in predisposed individuals may be associated with a variety of side effects, similar to those observed with systemic corticosteroid therapy. Side effects associated with long-term ICS use include reduction in growth velocity, cataracts, glaucoma, osteoporosis, and fractures. Fear of unwanted complications may be of concern in all patients using ICS, particularly in age- and gender-specific populations that are more prone to develop side effects or to reduce treatment adherence because of physical, behavioral, or psychological problems. In addition to concerns about ICS safety, dosing regimens that are difficult to follow may further reduce a patient's ability to comply with treatment. Ciclesonide, a new-generation ICS with unique pharmacokinetic properties, was developed to provide effective anti-inflammatory control for asthma with once-daily administration to improve patient adherence and a high safety profile to reduce the occurrence of local and systemic side effects.

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Int J Clin Pract. 2005 Dec;59(12):1488-95.
Idealhalers or realhalers? A comparison of Diskus and Turbuhaler.
Borgstrom L, Asking L, Thorsson L.
AstraZeneca R&D, Lund, Sweden. lars.borgstrom@astrazeneca.com

Medication for the treatment of asthma and chronic obstructive pulmonary disease should be given locally by inhalation. There is, however, no such thing as an ideal inhaler, or 'Idealhaler', which has all desired properties with no drawbacks. In this short review, we have compared the relative merits of the two most commonly used dry powder inhalers -- Turbuhaler and Diskus. Clinical effect is related to the amount of inhaled drug that reaches the lungs, and this in turn depends on the amount of fine particles generated at inhalation. Turbuhaler is more than twice as effective as Diskus at generating fine particles, and the higher lung deposition with Turbuhaler is accompanied by a lower variability in lung deposition. Compared with Diskus, the lung deposition with Turbuhaler is affected less by factors such as humidity.

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Clin Ther. 2005 Nov;27(11):1752-63.
Comparison of the efficacy of ciclesonide 160 mug QDand budesonide 200 mug BID in adults with persistent asthma: A phase III, randomized, double-dummy, open-label study.
Niphadkar P, Jagannath K, Joshi JM, Awad N, Boss H, Hellbardt S, Gadgil DA.
Sir H.N. Hospital & Research Centre, Mumbai, India.

OBJECTIVE:: The efficacy of ciclesonide 160 mug QD (given either in the morning or evening) was compared with budesonide 200 mug BID in adults with stable asthma that was pretreated with inhaled corticosteroids. METHODS:: This was a randomized, 3-arm, parallel-groupstudy comparing ciclesonide (given in a double-blind, double-dummy regimen) with open-label budesonide. After 2 to 2.5 weeks, during which patients were treated with budesonide 200 mug BID, patients (n = 405) were randomly assigned to receive ciclesonide 160 mug QD AM or 160 mug QD pm, or budesonide 200 mug BID (all administered by metered-dose inhaler) for 12 weeks. All patients received 2 puffs of medication (or placebo) in the morning and evening. The primary efficacy variable was the difference in spirometric forced expiratory volume in 1 second (FEV(1) in liters) from randomization to study end. Secondary efficacy end points were forced vital capacity, peak expiratory flow by spirometry, and diary assessments of peak expiratory flow, asthma symptoms, and rescue medication use. Adverse events were assessed by patient report, investigator observation, physical examination, and laboratory testing; events were classified as mild, moderate, or severe. RESULTS:: Baseline demographic characteristics with regard to sex, age, weight, smoking status, baseline medication use, and FEV(1) were balanced among the treatment groups. Over the course of treatment, both ciclesonide and budesonide maintained FEV(1) compared with baseline. Both ciclesonide regimens were as effective as budesonide 200 mug BID in maintaining FEV(1) during the treatment period versus baseline (ciclesonide 160 mug QD am: 95% CI, -0.120 to 0.045 vs budesonide; P = NS; ciclesonide 160 mug QD pm: 95% CI, -0.061 to 0.105 vs budesonide; P = NS). Ciclesonide 160 mug QD (morning or evening) was comparable with budesonide 200 mug BID for maintaining pulmonary function, asthma symptom scores, and rescue medication use. The incidence of adverse events was not significantly different among the treatment groups, and most adverse events were not related to study medication. CONCLUSIONS:: In this study, ciclesonide 160 mug QDwas as effective as budesonide 200 mug BID (400 mug total daily dose) in these adults with persistent asthma. Both treatments were well tolerated.

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Drugs Aging. 2005;22(12):1029-59.
Overcoming gaps in the management of asthma in older patients : new insights.
Barua P, O'mahony MS.
University Department of Geriatric Medicine, Academic Centre, Llandough Hospital, Cardiff, United Kingdom.

Asthma is under-recognised and undertreated in older populations. This is not surprising, given that one-third of older people experience significant breathlessness. The differential diagnosis commonly includes asthma, chronic obstructive pulmonary disease (COPD), heart failure, malignancy, aspiration and infections. Because symptoms and signs of several cardiorespiratory diseases are nonspecific in older people and diseases commonly co-exist, investigations are important. A simple strategy for the investigation of breathlessness in older people should include a full blood count, chest radiograph, ECG, peak flow diary and/or spirometry with reversibility as a minimum. If there are major abnormalities on the ECG, an echocardiogram should also be performed. Diurnal variability in peak flow readings >/=20% or >/=15% reversibility in forced expiratory volume in 1 second, spontaneously or with treatment, support a diagnosis of asthma.Distinguishing asthma from COPD is important to allow appropriate management of disease based on aetiology, accurate prediction of treatment response, correct prognosis and appropriate management of the chest condition and co-morbidities. The two conditions are usually readily differentiated by clinical features, particularly age at onset, variability of symptoms and nocturnal symptoms in asthma, supported by the results of reversibility testing. Full lung function tests may not necessarily help in differentiating the two entities, although gas transfer factor is characteristically reduced in COPD and usually normal or high in asthma. Methacholine challenge tests previously mainly used in research are now also used widely and safely to confirm asthma in clinical settings. Interest in exhaled nitric oxide as a biomarker of airways inflammation is increasing as a noninvasive tool in the diagnosis and monitoring of asthma.Regular inhaled corticosteroids (ICS) are the mainstay of treatment of asthma. Even in mild disease in older adults, regular preventive treatment should be considered, given the poor perception of bronchoconstriction by older asthmatic patients. If symptoms persist despite ICS, addition of long-acting beta(2)-adrenoceptor agonists (LABA) should be considered. Addition of LABA to ICS improves asthma control and allows reduction in ICS dose. However, older people have been grossly under-represented in trials of LABA, many trials having excluded those >/=65 years of age. On meta-analysis, beta(2)-adrenoceptor agonists (both short acting and long acting) are associated with increased cardiovascular mortality and morbidity in asthma and COPD. While the evidence for excess cardiovascular mortality is stronger for short-acting beta(2)-adrenoceptor agonists, it would be prudent to exercise particular care in using beta(2)-adrenoceptor agonists (long acting and short acting) in those at risk of adverse cardiovascular outcomes, including older people. Regular review of cardiovascular status (and monitoring of serum potassium concentration) in patients taking beta(2)-adrenoceptor agonists is crucial. The response to LABA should be carefully monitored and alternative 'add-on' therapy such as leukotriene receptor antagonists (LRA) should be considered. LRA have fewer adverse effects and in individual cases may be more effective and appropriate than LABA. Long-term trials evaluating beta(2)-adrenoceptor agonists and other bronchodilator strategies are needed particularly in the elderly and in patients with cardiovascular co-morbidities. There is no evidence that addition of anticholinergics improves control of asthma further, although the role of long-acting anticholinergics in the prevention of disease progression is currently being researched.Older patients need to be taught good inhaler technique to improve delivery of medications to lungs, minimise adverse effects and reduce the need for oral corticosteroids. Nurse-led education programmes that include a written asthma self-management plan have the potential to improve outcomes.

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Respir Care. 2005 Oct;50(10):1323-30.
The Role of the MDI and DPI in Pediatric Patients: "Children Are Not Just Miniature Adults".
Ahrens RC.
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa.

Metered-dose inhalers (MDIs) and dry powder inhalers play an important role in the treatment of asthma in children of all ages. Yet theses devices, which were originally developed for use in adults, interact differently with children. Through childhood there are progressive changes in pharmacokinetic handling and pharmacodynamic effects of inhaled antiasthmatic drugs, in the efficiency and distribution of aerosolized drugs in the respiratory tract, and in the patient\'s ability to successfully use aerosol devices. This, in turn, produces changes in potential for producing efficacy and adverse effects, and in the balance between risk and benefit. These differences from adults are greatest for children under 4\N5 years of age, who are unable to use DPIs or unassisted MDIs, and who therefore must rely on nebulizers and MDIs with valved holding chambers for inhaled drug delivery. Unfortunately, there are no drugs approved for delivery via MDI (with holding chamber) in children under 4 years of age, and there are insufficient data to ensure that many of the available drug-MDI-holding-chamber combinations are both safe and effective. In particular, the potential for effects of inhaled corticosteroids on growth are insufficiently studied in this age group and remains a concern. It is likely that the risk of adverse effects on growth are different for each of the many possible MDI/valved-holding-chamber combinations.

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Respir Care. 2005 Oct;50(10):1313-22.
Comparing clinical features of the nebulizer, metered-dose inhaler, and dry powder inhaler.
Geller DE.
The Nemours Children's Clinic, Orlando, Florida.

Topically inhaled bronchodilators and corticosteroids are the mainstay of treatment for asthma and chronic obstructive pulmonary disease. These medications are delivered via jet or ultrasonic nebulizer, metered-dose inhaler (MDI), or dry powder inhaler (DPI). While the number of devices may be confusing to patients and clinicians, each device has distinct advantages and disadvantages. Most clinical evidence shows that any of these devices will work for most situations, including exacerbations and in the stable outpatient setting. There is a high rate of errors in device use with all these devices, especially the MDI. In choosing a drug/device combination for a patient, the clinician must take into account several factors, including the cognitive and physical ability of the patient, ease of use, convenience, costs, and patient preferences. Clinicians should also have a rudimentary understanding of aerosol principles in order to be able to teach appropriate use of aerosol devices to their patients.

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Respir Care. 2005 Oct;50(10):1304-12.
Dry powder inhalers: an overview.
Atkins PJ.
Oriel Therapeutics, Research Triangle Park, North Carolina.

Dry powder inhalers (DPIs) are a widely accepted inhaled delivery dosage form, particularly in Europe, where they currently are used by a large number of patients for the delivery of medications to treat asthma and chronic obstructive pulmonary disease. The acceptance of DPIs in the United States after the slow uptake following the introduction of the Serevent Diskus in the late 1990s has been driven in large part by the enormous success in recent years of the Advair Diskus. This combination of 2 well-accepted drugs in a convenient and simple-to-use device has created an accepted standard in pulmonary delivery and disease treatment that only a few years ago could not have been anticipated. The DPI offers good patient convenience, particularly for combination therapies, and also better compliance. The design and development of any powder drug-delivery system is a highly complex task. Optimization of the choice of formulation when matched with device geometry is key. The use of particle engineering to create a formulation matched to a simple device is being explored, as is the development of active powder devices in which the device inputs the energy, making it simpler for patients to receive the correct dose. Patient interface issues are also critically important. However, one of the most important factors in pulmonary delivery from a DPI is the requirement for a good-quality aerosol, in terms of the aerosol's aerodynamic particle size, and its potential to consistently achieve the desired lung deposition in vivo.

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Pediatr Pulmonol. 2005 Sep 28; [Epub ahead of print]
Evaluation of the Safety and Efficacy of Levalbuterol in 2-5-year-Old Patients with Asthma.
Skoner DP, Greos LS, Kim KT, Roach JM, Parsey M, Baumgartner RA.
Allegheny General Hospital, Division of Allergy, Asthma and Immunology, Pittsburgh, Pennsylvania.

The purpose of this study was to evaluate the safety and efficacy of single-isomer (R)-albuterol (levalbuterol, LEV) in children aged 2-5 years. Children aged 2-5 years (n = 211) participated in this multicenter, randomized, double-blind study of 21 days of t.i.d. LEV (0.31 mg or 0.63 mg without regard to weight), racemic albuterol (RAC, 1.25 mg for children <33 pounds (lb); 2.5 mg for children >/=33 lb), or placebo (PBO). Endpoints included adverse-event (AE) reporting, safety parameters, peak expiratory flow (PEF), the Pediatric Asthma Questionnaire(c) (PAQ), and the Pediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ). Baseline disease severity was generally mild in all groups, as defined by PAQ scores that ranged from 6.3-7.3 on a scale of 0-27 and 1.5 days/week of uncontrolled asthma. After treatment, the PAQ decreased in all groups (P = NS). In the subset of subjects able to perform PEF (51.7%), all active treatments improved in-clinic PEF after the first dose (mean +/- SD: PBO, 1.4 +/- 20.8; LEV 0.31 mg, 12.4 +/- 12; LEV 0.63 mg, 16.7 +/- 15.4; RAC, 18.0 +/- 16.5 l/min; P < 0.01). PACQLQ measurements improved more than the minimally important difference only in the LEV-treated groups, and were significant in children <33 lb (P < 0.05). Asthma exacerbations occurred primarily in children >/=33 lb, and one serious asthma exacerbation occurred in the 2.5-mg RAC group. RAC and LEV 0.63 mg, but not LEV 0.31 mg or placebo, led to significant increases in ventricular heart rate. In this study of levalbuterol in children aged 2-5 years with asthma, LEV was generally well-tolerated, and in children able to perform PEF, led to significant bronchodilation compared with placebo. Pediatr Pulmonol. (c) 2005 Wiley-Liss, Inc.

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Chest. 2005 Sep;128(3):1136-1139.
Comparison of the Short-term Effects of Salmeterol and Formoterol on Heart Rate Variability in Adult Asthmatic Patients.
Eryonucu B, Uzun K, Guler N, Tuncer M, Sezgi C.
Correspondance to: Beyhan Eryonucu, Yuzuncu Yil dUniversitesi, Tip Fakultesi Kardiyoloji AD, 65200 Van, Turkey. drbeyhan@yahoo.com.

STUDY OBJECTIVES: We investigated the effects of beta(2)-adrenergic agonists salmeterol and formoterol on heart rate variability (HRV) in adult asthmatic patients using time-domain measures of HRV. PATIENTS: Thirty-nine adult patients with asthma were studied. All patients showed a mild-to-moderate decrease in baseline FEV(1). Any diseases that might have influenced the autonomic function were excluded. All patients underwent a complete physical examination and medical history that revealed no cardiovascular disease or medication. METHODS: The beta(2)-adrenergic inhaled agonists salmeterol, 50 mug, and formoterol, 12 mug, were used in the study. HRV analysis was performed for each 5-min segment: 5 min and 10 min before inhalation of the study drug, and 5, 10, 15, 20, 25, and 30 min after inhalation. Time-domain parameters of HRV were calculated: (1) the SD all normal-to-normal intervals; (2) the SD of the mean of all normal-to-normal intervals in all 5-min segments of the entire recording; (3) the root mean square of differences between adjacent normal-to-normal intervals; (4) the mean of the SD of all normal-to-normal intervals in all the 5-min intervals; and (5) the SD of the SD of all normal-to-normal intervals in all the 5-min intervals. RESULTS: Baseline HRV parameters were not significantly different between formoterol and salmeterol groups. There were no significant differences in HRV parameters after formoterol and salmeterol inhalation. The HRV parameters in each 5-min segment in the formoterol group were not statistically significant different when compared to the same segment in the salmeterol group. CONCLUSION: Salmeterol and formoterol have no short-term adverse effects on HRV.

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Chest. 2005 Sep;128(3):1128-35.
Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with Acid reflux symptoms.
Littner MR, Leung FW, Ballard ED 2nd, Huang B, Samra NK.
Veterans Affairs Medical Center (111P), Sepulveda, CA 91343. mlittner@ucla.edu.

BACKGROUND: Difficult-to-control asthma has been associated with gastroesophageal acid reflux. Acid-suppressive treatment has been inconsistent in improving asthma control. OBJECTIVE: To determine whether a proton-pump inhibitor improves asthma control in adult asthmatic patients with acid reflux symptoms. DESIGN: Multicenter, double-blind, randomized, placebo-controlled trial. SETTING: Twenty-nine private practices and 3 academic practices in the United States. PATIENTS: Two hundred seven patients receiving usual asthma care including an inhaled corticosteroid (ICS). Patients had acid reflux symptoms and moderate-to-severe persistent asthma. INTERVENTION: Lansoprazole, 30 mg bid, or placebo, bid, for 24 weeks. MEASUREMENTS: The primary outcome measure was daily asthma symptoms by diary. Secondary asthma outcomes included rescue albuterol use, daily morning and evening peak expiratory flow, FEV(1), FVC, asthma quality of life with standardized activities (AQLQS) questionnaire score, investigator-assessed symptoms, exacerbations, and oral corticosteroid-treated exacerbations. RESULTS: Daily asthma symptoms, albuterol use, peak expiratory flow, FEV(1), FVC, and investigator-assessed asthma symptoms at 24 weeks did not improve significantly with lansoprazole treatment compared to placebo. The AQLQS emotional function domain improved at 24 weeks (p = 0.025) with lansoprazole therapy. Fewer patients receiving lansoprazole (8.1% vs 20.4%, respectively; p = 0.017) had exacerbations and oral corticosteroid-treated (ie, moderate-to-severe) exacerbations (4% vs 13.9%, respectively; p = 0.016) of asthma. A post hoc subgroup analysis revealed that fewer patients receiving one or more long-term asthma-control medications in addition to an ICS experienced exacerbations (6.5% vs 24.6%, respectively; p = 0.016) and moderate-to-severe exacerbations (2.2% vs 17.5%, respectively; p = 0.021) with lansoprazole therapy. CONCLUSION: In adult patients with moderate-to-severe persistent asthma and symptoms of acid reflux, treatment with 30 mg of lansoprazole bid for 24 weeks did not improve asthma symptoms or pulmonary function, or reduce albuterol use. However, this dose significantly reduced asthma exacerbations and improved asthma quality of life, particularly in those patients receiving more than one asthma-control medication.

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Chest. 2005 Sep;128(3):1121-7.
Formoterol added to low-dose budesonide has no additional antiinflammatory effect in asthmatic patients.
Overbeek SE, Mulder PG, Baelemans SM, Hoogsteden HC, Prins JB.
Department of Pulmonary Medicine, SV020, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands. s.e.overbeek@erasmusmc.nl.

