β₂‐adrenoceptor agonists: current and future direction

Abstract

Despite the passionate debate over the use of b2-adrenoceptor agonists in the treatment of airway disorders, these agents are still central in the symptomatic management of asthma and COPD. A variety of b2-adrenoceptor agonists with long half-lives, also called ultra long-acting b2-adrenoceptor agonists (ultra-LABAs; indacaterol, olodaterol, vilanterol, carmoterol, LAS100977 and PF-610355) are currently under development with the hopes of achieving once-daily dosing. It is likely that the oncedaily dosing of a bronchodilator would be a significant convenience and probably a compliance-enhancing advantage, leading to improved overall clinical outcomes. As combination therapy with an inhaled corticosteroid (ICS) and a LABA is important for treating patients suffering from asthma, and a combination with an inhaled long-acting antimuscarinic agent (LAMA) is important for treating COPD patients whose conditions are not sufficiently controlled by monotherapy with a b2-adrenoceptor agonist, some novel once-daily combinations of LABAs and ICSs or LAMAs are under development. LINKED ARTICLESThis article is part of a themed issue on Respiratory Pharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-1 AbbreviationsACh, acetylcholine; cAMP, cyclic adenosine monophosphate; COPD, chronic obstructive pulmonary disease; EC50, median effective concentration required to induce a 50% effect; ECG, electrocardiogram; EFS, electric field stimulation; Emax, the maximum possible effect for the agonist; FDA, Food and Drug Administration; FEV1, Forced Expiratory Volume in One Second; HFA, hydrofluoroalkane; ICS, inhaled corticosteroid; IFN, interferon; IL, interleukin; LABA, long-acting b2-adrenoceptor agonist; LAMA, long-acting antimuscarinic agent; mL, milliliter; pEC50, negative logarithm of EC50; PK, pharmacokinetics; QTc, corrected QT interval Current directionb2-adrenoceptor agonists, mainly long-acting b2-adrenoceptor agonists (LABAs) such as formoterol and salmeterol, are an important pharmacological approach to induce bronchodilation in patients suffering from chronic obstructive pulmonary disease (COPD) (Celli and MacNee, 2004;Rabe et al., 2007) and asthma (National Asthma Education and Prevention Program, 2007;Bateman et al., 2008a), although controversy has reigned over their regular use prescribed as monotherapy, at least in the treatment of asthma (Wijesinghe et al., 2008). In effect, with chronic or high-dose exposure, b2-adrenoceptor agonists demonstrate proinflammatory effects. In vitro, they can enhance the Th2 inflammatory pathway by inhibiting interleukin (IL)-12 and interferon (IFN)-g (Panina-Bordignon et al., 1997;Agarwal and Marshall, 2000). In vivo, pretreatment with b2-adrenoceptor agonists increases the severity of the late asthmatic reaction (Lai et al., 1989), continuous treatment is associated with an increase in sputum eosinophils, notably when the patient is not taking concomitant inhaled corticosteroids (ICSs) (Aldridge et al., 2000;Lazarus et al., 2001)...

Development and Characterization of Pepducins as Gs-biased Allosteric Agonists*

“…␤-Antagonists have been used extensively in the treatment of hypertension, and some inverse agonists such as carvedilol have been used in the treatment of congestive heart failure (11,13). ␤ 2 AR agonists, including salbutamol and formoterol, are com-monly prescribed drugs for the treatment of asthma and chronic obstructive pulmonary disease (9,12).…”

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“…Although inhaled glucocorticosteroids are often prescribed in a (fixed) combination with a LABA, careful instruction and monitoring are needed to prevent potential negative side-effects in selected patients [36]. Several once daily b 2 -agonists (ultra-LABAs) such as indacaterol, carmoterol, olodaterol, vilanterol and LAS100977 are currently under investigation [37]. Because of the earlier described side-effects, once daily b 2 -agonists should also be prescribed in fixed dose combinations.…”

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“…These ultra LABAs should be in a fixed dose combination with corticosteroids. Indacaterol plus mometasone and Fluticasone furoate plus vilanterol are currently in clinical trial for the management of asthma (Cazzola et al, 2011).…”