Contact WAO | e-News Sign Up | Site Map | Home  
World Allergy Organization
WAO's mission: To be a global resource and advocate in the field of allergy, advancing excellence in clinical care through education, research and training as a world-wide alliance of allergy and clinical immunology societies.

Disease Summaries

A Synopsis on Pharmacotherapy for Allergic Diseases

Bookmark and Share

Posted: April 2007

Saha S1, Siddiqui S1, Bradding P1, Holgate ST2

1 Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, UK

2 Allergy and Inflammation Research, Division of Infection, Inflammation and Repair, School of Medicine, Southampton General Hospital, Southampton, UK

This synopsis reviews the major pharmacotherapies available for the treatment of allergic diseases, and outlines their mode of action.

Inhaled Corticosteroids (ICS)

Beclomethasone, fluticasone, mometasone, budesonide, flunisolide, triamcinolone, ciclesonide

Mode of Action

Corticosteroids bind to cytosolic glucocorticoid receptors to decrease transcription and production of inflammatory cytokines e.g. interleukin (IL)-4 (IL-4), IL-13, granulocyte macrophage colony stimulating factor (GM-CSF), eotaxin and regulated on activation, normal T cells expressed and secreted (RANTES), which function in bronchoconstriction and airway inflammation.

Corticosteroids suppress eosinophilic airway inflammation in asthma. Active eosinophilic airway inflammation (defined by sputum eosinophilia >3%) is associated with increased rates of asthma exacerbations. Management strategies that effectively suppress sputum eosinophilia have been found superior to standard monitoring of asthma (1).

Interventional endobronchial biopsy studies using ICS have repeatedly shown reduction in submucosal eosinophils and CD3+ lymphocytes. Most of these studies also report reduction in large airway reticular basement thickness, a feature of airway remodeling.

ICS administered through different devices have different therapeutic effects. For example, pressure metered dose inhalers (pMDIs) with spacer devices reduce systemic absorption, while use of turbohalers results in deeper deposition of ICS within the pulmonary tree. Ciclesonide is a newer pro-ICS drug metabolized to an active form by esterases following delivery to the lung. Delayed activation reduces local oropharyngeal effects and also the risk of suppressing the hypothalamic-pituitary-adrenal axis.

Side Effects

Local pharyngeal ICS-induced side effects such as oral candidiasis and hoarseness commonly occur. This risk is reduced by use of a dry powder inhaler (DPI) or a turbohaler, by using pMDIs with spacers, or by mouth washing and gargling following administration. High doses of ICS can induce systemic side effects with skin thinning and bruising, cataracts and osteopenia. Adrenal suppression is a particularly serious risk in children. In allergic bronchopulmonary aspergillosis (ABPA) concomitant use with triazoles (e.g. itraconazole) which inhibit P450-dependent CYP3A4, can lead to decreased clearance of synthetic corticosteroids and subsequent adrenal suppression and Cushing’s syndrome.

Comments

ICS improve asthma control, reduce exacerbations and prevent asthma deaths (2). They should be used in any patient requiring use of a short-acting β2-agonist more than three times per week. The aim of therapy is to titrate the ICS dose to the lowest effective dose that maintains asthma control, and to ensure that the patient can use their inhaler device properly. In general, DPIs are easier to use than pMDIs. It is unlikely that there is clinical benefit at doses above daily beclomethasone 2000 mcg or its equivalent. Chlorofluorocarbon (CFC) propellants in pMDIs for medication are being phased out and replaced by hydroxyfluoroalkane (HFA) propellants. For the HFA formulation of beclomethasone, the equivalent dose of beclomethasone is half that of current CFC formulations.

The Global Initiative for Asthma (GINA) classification of daily total beclomethasone diproprionate (BDP) dosing in adults is:

Low dose BDP-HFA 100-250 mcg
Medium dose BDP-HFA 250-500 mcg
High BDP-HFA >500 mcg

If patients remain symptomatic at a medium ICS dose, consideration should be given to additional treatments before increasing the dose.

Systemic Corticosteroids

prednisolone p.o., hydrocortisone i.v., triamcinolone i.m.