STUDY OBJECTIVE: Adding inhaled long-acting beta(2)-agonists to a low dose of inhaled corticosteroids (ICSs) results in better asthma control than increasing the dose of ICSs. An important, but as yet unresolved, question is whether this is due to an additional reduction of airway inflammation. DESIGN: Double-blind, parallel-group trial. PATIENTS: Forty asthma patients (FEV(1), 50 to 90% predicted; provocative concentration of a substance [methacholine] causing a 20% fall in FEV(1) of < 8 mg/mL; no ICSs in the last 4 weeks). INTERVENTIONS: Randomization to 8 weeks of treatment with 100 mug of budesonide bid plus placebo (BUD200) or 100 mug of budesonide bid plus 12 mug of formoterol (BUD200 + F). Then the dose of budesonide (BUD) was increased to 400 mug bid in both groups for another 8 weeks. Bronchial biopsy specimens were collected before, and after 8 and 16 weeks of treatment. Eosinophils (major basic protein [MBP]) and mast cells (tryptase) were analyzed by immunohistochemistry. RESULTS: BUD200 reduced the MBP staining (p = 0.008) and tryptase staining (p = 0.048) in the epithelium compared to baseline levels. There were no significant differences between the BUD200 and BUD200 + F groups. In both groups, increasing the dosage of BUD to 800 mug had no significant additional antiinflammatory effect. CONCLUSIONS: Our results demonstrate that BUD administered at a low dose has significant antiinflammatory effects in patients with mild asthma. No significant additional antiinflammatory effects could be demonstrated either by adding formoterol or by increasing the dose of BUD.

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Drugs. 2005;65(14):1973-89.
Budesonide inhalation suspension for the treatment of asthma in infants and children.
Berger WE.
Allergy & Asthma Associates of Southern California, Mission Viejo, California, USA.

On the basis of the well recognised role of inflammation in the pathogenesis of asthma, anti-inflammatory therapy, in the form of inhaled corticosteroids, has become the mainstay of treatment in patients with persistent asthma. Budesonide inhalation suspension (BIS) is a nonhalogenated corticosteroid with a high ratio of local anti-inflammatory activity to systemic activity. Furthermore, BIS is approved in >70 countries for the maintenance treatment of bronchial asthma in both paediatric and adult patients (approval is limited to paediatric patients in the US and France).Randomised, double-blind, placebo-controlled trials conducted in >1000 children have demonstrated the efficacy of BIS in children with persistent asthma of varying degrees of severity. In children frequently hospitalised with uncontrolled asthma, initiation of BIS therapy can reduce the need for emergency intervention. Moreover, limited data suggest that BIS is effective for the treatment of acute exacerbations of asthma in children and may reduce the need for short courses of oral corticosteroids.BIS is well tolerated in children, with an adverse event profile similar to that of placebo, and no clinically relevant changes in adrenal function have been demonstrated during the course of short- and long-term (1-year) studies. Small but statistically significant reductions in growth velocity have been demonstrated with BIS over 1 year of treatment. However, available evidence suggests that growth effects are transient in children receiving budesonide and that these children eventually achieve full adult height.

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J Allergy Clin Immunol. 2005 Sep;116(3):525-30.
Fluticasone propionate plasma concentration and systemic effect: Effect of delivery device and duration of administration.
Whelan GJ, Blumer JL, Martin RJ, Szefler SJ; on behalf of the Asthma Clinical Research Network and the Pediatric Pharmacology Research Unit Network.
>From the Department of Pediatrics.

BACKGROUND: Inhaled corticosteroids are the preferred therapy in persistent asthma. Dry powder inhalers (DPIs) generate a larger particle size compared with metered-dose inhalers (MDIs), which affects pulmonary deposition, bioavailability, and subsequent systemic effects of fluticasone propionate (fluticasone). OBJECTIVE: To examine the relationship of fluticasone pharmacokinetics and cortisol suppression for 2 fluticasone formulations (DPI and MDI) administered in adults over 1-week and 6-week treatment periods. METHODS: Two previous studies conducted in adults by the Asthma Clinical Research Network examined relative efficacy and systemic effect of fluticasone from MDI and DPI. Sample sets (n=33) were analyzed for fluticasone after administration of 352 mug from the MDI, and 400 mug from the DPI formulation, twice daily, after a 1-week treatment period. The second study's sample sets (n=9) were analyzed for fluticasone after 6 weeks therapy at 352 mug twice daily from the MDI formulation, allowing achievement of steady state. RESULTS: ANOVA revealed a significant trend of increasing fluticasone area under the curve from 0 to time t (AUC(0-->t)) when comparing DPI with MDI for 1 week with MDI for 6 weeks (P < .0001). Similarly, ANOVA revealed increasing cortisol suppression between these groups (P=.007). Linear regression demonstrated that increasing fluticasone AUC(0-->t) was significantly correlated with cortisol suppression (P < .0001; r(2)=0.41). MDI for 6 weeks showed increasing fluticasone AUC (P=.0008, t test) compared with MDI for 1 week, suggesting accumulation. CONCLUSION: Fluticasone plasma concentrations are significantly greater after MDI compared with DPI, and cortisol suppression is associated with fluticasone plasma concentrations. Accumulation of fluticasone concentrations suggests that time to steady state exceeds 1 week of treatment with MDI.

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J Allergy Clin Immunol. 2005 Sep;116(3):517-24.
Efficacy and tolerability of antiasthma herbal medicine intervention in adult patients with moderate-severe allergic asthma.
Wen MC, Wei CH, Hu ZQ, Srivastava K, Ko J, Xi ST, Mu DZ, Du JB, Li GH, Wallenstein S, Sampson H, Kattan M, Li XM.
>From the Weifang Asthma Hospital.

BACKGROUND: Chinese herbal medicine has a long history of human use. A novel herbal formula, antiasthma herbal medicine intervention (ASHMI), has been shown to be an effective therapy in a murine model of allergic asthma. OBJECTIVE: This study was undertaken to compare the efficacy, safety, and immunomodulatory effects of ASHMI treatment in patients with moderate-severe, persistent asthma with prednisone therapy. METHODS: In a double-blind trial, 91 subjects underwent randomization. Forty-five subjects received oral ASHMI capsules and prednisone placebo tablets (ASHMI group) and 46 subjects received oral prednisone tablets and ASHMI placebo capsules (prednisone group) for 4 weeks. Spirometry measurements; symptom scores; side effects; and serum cortisol, cytokine, and IgE levels were evaluated before and after treatment. RESULTS: Posttreatment lung function was significantly improved in both groups as shown by increased FEV(1) and peak expiratory flow findings (P < .001). The improvement was slightly but significantly greater in the prednisone group (P < .05). Clinical symptom scores, use of beta(2)-bronchodilators, and serum IgE levels were reduced significantly, and to a similar degree in both groups (P < .001). T(H)2 cytokine levels were significantly reduced in both treated groups (P < .001) and were lower in the prednisone-treated group (P < .05). Serum IFN-gamma and cortisol levels were significantly decreased in the prednisone group (P < .001) but significantly increased in the ASHMI group (P < .001). No severe side effects were observed in either group. CONCLUSION: Antiasthma herbal medicine intervention appears to be a safe and effective alternative medicine for treating asthma. In contrast with prednisone, ASHMI had no adverse effect on adrenal function and had a beneficial effect on T(H)1 and T(H)2 balance.

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Respir Med. 2005 Jul;99(7):836-49. Epub 2005 Mar 23.
Factors guiding the choice of delivery device for inhaled corticosteroids in the long-term management of stable asthma and COPD: Focus on budesonide.
Thorsson L, Geller D.
AstraZeneca R&D, Experimental Medicine, 221 87 Lund, Sweden.

Inhaled corticosteroids (ICSs) have become the mainstay of chronic controller therapy to treat airways inflammation in asthma and to reduce exacerbations in chronic obstructive pulmonary disease. An array of ICSs are now available that are aerosolized by a range of delivery systems. Such devices include pressurized (or propellant) metered-dose inhalers (pMDIs), pMDIs plus valved holding chambers or spacers, breath-actuated inhalers, and nebulizers. More recently, dry-powder inhalers (DPIs) were developed to help overcome problems of hand-breath coordination associated with pMDIs. The clinical benefit of ICSs therapy is determined by a complex interplay between the nature and severity of the disease, the type of drug and its formulation, and characteristics of the delivery device together with the patient's ability to use the device correctly. The ICSs budesonide is available by pMDI, DPI, and nebulizer-allowing the physician to select the best device for each individual patient. Indeed, the availability of budesonide in three different delivery systems allows versatility for the prescribing physician and provides continuity of drug therapy for younger patients who may remain on the same ICSs as they mature.

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Allergy. 2005 Jul;60(7):875-81.
Intranasal and inhaled fluticasone propionate for pollen-induced rhinitis and asthma.
Dahl R, Nielsen LP, Kips J, Foresi A, Cauwenberge P, Tudoric N, Howarth P, Richards DH, Williams M, Pauwels R; the SPIRA Study Group.
Department of Respiratory Diseases, Aarhus University Hospital, Aarhus, Denmark.

Background: Studies suggest that nasal treatment might influence lower airway symptoms and function in patients with comorbid rhinitis and asthma. We investigated the effect of intranasal, inhaled corticosteroid or the combination of both in patients with both pollen-induced rhinitis and asthma. Methods: A total of 262 patients were randomized to 6 weeks' treatment with intranasal fluticasone propionate (INFP) 200 mug o.d., inhaled fluticasone propionate (IHFP) 250 mug b.i.d., their combination, or intranasal or inhaled placebo, in a multicentre, double-blind, parallel-group study. Treatment was started 2 weeks prior to the pollen season and patients recorded their nasal and bronchial symptoms twice daily. Before and after 4 and 6 weeks' treatment, the patients were assessed for lung function, methacholine responsiveness, and induced sputum cell counts. Results: Intranasal fluticasone propionate significantly increased the percentages of patients reporting no nasal blockage, sneezing, or rhinorrhoea during the pollen season, compared with IHFP or intranasal or inhaled placebo. In contrast, only IHFP significantly improved morning peak-flow, forced expiratory volume in 1 second (FEV(1)) and methacholine PD(20), and the seasonal increase in the sputum eosinophils and methacholine responsiveness. Conclusions: In patients with pollen-induced rhinitis and asthma, the combination of intranasal and IHFP is needed to control the seasonal increase in nasal and asthmatic symptoms.

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Am J Med. 2005 Jun;118(6):649-57.
Short-term and long-term asthma control in patients with mild persistent asthma receiving montelukast or fluticasone: a randomized controlled trial.
Zeiger RS, Bird SR, Kaplan MS, Schatz M, Pearlman DS, Orav EJ, Hustad CM, Edelman JM.
Department of Allergy-Immunology, Kaiser Permanente Medical Center, Los Angeles, California, USA. robert.s.zeiger@kp.org

PURPOSE: To determine whether montelukast is as effective as fluticasone in controlling mild persistent asthma as determined by rescue-free days. SUBJECTS AND METHODS: Participants aged 15 to 85 years with mild persistent asthma (n = 400) were randomized to oral montelukast (10 mg once nightly) or inhaled fluticasone (88 mug twice daily) in a year-long, parallel-group, multicenter study with a 12-week, double-blind period, followed by a 36-week, open-label period. RESULTS: The mean percentage of rescue-free days was similar between treatments after 12 weeks (fluticasone: 74.9%, montelukast: 73.1%; difference = 1.8%, 95% confidence interval [CI]: -3.2% to 6.8%) but not during the open-label period (fluticasone: 77.3%, montelukast: 71.1%; difference = 6.2%, 95% CI: 0.8% to 11.7%). Although both fluticasone and montelukast significantly improved symptoms, quality of life, and symptom-free days during both treatment periods, greater improvements occurred with fluticasone in lung function during both periods and in asthma control during open-label treatment. Post hoc analyses revealed a difference in rescue-free days favoring fluticasone in participants in the quartiles for lowest lung function and greatest albuterol use at baseline. CONCLUSION: In patients with mild persistent asthma, rescue-free days and most asthma control measures improved similarly with fluticasone or montelukast over the short term, but with prolonged open-label treatment, asthma control improved more with fluticasone. Improved asthma control with fluticasone appeared to occur in those with decreased lung function and greater albuterol use at baseline. In the remaining patients, the two treatments appeared to be comparable. These results suggest that classification criteria for mild persistent asthma may need to be re-evaluated.

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Allergol Immunopathol (Madr). 2005 May-Jun;33(3):142-4.
Safety and tolerability of ultra-Rush (20 minutes) sublingual immunotherapy in patients with allergic rhinitis and/or asthma.
Gammeri E, Arena A, D'Anneo R, La Grutta S.
Respiratory Center Disease-USL 5. Messina. Italy.

Background: The safety and good tolerability of sublingual immunotherapy (SLIT) has already been proved in allergic patients, but only one study has investigated the occurrence of immediate adverse reactions in allergic patients after a 2-hour ultra-rush regimen of SLIT performed with a chemically modified extract (sublingual monomeric allergoid, Lais(R), Lofarma S.p.A., Milan). The objective of the present study was to evaluate the occurrence of immediate adverse reactions in allergic patients after a very fast (20 minutes) ultra-rush regimen of sublingual allergoid SLIT. Methods and results: We studied 105 patients: 28 children (20 male, mean age 13.3 +/- 2.1 yr) and 77 adults (29 male, mean age 34.7 +/- 9.9 years) with a history of intermittent/persistent rhinitis or intermittent/mild persistent asthma due to House Dust Mite (n = 56), Parietaria (n = 34) and Timothy-grass (n = 15) The build-up ultra-rush phase involved the administration, every five minutes, of increasing doses of the sublingual allergoid SLIT. All patients tolerated the treatment very well. Only one patient out of 105 (0.9 %) had a mild local symptom (gastric pirosis) that occurred 30 minutes after the last initial dose and spontaneously disappeared as the treatment was continued. CONCLUSIONS: These data show the excellent safety and tolerability profile of an ultra-rush SLIT regimen performed with a chemically modified extract, even when high doses were administered through an extremely short induction phase (20 minutes), thus confirming the previously reported results.

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Allergol Immunopathol (Madr). 2005 May;33(3):162-168.
[Treatment strategies in rhinoconjunctivitis and asthma during pregnancy.]
[Article in Spanish]
Prieto Lastra L, Perez Pimiento A, Gonzalez Sanchez L, Rodriguez Cabreros M, Rodriguez Mosquera M, Garcia Cubero J.
Servicio de Alergologia. Hospital Universitario Puerta de Hierro. Madrid. Espana.

Background: The incidence of asthma is high, especially in young people, a population group that includes women of reproductive age. We reviewed recent publications on asthma control during pregnancy to avoid undesired effects on both the mother and fetus. The prevalence of rhinoconjunctivitis is also high, although this disease is often under-treated by physicians. The use of beta2-agonists, corticoids (systemic/inhaled/nebulized), epinephrine and specific allergen immunotherapy is discussed. Methods: We reviewed recent publications on asthma during pregnancy as well as other articles of interest. Articles providing data on drug therapy, overall strategies and patient education were selected. Sufficient drugs are available for the management of this disease and under-treatment cannot be justified. CONCLUSIONS: Pregnancy is not a disease, but constitutes a period when special care must be taken with underlying diseases. The aim of asthma treatment during pregnancy is to prevent fetal complications due to the effects of medication and asthma crises by keeping the mother symptom free and preventing possible exacerbations. Almost all authors agree that asthma crises in pregnant women should be treated no differently from those in non-pregnant women. Treatment of rhinoconjunctivitis should not be stopped during pregnancy since a wide variety of FDA category B drugs is available. Specific allergen immunotherapy should not be suspended during pregnancy as it is not contraindicated. However, this therapy should not be initiated during pregnancy.

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Ann Allergy Asthma Immunol. 2005 May;94(5):543-8.
Yoga intervention for adults with mild-to-moderate asthma: a pilot study.
Sabina AB, Williams AL, Wall HK, Bansal S, Chupp G, Katz DL.
Yale-Griffin Prevention Research Center, Derby, Connecticut 06418, USA.

BACKGROUND: Preliminary studies investigating yoga and breath work for treating asthma have been promising. Several randomized controlled trials have shown a benefit from yoga postures and breathing vs control, but the control in these cases involved no intervention other than usual care. This study advances the field by providing an active control. OBJECTIVE: To determine the effectiveness and feasibility of a yoga and breath work intervention for improving clinical indices and quality of life in adults with mild-to-moderate asthma. METHODS: A randomized, controlled, double-masked clinical trial was conducted between October 1, 2001, and March 31, 2003. Random assignment was made to either a 4-week yoga intervention that included postures and breath work or a stretching control condition. Outcome measures were evaluated at 4, 8, 12, and 16 weeks and included the Mini Asthma Quality of Life Questionnaire, rescue inhaler use, spirometry, symptom diaries, and health care utilization. RESULTS: Sixty-two participants were randomized to the intervention and control groups, and 45 completed the final follow-up measures. Intention-to-treat analysis was performed. Significant within-group differences in postbronchodilator forced expiratory volume in 1 second and morning symptom scores were apparent in both groups at 4 and 16 weeks; however, no significant differences between groups were observed on any outcome measures. CONCLUSIONS: Iyengar yoga conferred no appreciable benefit in mild-to-moderate asthma. Circumstances under which yoga is of benefit in asthma management, if any, remain to be determined.

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Respir Med. 2005 May 22; [Epub ahead of print]
The efficacy and safety of fluticasone propionate in very young children with persistent asthma symptoms.
Carlsen KC, Stick S, Kamin W, Cirule I, Hughes S, Wixon C.
Ulleval University Hospital ,Oslo, Norway.

We aimed to evaluate the efficacy and safety of fluticasone propionate (FP) in children aged 12-47 months with recurrent/persistent asthma symptoms. One hundred and sixty children (12-47 months) were randomised into this multicentre, double-blind, placebo-controlled, parallel-group study, and treated with either FP (100mug bd) or placebo (2 puffs bd), both administered by metered-dose-inhaler and Babyhalertrade mark for 12 weeks. The primary endpoint was percentage of symptom-free 24h periods. Over weeks 1-12, FP-treated patients had significantly more percentage symptom-free 24-h periods compared with placebo (odds ratio 0.53; 95% CI 0.29-0.95; P=0.035). Relative to baseline, where all patients were symptomatic for at least 21/28 days of the run-in, the improvement equated to one additional symptom-free 24h period per week. FP patients also had a significantly higher percentage of 24h periods with no wheeze or cough, the odds ratio for treatment difference corresponding to two additional wheeze-free and one additional cough-free periods per week. FP was well-tolerated, with similar reported adverse events in both groups. Urinary cortisol-creatinine ratio was slightly decreased among FP patients after 12 weeks, but with no clinical correlates. FP is effective for the treatment of chronic persistent asthma symptoms in very young children.

