In addition, a further level 3 pharmacokinetic study was identified and included (Nave et al. 2006), along with 22 abstracts of meeting presentations, of which 4 were included following removal of duplicates. Disease overview Asthma, a chronic respiratory disease of both children and adults, is one of the most prevalent chronic diseases in the world affecting approximately 300 million people (Bousquet et al. 2005; Masoli et al. 2005). An estimated 250 000 deaths caused by asthma occur annually; one in every 250 deaths worldwide is thought to be secondary to asthma (Bousquet et al. 2005; Masoli et al. 2005). The impact of asthma is far-reaching in both the adult and pediatric population and includes an effect on activities of daily living that extends to participation in school, work, and family life. Globally, about 15 million disability-adjusted life years (DALYs) are lost annually due to asthma, a number similar to that associated with diabetes, cirrhosis, or schizophrenia (Masoli et al. 2005). Direct medical costs related to medications and hospital admissions, and indirect medical costs related to loss of work and premature mortality are significant. Direct medical costs of asthma treatment account for up to 3% of total medical expenditures for many countries (Bousquet et al. 2005). Although the exact etiology of asthma remains poorly understood it is thought to have both genetic and environmental causes and is considered a chronic inflammatory disease. Asthma is characterized by bronchial hyperreactivity caused by chronic inflammation of the airways. Bronchial hyperreactivity is associated with reversible airflow obstruction and episodes of wheezing, breathlessness, chest tightness, and coughing (especially in the early morning or at night). There is no cure for asthma and the goal of treatment is to achieve and maintain control of symptoms, prevent exacerbations, reduce/eliminate side effects from medications, and allow patients to have an optimal quality of life. The potential for development of adverse effects associated with asthma treatment has been noted to impact patient adherence to therapy (Goeman 2002). Current therapy options Over the past two decades the treatment of asthma has received increased attention and guidelines for the management of asthma have been published [Global Initiative for Asthma (GINA) strategy, World Health Organization (WHO)/National Heart, Lung, and Blood Institute (NHLBI); Anon. 2005b). A global strategy for asthma management and prevention—the result of a collaborative effort of GINA, WHO, and the NHLBI—was first issued in 1995. Updates to this guideline have been released with the most recent being in 2004. Asthma management protocols and guidelines focus on the inflammatory component of the disease and recommend a stepped-care approach to disease management (Table 2). Many pharmacologic entities are available for the chronic management of persistent asthma, but inhaled corticosteroids are Core Evidence 2006;1(4) Ciclesonide | place in therapy review the cornerstone of therapy. Corticosteroids can be administered either orally or via inhalation, although the adverse effect profile significantly favors the latter. Inhaled corticosteroids are considered the most effective therapy for persistent asthma and are the preferred treatment for all patients with persistent disease symptoms (Anon. 2005b). All of the available inhaled corticosteroids produce their effects by interacting with intracellular glucocorticoid receptors, which are present throughout the body. In the treatment of asthma, the effect of these agents on pulmonary glucocorticoid receptors produce the desired effects but interaction with glucocorticoid receptors outside the lungs can lead to unwanted adverse effects such as suppression of the hypothalamic–pituitary–adrenal axis (HPA), reduction of bone density, and growth suppression. Beneficial pharmacologic effects of these agents include decreasing inflammatory cells in the airway and increasing the release of antiinflammatory cytokines (Hübner et al. 2005). The decrease in inflammatory mediators results in a reduction of airway inflammation and hyperreactivity, improved pulmonary function, symptom control, and reduction of exacerbations (Kelly 2003). The principal goal of inhaled corticosteroid therapy is to have a high level of antiinflammatory effect with minimal adverse effects (Kelly 2003). Although differences in pharmacokinetic parameters and potency exist, the currently available agents (Table 3) are considered equally efficacious when administered at equipotent doses (O'Connell 2005). The ideal inhaled corticosteroid for patients with asthma has a high degree of lung deposition with a low level of systemic bioavailability providing therapeutic benefit (high glucocorticoid receptor affinity) without significant adverse effects. Systemic exposure can be minimized by high protein binding and a rapid clearance rate (Berger 2005). Use of a prodrug that is not pharmacologically active until it undergoes a metabolic transformation has been shown to decrease oropharyngeal effects and might result in improved pulmonary targeting (Hübner et al. 2005). Smaller particle size, physical properties of the compounds, delivery device used, and inhaler technique all have an impact on the rate of lung deposition (Hübner et al. 2005). Higher rates of lung deposition translate to an increased amount of drug available at the intended site of action (lungs) and a lower amount available for oral absorption and systemic availability, and hence fewer adverse effects. In addition, lipid conjugation of the compound can provide a reservoir in the lungs allowing for a slow release of active compound (Berger 2005). Of particular concern for long-term treatment of persistent asthma is an agent’s propensity to cause systemic side effects. Systemic exposure to an inhaled corticosteroid is tied to its potential for adverse effects. There is little concern about systemic effects with the use of low-dose inhaled corticosteroids (doses of ≤500 mcg budesonide or equivalent) (Anon. 2005b). However, at high doses concern remains that these medications may cause HPA axis suppression, decreased bone mineralization, cataracts, glaucoma, and a reduction in the rate of bone growth in children. It is important to note that while HPA axis suppression 235