Functional and Biochemical Rationales for the 24-Hour-Long Duration of Action of Olodaterol

Casarosa, Paola; Kollak, Ines; Kiechle, Tobias; Ostermann, Angela; Schnapp, Andreas; Kiesling, Ralf; Pieper, Michael; Sieger, Peter; Gantner, Florian

doi:10.1124/jpet.111.179259

Cited by 83 publications

(55 citation statements)

References 29 publications

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“…The pK i values determined were in good agreement with literature values generated against antagonist radioligands (Table 2). Vilanterol had a comparable affinity for the b 2 -AR as salmeterol but a 5-, 23-, and 31-fold higher affinity than olodaterol (Casarosa et al, 2011), formoterol, and indacaterol, respectively. Vilanterol was demonstrated to be highly selective for the b 2 -AR with at least a 1000-fold selectivity over both b 1 -and b 3 -AR subtypes (Table 3).…”

Section: Radioligand Binding Studiesmentioning

confidence: 99%

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In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ₂-Adrenoceptor Agonist with 24-Hour Duration of Action

Slack

Barrett

Morrison

et al. 2012

J Pharmacol Exp Ther

107

124

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Vilanterol trifenatate (vilanterol) is a novel, long-acting b 2 -adrenoceptor (b 2 -AR) agonist with 24 h activity. In this study, we describe the preclinical pharmacological profile of vilanterol using radioligand binding and cAMP studies in recombinant assays as well as human and guinea pig tissue systems to characterize b 2 -AR binding and functional properties. Vilanterol displayed a subnanomolar affinity for the b 2 -AR that was comparable with that of salmeterol but higher than olodaterol, formoterol, and indacaterol. In cAMP functional activity studies, vilanterol demonstrated similar selectivity as salmeterol for b 2 -over b 1 -AR and b 3 -AR, but a significantly improved selectivity profile than formoterol and indacaterol. Vilanterol also showed a level of intrinsic efficacy that was comparable to indacaterol but significantly greater than that of salmeterol. In cellular cAMP production and tissue-based studies measuring persistence and reassertion, vilanterol had a persistence of action comparable with indacaterol and longer than formoterol. In addition, vilanterol demonstrated reassertion activity in both cell and tissue systems that was comparable with salmeterol and indacaterol but longer than formoterol. In human airways, vilanterol was shown to have a faster onset and longer duration of action than salmeterol, exhibiting a significant level of bronchodilation 22 h after treatment. From these investigations, the data for vilanterol are consistent, showing that it is a novel, potent, and selective b 2 -AR receptor agonist with a long duration of action. This pharmacological profile combined with clinical data is consistent with once a day dosing of vilanterol in the treatment of both asthma and chronic obstructive pulmonary disease (COPD).

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Section: Radioligand Binding Studiesmentioning

confidence: 99%

“…for at least four separate determinations. P values were determined via ANOVA and were adjusted using the Holm (1979) for salmeterol, formoterol, and indacaterol (Casarosa et al, 2011). Vilanterol Reassertion.…”

Section: Isolated Guinea Pig Trachea Studiesmentioning

confidence: 99%

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ₂-Adrenoceptor Agonist with 24-Hour Duration of Action

Slack

Barrett

Morrison

et al. 2012

J Pharmacol Exp Ther

107

124

View full text Add to dashboard Cite

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“…These hypotheses have been proposed to explain different duration of action of SABAs, twice-daily and once-daily LABAs (Casarosa et al, 2011).…”

Section: Tablementioning

confidence: 99%

Pharmacological Characterization of Abediterol, a Novel Inhaled β₂-Adrenoceptor Agonist with Long Duration of Action and a Favorable Safety Profile in Preclinical Models

Aparici¹,

Gómez‐Angelats²,

Vilella³

et al. 2012

J Pharmacol Exp Ther

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Abediterol is a novel potent, long-acting inhaled ␤ 2 -adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human ␤ 2 -adrenoceptor and a functional selectivity over ␤ 1 -adrenoceptors higher than that of formoterol and indacaterol in both a cellular model with overexpressed human receptors and isolated guinea pig tissue. Abediterol is a full agonist at the human ␤ 2 -adrenoceptor (E max ϭ 91 Ϯ 5% of the maximal effect of isoprenaline). The potency and onset of action that abediterol shows in isolated human bronchi (EC 50 ϭ 1.9 Ϯ 0.4 nM; t 1 ⁄2 onset ϭ 7-10 min) is not significantly different from that of formoterol, but its duration of action (t 1 ⁄2 ϳ 690 min) is similar to that of indacaterol. Nebulized abediterol inhibits acetylcholine-induced bronchoconstriction in guinea pigs in a concentration-dependent manner, with higher potency and longer duration of action (t 1 ⁄2 ϭ 36 h) than salmeterol (t 1 ⁄2 ϭ 6 h) and formoterol (t 1 ⁄2 ϭ 4 h) and similar duration of action to indacaterol up to 48 h. In dogs, the bronchoprotective effect of abediterol is more sustained than that of salmeterol and indacaterol at doses without effects on heart rate, thus showing a greater safety margin (defined as the ratio of dose increasing heart rate by 5% and dose inhibiting bronchospasm by 50%) than salmeterol, formoterol, and indacaterol (5.6 versus 3.3, 2.2, and 0.3, respectively). In conclusion, our results suggest that abediterol has a preclinical profile for once-daily dosing in humans together with a fast onset of action and a favorable cardiovascular safety profile.