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Ann Allergy Asthma Immunol. 2005 May;94(5):517-27; quiz 527-9, 574.
The challenge of mild persistent asthma.
Irani AM.
Department of Pediatrics and Internal Medicine, Virginia Commonwealth University Health Systems, Richmond, Virginia 23298, USA. airani@vcu.edu

OBJECTIVE: To review the current data and treatment options for mild persistent asthma. DATA SOURCES: A MEDLINE search was performed for relevant articles. STUDY SELECTION: The expert opinion of the author was used to select studies for inclusion in this review. RESULTS: Current data suggest that asthma severity is determined early in life and that disease progression may not occur outside early childhood. Furthermore, no therapy has been demonstrated to clearly prevent or reverse structural airway changes in patients with persistent asthma. Thus, the primary goal of asthma therapy is to prevent disease exacerbations rather than to halt disease progress, at least in patients past early childhood. Published reports of severe exacerbations in patients with reported mild asthma may actually reflect inclusion of patients with more severe forms of the disease who were inappropriately classified in terms of asthma severity. CONCLUSION: Unlike the case for moderate and severe asthma, where regular therapy with inhaled corticosteroids is clearly the treatment of choice, clear guidelines for treating patients with mild persistent asthma have not been established. Patients with mild disease without severe exacerbations may require only the minimum therapy necessary for disease control.

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Am Fam Physician. 2005 May 15;71(10):1959-68.
Childhood asthma: treatment update.
Courtney AU, McCarter DF, Pollart SM.
Department of Family Medicine, University of Virginia Health System, Charlottesville, Virginia 22908, USA. aun2v@virginia.edu

The prevalence of childhood asthma has risen significantly over the past four decades. A family history of atopic disease is associated with an increased likelihood of developing asthma, and environmental triggers such as tobacco smoke significantly increase the severity of daily asthma symptoms and the frequency of acute exacerbations. The goal of asthma therapy is to control symptoms, optimize lung function, and minimize days lost from school. Acute care of an asthma exacerbation involves the use of inhaled beta2 agonists delivered by a metered-dose inhaler with a spacer, or a nebulizer, supplemented by anticholinergics in more severe exacerbations. The use of systemic and inhaled corticosteroids early in an asthma attack may decrease the rate of hospitalization. Chronic care focuses on controlling asthma by treating the underlying airway inflammation. Inhaled corticosteroids are the agent of choice in preventive care, but leukotriene inhibitors and nedocromil also can be used as prophylactic therapy. Long-acting beta2 agonists may be added to one of the anti-inflammatory medications to improve control of asthma symptoms. Education programs for caregivers and self-management training for children with asthma improve outcomes. Although the control of allergens has not been demonstrated to work as monotherapy, immunotherapy as an adjunct to standard medical therapy can improve asthma control. Sublingual immunotherapy is a newer, more convenient option than injectable immunotherapy, but it requires further study. Omalizumab, a newer medication for prevention and control of moderate to severe asthma, is an expensive option.

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Eur Rev Med Pharmacol Sci. 2005 Mar-Apr;9(2):103-11.
Significant decrease of IgE antibodies after a three-year controlled study of specific immunotherapy to pollen allergens in children with allergic asthma.
Cantani A, Micera M.
Allergy and Clinical Immunology Division, Department of Pediatrics, University La Sapienza, Rome, Italy.

BACKGROUND: Specific immunotherapy (SIT) in children being not an optional treatment should be administered as soon as possible, also in children aged 2-3 years, due to the very early asthma and rhinitis onset, contrarily to opponents continuing to stress the danger of anaphylactic reactions without displaying reliable data. MATERIALS AND METHODS: We report 56 children who underwent SIT and 56 controls seen consecutevely at the Allergy and Immunology Division, Department of Pediatrics, University of Rome "La Sapienza". The control group was treated with all appropriate medications. RESULTS: They were highly in favor of SIT with statistically significant differences. We stress that IgE antibodies significantly decreased after treatment only in the study group, and IgG antibodies very significantly increased after treatment only in the study group. DISCUSSION: We demonstrate that SIT is the only treatment which can alter the natural course of respiratory diseases, whereas drugs represent only a symptomatic treatment.

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Respir Med. 2005 Apr;99(4):461-70.
Formoterol used as needed in patients with intermittent or mild persistent asthma.
Chuchalin A, Kasl M, Bengtsson T, Nihlen U, Rosenborg J.
Russian Research Pulmonology Institute, 11th Parkovaya Street, 105077 Moscow, Russia.

Objective: To study the effectiveness and safety of as-needed treatment of formoterol compared with the short-acting alternative terbutaline. Methods: Two double-blind, 12-month, parallel-group, non-inferiority trials comparing as-needed use of formoterol (Oxis((R))) 4.5mug and terbutaline (Bricanyl((R))) 0.5mg via dry-powder inhaler (Turbuhaler((R))), one in 675 patients with intermittent and one in 455 patients with mild persistent asthma, overall 6-87 years of age. Peak expiratory flow (PEF), symptoms, rescue medication use, exacerbations, airway responsiveness (metacholine challenge; subgroup of 127 patients), systemic effects (high single-dose test; subgroup of 87 patients), and safety (adverse events) were assessed. Results: Formoterol 4.5mug was as effective as terbutaline 0.5mg with regard to morning PEF (non-inferiority; lower 95% confidence interval limit above -10L/min). Metacholine sensitivity, exacerbation rates or use of rescue medication did not differ between treatments. Formoterol 54mug was shown to give less systemic effects than terbutaline 6mg. Both treatments were safe and well tolerated. Conclusions: Formoterol 4.5mug used as needed was at least as effective and safe as terbutaline 0.5mg used as needed in intermittent and mild persistent asthma, and was associated with less systemic effects when administered as high single doses.

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Respir Med. 2005 Apr;99(4):384-95.
Long-acting beta(2)-agonists in asthma: an overview of Cochrane systematic reviews.
Walters JA, Wood-Baker R, Walters EH.
Discipline of Medicine, University of Tasmania, GPO Box 252-34, Hobart, Tasmania 7001, Australia.

According to major asthma management guidelines, long-acting beta(2)-agonists (LABAs) should be used only when asthma remains symptomatic in patients already receiving regular inhaled corticosteroids (ICSs). A large Cochrane systematic review provides evidence that LABAs are safe and beneficial in control of asthma; sub-group analyses indicating that this is true when ICSs are used and in their absence. Two other Cochrane systematic reviews have found that LABAs are more effective than regular short-acting beta(2)-agonists, and are as effective as theophylline with fewer side-effects. These reviews support guidelines in the use of LABA as additional therapy when asthma is inadequately controlled by ICS at moderate dose. However, guidelines may be too conservative, and more studies in stable mild asthma comparing their use and safety with placebo and ICS are required.

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Lancet. 2005 Mar 9;365(9463):974-6.
Severe asthma treatment: need for characterising patients.
Heaney LG, Robinson DS.
Regional Respiratory Centre, Belfast City Hospital, Belfast, UK. l.heaney@qub.ac.uk

CONTEXT: Asthma is readily diagnosed in most cases and usually responds to inhaled corticosteroids with or without long-acting beta agonists, theophyllines, or leukotriene-receptor antagonists, adjusted stepwise according to symptoms and lung function. However, up to 40% of adult patients with asthma remain symptomatic, and up to 5% have difficult-to-control asthma despite multiple therapies. It is suggested that higher doses of inhaled steroids with long-acting beta2 agonists should be used for total control of symptoms; and anti-IgE therapy is newly licensed in the USA. However, difficult-to-control asthma is complex and multifactorial, and is often not due to severe or therapy-resistant asthma. STARTING POINT: Last year saw encouraging reports on omalizumab (anti-IgE therapy) in severe allergic asthma, by Stephen Holgate, Jon Ayres, and their respective colleagues (Clin Exp Allergy 2004; 34: 632-38; Allergy 2004; 59: 701-08). Omalizumab reduced exacerbation rates, improved asthma symptoms and quality of life, and allowed lower doses of inhaled steroid compared with placebo. In placebo-controlled studies with anti-IgE, many patients were able to substantially reduce and even withdraw inhaled steroids in the placebo arm. WHERE NEXT: Severe asthma is often defined as persisting symptoms despite high-dose inhaled steroids. This definition is likely to include patients with various reasons for their persisting symptoms, for whom additional treatment is not always required. Before starting new therapy, it is important to systematically evaluate asthmatic patients to accurately define their disease and to identify those whose symptoms are caused by other factors, and thus avoid unnecessary medication. There might also be subgroups that have differing underlying inflammatory processes and who will respond differently to individual treatments.

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Pneumologie. 2005 Mar;59(3):167-73.
[Asthma control with the salmeterol-fluticasone-combination disc compared to standard treatment.]
[Article in German]
Molitor S, Liefring E, Trautmann M.
Arzt fur Allgemeinmedizin, Allergologie, Betriebsmedizin, Umweltmedizin, Allergo Medic Klinisches Institut, Hannover.

BACKGROUND: The present study aimed to investigate whether a fixed combination of salmeterol and fluticasone (SFC) from a single inhaler provides sufficient asthma control comparable to that achieved with standard treatment (inhaled steroid in a dose of 1,000 mcg BDP- (beclomethasone dipropionate) equivalent plus a LABA and/or theophylline and/or montelukast). PATIENTS AND METHODS: In a prospective, randomised study patients with moderate or severe asthma were either switched to a twice daily inhalation of 50 mcg salmeterol plus 500 mcg fluticasone from the Viani(R) forte 50/500 mcg Diskus(R) (n = 142 patients), or they were maintained on standard treatment (n = 89 patients). If adequate asthma control was achieved after 8 weeks, the dose of the inhaled steroid was reduced by 50 % during weeks 9 to 16. RESULTS: After 8 weeks, 81 % of the patients who had been switched to SFC and 80 % of patients on standard treatment achieved sufficient asthma control. After reducing the ICS dose by 50 %, asthma control remained appropriate in 90 % of SFC-patients, but only in 75 % of patients receiving standard treatment (p = 0.031). In addition, asthma symptoms and use of rescue medication were significantly more stable in SFC patients (p < 0.05). CONCLUSIONS: With the salmeterol fluticasone combination product, patients with moderate asthma can achieve a control of their asthma, which is as good as that after standard treatment. In most SFC patients the fluticasone dosage can be reduced by 50 % without losing asthma control.

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Chest. 2005 Mar;127(3):866-870.
Life-Threatening Asthma in Children: Treatment With Sodium Bicarbonate Reduces PCO2.
Buysse CM, de Jongste JC, de Hoog M.
Department of Pediatric Intensive Care, Erasmus MC-Sophia Children's Hospital, Dr. Molewaterplein 60, 3015 GJ Rotterdam, the Netherlands; c.buysse@erasmusmc.nl.

OBJECTIVES: To assess the effect of administration of sodium bicarbonate on carbon dioxide levels in children with life-threatening asthma (LTA) and to evaluate the clinical effect of this treatment.Study DESIGN: Retrospective study. SETTING: A pediatric ICU (PICU) of a tertiary care university hospital. PATIENTS: Seventeen children with LTA who received sodium bicarbonate. MEASUREMENTS AND RESULTS: In January 1999, a new protocol for the treatment of LTA was initiated in our institution, incorporating the use of IV sodium bicarbonate in acidotic patients (pH < 7.15) with refractory status asthmaticus. Since January 1999, sodium bicarbonate was administered to 17 patients; 5 patients received two or three doses of sodium bicarbonate. In three patients, sodium bicarbonate was administered after intubation. Intubation and mechanical ventilation were performed in five patients before admission to the PICU, and in one patient during admission. There was a significant decrease of Pco(2) after sodium bicarbonate infusion (p = 0.007). An improvement of respiratory distress in all but one patient was seen as well. CONCLUSIONS: Administration of sodium bicarbonate in 17 children with LTA was associated with a significant decrease in Pco(2) and an improvement of respiratory distress. The possible benefits of sodium bicarbonate in LTA deserve further study in a controlled, prospective design.

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Am J Respir Crit Care Med. 2005 Mar 11; [Epub ahead of print]
Comparison of Inhaled Fluticasone With IV Hydrocortisone in the Treatment of Adult Acute Asthma.
Rodrigo GJ.
Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay.

Rationale: Several studies published in the second half of the 90's have showed a therapeutic early effect of inhaled corticosteroids in acute asthma. However, systemic corticosteroids are considered the standard of care. Objectives: To compare the effect of repeated doses of inhaled fluticasone with the standard treatment of systemic corticosteroids in adult patients with severe acute asthma. Methods: One hundred six patients (mean age 33.5 +/- 8.8 y) were randomly assigned to received fluticasone (3000 mcg/h) administered through a meter-dose inhaler and spacer at 10 min intervals for 3 h., or 500 mg of intravenous hydrocortisone. Additionally, all patients received inhaled albuterol and ipratropium bromide. Main Results: Subjects treated with fluticasone showed 30.5% and 46.4% greater improvements in PEF and FEV1 respectively compared with the hydrocortisone group. The fluticasone group had better PEF and FEV1 at 120, 150 and 180 min (p < 0.05). Also, fluticasone group showed higher rates of patients that obtain the discharge threshold at 90, 120 and 150 min. This therapeutic benefit was particularly evident in those patients with most severe obstruction. Subjects with a baseline FEV1 < 1 L treated with fluticasone showed a significant increase in pulmonary function (p = 0.001) and a significant decrease in hospitalization rate (p = 0.05). Conclusions: The use of repeated doses of inhaled fluticasone was more effective than intravenous hydrocortisone and was associated with an early improvement. This therapeutic benefit was particularly evident in those patients with the most severe obstruction.

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Allergy. 2005 Jan;60(1):65-70.
Differential effects of fluticasone and montelukast on allergen-induced asthma.
Palmqvist M, Bruce C, Sjostrand M, Arvidsson P, Lotvall J.
Section of Allergy, The Lung Pharmacology Group, Department of Respiratory Medicine and Allergology, Goteborg University, Gothenburg, Sweden.

Early asthmatic responses (EAR) and late asthmatic responses (LAR) to allergen are induced by the local release of a series of bronchoconstrictor mediators, including leukotrienes and histamine. Both anti-leukotrienes and other anti-asthma drugs, such as inhaled glucocorticoids, have been shown to reduce both EAR and LAR. The aim of the present study was to directly compare the effects of regular treatment with an oral anti-leukotriene, montelukast (Mont; 10 mg once daily, for 8 days), and an inhaled glucocorticoid [fluticasone propionate (FP) 250 mug twice daily for 8 days] on the EAR and LAR to an inhaled allergen challenge. Patients with a documented EAR and LAR at a screening visit were randomized to these treatments, or placebo, in a double-blind, double-dummy, crossover fashion. Allergen challenge at a dose causing both an EAR and LAR was given on the eighth day of treatment. The maximum fall in FEV(1) during the EAR was 17.8% during placebo treatment, 8.3% during Mont and 16.3% during FP (P < 0.05 for Mont vs placebo). The maximum fall during the EAR was 13.8% during placebo treatment, 11.8% during Mont and 2% during FP treatment (P < 0.05 for FP vs placebo and FP vs Mont). PC(20) methacholine was significantly higher 24 h after allergen challenge during FP-treatment compared with Mont (P < 0.05). Both montelukast and fluticasone reduced the relative amount of sputum eosinophils after allergen compared with placebo treatment. This study shows that anti-leukotrienes are effective to attenuate the EAR, whereas inhaled glucocorticoids are more effective than anti-leukotrienes in attenuating the EARs and improves bronchial hyperresponsiveness to a greater extent. In conclusion, inhaled glucocorticoids have overall greater efficacy than oral anti-leukotrienes to attenuate allergen-induced airway responses in mild asthmatic patients.

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Bioorg Med Chem. 2004 Dec 15;12(24):6331-42.
Corticosteroids: the mainstay in asthma therapy.
Gupta R, Jindal DP, Kumar G.
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.

Inflammation is now marked as a central feature of asthma pathophysiology and aims of current asthma management are not only to treat acute symptoms of wheezing, breathlessness, chest tightness, cough but also to suppress the underlying inflammatory component. Despite the availability of a number of drugs, corticosteroids remain the mainstay in the management of all types of asthma as these are the most potent and effective antiinflammatory agents available so far. Corticosteroids suppress virtually every step in inflammation. However therapeutic doses of oral glucocorticoids are associated with a range of adverse reactions. To overcome these side effects, inhalations have been developed to deliver glucocorticoids directly to the lungs and in the process a number of aerosol preparations have become available, which have advantage of significantly lower toxicity due to low systemic absorption from the respiratory tract and rapid inactivation. Despite considerable efforts by pharmaceutical industry, it has been difficult to develop novel therapeutic agents for asthma management, which could surpass inhaled corticosteroids. Currently the data favours using inhaled corticosteroids as monotherapy in the majority of patients in all kinds of asthma. If combination therapy is recommended to achieve additional control in severe asthma cases, other drugs such as beta-agonists, antileukotrienes, theophylline, etc. are considered as adjunct therapies to corticosteroids. This review discusses the importance of corticosteroids as first line therapy for asthma treatment with the availability of inhaled corticosteroids for chronic treatment and oral formulations for treating acute exacerbations of moderate to severe asthma.

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Clin Pediatr (Phila). 2004 Nov;43(9):793-802.
Update on national asthma education and prevention program pediatric asthma treatment recommendations.
Eid NS.

SUMMARY: The National Asthma Education and Prevention Program (NAEPP) published an update on selected topics from the 1997 Guidelines for the Diagnosis and Management of Asthma and provided new evidence-based recommendations for asthma treatment. Selected topics on the long-term management of asthma in children addressed the efficacy of inhaled corticosteroids (ICSs) compared with other asthma medications (i.e., as-needed beta(2)-adrenergic agonists and other controllers) in mild and moderate persistent asthma and the safety of long-term ICS use. The effects of early intervention with ICSs on asthma progression also were evaluated. An important new aspect of the treatment update entails the recommendation of ICSs as the controller medication of choice for all severities of persistent asthma in children. Additionally, on the basis of studies in adults, the Expert Panel suggested that long-acting beta(2)-adrenergic agonists are now the preferred adjunct to ICSs in children with moderate or severe persistent asthma. Based on long-term data in children, ICS therapy was deemed safe in terms of growth, bone mineral density, ocular effects, and hypothalamic pituitary adrenal axis function. Although members of the NAEPP Expert Panel determined that the effects of early intervention with ICSs on decline in lung function have not been adequately studied, they found that the effects on asthma control were substantial. Clin Pediatr. 2004;43:793-802.