Mode of Action

Like inhaled corticosteroids, systemic corticosteroids act predominantly by suppressing transcription of pro-inflammatory genes, although some acute non-transcriptional modes of action have been proposed. Enteral or parenteral use of corticosteroids is usually indicated for emergency situations. Time to effect is equal between enteral and parental corticosteroid routes, and effects are usually detectable by 6 hours. Oral prednisolone reduces numbers of CD3+ and CD4+ lymphocytes, eosinophils and mast cells in large airway tissue from asthmatics. Reduction in expression of the TH2 cytokines, IL-4 and IL–5, also occurs with an increase in interferon-gamma. Parenteral use of triamcinolone can abolish persisting eosinophilia and improve symptoms in patients with severe asthma; its mechanism is not understood.

Side Effects

Side effects can include glycemia, psychiatric changes, appetite stimulation and weight gain, peptic ulcer disease, fluid retention, skin bruising and thinning, hypertension, adrenal suppression, osteoporosis, menstrual irregularities, and cataracts.

Comments

Long-term use of oral corticosteroids is reserved strictly for patients still symptomatic despite high dose inhaled corticosteroid and adjunctive therapy. Courses of 7-10 days of prednisonlone 40-50 mg/daily or its equivalent, given in divided doses are recommended for exacerbations until symptoms and peak flow readings improve. Intramuscular triamcinolone can be used in situations when compliance is a confounding factor or when response to oral corticosteroids is poor.

Long-term use of systemic corticosteroids requires careful monitoring for side effects.

Beta Agonists (short acting)

salbutamol inh./p.o./s.c./i.v., terbutaline inh./p.o./s.c./i.v./i.m., bambuterol p.o.

Mode of Action

Inhaled short-acting β-agonists produce immediate bronchodilation lasting 4-6 hours. These drugs stimulate β2 receptors present in airway smooth muscle, increasing levels of intracellular cyclic AMP, which in turn activates protein kinase A (PKA). PKA phosphorylates several proteins to reduce intracellular Ca2+ levels and promote smooth muscle relaxation. This action is enhanced by changes in the activity of plasma membrane K+ channels. β-agonists are unlikely to mediate anti-inflammatory effects directly but, when given intermittently, can attenuate mast cell mediator release, microvascular edema and leakage, mucus hypersecretion and cholinergic neurotransmission. Tolerance to repeated and excessive short-acting β-agonist use is described. For example, bronchoprotection against allergen challenge is lost and mast cell degranulation is enhanced after 1 week of use of a short-acting β-agonist (3).

Side Effects

Side effects occur in a dose-dependent manner and include: fine tremor, nervousness, headache, tachycardia and palpitations, pupil dilatation and hypokalaemia.

Comments

Short-acting β-agonists provide short-term symptomatic relief for asthma. Salbutamol and terbutaline are available in dry powder and aerosol forms. Intravenous preparations are reserved for emergency use. Oral preparations are primarily used for patients who cannot use inhaled medications. Bambuterol can be used for patients with nocturnal symptoms but inhaled long acting β-agonists are preferred. Subcutaneous terbutaline has been used for the long-term management of brittle asthma, but evidence of success has only been reported in small case series.

Long Acting Beta Agonists (LABA)

formoterol inh., salmeterol inh.

Mode of Action

LABA are highly specific for β2 adrenoceptors and have a prolonged duration of action of 12 hours. Both formoterol and salmeterol remain in tissue despite antagonism and extensive perfusion. LABA are very potent at low concentrations, thus reducing stimulation of β2 receptors in non-pulmonary tissue.

Salmeterol is a partial agonist (approximately 70% agonist activity compared to isoprenaline), while formoterol is a full agonist of β2 receptors. The implications of this finding for disease control are unclear. Cardiac and metabolic effects of formoterol are comparable to those of salbutamol, but formoterol has a rapid onset (2-3 minutes) of bronchodilator action, while salmeterol activity commences at 10 minutes and reaches a maximal effect at about 30 minutes. Both formoterol and salmeterol provide dose responsive bronchodilatation.

While LABA appear to have minimal effects on in vivo airway inflammation, they enhance the effect of inhaled corticosteroids via different mechanisms. They improve glucorticoid receptor availability and synergistically suppress inflammatory mediator release. Corticosteroids in turn improve β2 receptor expression and prevent receptor downregulation.

