Outpatient treatment of chronic obstructive pulmonary disease: Comparisons with asthma

Sutherland, E. Rand

doi:10.1016/j.jaci.2004.07.044

Cited by 17 publications

(10 citation statements)

References 115 publications

(98 reference statements)

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“…However, its major drawback is its short duration of action (4 -6 h), requiring the drug to be administered several times a day. Two longer acting inhaled ␤ 2 adrenoceptor agonists, formoterol and salmeterol, are now available and are used in the management of asthma and COPD (Sutherland, 2004). These two drugs have a bronchodilating effect lasting for 12 h after a single inhalation and are therefore given twice daily.…”

Section: Introductionmentioning

confidence: 99%

In Vitro and in Vivo Pharmacological Characterization of 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (Indacaterol), a Novel Inhaled β₂Adrenoceptor Agonist with a 24-h Duration of Action

Battram

Charlton²,

Cuenoud³

et al. 2006

J Pharmacol Exp Ther

154

125

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Here, we describe the preclinical pharmacological profile of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (indacaterol), a novel, chirally pure inhaled ␤ 2 adrenoceptor agonist, in comparison with marketed drugs. Indacaterol is close to a full agonist at the human ␤ 2 adrenoceptor (E max ϭ 73 Ϯ 1% of the maximal effect of isoprenaline; pEC 50 ϭ 8.06 Ϯ 0.02), whereas salmeterol displays only partial efficacy (38 Ϯ 1%). The functional selectivity profile of indacaterol over ␤ 1 human adrenoceptors is similar to that of formoterol, whereas its ␤ 3 adrenoceptor selectivity profile is similar to that of formoterol and salbutamol. In isolated superfused guinea pig trachea, indacaterol has a fast onset of action (30 Ϯ 4 min) similar to formoterol and salbutamol, and a long duration of action (529 Ϯ 99 min) comparable with salmeterol. In the conscious guinea pig, when given intratracheally as a dry powder, indacaterol inhibits 5-hydroxytryptamine-induced bronchoconstriction for at least 24 h, whereas salmeterol, formoterol, and salbutamol have durations of action of 12, 4, and 2 h, respectively. When given via nebulization to anesthetized rhesus monkeys, all of the compounds dose-dependently inhibit methacholine-induced bronchoconstriction, although indacaterol produces the most prolonged bronchoprotective effect and induces the lowest increase in heart rate for a similar degree of antibronchoconstrictor activity. In conclusion, the preclinical profile of indacaterol suggests that this compound has a superior duration of action compatible with once-daily dosing in human, together with a fast onset of action and an improved cardiovascular safety profile over marketed inhaled ␤ 2 adrenoceptor agonists.Agents that act as agonists of the ␤ 2 adrenoceptor are effective in the management of asthma and chronic obstructive pulmonary disease (COPD), primarily through their bronchodilatating properties. These drugs induce bronchodilatation by causing direct relaxation of airway smooth muscle through activation of adenylate cyclase, which in turn increases intracellular cAMP levels.Salbutamol is an inhaled ␤ 2 adrenoceptor agonist that provides rapid bronchodilatation and has been widely used over the past 30 years. However, its major drawback is its short duration of action (4 -6 h), requiring the drug to be administered several times a day. Two longer acting inhaled ␤ 2 adrenoceptor agonists, formoterol and salmeterol, are now available and are used in the management of asthma and COPD (Sutherland, 2004). These two drugs have a bronchodilating effect lasting for 12 h after a single inhalation and are therefore given twice daily. Despite the decrease in dosing frequency with the longer acting inhaled ␤ 2 adrenoceptor agonists, patient compliance is still an issue (Ying et al., 1999). In addition, the recent launch of tiotropium bromide, a once-daily inhaled muscarinic antagonist for the treatment of COPD (Gross, 2004), and the development of once-daily inhaled corticosteroids for the...