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Indian J Pediatr. 2004 Nov;71(11):961-3.
Comparison of terbutaline and salbutamol inhalation in children with mild or moderate acute exacerbation of asthma.
Chandra P, Paliwal L, Lodha R, Kabra SK.
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. skkabra@hotmail.com.

OBJECTIVE: To compare the clinical efficacy and side effects of terbutaline and salbutamol administered by metered dose inhaler and holding chamber in the mild to moderate acute exacerbations of asthma in children. METHODS: The study subjects were children in the age group of 5- 15 years who presented with a mild or moderate acute exacerbation of asthma. Baseline assessment included clinical parameters and spirometry. The children were then randomized to receive salbutamol or terbutaline. Three puffs each of either 100 mcg salbutamol or 250 mcg of terbutaline were administered using 750 ml holding chamber with valve. Thirty minutes after drug administration, the children were reevaluated for clinical parameters and spirometry. RESULTS: Of the total 60 subjects studied, 31 were administered terbutaline and 29 salbutamol. The baseline spirometric parameters were comparable. After drug administration, all the studied variables showed significant improvement within each group. However, there were no statistically significant differences when the two groups were compared with each other. There was no significant difference in the side effects between two groups. CONCLUSION: Terbutaline and salbutamol, when administered by MDI with holding chamber, are equally efficacious in children with mild or moderate acute exacerbation of asthma.

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BioDrugs. 2004;18(6):415-8.
Spotlight on omalizumab in allergic asthma.
Bang LM, Plosker GL.
Adis International Limited, Yardley, Pennsylvania, USA.

Omalizumab (Xolair((R))) is a humanized monoclonal antibody used in the treatment of adolescent and adult patients with moderate to severe allergic asthma inadequately controlled with inhaled corticosteroids (ICS). It selectively binds to circulating immunoglobulin E (IgE) and, thereby, prevents binding of IgE to mast cells and other effector cells. Without surface-bound IgE, these cells are unable to recognize allergens, thus preventing cellular activation by antigens and the subsequent allergic/asthmatic symptoms. Omalizumab decreases free serum IgE levels in a dose-dependent manner, reduces IgE receptor density on effector cells, and significantly improves airway inflammation parameters.Omalizumab is slowly absorbed after subcutaneous administration, and mean elimination half-life is 26 days, thus allowing infrequent administration of the drug. Omalizumab dosage is determined by bodyweight and pretreatment serum total IgE levels. Patients treated with subcutaneous omalizumab in clinical trials received a dosage that was approximately equal to 0.016 mg/kg/IgE (IU/mL) per 4 weeks. Thus, patients received 150 or 300mg every 4 weeks, or 225, 300, or 375mg every 2 weeks.In adults and adolescents (>/=12 years of age) with moderate to severe allergic asthma, subcutaneous administration of omalizumab as add-on therapy with ICS improved the number of asthma exacerbations, rescue medication use, asthma symptom scores, and quality-of-life (QOL) scores compared with placebo during 28- and 32-week double-blind trials. In addition, concomitant ICS use was significantly decreased in patients receiving omalizumab, and in the two largest double-blind trials approximately 40% of omalizumab recipients completely withdrew from ICS therapy while maintaining effective asthma control. In general, results of extension studies showed that the beneficial effects of omalizumab were maintained over a total period of 52 weeks.Omalizumab was well tolerated as add-on therapy with ICS during treatment for up to 52 weeks. Common adverse events in clinical trials included injection site reaction, viral infection, upper respiratory tract infection, sinusitis, headache, and pharyngitis, although the incidence of adverse events with omalizumab was similar to that with placebo.In conclusion, omalizumab, as add-on therapy with ICS, is an effective and well tolerated agent for the treatment of moderate to severe allergic asthma in adolescents and adults. In addition to its symptomatic and QOL benefits, omalizumab therapy allows ICS dosage reduction or discontinuation of ICS in many patients. Comparisons of omalizumab with other asthma therapies have yet to be conducted; however, clinical efficacy and tolerability data indicate that omalizumab is a valuable option in the treatment of allergic asthma.

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Br J Clin Pharmacol. 2004 Oct;58(4):411-8.
Cumulative high doses of inhaled formoterol have less systemic effects in asthmatic children 6-11 years-old than cumulative high doses of inhaled terbutaline.
Kaae R, Agertoft L, Pedersen S, Nordvall SL, Pedroletti C, Bengtsson T, Johannes-Hellberg I, Rosenborg J.
Kolding Hospital, Kolding, Denmark.

Objectives To evaluate high dose tolerability and relative systemic dose potency between inhaled clinically equipotent dose increments of formoterol and terbutaline in children. Methods Twenty boys and girls (6-11 years-old) with asthma and normal ECGs were studied. Ten doses of formoterol (Oxis((R))) 4.5 micro g (F4.5) or terbutaline (Bricanyl((R))) 500 micro g (T500) were inhaled cumulatively via a dry powder inhaler (Turbuhaler((R))) over 1 h (three patients) or 2.5 h (17 patients) and compared to a day of no treatment, in a randomised, double-blind (active treatments only), crossover trial. Blood pressure (BP), ECG, plasma potassium, glucose, lactate, and adverse events were monitored up to 10 h to assess tolerability and relative systemic dose potency. Results Formoterol and terbutaline had significant beta(2)-adrenergic effects on most outcomes. Apart from the effect on systolic BP, QRS duration and PR interval, the systemic effects were significantly more pronounced with terbutaline than with formoterol. Thus, mean minimum plasma potassium, was suppressed from 3.56 (95% confidence interval, CI: 3.48-3.65) mmol l(-1) on the day of no treatment to 2.98 (CI: 2.90-3.08) after 10 x F4.5 and 2.70 (CI: 2.61-2.78) mmol l(-1) after 10 x T500, and maximum Q-Tc (heart rate corrected Q-T interval [Bazett's formula]) was prolonged from 429 (CI: 422-435) ms on the day of no treatment, to 455 (CI: 448-462) ms after 10 x F4.5 and 470 (CI: 463-476) ms after 10 x T500. Estimates of relative dose potency indicated that F4.5 micro g had the same systemic activity as the clinically less effective dose of 250 micro g terbutaline. The duration of systemic effects differed marginally between treatments. Spontaneously reported adverse events (most frequently tremor) were fewer with formoterol (78% of the children) than with terbutaline (95%). A serious adverse event occurred after inhalation of 45 micro g formoterol over the 1 h dosing time, that prompted the extension of dosing time to 2.5 h. Conclusions Multiple inhalations over 2.5 h of formoterol (4.5 micro g) via Turbuhaler((R)) are at least as safe as and associated with less systemic effects than multiple inhalations of the clinically equipotent dose of terbutaline (500 micro g) in children with asthma.

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Dtsch Med Wochenschr. 2004 Sep 24;129(39):2048-52.
[Dry powder inhalers - a review]
[Article in German]
Kohlhaufl M, Haidl P, Voshaar T, Haussinger K, Kohler D.
Asklepios Fachklinik Munchen-Gauting, Zentrum fur Pneumologie und Thoraxchirurgie.

Summary. Inhalation of bronchodilators and corticosteroids is the mainstay treatment for patients with obstructive lung diseases. Many dry powder inhaler devices and drug combinations are now available, and competing promotional claims can confuse both prescribers and patients. The appropriate dose of a given drug may be different for a pressurized metered dose inhaler (pMDI) and a dry powder inhaler (DPI). DPIs create aerosols by drawing air through an aliquot of dry powder. The powder contains either micronized (< 5 micro m in diameter) drug particles bound into loose aggregates, or micronized drug particles that are loosely bound to large (> 30 micro m in diameter) lactose or glucose particles. Usually, the drug particles are bound to carrier particles and are stripped form the carrier particles by the energy provided by the patientacute;s inhalation. The release of respirable particles of the drug requires inspiration at relatively high flow rates (30 - 120 L/min). Other important factors influencing aerosol generation and lung deposition are device design (resistance to airflow) and environmental conditions (humidity, temperature). Preferably, patients should employ only one type of aerosol-generating device for inhalation therapy. The technique of use varies among devices, and repeated instruction is highly advisable, to ensure that the patient uses the device appropriately. At present, DPIs are recommended for prophylactic and maintenance therapy in patients with asthma and chronic obstructive pulmonary disease, but not for patients with acute severe bronchoconstriction or children less than 5 years of age.

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Curr Med Res Opin. 2004 Sep;20(9):1403-18.
Efficacy and safety of budesonide/formoterol single inhaler therapy versus a higher dose of budesonide in moderate to severe asthma.
Scicchitano R, Aalbers R, Ukena D, Manjra A, Fouquert L, Centanni S, Boulet LP, Naya IP, Hultquist C.
Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia.

OBJECTIVES: This study evaluated the efficacy and safety of a novel asthma management strategy - budesonide/formoterol for both maintenance and symptom relief (Symbicort Single Inhaler Therapy) - compared with a higher maintenance dose of budesonide in patients with moderate to severe asthma. METHODS: This was a 12-month, randomised, double-blind, parallel-group study. Symptomatic patients with asthma (n = 1890; mean age 43 years [range 11 years-80 years], mean baseline forced expiratory volume in 1 s [FEV(1)] 70% of predicted, mean inhaled corticosteroid [ICS] dose 746microg/day) received either budesonide (160 microg, 2 inhalations twice daily) plus terbutaline 0.4 mg as needed or a daily maintenance dose of budesonide/formoterol (160/4.5 microg, 2 inhalations once daily) with additional inhalations of budesonide/formoterol 160/4.5 microg as needed. Time to first severe exacerbation (hospitalisation/emergency room [ER] treatment or systemic steroids due to asthma worsening or a fall in morning peak expiratory flow [PEF] to </= 70% of baseline on 2 consecutive days) was the primary outcome variable. RESULTS: A total of 1890 patients were randomised, of whom 1563 (83%) had severe asthma. The time to first severe exacerbation was prolonged by budesonide/formoterol single inhaler therapy (p < 0.001) compared with a higher dose of budesonide. The risk of having a severe exacerbation was 39% lower with budesonide/formoterol single inhaler therapy compared with budesonide (p < 0.001). The number needed to treat to prevent one severe exacerbation per year with budesonide/formoterol compared with budesonide was 5. The budesonide/formoterol group had 45% fewer severe exacerbations requiring medical intervention per patient compared with the budesonide group (p < 0.001). Budesonide/formoterol patients had fewer hospitalisations/ER treatments (15 vs 25 events, respectively [descriptive statistics]) and fewer treatment days with systemic steroids (1776 days vs 3177 days, respectively [descriptive statistics]) compared with budesonide patients. Budesonide/formoterol single inhaler therapy patients used less as-needed medication compared with budesonide patients (0.90 vs 1.42 inhalations/day; p < 0.001). The mean daily ICS dose was lower in the budesonide/formoterol group than in the budesonide group (466 microg/day vs 640 microg/day). Over the 12-month study period, the budesonide/formoterol group achieved asthma control sufficient to not require any additional as-needed medication on 60% of days. Overall, budesonide/formoterol single inhaler therapy gave 31 more asthma control days (a night and day with no asthma symptoms and no as-needed medication use) per patient-year and 12 additional undisturbed nights per patient-year compared with a higher dose of budesonide. Both treatments were well tolerated. CONCLUSION: Budesonide/formoterol single inhaler therapy has the potential to provide a complete asthma management approach with one inhaler, demonstrating a high level of efficacy in patients with moderate to severe asthma.

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Curr Drug Targets Inflamm Allergy. 2004 Sep;3(3):271-7.
Anti-inflammatory activities of beta2-agonists.
Hanania NA, Moore RH.
Pulmonary and Critical Care Medicine, Baylor College of Medicine, 1504 Taub Loop Houston 77030, USA. Hanania@bcm.tmc.edu

Beta2-adrenergic agonists (beta2-agonists) play a pivotal role in the acute and chronic management of asthma. Their major action on the airways is the relaxation of smooth muscle cells. In addition to their bronchodilator properties, beta2-agonists may have other effects through their activation of beta2-receptors expressed on resident airway cells such as epithelial cells and mast cells and circulating inflammatory cells such as eosinophils and neutrophils. These non-bronchodilator activities of beta2-agonists may enhance their efficacy in the management of asthma. In pre-clinical studies, the anti-inflammatory effects of beta2-agonists are demonstrated through their stabilizing effect on mast cells and their inhibition of mediator release from eosinophils, macrophages T-lymphocytes, and neutrophils. In addition, beta2-agonists may inhibit plasma exudation in the airway, the release of neuropeptides from sensory nerves, and mediator release from epithelial cells. These in vitro observations are not as clearly demonstrated in clinical trials, which may be explained by the rapid desensitization of beta2-adrenergic receptors on airway inflammatory cells. The regular use of short-acting beta2-agonists alone has been shown to have deleterious effects on asthma control. Therefore, short-acting agents should only be used when needed for rescue of acute symptoms. Monotherapy with long-acting beta2-agonists has also been associated with poor asthma control. However, when given concomitantly with inhaled corticosteroids, beta2-agonists may potentiate the anti-inflammatory effect of corticosteroids, improve asthma control and prevent exacerbations.

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Curr Drug Targets Inflamm Allergy. 2004 Sep;3(3):237-42.
Potential role of antibiotics in the treatment of asthma.
Blasi F, Cosentini R, Tarsia P, Allegra L.
Institute of Respiratory Diseases, University of Milan, IRCCS Ospedale Maggiore Milano, Italy. francesco.blasi@unimi.it

Although the role of antibiotic treatment in asthma is still disputed, clinical use of antimicrobials in this setting is more widespread than warranted on the basis of indications in the literature. Viral upper respiratory tract infections are known to be involved in asthma exacerbations. More recently, evidence of Mycoplasma pneumoniae and Chlamydia pneumoniae involvement in asthma attacks has been reported both in adult and paediatric populations. These pathogens are also involved in chronic asthma, and both in vitro and animal model studies indicate that atypical agents may play a role in the pathogenesis of the disease. Recent studies on asthma patients with evidence of atypical infection suggest that specific antimicrobial treatment (basically macrolides or fluoroquinolones) may confer additional advantages compared to standard therapy alone. Furthermore, a considerable amount of data has been gathered describing additional effects associated with macrolide treatment (reduced bronchial hyper-responsiveness, altered cytokine production, etc.). These non-antimicrobial effects have been defined as "anti-inflammatory activity". Should this information be confirmed, the use of macrolides in patients with asthma may be twofold: eradication of occult atypical infection; and reduction in the airway inflammation burden. Future lines of research in this field should attempt to determine whether specific antibiotic treatment may alter the natural history of asthma.

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J Asthma. 2004 Aug;41(5):575-82.
Efficacy and safety of inhaled corticosteroids in combination with a long-acting beta2-agonist in asthmatic children under age 5.
Sekhsaria S, Alam M, Sait T, Starr B, Parekh M.
Union Memorial Hospital, Baltimore, Maryland 21218, USA. asthma4@yahoo.com

The incidence of asthma in children under age 5 is higher than in any other segment of the population. Current NAEPP guidelines recommend treatment of some asthmatics in this age group with the combination of an inhaled corticosteroid and a long-acting beta2-agonist even though this practice has never been studied with children younger than 4. This retrospective study analyzes the efficacy and safety of a combination of fluticasone propionate (FP) and salmeterol (SA) in children under 5. Fifty patients who started using FP/SA before the age of 60 months were included in the analysis. To determine efficacy, we tracked the change in emergency room visits, hospitalizations, and the frequency of wheezing as a result of treatment. Emergency room visits were reduced from 78 to 5 (p<0.001), hospitalizations were reduced from 43 to 2 (p<0.001) and frequency of wheezing, daily, weekly, or monthly, was also reduced significantly (p<0.003). In terms of safety, there was only a 3.4% reduction in height percentile (p=0.37). Combination therapy is highly efficacious and safe for asthmatics under the age of 5. A well-designed prospective study is necessary to further evaluate the benefits and risks of this treatment method.

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Postgrad Med J. 2004 Sep;80(947):535-40.
Management of paediatric asthma.
Grigg J.
Leicester Children's Asthma Centre, University of Leicester, Leicester LE2 7LX, UK. jg33@le.ac.uk

Paediatric asthma best practice not only includes prescribing the correct therapeutic mix based on consensus guidelines, but also reducing therapy once control has been achieved. Clinicians should also be aware that asthma in young children is a heterogeneous entity, and a beneficial response to bronchodilators and/or inhaled steroids is not inevitable. In general, preschool children and infants should not be prescribed inhaled corticosteroids above 200 microg beclometasone dipropionate equivalent twice a day, or regular oral steroids, or long acting beta2-adrenoceptor agonists. New therapies such as anti-IgE antibodies are on the horizon, but these are unlikely to replace the established drug combinations. More likely is that the delivery of established drugs will become more convenient (for example, once a day inhaled corticosteroids, or season dependent prophylactic therapy).

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J Fam Pract. 2004 Sep;53(9):692-700.
Changes in recommended treatments for mild and moderate asthma.
Redding GJ, Stoloff SW.
Children's Hospital and Regional Medical Center, 4800 Sand Point Way, NE, Seattle, WA 98105-0371 USA. E-mail: gredding@u.washington.edu

Every patient with persistent asthma, regardless of disease severity, should use a daily controller medication. Consider an inhaled corticosteroid (ICS) first when choosing controller medications for long-term treatment of mild, moderate, and severe persistent asthma in adults and children. Leukotriene modifiers, cromolyn, and nedocromil may be considered as alternative, not preferred, controller medications for patients with persistent asthma. Long-acting b2-adrenergic-agonists should not be used as monotherapy. Long-term use of ICSs within labeled doses is safe for children in terms of growth, bone mineral density, and adrenal function; nonetheless, asthma should be monitored and ICS therapy stepped down to the lowest effective dose. Low- to medium-dose ICSs are not associated with the development of cataracts or glaucoma in children, but high cumulative lifetime doses may slightly increase the prevalence of cataracts in adults and elderly patients. ICSs are recommended for use in pregnant women with asthma; budesonide is the only ICS rated Pregnancy Category B.