Side Effects

See above. LABA use has been associated with a small increase in respiratory-related deaths in asthma. The US based SMART study was designed to assess the safety of salmeterol vs placebo and suggested a further increase in relative risk for the African-American population vs the Caucasian population; the reason for this observation remains unclear (4). The increase in mortality may also be associated with patients using LABA as monotherapy for control instead of concurrent use with inhaled corticosteroid treatment.

Comments

The US Food & Drug Administration has issued a "black box" warning based on concerns over safety suggesting LABA should not be used as first line therapy to maintain control or as short term-reliever therapy.

LABA should be reserved for symptomatic patients using a moderate dose of inhaled corticosteroid (>500 mg BDP-HFA or its equivalent daily).

Salmeterol and formoterol are available both in dry powder and aerosol forms.

Clinical trials demonstrate greater efficacy in controlling symptoms, improving peak flow rates and reduction of diurnal variation with the addition of a LABA to moderate doses of ICS in comparison with doubling the ICS dose. Nocturnal LABA use can ameliorate night-time symptoms, and premedication (30 minutes for salmeterol) prior to exercise can reduce exercise-induced bronchoconstriction. Several randomized double-blind, placebo-controlled clinical trials, primarily with formoterol, demonstrate that adding a LABA to an ICS markedly reduces the rate of severe asthma exacerbations.

LABAs and ICS are now marketed as a combination treatment in the same inhaler (formoterol + budesonide, fluticasone + salmeterol). This formulation improves compliance, since it requires one rather than two prescriptions, and reduces costs, in that the combination devices are usually cheaper than two individual components alone. The formoterol/budesonide combination has been suggested as single inhaler therapy for both maintenance and reliever therapy.

Cromone Therapy

Sodium Cromoglycate inh, Nedocromil Sodium inh.

Mode of Action

Cromone therapy is thought to inhibit IgE-dependent histamine release from mast cells, although the effects of sodium cromoglycate on human lung mast cells are weak. Both agents have weak effects on eosinophils and on macrophage activity but do not affect airway smooth muscle tone.

Side Effects

Sodium cromoglycate can cause transient cough and throat irritation. These symptoms can be relieved by pre-treatment with short-acting β-agonists.

Nedocromil sodium can leave a bitter taste and cause nausea and headache.

Comments

Nedocromil sodium ameliorates daytime asthma symptoms similarly to low dose ICS but has no effect on preventing exacerbations suggesting it should not have a primary role in maintaining control. A meta-analysis for the use of sodium cromoglycate in children has not shown a beneficial effect.

Immunomodulation

Anti-IgE

Omalizumab, s.c.

Mode of Action

Omalizumab is a humanized murine anti-human IgE monoclonal antibody directed against an IgE fragment (Cε3) epitope that binds to the high affinity IgE receptor (FcεRI). Omalizumab interferes with IgE binding to that receptor, thus attenuating IgE-mediated release of inflammatory mediators from mast cells, basophils and possibly other inflammatory cells.

Omalizumab reduces airway inflammation but does not attenuate bronchial hyperresponsiveness (5).

Administration is based on 2 or 4 weekly regimes.

Side Effects

Most common side effects are lower respiratory tract infections and nasopharyngitis. In controlled studies, however, the incidence of adverse events was comparable to placebo effects.

Severe hypersensitivity reactions occur in <0.1% of patients.

Comments

Omalizumab reduces the frequency of asthma exacerbations regardless of the underlying allergen-specific IgE sensitization and improves symptom scores and asthma quality of life.

Omalizumab can be used for its steroid sparing effect, and it reduces rescue medication usage. Improvement in upper airway symptoms in patients with allergic rhinitis has also been demonstrated.

The US Food and Drug Administration (FDA) has approved Omalizumab in adults with moderate-severe persistent allergic asthma not controlled by ICS.

Treatment is limited to individuals weighing < 150kg and exhibiting elevated IgE between 30-700 IU and allergy to common perennial allergens, as evidenced by skin tests or a radioallergosorbent test (RAST).

Antihistamines

1st generation (Sedating): Chlorphenamine, hydroxyzine, promethazine
2nd generation (Non-sedating): Cetirizine, loratidine, fexofenadine

Mode of Action

Histamine is released from cytoplasmic granules in mast cells and basophils in the early allergic response. Histamine binds to H1 and H2 receptors on endothelial cells to increase cyclic guanosine monophosphate levels, which promote vasodilation, erythema, increased vascular permeability and edema. Histamine interacts with H1 receptors on airway smooth muscle to cause contraction and on afferent C fibres to cause itching of mucosal and skin surfaces. Histamine affinity for H1 receptors is 10 times greater than that for H2 receptors.