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Section: Introductionmentioning

confidence: 99%

In Vitro and in Vivo Pharmacological Characterization of 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (Indacaterol), a Novel Inhaled β₂Adrenoceptor Agonist with a 24-h Duration of Action

Battram

Charlton²,

Cuenoud³

et al. 2006

J Pharmacol Exp Ther

154

125

View full text Add to dashboard Cite

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“…, 2008; Knox and Mortimer, 2008). In patients with mild disease, short‐acting agonists are recommended, but for patients in whom these are not effective, longer‐acting β 2 ‐adrenoceptor agonists (LABAs) have been developed that more effectively maintain airway tone over a longer period of time (Sutherland, 2004). One risk of long‐term exposure of a G protein‐coupled receptor (GPCR) agonist is desensitization of the response, most commonly via receptor phosphorylation and internalization (Johnson, 2006).…”

mentioning

confidence: 99%

Agonist efficacy and receptor desensitization: from partial truths to a fuller picture

Charlton

2009

British J Pharmacology

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It has been demonstrated that the degree of agonist-induced desensitization of the b2-adrenoceptor is related to agonist efficacy (strength of signalling), whereby high-efficacy agonists (e.g. formoterol) cause more phosphorylation and internalization of the receptor than low-efficacy agonists (e.g. salmeterol). These early studies, however, used a protocol where agonists were matched for receptor occupancy rather than functional effect. In this issue of the BJP, Duringer and colleagues have extended these studies to compare the ability of agonists to cause desensitization at equi-effective (cAMP signalling) concentrations rather than equal occupancy. Their data and conclusions are quite different from those previously described. After prolonged exposure, all the agonists caused a similar degree of desensitization, whereas a pulse protocol uncovered a greater loss of responsiveness with the low-efficacy ligands. This is consistent with the notion that high-efficacy agonists have 'spare receptors', and are therefore less sensitive to loss of receptors through desensitization. It also reflects experience in the clinic, where both formoterol and salmeterol show a similar early decline in bronchoprotection, after which their effects remain stable. These findings challenge the notion that high-efficacy ligands always cause more functional desensitization.

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“…В связи с этим бóльшая часть информации о них получена при исследованиях образцов тканей от пациентов-курильщиков, перенесших резекцию легких по поводу опухолей, или посмертных образцов. Морфологические проявления ремоделирования включают фиброз субэпителиальной базальной мембраны, гиперплазию бокаловидных клеток в покровном эпителии, увеличение кровеносных сосудов и пролиферацию гладких мышц дыхательных путей с увеличением их массы за счет гиперплазии и гипертрофии [11,[14][15][16]. Наличие патоморфологических изменений при ремоделировании описано и в крупных дыхательных путях с деструкцией хрящевых пластинок, вплоть до их полной атрофии и/или замещения костной тканью [6,17].…”

Section: изменения стенки бронхов при хоблunclassified

Morphological changes in the respiratory organs in chronic obstructive pulmonary disease

Малыхин¹,

Kostornaya²

2016

Arkh. patol.

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The basis for airway remoldeling in patients with chronic obstructive pulmonary disease (COPD) is tissue changes contributing to thickening of the walls of the airway and its obstruction. As the disease becomes severer, there are increases in mucosal metaplasia, submucosal hypertrophy, peribronchial fibrosis, and airway smooth muscle mass. Drug therapy for COPD does not virtually lead to regression of airway obstruction, except when eosinophilia is present.

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Outpatient treatment of chronic obstructive pulmonary disease: Comparisons with asthma

Cited by 17 publications

References 115 publications

In Vitro and in Vivo Pharmacological Characterization of 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (Indacaterol), a Novel Inhaled β₂Adrenoceptor Agonist with a 24-h Duration of Action

In Vitro and in Vivo Pharmacological Characterization of 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (Indacaterol), a Novel Inhaled β₂Adrenoceptor Agonist with a 24-h Duration of Action

Agonist efficacy and receptor desensitization: from partial truths to a fuller picture

Morphological changes in the respiratory organs in chronic obstructive pulmonary disease

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Outpatient treatment of chronic obstructive pulmonary disease: Comparisons with asthma

Cited by 17 publications

References 115 publications

In Vitro and in Vivo Pharmacological Characterization of 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (Indacaterol), a Novel Inhaled β2Adrenoceptor Agonist with a 24-h Duration of Action

In Vitro and in Vivo Pharmacological Characterization of 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (Indacaterol), a Novel Inhaled β2Adrenoceptor Agonist with a 24-h Duration of Action

Agonist efficacy and receptor desensitization: from partial truths to a fuller picture

Morphological changes in the respiratory organs in chronic obstructive pulmonary disease

Contact Info

Product

Resources

About

In Vitro and in Vivo Pharmacological Characterization of 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (Indacaterol), a Novel Inhaled β₂Adrenoceptor Agonist with a 24-h Duration of Action

In Vitro and in Vivo Pharmacological Characterization of 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (Indacaterol), a Novel Inhaled β₂Adrenoceptor Agonist with a 24-h Duration of Action