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Treat Respir Med. 2004;3(4):235-46.
Current and emerging nonsteroidal anti-inflammatory therapies targeting specific mechanisms in asthma and allergy.
Bjermer L, Diamant Z.
Department of Respiratory Medicine & Allergology, University Hospital, Lund, Sweden.

Today inhaled corticosteroids (ICS) are regarded as the first-line controller anti-inflammatory treatment in the management of asthma. However, there is an increasing awareness of the risk of long-term adverse effects of ICS and that asthma is not only an organ-specific disease but also a systemic and small airway disease. This thinking has called for systemic treatment alternatives to treat asthma targeting more disease-specific mechanisms without influencing normal physiologic functions.Blocking of disease-specific mediators is a mechanism utilized by anti-leukotrienes and anti-immunoglobulin E treatment, each proven to be effective in both asthma and allergic rhinitis.Different cytokine-modifying strategies have been tested in clinical trials with variable results, some disappointing and some encouraging. Anti-interleukin (IL)-5 monoclonal antibody treatment effectively reduces the number of eosinophils locally in the airways and in peripheral blood in asthmatic patients. Unfortunately, this marked effect on eosinophils was not associated with an improvement in bronchial hyperresponsiveness and/or symptoms. Clinical trials with a recombinant soluble IL-4 receptor have been somewhat more successful at improving asthma control and allowing reduction of ICS therapy in asthma. Treatment with recombinant IL-12 had an effect on bronchial hyperresponsiveness and eosinophilic response, but was associated with unacceptable adverse effects. Other interesting cytokine-modulating treatments include those targeting IL-9, IL-10, IL-12 and IL-13.Immune-modulating treatment with bacterial antigens represents another strategy, originating from the hypothesis that some bacterial infections guide the immune system towards a T helper (Th) type 1 immune response. Mycobacterium vaccae, Bacille Calmette-Guerin (BCG) and immunostimulatory DNA sequences have all been tested in clinical trials, with encouraging results.Future asthma and allergy treatment will probably include not only one but also two or more disease-modifying agents administered to the same patient.

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Clin Mol Allergy. 2004 Mar 16;2(1):4.
Low-dose, long-term macrolide therapy in asthma:An overview.
Hatipoglu US MD, Rubinstein I MD.

Macrolides, a class of antimicrobials isolated from Streptomycetes more than 50 years ago, are used extensively to treat sinopulmonary infections in humans. In addition, a growing body of experimental and clinical evidence indicates that long-term (years), low (sub-antimicrobial)-dose 14- and 15-membered ring macrolide antibiotics, such as erythromycin, clarithromycin, roxithromycin and azithromycin, express immunomodulatory and tissue reparative effects that are distinct from their anti-infective properties. These salutary effects are operative in various lung disorders, including diffuse panbronchiolitis, cystic fibrosis, persistent chronic rhinosinusitis, nasal polyposis, bronchiectasis, asthma and cryptogenic organizing pneumonia. The purpose of this overview is to outline the immunomodulatory effects of macrolide antibiotics in patients with asthma

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Expert Opin Pharmacother. 2004 Mar;5(3):679-86.
A review of montelukast in the treatment of asthma and allergic rhinitis.
Nayak A.
University of Illinois College of Medicine.

Montelukast sodium (Singulair (R), Merck) is a selective and orally-active leukotriene-receptor antagonist (LTRA) that inhibits the cysteinyl leukotriene 1 (CysLT1) receptor. Montelukast is an effective and well-tolerated preventative treatment for asthma and allergic rhinitis in adults and children. The upper and lower airway show similar inflammatory responses to allergen challenge. Leukotrienes are inflammatory mediators that are known as the slow-reacting substance of anaphylaxis produced by a number of cell types including mast cells, eosinophils, basophils, macrophages and monocytes. Synthesis of these mediators results from the cleavage of arachidonic acid in cell membranes and they exert their biological effects by binding and activating specific receptors. This occurs in a series of events that lead to contraction of the human airway smooth muscle, chemotaxis and increased vascular permeability. These effects have led to their important role in the diseases of asthma and allergic rhinitis. As these agents lead to the production of symptoms in patients that are asthmatic or allergic, the use of LTRAs, particularly montelukast, may seem appropriate. Clinical trials have shown that montelukast is effective and safe in the treatment of patients with asthma, allergic rhinitis or both diseases.

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Respir Med. 2003 May;97(5):555-62.
Addition of salmeterol to fluticasone propionate treatment in moderate-to-severe asthma.
Ind PW, Dal Negro R, Colman NC, Fletcher CP, Browning D, James MH.
Hammersmith Hospital, Ducane Road, London, UK. p.ind@ic.ac.uk

This study was designed to determine whether the benefit of adding salmeterol was superior to doubling the dose of fluticasone propionate (FP) over 6 months, compared to a control group who remained on a lower dose of FP. The multi-centre, double-blind, parallel group study involved 496 symptomatic asthmatic patients with a history of exacerbations on 500-800 micrograms (microg) inhaled corticosteroids (ICS) twice daily (b.d.) in a broadly representative group of 100 hospitals and general practices in six countries. Two doses of FP--250 microg b.d. (FP250) or 500 microg b.d. (FP500)--were compared with the lower dose of FP plus a long-acting beta2-agonist, salmeterol 50 microg b.d. (SM/FP250). Patients symptomatic on the run-in dose of FP250 alone formed the control group in the treatment period. Over 6 months, SM/FP250 significantly improved mean morning peak expiratory flow rates (amPEF) by 42.1 l/min, more than twice the improvement achieved with either dose of FP alone. SM/FP250 also resulted in more symptom-free days and nights (P < 0.002) and days and nights with no relief medication (P < 0.001). The number of severe exacerbations was low: 3, 6 and 8% in the SM/FP250, low- and high-dose FP groups, respectively. This study confirms that adding salmeterol to low-dose inhaled FP offers greater improvements than either maintaining or doubling the dose of FP. Significant benefit was gained from adding salmeterol in a group of patients who appeared to have been at the top of their steroid dose-response curve receiving FP250. There was no evidence of tolerance and a low incidence of exacerbations in all treatment groups.

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J Asthma. 2003 Apr;40(2):107-18.
Inhaled corticosteroids for asthma: common clinical quandaries.
Parameswaran K, O'Byrne PM, Sears MR.
Asthma Research Group, Firestone Institute for Respiratory Health, St. Joseph's Healthcare and Department of Medicine, McMaster University, Hamilton, Ontario, Canada. parames@mcmaster.ca

This narrative review provides evidence-based explanations to some of the common clinical concerns regarding inhaled corticosteroids. Inhaled corticosteroids are the treatment of choice for a newly diagnosed asthmatic patient. Better results are obtained when treatment is initiated as soon as the diagnosis is made. Asthma control can be achieved and maintained in most patients with a low or moderate dose of inhaled corticosteroid administered in two daily doses. Longer duration of treatment provides more sustained benefits than treatment that is intermittent and for short periods of time. The clinical benefits can be observed within 24 hours of commencing treatment and may be more pronounced in patients with an eosinophilic bronchitis. Inhaled corticosteroids provide additional benefit when used in conjunction with prednisone in acute severe asthma. Low doses do not have clinically deleterious side effects on the bones, growth, eye, or hypothalamo-pituitary-adrenal-axis. However, they do not normalize lung function and prevent structural changes in the airway wall in all asthmatic patients.

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Pediatrics. 2003 Jun;111(6 Pt 1):e706-13.
Long-term safety of fluticasone propionate and nedocromil sodium on bone in children with asthma.
Roux C, Kolta S, Desfougeres JL, Minini P, Bidat E.
Hopital Cochin, Assistance Publique-Hopitaux de Paris, Universite Rene Descartes, Paris, France. christian.roux@cch.ap-hop-paris.fr

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.

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Chest. 2003 May;123(5):1480-7.
Budesonide and formoterol in a single inhaler improves asthma control compared with increasing the dose of corticosteroid in adults with mild-to-moderate asthma.
Lalloo UG, Malolepszy J, Kozma D, Krofta K, Ankerst J, Johansen B, Thomson NC.
Nelson R. Mandela School of Medicine, University of Natal, Durban, South Africa. lalloo@nu.ac.za

BACKGROUND: We evaluated the efficacy and safety of low-dose budesonide/formoterol, 80 micro g/4.5 micro g, bid in a single inhaler (Symbicort Turbuhaler; AstraZeneca; Lund, Sweden) compared with an increased dose of budesonide, 200 micro g bid, in adult patients with mild-to-moderate asthma not fully controlled on low doses of inhaled corticosteroid alone. METHODS: All patients received budesonide, 100 micro g bid, during a 2-week run-in period. At the end of the run-in phase, 467 patients with a mean FEV(1) of 82% predicted received 12 weeks of treatment with budesonide/formoterol in a single inhaler or budesonide alone in a higher dose. Patients kept daily records of their morning and evening peak expiratory flow (PEF), nighttime and daytime symptom scores, and use of reliever medication. RESULTS: The increase in mean morning PEF-the primary efficacy measure-was significantly higher for budesonide/formoterol compared with budesonide alone (16.5 L/min vs 7.3 L/min, p = 0.002). Similarly, evening PEF was significantly greater in the budesonide/formoterol group (p < 0.001). In addition, the percentage of symptom-free days and asthma-control days (p = 0.007 and p = 0.002, respectively) were significantly improved in the budesonide/formoterol group. Budesonide/formoterol decreased the relative risk of an asthma exacerbation by 26% (p = 0.02) compared with budesonide alone. Adverse events were comparable between the two treatment groups. CONCLUSION: This study shows that in adult patients whose mild-to-moderate asthma is not fully controlled on low doses of inhaled corticosteroids, single-inhaler therapy with budesonide and formoterol provides greater improvements in asthma control than increasing the maintenance dose of inhaled corticosteroid.

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Respir Med. 2003 May;97(5):501-7.
Breathing retraining for asthma.
Ram FS, Holloway EA, Jones PW.
Department of Physiological Medicine, St. George's Hospital Medical School, University of London, Tooting, UK. fram@sghms.ac.uk

Breathing retraining is used increasingly throughout the world by many patients with asthma in addition to their usual medical care. We undertook a systematic review of the literature in order to determine the effectiveness of breathing retraining in the management of asthma. Six randomised-controlled trials were identified that involved breathing retraining in asthma. Due to the variation in reported trial outcomes, limited reporting of study data and small number of included trials it was not possible to draw any firm conclusions as to its effectiveness. However, outcomes that were reported from individual trials do show that breathing retraining may have a role in the treatment and management of asthma. Further large-scale trials using breathing retraining techniques in asthma are required to address this important issue.

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Respir Med. 2003 May;97(5):463-7.
Fifty microg b.i.d. of inhaled fluticasone propionate (FP) are effective in stable asthmatics previously treated with a higher dose of FP.
Giannini D, Di Franco A, Tonelli M, Bartoli ML, Carnevali S, Cianchetti S, Bacci E, Dente FL, Vagaggini B, Paggiaro PL.
Cardio-Thoracic Department, University of Pisa, Italy.

Twenty-seven subjects with moderate asthma at the time of diagnosis, well controlled under regular fluticasone propionate (FP) (250 microg b.i.d.) for 6 months at least, were randomized to receive in double-blind fashion: FP 125 microg b.i.d. (Group 1) or FP 50 microg b.i.d. (Group 2) or placebo (Group 3) for 3 months or until symptom recurrence. Daily symptom score and peak expiratory flow were monitored. At the beginning and at the end of the study subjects underwent methacholine challenge and sputum induction. Recurrence of symptoms occurred shortly after randomization in all subjects receiving placebo. None from Group 1 or 2 experienced symptom recurrence during the study. No significant difference in clinical and functional data, and in sputum eosinophil percentages was observed between the beginning and the end of the study in both Groups 1 and 2. Subjects from Group 3 showed a significant increase of sputum eosinophils (P<0.05) and a significant decrease in provocative dose of methacholine (P<0.05) when asthma symptoms recurred. Therefore, very low doses of FP (50 microg b.i.d.) are effective in maintaining for 3 months a good control of the disease in asthmatics already stable under high-dose fluticasone, considering both clinical and functional outcomes and markers of airway inflammation.

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Pediatrics. 2003 May;111(5 Pt 1):981-5.
Herbal therapy use in a pediatric emergency department population: expect the unexpected.
Lanski SL, Greenwald M, Perkins A, Simon HK.
Department of Pediatrics, Division of Pediatric Emergency Medicine, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia 30322, USA. steve_lanski@oz.ped.emory.edu

BACKGROUND: In recent years investigators have reported widespread use of alternative medicine. Some herbal therapies have potentially harmful side effects as well as adverse interactions with medications. Data are lacking on the use in children and caregiver understanding of these products. OBJECTIVES: To determine the reported use of herbal products among a pediatric emergency department population and to evaluate the caregivers' understanding and source of information concerning these products. DESIGN/METHODS: A convenience sampling of pediatric emergency department patients and their caregivers occurred during a 3-month period in 2001. The interview consisted of 18 questions regarding the types of non-Food and Drug Administration-regulated herbal products and home remedies used, general product knowledge and sources of information used by the child's caregiver (including discussions with their child's primary physician). RESULTS: One hundred forty-two (93%) of 153 families approached participated in the study. The mean patient age was 5.3 years (range: 3 weeks-18 years). Forty-five percent of caregivers reported giving their child an herbal product, and 88% of these caregivers had at least 1 year of college education. Of the children receiving these therapies, 53% had been given 1 type and 27% were given 3 or more in the past year. The most common therapies reportedly used were aloe plant/juice (44%), echinacea (33%), and sweet oil (25%). The most dangerous potential herbal and prescription medication combination reported was ephedra and albuterol in an adolescent with asthma. The most unusual products reportedly used included turpentine, pine needles, and cowchips. Of all people interviewed, 77% did not believe or were uncertain if herbal products had any side effects and only 27% could name a potential side effect. Sixty-six percent were unsure or thought that herbal products did not interact with other medications and only 2 people correctly named a drug interaction. Of the people who used these therapies, 80% reported either friends or relatives as their primary source of information. Only 45% of those giving their children herbal products report discussing the use with their child's primary health care provider. CONCLUSION: Herbal and home therapies are commonly used in this pediatric population. An unexpectedly wide variety of products were reportedly given to this patient population. Caregivers reported limited knowledge regarding potential adverse medication interactions and side effects. Limited discussions with the child's primary health care provider were reported. It is therefore important for health care providers to have knowledge about herbal medications, to inquire about their use and to educate families about the risk/benefit as well as potential interactions these products may have with over-the-counter and prescription medications.

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Phytomedicine. 2003 Mar;10(2-3):213-20.
Efficacy of dry extract of ivy leaves in children with bronchial asthma--a review of randomized
controlled trials.
Hofmann D, Hecker M, Volp A.
Zentrum fur Kinderheilkunde, Klinikum der Johann Wolfgang Goethe-Universitat, Frankfurt am Main, Germany.

OBJECTIVES: To investigate if extracts from dried ivy leaves (Hedera helix L.) are effective in the treatment of chronic airway obstruction in children suffering from bronchial asthma. DESIGN: Systematic review of trials documented in the literature with re-analysis of original data. TRIALS: 5 randomized controlled trials investigating the efficacy of ivy leaf extract preparations in chronic bronchitis, 3 of which were conducted in children and met our selection criteria. One compared ivy leaf extract cough drops to placebo, one compared suppositories to drops and one tested syrup against drops. MAIN OUTCOME MEASURES: Body-plethysmographic and spirometric measures. RESULTS: Drops were significantly superior to placebo in reducing airway resistance (primary outcome measure; p = 0.04 two-sided) and descriptively superior in all other 'objective' measures. For syrup and suppositories, at least 54%, resp. 35% of the effect against placebo were preserved. CONCLUSIONS: The trials included in this review indicate that ivy leaf extract preparations have effects with respect to an improvement of respiratory functions of children with chronic bronchial asthma, but more far-reaching conclusions can hardly be drawn because of a meagre database, including the fact that only one primary trial included a placebo control. Further research, particularly into the long-term efficacy of the herbal extract, is needed.

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Ann Allergy Asthma Immunol. 2003 Apr;90(4):371-7; quiz 377-8, 421.
Diet and asthma: has the role of dietary lipids been overlooked in the management of asthma?
Spector SL, Surette ME.
University of California-Los Angeles, Los Angeles, California, USA. calallergy@dnamail.com

OBJECTIVE: This article discusses the role of diet in the management of asthma. Readers will gain an understanding of how evolution of the western diet has contributed to increased asthma prevalence and how dietary modification that includes management of dietary lipids may reduce symptoms of asthma. DATA SOURCES: Relevant studies published in English were reviewed. STUDY SELECTION: Medline search to identify peer-reviewed abstracts and journal articles. RESULTS: Asthma and obesity, which often occur together, have increased in prevalence in recent years. Studies suggest adaption of a western diet has not only contributed to obesity, but that increased intake of specific nutrients can cause changes in the frequency and severity of asthma. Increased asthma prevalence has also been proposed to arise from increased exposure to diesel particles or lack of exposure to infectious agents or endotoxins during childhood, generating a biased Th2 immune response, and increased cytokine and leukotriene production. Antagonists directed against these pro-inflammatory mediators include anticytokines and antileukotrienes. A reduction in the levels of inflammatory mediators associated with asthma has also been seen with dietary interventions, such as the administration of oils containing gamma-linolenic acid and eicosapentaenoic acid. CONCLUSIONS: Evidence suggests elevated body mass index and dietary patterns, especially intake of dietary lipids, contribute to symptoms of asthma. Dietary modification may help patients manage their asthma as well as contribute to their overall health.

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Rev Mal Respir. 2003 Feb;20(1 Pt 1):95-103.
[Asthma in the elderly]
[Article in French]
Radenne F, Verkindre C, Tonnel AB.
Service de Pneumologie et Immunoallergologie, CHRU, Lille, France.

INTRODUCTION: Asthma in the elderly is a growing clinical problem. It affects 6 to 7% of this age-group, but making the distinction between asthma and chronic obstructive pulmonary disease is more difficult as patients get older. STATE OF THE ART: This difficulty is due to a number of factors: the confounding role of smoking, and also the physiological effects of ageing on the airways which renders airway obstruction more resistant to bronchodilation. Elderly asthmatics can be divided on clinical grounds into two arbitrary groups: "ageing asthmatics" who have had asthma since childhood or adolescence and "late-onset asthmatics" who may present following an infective episode. Certain features of asthma in the elderly include: poor perception of breathlessness, technical difficulties in making reliable pulmonary function measurements and the extra-pulmonary manifestations (impact on quality of life). PERSPECTIVES: The therapeutic strategy is much the same as for younger asthmatics but certain aspects take on greater importance: concerns about osteoporosis with long-term corticosteroid therapy (both oral and inhaled), the risk of arrhythmias with beta-2 adrenergic drugs and the significant side-effects of theophylline justifies, in difficult cases, consideration of anti-cholinergic and/or anti-leukotriene therapy. CONCLUSION: Most importantly, for elderly asthmatics it is a treatment regimen that is as simple as possible and is backed up by a written self-management plan that will improve outcomes.