Antihistamines counteract the effect of histamine at H1 receptors, prevent mediator release from mast cells and basophils, and downregulate nuclear factor κB (NFκB) and subsequent generation of inflammatory cytokines. Onset of action is 1-2 hours, and effects often last 24 hours post single dose. The dose-response curve for symptom relief is relatively flat.

Side Effects

Side effects have predominantly been associated with 1st generation antihistamines.

1st generation antihistamines are associated with neurological symptoms e.g. drowsiness, dizziness, dystonia, dyskinesia, cognitive impairment; cardiac abnormalities e.g. tachyarrhythmias, prolongation of the QT interval; autonomic dysfunction e.g. mydriasis, dry mouth, urinary retention, postural hypotension.

2nd generation antihistamines have much reduced neurological side effects with only ceterizine potentially leading to sedation. Astemizole & terfenadine have been associated with cardiac arrhythmias and both have been removed from the UK & US market. Autonomic dysfunction has not been reported with this generation of antihistamines.

Comments

Antihistamines are employed to control allergic rhinitis, urticaria and atopic dermatitis. Relief of erythema in urticaria can be incomplete as this is mediated in part by H2 receptors.

Use of antihistamines in asthma management is controversial; little evidence supports their regular use but some reports indicate amelioration of mild seasonal asthmatic symptoms.

Decongestants

ephedrine HCl, xylometazoline HCl

Mode of Action

These drugs act through α1- & α2 adrenoceptors present on nasal capacitance vessels responsible for local oedema and consequent nasal congestion. Topical therapy can lead to improvement in nasal patency within 10 minutes and last between 8-12 hours.

Side Effects

Local irritation, nausea and headache are the most common problems. Mucosal ulceration is a less common problem. Rebound congestion may occur after excessive use of topical decongestants, particularly with the more potent sympathomimetic xylometazoline.

Hypertensive crises have been reported if oral or topical decongestants are used with monoamine-oxidase inhibitors.

Ephedrine hydrochloride 0.5%: 1-2 drops/nostril (3-4 times daily)
Xylometazoline hydrochloride 0.1%:
Nasal drops: 2-3 drops/nostril 2-3 times daily (maximum 7 days)
Nasal spray: 2-3 times daily (maximum 7 days)

Non-allergic Watery Rhinorrhea

Intranasal ipratropium bromide

Mode of Action

Anti-muscarinic topical therapy

Side Effects

Frequent problems are epistaxis, nasal dryness and local irritation. Less frequent problems are nausea, headache, pharyngitis, urinary retention and gastric motility.

Comment

Symptoms of nasal congestion associated with nonallergic rhinitis can be relieved by short-term (usually <7 days) use of nasal decongestants Treatment past 1 week can result in tolerance and rebound congestion (rhinitis medicamentosa). Decongestants as the sole therapy for allergic rhinitis, is usually insufficient and often requires additional oral antihistamine therapy unless nasal congestion is the sole symptom.

Topical Therapy for Eczema and Contact Dermatitis

Topical corticosteroids – creams and ointments

Mild hydrocortisone 0.1-2.5%.
Moderate betamethasone valerate 0.025%, fludroxycortide 0.0125%, clobetasone butyrate 0.05%, aclometasone diproprinate 0.05%, fluocinolone acetonide 0.00625%, fluocortolone caproate 0.25%
Potent betamethasone valerate 0.1%, betamethasone valerate 0.05%, fluticasone propionate 0.05%, fluocinomide 0.05%, diflucortolone valerate 0.1%, hydrocortisone butyrate 0.1%, mometasone furoate 0.1%, beclometasone diproprionate 0.025%, , fluocinolone acetonide 0.025%
Very potent clobetasol propionate 0.05%, halcinonide 0.1%, diflucortolone valerate 0.3%
Mode of Action

Anti-inflammatory and immunosuppressive effects are mediated by regulation of corticosteroid responsive genes.

Side Effects

Potent and very potent topical steroids may cause adrenal suppression. Local side effects include skin atrophy, spread of untreated infection, contact dermatitis, acne and hypertrichosis.