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“…A novel LABA, olodaterol, is highly selective and a near full agonist at β 2 receptors providing 24-h bronchodilation in patients with COPD. Preliminary data suggest that olodaterol might also afford symptomatic benefit and enhanced exercise capacity [12][13][14].…”

mentioning

confidence: 99%

Treatment of COPD and the TOnado trial: a tempest in a teapot?

Rabe

2015

Eur Respir J

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@ERSpublicationsDespite encouraging results for LABA/LAMA combination therapy in mild COPD, can we justify the additional costs? http://ow.ly/JVNb6The treatment of COPD follows a stepwise approach in practically all clinical practice guidelines and also current strategy documents [1]. Lung function impairment or low forced expiratory volume in 1 s (FEV1), once considered the single most important treatment parameter, now represents one of the target parameters for risk reduction in patients with chronic obstructive pulmonary disease (COPD), alongside exacerbations and respiratory symptoms, dyspnoea in particular. Furthermore, more holistic COPD approaches increasingly recognise the importance of physical activity and multimorbidity for disease outcome, mortality in particular [2].Long-acting bronchodilators, such as long-acting muscarinic antagonists (LAMAs) and long-acting β 2 -adrenoceptor agonists (LABAs) are the cornerstone of maintenance therapy for patients with moderate-to-severe COPD whose symptoms are not adequately controlled by short-acting bronchodilators alone [1,3]. The crucial role of these drugs has, in part, been helped by the fact that long-acting bronchodilators, and LAMAs in particular, have demonstrated efficacy in preventing COPD exacerbations, a good safety record and might even decrease mortality [4,5]. Also, the role of inhaled steroids for chronic treatment remains controversial and largely unresolved, despite recent efforts to identify a COPD phenotype that might benefit from this form of treatment [6].Since anticholinergic drugs and β 2 -adrenoceptor agonists differ in their pharmacology and their target receptors, but both act on the level of airway smooth muscle tone, combinations of these drug classes have been used and have been advocated for the treatment of COPD for decades. It comes therefore with little surprise that also the combination of LAMA and LABA is recommended for COPD patients not adequately controlled on a single bronchodilator drug alone [1] resulting in the development of an increasingly confusing variety of LAMA+LABA fixed-dose combinations (FDCs), and their respective generic clones [3].In the current issue of the European Respiratory Journal, a novel candidate of this drug combination principle is presented by BUHL et al. [7]. Two replicate phase III trials aimed to assess the efficacy and safety of inhaled tiotropium+olodaterol FDC 5/5 µg or 2.5/5 µg delivered via the Respimat Soft Mist inhaler compared with their individual mono-components in patients with moderate-to-very-severe COPD (Global Initiative for Chronic Obstructive Lung Disease stage 2-4) over 52 weeks. The authors hypothesised that combination therapy with tiotropium+olodaterol FDC would provide improvements in lung function, health-related quality of life (St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks) and other COPD disease parameters compared to monotherapy with either component alone, and with a comparable safety profile.

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Functional and Biochemical Rationales for the 24-Hour-Long Duration of Action of Olodaterol

Cited by 83 publications

References 29 publications

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ₂-Adrenoceptor Agonist with 24-Hour Duration of Action

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ₂-Adrenoceptor Agonist with 24-Hour Duration of Action

Pharmacological Characterization of Abediterol, a Novel Inhaled β₂-Adrenoceptor Agonist with Long Duration of Action and a Favorable Safety Profile in Preclinical Models

Treatment of COPD and the TOnado trial: a tempest in a teapot?

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Functional and Biochemical Rationales for the 24-Hour-Long Duration of Action of Olodaterol

Cited by 83 publications

References 29 publications

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ2-Adrenoceptor Agonist with 24-Hour Duration of Action

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ2-Adrenoceptor Agonist with 24-Hour Duration of Action

Pharmacological Characterization of Abediterol, a Novel Inhaled β2-Adrenoceptor Agonist with Long Duration of Action and a Favorable Safety Profile in Preclinical Models

Treatment of COPD and the TOnado trial: a tempest in a teapot?

Contact Info

Product

Resources

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In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ₂-Adrenoceptor Agonist with 24-Hour Duration of Action

In Vitro Pharmacological Characterization of Vilanterol, a Novel Long-Actingβ₂-Adrenoceptor Agonist with 24-Hour Duration of Action

Pharmacological Characterization of Abediterol, a Novel Inhaled β₂-Adrenoceptor Agonist with Long Duration of Action and a Favorable Safety Profile in Preclinical Models