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J Allergy Clin Immunol. 2003 Apr;111(4):757-62.
Response to montelukast among subgroups of children aged 2 to 14 years with asthma.
Meyer KA, Arduino JM, Santanello NC, Knorr BA, Bisgaard H.
Department of Pulmonary-Immunology, Merck Research Laboratories, Rahway, USA.

BACKGROUND: Determining who responds to asthma therapies, particularly leukotriene modifiers, continues to be explored. OBJECTIVE: We sought to identify patient characteristics predictive of response to montelukast. METHODS: We used data from 2 clinical trials in which children with asthma received either montelukast or placebo. Symptoms, beta-agonist use, and unanticipated health resource use caused by asthma were recorded in validated daily diaries for children 2 to 5 (n = 689) and 6 to 14 (n = 336) years old. We defined primary end points of days without asthma in 2- to 5-year-old patients (24 hours without symptoms, beta-agonist use, or asthma attack) and change in percent predicted FEV(1) in 6- to 14-year-old children. Asthma attack was defined by the use of rescue oral corticosteroids or by an unscheduled visit to a medical provider. Patients were grouped according to baseline characteristics, such as family history of asthma, personal history of allergy, frequency of asthma symptoms, eosinophilia, and concomitant use of inhaled corticosteroids or cromolyn. We examined the stratum-specific effects of montelukast on the percentage of days without asthma, change in percent predicted FEV(1), asthma attack, and a variety of secondary symptom and FEV(1) end points. RESULTS: We did not identify characteristics that predicted response to montelukast in either preschool or 6- to 14-year-old children. These findings were consistent across all symptom and FEV(1) outcomes. There was also no differential response to montelukast in either age group when asthma attack was the outcome. CONCLUSION: The patient characteristics studied do not appear to provide an indication of who will benefit most from treatment with montelukast.

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Respir Med. 2003 Apr;97(4):323-30.
Once-daily budesonide/formoterol in a single inhaler in adults with moderate persistent asthma.
Buhl R, Creemers JP, Vondra V, Martelli NA, Naya IP, Ekstrom T.
Pulmonary Division, University Hospital, Mainz Germany. R.Buhl@3-med.klinik.uni-mainz.de

Patients with moderate persistent asthma (n = 523; mean FEV1 77.4%) not fully controlled with inhaled corticosteroids (ICS; 400-1000 microg/day) were randomized to receive either once-daily budesonide/formoterol (160/4.5 microg, two inhalations); or twice-daily budesonide/formoterol (160/4.5 microg, one inhalation); or budesonide (400 microg) once-daily for 12 weeks. Once-daily dosing was administered in the evening and twice-daily dosing was administered in the morning and evening. All patients received twice-daily budesonide (200 microg) during a 2-week run-in. Compared with budesonide alone, change in mean morning and evening peak expiratory flow was greater in the once-daily budesonide/formoterol group (27 and 171 min(-1), respectively; P < 0.001) and twice-daily budesonide/formoterol group (23 and 24 l min(-1), respectively; P < 0.001). Night awakenings, symptom-free days, reliever-use-free days and asthma-control days were all improved during once-daily budesonide/formoterol therapy vs. budesonide (P < or = 0.05). Similar improvements were also seen with twice-daily budesonide/formoterol (P < or = 0.05). The risk of a mild exacerbation was reduced after once- and twice-daily budesonide/formoterol vs. budesonide (38% and 35%, respectively; P < 0.002). All treatments were well tolerated. Budesonide/formoterol, once- or twice-daily, in a single inhaler improved asthma symptoms and exacerbations compared with budesonide. In the majority of patients with moderate persistent asthma requiring ICS and long-acting beta-agonists, once-daily formoterol/budesonide provided sustained efficacy over 24 h, similar to twice-daily dosing.

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MMW Fortschr Med. 2003 Mar 6;145(10):34-8.
[Asthma, alveolitis, aspergillosis, berylliosis. What to do when there is allergic reaction of the lung?]
[Article in German]
Vier H, Protze M, Brunner R, Gillissen A.
Robert-Koch-Klinik, Stadtisches Klinikum St. Georg, Leipzig. hannelore.vier@sanktgeorg.de

Among the major allergic pulmonary disorders are bronchial asthma, extrinsic allergic alveolitis, allergic aspergillosis and berylliosis. Asthma is diagnosed on the basis of clinical symptoms (wheezing, respiratory distress, tight chest, coughing) and lung function tests possibly supplemented by allergic and provocative testing. Asthma treatment is differentiated into long-term medication and as-required medication. Specific immunotherapy is considered the sole causal therapy. Extrinsic allergic alveolitis is work- or hobby-related (farmer's/cheese worker's/bird-fancier's lung) and manifests as diffuse pneumonitis with dyspnea, coughing and fever. For the diagnosis, the antigen provocative test in particular plays a major role. In the main, treatment comprises strict avoidance of allergens. The diagnosis of allergic pulmonary aspergillosis is based on the history, clinical findings, skin tests, serology and radiography. Treatment is stage-related by means of immunosuppressive agents. In terms of radiographic and pulmonary function findings, berylliosis is similar to sarcoidosis. Here, too, immunosuppressive agents are to the fore.

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Chest. 2003 Apr;123(4):1018-25.
A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway pressure in acute asthmatic attack.
Soroksky A, Stav D, Shpirer I.
Pulmonary Institute, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel. ArieS@asaf.health.gov.il

STUDY OBJECTIVE: Noninvasive ventilation has been shown to be effective in patients with acute respiratory failure due to pulmonary edema and exacerbations of COPD. Its role in an acute asthmatic attack, however, is uncertain. The purpose of this pilot study was to compare conventional asthma treatment with nasal bilevel pressure ventilation (BPV) [BiPAP; Respironics; Murrysville, PA] plus conventional treatment in patients with a severe asthmatic attack admitted to the emergency department. DESIGN: A prospective, randomized, placebo-controlled study. SETTING: An emergency department at a university hospital. PATIENTS: Thirty patients with a severe asthma attack were recruited from a larger group of 124 asthmatic patients seen in the emergency department. Fifteen patients were randomly assigned to BPV plus conventional therapy and 15 patients to conventional therapy alone. The two groups had similar clinical characteristics on hospital admission. Mean (+/- SD) FEV(1) on recruitment was 37.3 +/- 10.7% in the BPV group and 33.8 +/- 10.2% in the control group (p = not significant). Interventions and measurements: BPV with predetermined inspiratory and expiratory pressures was applied for 3 h in the BPV group; in the control group, a similar sham device with subtherapeutic pressures was applied for 3 h. Bedside lung function test results and vital signs were obtained at baseline, and during and at the completion of the study protocol. RESULTS: The use of BPV significantly improved lung function test results. Eighty percents of the patients in the BPV group reached the predetermined primary end points (an increase of at least 50% in FEV(1) as compared to baseline), vs 20% of control patients (p < 0.004). Mean rise in FEV(1) was 53.5 +/- 23.4% in the BPV group and 28.5 +/- 22.6% in the conventional treatment group (p = 0.006). The intention-to-treat analysis of the secondary end point rate of hospitalization included 33 patients. Hospitalization was required for 3 of 17 patients (17.6%) in the BPV group, as compared with 10 of 16 patients (62.5%) in the control group (p = 0.0134). CONCLUSION: In selected patients with a severe asthma attack, the addition of BPV to conventional treatment can improve lung function, alleviate the attack faster, and significantly reduce the need for hospitalization.

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Nurs Times. 2003 Mar 18-24;99(11):48-9.
Inhaler devices for children.
Shepherd K.

The use of inhaled medicines for the management of asthma is common and is the preferred method of treatment (NICE, 2000a). It is recommended that bronchodilating drugs, such as beta 2-agonists, which provide symptom relief, and anti-inflammatory drugs, such as corticosteroids, are administered by inhalation (NICE 2000a). However, the number of devices available can leave the practitioner and the patient confused about which is the most appropriate inhaler. Guidance from the National Institute for Clinical Excellence states that: 'It is important to ensure that an inhaler device delivers the drugs to the airways consistently and in the appropriate quantity' (NICE, 2000a).

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Lancet. 2003 Mar 29;361(9363):1071-6.
Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial.
Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohlsson SV, Ullman A, Lamm CJ, O'Byrne PM; START Investigators Group.
Department of Respiratory Diseases, Ghent University Hospital, Ghent, Belgium. romain.pauwels@rug.ac.be <romain.pauwels@rug.ac.be>

BACKGROUND: Although inhaled glucocorticosteroids are recommended for persistent asthma, their long-term effect on recent onset, mild, persistent asthma has yet to be established. METHODS: We did a randomised, double-blind clinical trial in 7241 patients in 32 countries to assess the effects of budesonide in patients who had had mild persistent asthma for less than 2 years and who had not had previous regular treatment with glucocorticosteroids. Patients aged 5-66 years received either budesonide or placebo once daily for 3 years in addition to their usual asthma medications. The daily budesonide dose was 400 microg, or 200 microg for children younger than 11 years. The primary outcome was time to first severe asthma-related event, and analysis was by intention to treat. FINDINGS: 198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation; hazard ratio 0.56 (95% CI 0.45-0.71, p<0.0001). Patients on budesonide had fewer courses of systemic corticosteroids and more symptom-free days than did those on placebo. Compared with placebo, budesonide increased postbronchodilator forced expiratory volume in 1 s (FEV1) from baseline by 1.48% (p<0.0001) after 1 year and by 0.88% (p=0.0005) after 3 years (expressed as percent of the predicted value). The corresponding increase in prebronchodilator FEV1 was 2.24% after 1 year and 1.71% after 3 years (p<0.0001 at both timepoints). The effect of treatment on all outcome variables was independent of the baseline lung function (prebronchodilator or postbronchodilator) or baseline medication. In children younger than 11 years, 3-year growth was reduced in the budesonide group by 1.34 cm. The reduction was greatest in the first year of treatment (0.58 cm) than years 2 and 3 (0.43 cm and 0.33 cm, respectively). INTERPRETATION: Long-term, once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset.

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Ann Allergy Asthma Immunol. 2003 Mar;90(3):331-7.
Efficacy of a consensus protocol therapy in adults with acute, severe asthma.
Nakano Y, Morita S, Kawamoto A, Naito T, Enomoto N, Suda T, Chida K, Nakamura H.
Department of Internal Medicine, Hamamatsu Rosai Hospital, Hamamatsu, Shizuoka, Japan. ynakano@sis.seirei.or.jp

BACKGROUND: International guidelines recommend multiple doses of inhaled beta2-agonists and anticholinergics plus early administration of systemic corticosteroids for acute, severe asthma. This study examined the efficacy of this protocol in adults and analyzed those factors associated with unresponsiveness to the protocol therapy. OBJECTIVE: Ninety-three consecutive patients 18 to 55 years old presenting for treatment of acute asthma with a peak expiratory flow rate (PEFR) < or = 50% of the predicted value were analyzed. METHODS: All subjects received 400 microg of salbutamol every 20 minutes for three doses and 400 microg of oxitropium bromide with each of the three salbutamol doses by means of a metered-dose inhaler with a spacer device, plus intravenously 8 mg betamethasone. PEFR was measured at baseline and at 20, 40, 60, and 120 minutes. RESULTS: Sixty-nine percent of subjects improved sufficiently to be discharged. In 31% of subjects, the protocol therapy failed. There were no significant differences in age, sex, smoking status, or beta-agonist use within 6 hours between the two groups. Logistic regression analysis demonstrated that a PEFR < 35% of the predicted value at presentation (odds ratio [OR]; 16.3, 95% confidence interval [CI] 4.5 to 59.9), viral respiratory tract infection symptoms > or = 2 days (OR, 4.8, 95% CI 1.3 to 17.1), and asthma hospitalization in the past year (OR, 4.6, 95% CI 1.1 to 19.9) were significantly associated with unresponsiveness to the protocol. CONCLUSIONS: Unresponsiveness to protocol therapy occurs in nearly one-third of individuals presenting with acute, severe asthma. Our findings underscore the need to explore more effective strategies for improving lung function and reducing hospital admission rates.

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Ann Allergy Asthma Immunol. 2003 Mar;90(3):323-30.
Budesonide Turbuhaler delivered once daily improves health-related quality of life and maintains improvements with a stepped-down dose in adults with mild to moderate asthma.
Casale TB, Nelson HS, Kemp J, Parasuraman B, Uryniak T, Liljas B.
Department of Medicine, Creighton University, Omaha, Nebraska 68131, USA. tbcasale@creighton.edu

BACKGROUND: Budesonide inhalation powder administered via Turbuhaler (budesonide Turbuhaler, AstraZeneca LP, Wilmington, DE) is proven efficacious and safe in the treatment of mild to severe asthma. OBJECTIVE: To evaluate the effect of once-daily budesonide Turbuhaler on health-related quality of life (HRQL) in adults with mild to moderate asthma. METHODS: In this double-blind, parallel-group study, 309 asthmatic patients between 18 and 70 years of age were randomized to receive once-daily treatment with budesonide 200 or 400 microg or placebo for 6 weeks. Patients initially receiving 400 microg budesonide had their dose reduced to 200 microg (400/200-microg group), and patients receiving 200 microg (200/200-microg group) or placebo continued to receive their assigned doses for a 12-week maintenance phase. HRQL was evaluated using the Asthma Quality of Life Questionnaire at randomization, week 6, and week 18. RESULTS: Compared with placebo, patients initially receiving 400 and 200 microg budesonide Turbuhaler demonstrated significantly greater HRQL scores at week 6 (P < or = 0.001 and P < or = 0.010, respectively) that were maintained at week 18 (P < or = 0.001). Clinically important (> or = 0.5 unit) improvement in Asthma Quality of Life Questionnaire overall at week 18 was demonstrated by 55% and 43% of patients in the 400/200-microg and 200/200-microg budesonide Turbuhaler groups, respectively. Conclusions: In patients with mild to moderate asthma, once-daily budesonide Turbuhaler 200 and 400 microg demonstrates statistically significant and clinically important improvements in HRQL that can be maintained with a low dose of 200 microg.

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Thorax. 2003 Apr;58(4):317-21.
Individualised homeopathy as an adjunct in the treatment of childhood asthma: a randomised
placebo controlled trial.
White A, Slade P, Hunt C, Hart A, Ernst E.
Complementary Medicine, Peninsula Medical School, University of Exeter, Exeter EX2 4NT, UK. adrian.white@pms.ac.uk

BACKGROUND: Homeopathy is frequently used to treat asthma in children. In the common classical form of homeopathy, prescriptions are individualised for each patient. There has been no rigorous investigation into this form of treatment for asthma. METHODS: In a randomised, double blind, placebo controlled trial the effects of individualised homeopathic remedies were compared with placebo medication in 96 children with mild to moderate asthma as an adjunct to conventional treatment. The main outcome measure was the active quality of living subscale of the Childhood Asthma Questionnaire administered at baseline and follow up at 12 months. Other outcome measures included other subscales of the same questionnaire, peak flow rates, use of medication, symptom scores, days off school, asthma events, global assessment of change, and adverse reactions. RESULTS: There were no clinically relevant or statistically significant changes in the active quality of life score. Other subscales, notably those measuring severity, indicated relative improvements but the sizes of the effects were small. There were no differences between the groups for other measures. CONCLUSIONS: This study provides no evidence that adjunctive homeopathic remedies, as prescribed by experienced homeopathic practitioners, are superior to placebo in improving the quality of life of children with mild to moderate asthma in addition to conventional treatment in primary care.

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Thorax. 2003 Apr;58(4):306-10.
Intravenous salbutamol bolus compared with an aminophylline infusion in children with severe asthma: a randomised controlled trial.
Roberts G, Newsom D, Gomez K, Raffles A, Saglani S, Begent J, Lachman P, Sloper K, Buchdahl R, Habel A; North West Thames Asthma Study Group.
Imperial College School of Medicine at St Mary's Hospital, London, UK. g.c.roberts@ic.ac.uk

BACKGROUND: The relative efficacies of aminophylline and salbutamol in severe acute childhood asthma are currently unclear. A single bolus of salbutamol was compared with a continuous aminophylline infusion in children with severe asthma in a randomised double blind study. METHODS: Children aged 1-16 years with acute severe asthma were enrolled if they showed little improvement with three nebulisers (combined salbutamol and ipratropium) administered over an hour and systemic steroids. Subjects were randomised to receive either a short intravenous bolus of salbutamol (15 micro g/kg over 20 minutes) followed by a saline infusion or an aminophylline infusion (5 mg/kg over 20 minutes) followed by 0.9 mg/kg/h. RESULTS: Forty four subjects were enrolled, with 18 randomly allocated to receive salbutamol and 26 to receive aminophylline. The groups were well matched at baseline. An intention to treat analysis showed that there was no statistically significant difference in the asthma severity score (ASS) at 2 hours between the two groups (median (IQR) 6 (6, 8) and 6.5 (5, 8) for salbutamol and aminophylline respectively, p=0.93). A similar improvement in ASS to 2 hours was seen in the two groups (mean difference -0.08, 95% CI -0.97 to 0.80), there was a trend (p=0.07) towards a longer duration of oxygen therapy in the salbutamol group (17.8 hours (95% CI 8.5 to 37.5) v 7.0 hours (95% CI 3.4 to 14.2)), and a significantly (p=0.02) longer length of hospital stay in the salbutamol group (85.4 (95% CI 66.1 to 110.2) hours v 57.3 hours (95% CI 45.6 to 72.0)). There was no significant difference in adverse events between the two groups. CONCLUSIONS: This study suggests that, in severe childhood asthma, there is no significant difference in the effectiveness of a bolus of salbutamol and an aminophylline infusion in the first 2 hours of treatment. Overall, the aminophylline infusion was superior as it significantly reduced the length of stay in hospital.