Comments

Topical corticosteroids are first line anti-inflammatory treatment applied to inflamed skin according to need (pruritis, new flare, sleeplessness).

One fingertip unit (distance from the tip of the adult index finger to the first crease) equals approximately 500 mg and is sufficient to cover an area approximately twice the size of an adult palm.

With mild disease, a small amount 2-3 times weekly, equal to a cumulative dose of 90 g/month in adults, along with liberal use of emollients, usually leads to good maintenance with scoring of atopic dermatitis scores (SCORAD) below 15-20. Relief from itch is a key outcome used to evaluate treatment response, and steroids should not be tapered until itch has resolved.

Topical Calcineurin Inhibitors

Pimecrolimus 1%, tacrolimus 0.1%-0.03%

Mode of Action

Calcineurin inhibitors are macrocyclic compounds that bind to the intracellular protein macrophilin-12 and function as macrolactam immunomodulators, which inhibit activity of the phosphatase calcineurin. Most therapeutic effects of tacrolimus are due to loss of calcineurin activity and the resulting alterations in phosphorylation of transcription factors such as nuclear factor of activated T cells (NFAT) and NFkB in T lymphocytes.

Side Effects

Side effects depend on area of application and include a burning sensation, pruritis, erythema and skin infection (including folliculitis and rarely impetigo, herpes simplex and zoster, and molluscum contagiosum). Long-term effects are as yet unknown. Skin malignancy and lymphoma have been reported in association with topical calcineurin inhibitor use. The US FDA has consequently issued a "black box" warning recommending avoidance of long-term therapy and use in infants less than 2 years in age. In contrast, assessment of clinical trial data and post-marketing surveillance has not indicated systemic immunosuppresion or increased risk of malignancy.

Comments

Treatment with calcineurin inhibitors is a second line option for atopic eczema not controlled by maximal corticosteroid treatment. They are also employed when there is a risk of significant corticosteroid-related side effects (particularly skin atrophy).

Pimecrolimus is prescribed for mild to moderate eczema, while tacrolimus is used for moderate to severe disease.

Anticholinergics

Short acting: Ipratropium Bromide
Long acting: Tiotropium

Mode of Action

The bronchodilator ipratropium is a competitive inhibitor of acetylcholine at muscarinic receptors. Inhaled anticholinergics are less potent bronchodilators than inhaled β2-agonists. Tiotropium can provide bronchoprotection against methacholine airway challenging and shows slow dissociation from Hm1 and Hm3 receptors in vitro. In acute severe asthma, addition of ipratropium to nebulized salbutamol leads to more rapid improvement in lung function.

Side Effects

Side effects include dry mouth, nausea, constipation and headache. Tachycardia and atrial fibrillation have also been reported. Antimuscarinic bronchodilators should be used with caution in glaucoma (see below), prostatic hyperplasia and bladder outflow obstruction.

Comments

Due to their reduced potency in comparison to β2-agonists, the benefit of short acting cholinergics in chronic asthma disease is unclear. Tiotropium has demonstrated benefit in COPD but evidence for use in asthma is lacking and is not licenced for this condition.

Leukotriene Antagonists

Zafirlukast p.o., montelukast p.o., pranlukast, p.o.

Mode of Action

Montelukast, zafirlukast and pranlukast are selective leukotriene antagonists acting on the CysLT1 receptor. Leukotrienes are derived from arachidonic acid, a constituent of the membrane phospholipid bilayer, and are produced by inflammatory cells (neutrophils, eosinophils, mast cells/basophils, monocytes/macrophages and lymphocytes) and potentially by airway epithelial cells. Cysteinyl leukotrienes LTC4, LTD4 and LTE4 stimulate smooth muscle contraction and contribute to eosinophil chemoattraction. Leukotrienes promote microvascular leakage, airway mucus secretion and airway edema.

Some asthma subjects exhibit increased leukotriene production. Leukotrienes are generally insensitive to anti-inflammatory effects of glucocorticoids.

Use of aspirin and NSAIDs promotes asthma symptoms in 3-8% of asthmatics, most likely by inhibiting the cyclo-oxygenase pathway, which stimulates leukotriene synthesis from arachidonic acid. Pulmonary transmembrane cysteinyl leukotriene receptors are expressed primarily in smooth muscle and macrophages.