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BMJ. 2003 Mar 22;326(7390):621.
Inhaled glucocorticoids versus leukotriene receptor antagonists as single agent asthma treatment: systematic review of current evidence.
Ducharme FM.
Department of Paediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada. Francine.ducharme@muhc.mcgill.ca

OBJECTIVE: To compare the safety and efficacy of anti-leukotrienes and inhaled glucocorticoids as monotherapy in people with asthma. DESIGN: Systematic review of randomised controlled trials comparing anti-leukotrienes with inhaled glucocorticoids for 28 days or more in children and adults. MAIN OUTCOME MEASURE: Rate of exacerbations that required treatment with systemic glucocorticoids. RESULTS: 13 trials (12 in adults, one in children) met the inclusion criteria; all were in people with mild and moderate asthma. Leukotriene receptor antagonists were compared with inhaled glucocorticoids at a daily dose equivalent to 400-450 microg beclometasone dipropionate. Patients treated with leukotriene receptor antagonists were 60% more likely to suffer an exacerbation requiring systemic glucocorticoids (relative risk 1.6, 95% confidence interval 1.2 to 2.2; number needed to treat 27, 13 to 81). A 130 ml greater improvement (80 ml to 170 ml) in forced expiratory volume in one second and a 19 l/min greater increase (14 l to 24 l) in morning peak expiratory flow rate were noted in favour of inhaled glucocorticoids. Differences in favour of inhaled glucocorticoids were also observed for nocturnal awakenings, use of rescue beta2 agonists, and days without symptoms. Risk of side effects was no different between groups, but leukotriene receptor antagonists were associated a 2.5-fold increase risk of withdrawals due to poor asthma control (relative risk 2.5, 1.8 to 3.5). CONCLUSIONS: Inhaled glucocorticoids doses equivalent to 400 microg/day beclometasone are more effective than leukotriene receptor antagonists in the treatment of adults with mild or moderate asthma. There is insufficient evidence to conclude on the efficacy of anti-leukotrienes in children.

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Respir Med. 2003 Mar;97(3):250-6.
Anti-inflammatory activity of 1.8-cineol (eucalyptol) in bronchial asthma: a double-blind placebo-controlled trial.
Juergens UR, Dethlefsen U, Steinkamp G, Gillissen A, Repges R, Vetter H.
Department of Pneumology, Medical Outpatient Clinic, Bonn University Hospital, Germany. uwejuergens@t-online.de

Airway hypersecretion is mediated by increased release of inflammatory mediators and can be improved by inhibition of mediator production. We have recently reported that 1.8-cineol (eucalyptol) which is known as the major monoterpene of eucalyptus oil suppressed arachidonic acid metabolism and cytokine production in human monocytes. Therefore, the aim of this study was to evaluate the anti-inflammatory efficacy of 1.8-cineol by determining its prednisolone equivalent potency in patients with severe asthma. Thirty-two patients with steroid-dependent bronchial asthma were enrolled in a double-blind, placebo-controlled trial. After determining the effective oral steroid dosage during a 2 month run-in phase, subjects were randomly allocated to receive either 200 mg 1.8-cineol t. i.d. or placebo in small gut soluble capsules for 12 weeks. Oral glucocorticosteroids were reduced by 2.5 mg increments every 3 weeks. The primary end point of this investigation was to establish the oral glucocorticosteroid-sparing capacity of 1.8-cineol in severe asthma. Reductions in daily prednisolone dosage of 36% with active treatment (range 2.5-10 mg, mean: 3.75 mg) vs. a decrease of only 7% (2.5-5 mg, mean: 0.91 mg) in the placebo group (P = 0.006) were tolerated. Twelve of 16 cineol vs. four out of 16 placebo patients achieved a reduction of oral steroids (P = 0.012). Long-term systemic therapy with 1.8-cineol has asignificant steroid-saving effect in steroid-depending asthma. This is the first evidence suggesting an anti-inflammatory activity of the monoterpene 1.8-cineol in asthma and a new rational for its use as mucolytic agent in upper and lower airway diseases.

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Respir Med. 2003 Mar;97(3):234-41.
The salmeterol/fluticasone combination is more effective than fluticasone plus oral montelukast in asthma.
Ringdal N, Eliraz A, Pruzinec R, Weber HH, Mulder PG, Akveld M, Bateman ED; International Study Group.
Kaplan Medical Centre, Rehovot, Israel.

The aim of this study was to compare the efficacy and safety of salmeterol/fluticasone propionate combination product (SFC) with fluticasone propionate (FP) plus oral montelukast (M) over 12 weeks in symptomatic asthma patients. The study was a multinational, randomised, double-blind, double-dummy, parallel-group design in patients aged > or = 15 years. After a 4-week run-in during which all patients received FP 100 microg twice daily, patients were randomised to inhaled SFC (50/100 microg) twice daily or inhaled FP 100 microg twice daily and oral M 10 mg once daily. Patients kept daily records of their peak expiratory flow (PEF) symptom scores and use of rescue medication. Over the 12-week treatment period, the adjusted increase in mean morning PEF was significantly greater in the SFC group (36 l/min) than the FP/M group (19 l/min; P < 0.001).The improvement in FEV1 was also significantly greater in the SFC group (mean treatment difference 0.11 l; P < 0.001). SFC provided significantly better control of daytime and night-time symptoms and there were fewer exacerbations. Patients in the SFC group were also significantly more likely to have a rescue-free day. Both treatments were equally well tolerated. Combination therapy with FP plus salmeterol (SFC) produced significantly greater improvements in lung function and asthma control than the addition of montelukastto FP.

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Indian J Pediatr. 2003 Feb;70(2):129-32.
Salbutamol and/or beclomethasone diproprionate in asthma.
Sharma S, Godatwar P, Kulkarni LR.
Department of Pharmacology, Indira Gandhi Medical College, Nagpur, India. drsmsin@hotmail.com

OBJECTIVE: Acute severe exacerbation of asthma is potentially life threatening and requires critical assessment and appropriate therapy. Now a days, steroids are often combined with bronchodilators for the treatment of bronchial asthma. Therefore, the present study was undertaken to compare effectiveness of beclomethasone diproprionate-salbutamol combination versus salbutamol alone by MDI (with or without spacer) in acute asthma. METHODS: A total of 57 paediatric patients (5-12 years) with acute attack of bronchial asthma attending emergency department of Indira Gandhi Medical College and Hospital was randomised to receive salbutamol (100 microg/puff) alone or with BDP (50 microg/puff) by metered dose inhaler with or without spacer. All baseline investigations were repeated one hour after the therapy. RESULTS: Clinical parameters indicative of severity of asthma improved statistically in all treatment groups. The increase in PEFR was better with MDI-S+B with spacer as compared to other groups, though it failed to reach statistical significance. The fall in serum potassium level is significantly more with MDI-S+B group when spacer was not used. No serious adverse effects were observed in any of the treatment groups. CONCLUSIONS: Metered dose inhalation of BDP-salbutamol combination with spacer provides better recovery whereas fall in serum potassium with MDI-S+B suggests use of spacer and monitoring of serum potassium during treatment.

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Pneumologie. 2003 Mar;57(3):137-43.
[Miflonide/Foradil via Aerolizer compared with other anti-inflammatory and anti-obstructive
therapeutic regimens]
[Article in German]
Gessner C, Stenglein S, Brautigam M, Muller A, Schauer J.
Medizinische Klinik und Poliklinik I, Universitatsklinikum Leipzig. gesc@medizin.uni-leipzig.de

Standard therapy of asthma consists of combined, antiinflammatory (steroids) and anti-obstructive (long acting/short acting beta-agonist) treatment via inhalation using two separate or a single inhalation device. Here, we report the results of using Miflonide (Budesonide 400 - 800 microg per day) and Foradil (Formoterol 24 - 48 microg per day) in cases of moderate and severe asthma previously treated insufficiently with another combination therapy. 80 patients with asthma previously treated insufficiently with any other combination therapy of steroid and long acting beta-agonist were included. Instead of their previous therapy all were switched to therapy with Miflonide and Foradil for eight weeks (two office visits at 4 and 8 weeks). Lung function (peak flow [l/min], FEV1 [I], FVC [I], R(tot) [kPa*s/l]) was performed at every visit. Doctors' and patients' estimation of disease severity, physical examination, drug related side-effects and the use of short acting beta-agonist aerosols were registered. Lung function parameters improved significantly compared to the run in phase prior to the change in medication (peak flow: + 18.4 %, FEV 1 : + 10.7 %, FVC: + 6.8 %, R(tot) : -18.0 %). Use of additional short acting inhalative beta-agonists was reduced. Subjectively, patients judged their general condition as improved, effectiveness as greater compared to previous medication and side effects as tolerable. The use of a combination of Miflonide/Foradil lead to an improvement in subjective and objective parameters in asthma patients that had previously been treated with a variety of other antiinflammatory and anti-obstructive therapy regimens. Reasons for this observation are beside change in medication, patients training in asthma therapy, change of application system, and increase of patients compliance.

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Chest. 2003 Mar;123(3):891-6.
Use of helium-oxygen mixtures in the treatment of acute asthma: a systematic review.
Rodrigo GJ, Rodrigo C, Pollack CV, Rowe B.
Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay. gurodrig@adinet.com.uy

STUDY OBJECTIVE: To determine the effect of the addition of heliox to standard medical care on the course of acute asthma. DESIGN: Systematic review of randomized and nonrandomized prospective, controlled trials of children and adults that compared heliox to placebo when used in conjunction with other standard acute treatments. MAIN OUTCOME MEASURES: Pulmonary function tests, hospital admissions, physiologic measures, side effects, and clinical outcomes. RESULTS: Seven trials were selected for inclusion, with a total of 392 patients with acute asthma. Six studies involved adults, and one study dealt solely with children. The main outcome variable was spirometric measurements (peak expiratory flow or FEV(1)) in six trials. Two studies evaluated the effect of heliox on airways resistance. No significant differences were demonstrated between heliox or oxygen/air groups (standardized mean difference [SMD], - 0.20; 95% confidence interval [CI], - 0.91 to 0.51; p = 0.6). However, the four studies that used heliox to deliver nebulized therapy showed a nonsignificant increase in pulmonary function (SMD, - 0.21; 95% CI, - 0.43 to 0.01; p = 0.06). In two studies of the same subgroup, heliox mixtures produced a significantly greater increase of heart rate than oxygen/air (weighted mean difference, 9.0; 95% CI, 1.27 to 16.8; p = 0.02). However, the four studies that used heliox to deliver nebulized therapy reported a nonsignificant difference in hospital admissions (odds ratio, 1.07; 95% CI, 0.46 to 2.48; p = 0.9). Overall, heliox appears to be safe and well tolerated. CONCLUSIONS: The existing evidence does not provide support for the administration of helium-oxygen mixtures to emergency department patients with moderate-to-severe acute asthma. However, these conclusions are based on between-group comparisons and small studies, and these results should be interpreted with caution.

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Chest. 2003 Mar;123(3):882-90.
Heliox vs air-oxygen mixtures for the treatment of patients with acute asthma: a systematic overview.
Ho AM, Lee A, Karmakar MK, Dion PW, Chung DC, Contardi LH.
Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, SAR. hoamh@cuhk.edu.hk

OBJECTIVE: To evaluate, by systematic review, the efficacy of heliox on respiratory mechanics and outcomes in patients with acute asthma. METHODS: The search strategy included searching electronic databases (MEDLINE, EMBASE, and The Cochrane Library) and the references of relevant articles. Study quality was assessed based on allocation concealment. Randomized controlled trials (RCTs) comparing heliox to an air-oxygen mixture (airO(2)) as an adjunct treatment in patients with acute asthmatic attacks were analyzed. For the qualitative portion of the analysis, all reports of the use of heliox in patients with acute asthma were included. RESULTS: Four RCTs (n = 278) were found to have a common respiratory parameter (peak expiratory flow rate as a percentage of predicted) suitable for meta-analysis. Within the 92% confidence interval (CI), there was a small benefit with the use of heliox compared to airO(2) (weighted mean difference, + 3%; 95% CI, - 2 to + 8%). There was also a slight improvement in the dyspnea index (weighted mean difference, 0.60; 95% CI, 0.04 to 1.16) with the use of heliox over airO(2). Overall, five RCTs, one nonrandomized unblinded parallel trial, one retrospective case-matched control trial, three case series, and one case report had results in favor of heliox; one RCT and one case series showed no improvement with heliox; one RCT showed a possible detrimental effect with heliox; and 1 small RCT was inconclusive. Most investigators did not prevent entrainment of room air during heliox use or compensate for the lower nebulizing efficiency of heliox. CONCLUSION: Based on surrogate markers, heliox may offer mild-to-moderate benefits in patients with acute asthma within the first hour of use, but its advantages become less apparent beyond 1 h, as most conventionally treated patients improve to similar levels, with or without it. The effect of heliox may be more pronounced in more severe cases. There are insufficient data on whether heliox can avert tracheal intubation, or change intensive care and hospital admission rates and duration, or mortality.

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Indian J Pediatr. 2003 Jan;70(1):63-72.
Long-term management of asthma.
Kabra SK, Lodha R.
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. skkabra@hotmail.com

Long-term management of asthma includes identification and avoidance of precipitating factors of asthma, pharmacotherapy and home management plan. Common precipitating factors include viral upper respiratory infections, exposure to smoke, dust, cold food and cold air. Avoidance of common precipitating factors has been shown to help in better control of asthma. Pharmacotherapy is the main stay of treatment of asthma. Commonly used drugs for better control of asthma are long and short acting bronchodilators, mast cell stabilizers, inhaled steroids, theophylline and steroid sparing agents. After assessment of severity most appropriate medications are selected. For mild episodic asthma the medications are short acting beta agonists as and when required. For mild persistent asthma: as and when required bronchodilators along with a daily maintenance treatment in form of low dose inhaled steroids or cromolyn or oral theophylline or leukotriene antagonists are required. Moderate persistent asthma should be treated with inhaled steroids along with long acting beta agonists for symptom control. For severe persistent asthma the recommended treatment includes inhaled steroids, long acting beta agonists with or without theophylline. If symptoms are not well controlled, a minimal dose of oral prednisolone preferably on alternate days may be needed in few patients. Patients should be followed up every 8-12 weeks. On each follow up visit patients should be examined by a doctor, compliance to medications should be checked and actual inhalation technique is observed. Depending on the assessment, medications may be decreased or stepped up. For exercise induced bronchoconstriction: cromolyn, short or long acting beta agonists or leukotriene antagonists may be used. In children with seasonal asthma, maintenance treatment according to assessed severity should be started 2 weeks in advance and continued throughout the season. These patients should be reassessed after discontinuing the treatment. Parents should be given a written plan for management of acute exacerbation at home.

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Thorax. 2003 Mar;58(3):211-6.
Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma.
Price DB, Hernandez D, Magyar P, Fiterman J, Beeh KM, James IG, Konstantopoulos S, Rojas R, van Noord JA, Pons M, Gilles L, Leff JA; Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) International Study Group.
Department of General Practice and Primary Care, University of Aberdeen, Foresterhill Health Centre, Westburn Road, Aberdeen AB25 2AY, Scotland, UK. d.price@abdn.ac.uk

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 microg/day) were randomised to receive montelukast 10 mg + inhaled budesonide 800 microg/day (n=448) or budesonide 1600 microg/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" beta 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.

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Respir Med. 2003 Feb;97 Suppl B:S21-6.
Comparison of the efficacy and safety of high doses of beclometasone dipropionate suspension for nebulization and beclometasone dipropionate via a metered-dose inhaler in steroid-dependent adults with moderate to severe asthma.
Grzelewska-Rzymowska I, Kroczynska-Bednarek J, Zarkovic J.
Institute of Internal Medicine, Faculty of Medicine of TBC.

Nebulization for the administration of high doses of inhaled corticosteroids can benefit steroid-dependent asthmatics. The objective of this double-blind, double-dummy, multicentre, randomized, parallel-group study was to compare the efficacy and safety of high-dose corticosteroids given by nebulization or metered-dose inhalation in adult patients with asthma. Following a 2-week run-in period, 124 patients, aged 18-70 years, with moderate to severe asthma treated with high-dose inhaled steroids were randomized to one of two treatment groups for 12 weeks: beclometasone dipropionate (BDP) suspension for nebulization 3,000-4,000 microgday(-1) b.i.d. given via a nebulizer (n = 63), or BDP spray 1,500-2000 microgday(-1) b.i.d. given via a metered-dose inhaler (MDI) plus spacer (BDP MDI) (n = 61). Comparable improvements over baseline, which were statistically significant in most cases, were reported at study end for the two treatment groups in the various efficacy parameters evaluated (pulmonary function tests, clinical symptoms scores, and the use of rescue salbutamol).The primary efficacy endpoint was morning pulmonary expiratory flow rate (PEFR). For the intent-to-treat population, in the BDP nebulization group mean morning PEFR increased statistically significantly from 308.7 +/- 107.81 min(-1) to 3 19.2 +/- 104.01 min(-1) while in the BDP MDI group the increase was from 301.5 +/- 94.71 min(-1) to 309.3 +/- 86.71 min(-1). The two treatments were equally well tolerated.A total of 19 patients in each group reported adverse events during the treatment period, and these were generally mild-moderate in severity. In conclusion, the results of this study demonstrate that BDP suspension for nebulization 3,000-4,000 microg day(-1) given via a nebulizer and BDP spray 1,500-2,000 microg day(-1) given via an MDI plus spacer are equally effective, with an acceptable safety and tolerability profile, when used in steroid-dependent adult patients with moderate to severe asthma.

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Respir Med. 2003 Feb;97 Suppl B:S35-40.
Comparison of the efficacy of beclometasone dipropionate and fluticasone propionate suspensions for nebulization in adult patients with persistent asthma.
Terzano C, Ricci A, Burinschi V, Nekam K, Lahovsky J.
University La Sapienza, Rome, Italy.