Leukotriene receptor antagonists can reduce sputum and blood eosinophilia.

Side Effects

Side effects are headache, nausea, vomiting, gastro-intestinal disturbance, hypersensitivity reactions, skin rash, elevated serum transaminases, sleep disorders, arthralgia and myalgia.

Comments

When used in adjunctive therapy, leukotriene antagonists reduce β-agonist use, reduce nocturnal and daytime symptoms and improve lung function in mild-moderate asthmatics. With severe asthmatics, they can be utilized for their steroid sparing properties.

Leukotrienes are elevated in urine with exercise. In a manner similar to aspirin-related asthma, leukotriene antagonists reduce exercise-related bronchoconstriction.

Duration of action can be up to 8 hours post exercise (zafirlukast) with greater efficacy than salmeterol (montelukast).

Theophylline

Short acting p.o., modified release p.o.

Mode of Action

Mechanisms of action are unclear. One mechanism was thought to be phosphodiesterase (PDE) inhibition and subsequent increases in intracellular cyclic AMP and guanosine 3’, 5’-monophosphate, which mediate smooth muscle relaxation. However, therapeutic serum concentrations (10-20 mg/L) result in weak PDE inhibition.

Levels of the anti-inflammatory cytokine IL-10 are reduced in asthma. Theophylline can increase IL-10 levels, but this typically does not occur at therapeutic doses.

Theophylline can also block transcription of pro-inflammatory genes (by antagonizing NFκB activity) associated with airway diseases and induce T cell apoptosis.

Theophylline also promotes histone deacetylase (HDAC) activity, thereby antagonizing core histone acetylation and expression of inflammatory genes. A more plausible mode of action is antagonism of the adenosine A2B receptor.

Theophylline can reduce tissue eosinophilia and increase the number of CD4+ cells seen in bronchial biopsies upon withdrawal.

Side Effects

Serious side effects are mainly dose related. At <20 mg/L, nausea, vomiting, headaches, dyspepsia, diuresis and behaviorial disturbances can occur. At >20 mg/L, additional side effects include cardiac arrhythmias and fitting. Side effects can be avoided by gradually increasing the dose.

Comments

Although addition of theophylline to ICS can result in better efficacy than doubling the ICS dose, development of LABA has replaced this regime.

Some efficacy is reported with low (5-10 mg/L) doses. Modified release is useful with nocturnal symptoms. Currently, use is reserved for patients symptomatic despite high dose ICS use.

Intravenous aminophylline (2:1 mixture of aminophylline and ethylenediamine) produces little added benefit compared to continuous administration of β-agonists in emergency situations but can be reserved for patients whose condition is deteriorating despite aggressive therapy.

Magnesium Sulphate

Intravenous, nebules

Mode of Action

How magnesium ameliorates acute asthma is unclear, although magnesium functions as a smooth muscle relaxant, probably through antagonizing calcium activity. Emergency department-based clinical trials show improvement in lung function post intravenous administration but no overall impact on admissions to intensive care units or discharge rates.

Side Effects

Intravenous forms are usually well tolerated in single bolus form, although local irritation at the injection site has been reported.

Randomized control trials using nebulized magnesium have not demonstrated significant differences in adverse events.

Comments

Intravenous magnesium is reserved for acute severe exacerbations when the response to continuous β-agonist therapy is poor. Administration is via a single bolus dose, and the consequences of repeated administration are unknown. High magnesium levels may promote respiratory muscle weakness.

Nebulized magnesium is not widely used but can be an adjunct to nebulized β-agonist therapy in adults and children in the emergency department.

Reference List

  1. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. The Lancet 2002;360(9347):1715-21.

  2. Suissa S, Ernst P. Inhaled corticosteroids: impact on asthma morbidity and mortality. J Allergy Clin.Immunol 2001;107(6):937-44.

  3. Swystun VA, Gordon JR, Davis EB, Zhang X, Cockcroft DW. Mast cell tryptase release and asthmatic responses to allergen increase with regular use of salbutamol. J Allergy Clin.Immunol 2000;106(1 Pt 1):57-64.

  4. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006;129(1):15-26.

  5. Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF et al. Effects of Treatment with Anti-immunoglobulin E Antibody Omalizumab on Airway Inflammation in Allergic Asthma. Am.J.Respir.Crit.Care Med. 2004;170(6):583-93.