The use of nebulization for the administration of inhaled steroids plays an important role in asthma patients who are unable to use pressurized aerosol or dry-powder inhalers effectively. Moreover, the type of nebulizer used may affect how much drug is delivered to the lungs. The objective of this multinational, multicentre, randomized, active-controlled, parallel-group study was to compare the efficacy and safety of nebulized corticosteroids in adult patients with chronic asthma. Following a 1-week placebo run-in period, 205 patients, aged 18-65 years, with moderate persistent asthma were randomized to one of two treatment groups for 12 weeks: beclometasone dipropionate (BDP) suspension for nebulization 2,400 microg day(-1) b.i.d. (n = 103), or fluticasone propionate (FP) suspension for nebulization 2,000 microg day(-1) b.i.d. (n = 102), both administered by a jet nebulizer Comparable efficacy in controlling asthma was demonstrated by the two treatments at study end, as evident when evaluating various efficacy parameters (pulmonary function tests, asthma exacerbations and symptoms, and the use of rescue salbutamol).The primary efficacy endpoint was the variation in the pulmonary expiratory flow (PEF) at treatment end over the baseline visit. For the intent-to-treat population, in the BDP group mean PEF values increased statistically significantly from 5.2 +/- 1.31 s(-1) to 5.7 +/- 1.61 s(-1), while in the FP group the increase was from 5.2 +/- 1.21 s(-1) to 5.8 +/- 1.81 s(-1). Mean PEF values as per cent of predicted also increased in a statistically significant way, from 71% to 77.1 % in the BDP group, and from 70.1% to 76.9% in the FP group. The two treatments were equally well tolerated.A total of 23 and 32 patients in the BDP and FP groups, respectively, reported adverse events during the treatment period, and these were generally mild. In conclusion, the results of this study demonstrate that BDP 2,400 microg day(-1) and FP 2,000 microg day(-1), both suspensions for nebulization administered via a jet nebulizer, are equally effective, with an acceptable safety and tolerability profile, when used in adult patients with moderate persistent asthma.

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Respir Med. 2003 Feb;97 Suppl B:S27-33.
Comparison of the efficacy and safety of nebulized beclometasone dipropionate and budesonide in severe persistent childhood asthma.
Delacourt C, Dutau G, Lefrancois G, Clerson P; Beclospin Clinical Development Group.
Centre Hospitalier Intercommunal de Creteil, Service de Pediatrie, Creteil, France.

Inhaled steroids are recommended for long-term control of asthma, but their use may be limited in young children because of difficulties in using the associated inhaler device. The use of nebulizers may help to overcome this issue, without compromising therapeutic efficacy or safety.This 14-week, multicentre, randomized, controlled, open-label, parallel-group study compared the efficacy and safety of nebulized corticosteroids in paediatric patients (aged 6 months to 6 years) with severe persistent asthma. Beclometasone dipropionate (BDP) 800 microgday(-1) suspension for nebulization and budesonide (BUD) 750 microg day(-1) given by nebulization in a twice-daily regimen, and when used in addition to the usual maintenance therapy, resulted in comparable clinical efficacy across all parameters.The primary efficacy endpoint was the number of patients who did not experience any major exacerbation, this being 40.4% and 51.7% in the BDP and BUD groups respectively in the ITT population (P = 0.28), and the mean number of global exacerbations (major plus minor) decreased respectively by -37.5% in the BDP group and -23.3% in the BUD group. Both treatments were also associated with marked reductions in the number of nights with wheezing and the number of days of oral steroid use. Moreover, the two treatment groups had a similar adverse-event incidence and profile. Only 11 adverse events were reported, and no serious adverse events were related to treatment. Urinary cortisol and the time course of height and weight were unaffected by both treatments, and BDP was confirmed to have a neutral effect on bone metabolism. In conclusion, this study demonstrates that both BDP 800 microg day(-1) suspension for nebulization and BUD 750 microgday(-1) administered by nebulization are effective, with an acceptable safety profile, for treatment of severe persistent asthma in infants and young children.

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Thorax. 2003 Mar;58(3):204-10.
Effect of montelukast added to inhaled budesonide on control of mild to moderate asthma.
Vaquerizo MJ, Casan P, Castillo J, Perpina M, Sanchis J, Sobradillo V, Valencia A, Verea H, Viejo JL, Villasante C, Gonzalez-Esteban J, Picado C; CASIOPEA (Capacidad de Singulair Oral en la Prevencion de Exacerbaciones Asmaticas) Study Group.
Merck Sharp & Dohme, c/Josefa Valcarcel 38, 28027 Madrid, Spain. maria_jose_vaquerizo@merck.com

BACKGROUND: Proinflammatory leukotrienes, which are not completely inhibited by inhaled corticosteroids, may contribute to asthmatic problems [corrected]. A 16 week multicentre, randomised, double blind, controlled study was undertaken to study the efficacy of adding oral montelukast, a leukotriene receptor antagonist, to a constant dose of inhaled budesonide. METHODS: A total of 639 patients aged 18-70 years with forced expiratory volume in 1 second (FEV(1)) > or =55% predicted and a minimum predefined level of asthma symptoms during a 2 week placebo run in period were randomised to receive montelukast 10 mg (n=326) or placebo (n=313) once daily for 16 weeks. All patients received a constant dose of budesonide (400-1600 microg/day) by Turbuhaler throughout the study. RESULTS: Mean FEV(1) at baseline was 81% predicted. The median percentage of asthma exacerbation days was 35% lower (3.1% v 4.8%; p=0.03) and the median percentage of asthma free days was 56% higher (66.1% v 42.3%; p=0.001) in the montelukast group than in the placebo group. Patients receiving concomitant treatment with montelukast had significantly (p<0.05) fewer nocturnal awakenings and significantly (p<0.05) greater improvements in beta agonist use and morning peak expiratory flow rate (PEFR). CONCLUSIONS: For patients with mild airway obstruction and persistent asthma symptoms despite budesonide treatment, concomitant treatment with montelukast significantly improves asthma control.

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J Allergy Clin Immunol. 2003 Feb;111(2 Suppl):S712-9.
Immunotherapy of allergic disease.
Frew AJ.
Medical Specialties Clinical Group, University of Southampton School of Medicine, Mailpoint 810, Southampton General Hospital, Southampton SO16 6YD, UK.

Specific immunotherapy involves the administration of allergen extracts to achieve clinical tolerance of the allergens which cause symptoms in patients with allergic conditions. Immunotherapy has been shown to be effective in patients with mild forms of allergic disease, and also in those who do not respond well to standard drug therapy. Recent studies suggest that specific immunotherapy may also modify the course of allergic disease, by reducing the risk of developing new allergic sensitizations, and also inhibiting the development of clinical asthma in children treated for allergic rhinitis. Specific immunotherapy remains the treatment of choice for patients with systemic allergic reactions to wasp and bee stings. The precise mechanisms responsible for the beneficial effects of SIT remain a matter of research and debate. An effect on regulatory T cells seems most probable, associated with switching of allergen-specific B cells towards IgG4 production. Few direct comparisons of specific immunotherapy and drug therapy have been made. Existing data suggest that the effects of specific immunotherapy take longer to come on, but once established, specific immunotherapy will give long-lasting relief of allergic symptoms, whereas the benefits of drugs only last as long as they are continued.

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J Allergy Clin Immunol. 2003 Feb;111(2 Suppl):S502-19.
Asthma.
Lemanske RF Jr, Busse WW.
Departments of Medicine and Pediatrics, University of Wisconsin Medical School, Madison, WI 53792, USA.

The increasing incidence and prevalence of asthma in many parts of the world continue to make it a global health concern. The heterogeneous nature of the clinical manifestations and therapeutic responses of asthma in both adult and pediatric patients indicate that it may be more of a syndrome rather than a specific disease entity. Numerous triggering factors including viral infections, allergen and irritant exposure, and exercise, among others, complicate both the acute and chronic treatment of asthma. Therapeutic intervention has focused on the appreciation that airway obstruction in asthma is composed of both bronchial smooth muscle spasm and variable degrees of airway inflammation characterized by edema, mucus secretion, and the influx of a variety of inflammatory cells. The presence of only partial reversibility of airflow obstruction in some patients indicates that structural remodeling of the airways may also occur over time. Choosing appropriate medications depends on the disease severity (intermittent, mild persistent, moderate persistent, severe persistent), extent of reversibility, both acutely and chronically, patterns of disease activity (exacerbations related to viruses, allergens, exercise, etc), and the age of onset (infancy, childhood, adulthood).

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J Allergy Clin Immunol. 2003 Feb;111(2):278-84.
Omalizumab improves asthma-related quality of life in patients with severe allergic asthma.
Finn A, Gross G, van Bavel J, Lee T, Windom H, Everhard F, Fowler-Taylor A, Liu J, Gupta N.
National Allergy, Asthma and Urticaria Centers of Charleston, Charleston, South Carolina, USA.

BACKGROUND: We have previously shown that omalizumab, a recombinant humanized monoclonal anti-IgE antibody, reduces asthma exacerbations and decreases inhaled corticosteroid (ICS) requirement in patients with severe allergic asthma who were symptomatic despite moderate-to-high doses of ICSs. OBJECTIVE: The aim of the present study was to assess the effects of omalizumab on asthma-related quality of life (QOL). METHODS: These analyses were part of a multicenter, 52-week, randomized, double-blind, placebo-controlled study assessing the efficacy, safety, and tolerability of subcutaneous omalizumab (> or =0.016 mg/kg of IgE [in international unit per milliliter] per 4 weeks) in 525 adults with severe allergic asthma. A 16-week steroid-stable phase was followed by a 12-week steroid-reduction phase and a 24-week double-blind extension phase. The effect of treatment on asthma-related QOL was evaluated by using the Asthma Quality of Life Questionnaire (AQLQ) administered at baseline and at weeks 16, 28, and 52. RESULTS: The 2 treatment groups were comparable in terms of baseline AQLQ scores. At weeks 16, 28, and 52, omalizumab-treated patients demonstrated statistically significant improvements across all AQLQ domains, as well as in overall score. Moreover, a greater proportion of patients receiving omalizumab achieved a clinically meaningful improvement in asthma-related QOL during each phase of the study. Greater than 50% of both patients and investigators rated treatment similarly with omalizumab as excellent or good compared with less than 40% of placebo recipients. CONCLUSION: In patients requiring moderate-to-high doses of ICSs for severe allergic asthma, the measurably improved disease control afforded by add-on omalizumab therapy is paralleled by clinically meaningful improvements in asthma-related QOL.

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Expert Opin Investig Drugs. 2003 Apr;12(4):647-53.
A new class of cyclosporin analogues for the treatment of asthma.
Eckstein JW, Fung J.
Enanta Pharmaceuticals,500 Arsenal Street, Watertown, MA 02472, USA. eckstein@enanta.com

The disease management of asthma - in particular severe and steroid-resistant asthma - remains a real and daily challenge in the clinic. Cyclosporin A has been a mainstay of immunosuppression therapy in organ transplantation for many years. While its application clearly is efficacious in the inhibition of T-cell proliferation and results in the decrease of inflammatory processes, its side effects in long-term use manifested most prominently through nephrotoxicity have been the main concern against broader use of the drug in inflammatory and immune diseases other than organ transplantation. Several new strategies are currently being pursued to address cyclosporin A toxicity, as summarised in this review. The improved safety profile of novel cyclosporin analogues appear to promise potential new treatments of asthma.

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Eur Rev Med Pharmacol Sci. 2002 Jul-Aug;6(4):61-5.
Clinical benefits of switching to an inhaled corticosteroid extrafine aerosol; a case series.
Prenner BM, Bernstein JA.
UCSD School of Medicine, La Jolla, California, USA.

Hydrofluoroalkane beclomethasone dipropionate (HFA-BDP) extrafine aerosol is the first in a new generation of inhaled corticosteroid (ICS) formulations that have an improved deposition profile in comparison with conventional ICS preparations. This reformulation offers potential benefits to patients with asthma in terms of improved symptom control and reduced oropharyngeal adverse effects, such as dysphonia and candidiasis. This article presents four cases that illustrate the clinical benefits that can be obtained following a switch from conventional ICS preparations to treatment with HFA-BDP extrafine aerosol. The patients described were experiencing significant exacerbations of their asthma and increasing asthma symptoms and/or oropharyngeal adverse effects during treatment with conventional ICS preparations. On switching to HFA-BDP extrafine aerosol, the patients experienced an improvement in their asthma control and resolution of any oropharyngeal adverse effects.

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Clin Cornerstone. 2002;4(6):1-17.
Management of asthma exacerbations.
Chesnutt MS.
Oregon Health Sciences University, Portland, Oregon, USA.

The 1997 Expert Panel Report 2 from the National Asthma Education and Prevention Program* details principles and goals for managing asthma exacerbations, based on scientific literature and the opinion of the panel. The panel's recommendations are summarized here, along with approaches to the evaluation and management of patients with asthma exacerbations. Methods to assess and classify the severity of asthma exacerbations are discussed, and treatment objectives for mild, moderate, and severe exacerbations are presented, along with a discussion of postinfectious acute airway hyperresponsiveness. A review of pharmacologic agents used in the treatment of asthma exacerbations is also included. Key points in the management of asthma exacerbations include the notion that early treatment is the best strategy for management. Important elements of early treatment include recognition of early signs of worsening asthma, a written action plan to guide patient self-management, appropriate intensification of therapy, and prompt communication between patient and provider about deterioration in asthma control. Other key points include the use of inhaled beta 2-adrenergic agonists to provide prompt relief of airflow obstruction, the early use of systemic corticosteroids for patients with moderate to severe exacerbations or for patients who fail to respond promptly and completely to an inhaled beta 2-adrenergic agonist, and monitoring response to therapy with serial measurements of lung function.

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West Afr J Med. 2002 Oct-Dec;21(4):297-301.
The clinical efficacy of fluticasone propionate (Fluvent) compared with beclomethasone dipropionates (Becotide) in patients with mild to moderate brochial asthma.
Ige OM, Sogaolu OM.
Chest Unit, Department of Medicine, University College Hospital, Ibadan.

This open, randomized trial was conducted at the Medical Out patient Department of University College Hospital, Nigeria to compare the clinical efficacy of Beclomethasome dipropionate (Becotide) with Fluticasone propionate (Fluvent) in patients with mild to moderate bronchial asthma. The study was performed as a week screening, 8-weeks open comparative clinical trial involving Fluticasone propionate (Fluvent) at a daily dose of 22 microg and Beclomethasone Dipropionate (Becotide) at a dose of 400 microg daily delivered through pressurized metered-dose inhaler (pMDI). The main objective of this study is to assess the efficacy of Fluvent in patients with mild to moderate asthma compared to Becotide. At the second visit (end of 1 week), 10 patients were given either Becotide of Fluvent but all were maintained on as needed beta2agonist (Salbutamol inhaler) therapy throughout the study. Efficacy was assessed by changes in symptoms, number of times beta2-agonist was used and results of pulmonary function tests (PEFR and FEV1) while safety was assessed by adverse event experiences. The baseline characteristics of the patients randomized into the two drug groups were comparable and of no statistical significance. The changes in the pulmonary function tests as well as the reduction in the asthma symptoms suggest a statistically significant improvement in the asthma status of the patients. However, these changes were more rapid among the patients using Fluvent. Also, there was higher percentage decline in the episodes of asthma symptoms either in the morning, day or night in the Fluvent group than Becotide group. The drugs were well tolerated and no adverse event was noticed on any of the patients. We therefore concluded that Fluvent would be more efficacious than Becotide in the treatment of Asthma.

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Rev Med Chir Soc Med Nat Iasi. 2002 Apr-Jun;107(2):298-302.
[Clinical benefits of montelukast sodium treatment in chronic adult asthma]
[Article in Romanian]
Trofor A, Rascarachi G, Popa E, Chiselita I.
Facultatea de Medicina Stomatologica Clinica de Pneumologie, Universitatea de Medicina si Farmacie Gr.T. Popa Iasi.

This paper presents the results of Montelukast sodic therapy in 16 asthmatic patients, in a prospective study. Montelukast sodic was given in severe chronic asthma treated by inhaled or systemic steroids before. Patients were followed up for three months regarding: clinical symptoms, respiratory function (FEV), blood and sputum eozinophyls. Short term therapy showed a great improvement in day and night symptoms, a reduction of sputum and blood eozinophyls and an increased FEV. Long term therapy could be protective for asthma exacerbations and will provide constant good life quality of asthmatics.

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Tunis Med. 2002 Oct;80(10):575-80.
[Anti-IGE therapy in asthma]
[Article in French]
Mehiri Ben Rhouma N, Beji M, Louzir B, Daghfous J.
Service Pneumo-Allergologie, Hopital La Rabta Tunis.

Immunoglobulin E (IgE) is the hallmark of allergic diseases and asthma. Regulating IgE production has been the focus over several years as an important strategy in the treatment of allergic diseases. Recently, nonanaphylactogenic antihuman IgE antibodies have been under clinical evaluation as a therapeutic agent against atopic disease. In asthmatic subjects, the administration of these monoclonal anti-IgE antibody has been shown to reduce plasma IgE levels, reduce early and late phase allergic responses after allergen provocation, improve symptoms and reduce rescue medication. No serious side effects were reported. Thus, the clinical effectiveness of these medications supports the viability of anti-IgE therapy as a potentially effective treatment option for asthma.

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Rev Med Suisse Romande. 2002 Dec;122(12):637-9.
[Heliox in pediatrics]
[Article in French]
Stucki P, Scalfaro P, Cotting J.
CHUV, BHO5, Rue du Bugnon 46 1011 Lausanne.

Heliox is composed of oxygen and helium and its low specific gravity allows a modification of the gas flow within the airway. Breathing heliox favors a laminar flow and therefore decreases the work of breathing. Its usefulness in the child is established in croup or in post-extubation stridor. It can be considered if conventional treatment fails to improve the child's breathing pattern. Its major goal is to avoid invasive manoeuvers as much as possible.

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Med Klin. 2002 Dec 15;97 Suppl 2:12-4.
[State of the art of the inhalation therapy of asthma]
[Article in German]
Gillissen A, Welte T.
Robert-Koch-Klinik, Stadtisches Klinikum St. Georg, Leipzig.

The current concept of asthma pathogenesis is that a characteristic chronic inflammatory process involving the airway wall causes the development of airflow limitation and increased responsiveness, thereby predisposing the airways to narrow in response to a variety of specific (allergic) or unspecific stimuli. Medications for asthma are used to reverse and prevent symptoms and airflow limitation and include controllers and relievers. The major advantage of delivering drugs directly into the airways via inhalation is that high concentrations can be delivered more effectively to the airways, and systemic side effects are avoided or minimized. Bronchodilators with or without anti-inflammatory substances are used as basic therapeutic approach in these patients. The stepwise approach to therapy recommends that the number/type and frequency of medications are increased with increasing asthma severity by adding systemic medications to existing inhalation therapy (step III-IV in asthma management guidelines). Combination therapy using a long acting beta 2-agonist and a glucocorticosteroid resulted in higher lung function improvement, and was superior in reduction of exacerbation rates compared with an inhaled glucocorticosteroid alone. Hence, the development of a fixed combination containing both substances in one device is a logic consequence, and thus, simplifying asthma therapy.

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