US Food and Drug Administration-Mandated Trials of Long-Acting β-Agonists Safety in Asthma

Suissa, Samy; Ariel, Amnon

doi:10.1378/chest.12-2881

Cited by 16 publications

(15 citation statements)

References 13 publications

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“…Xenopus laevis oocytes (Nasco, Fort Atkinson, WI) were coinjected with synthesized rat GABA A R subunit messenger RNAs (each a subunit [1][2][3][4][5][6] with b3 and g2, or a4 with b3 and d), as described previously (17), to express GABA A Rs of prescribed subunit composition. Concentration ranges of CMD-45 or XHe-III-74 were applied for 30 seconds before the addition of a 3% maximal effective concentration (EC 3 ) of GABA, and voltage-clamp current recordings were performed at a holding potential of 260 mV.…”

Section: Oocyte Electrophysiological Studiesmentioning

confidence: 99%

“…However, these therapies inadequately control symptoms for as many as 55% of subjects with asthma, even when care is consistent with current standards (3). Furthermore, the long-acting b 2 -agonists are under scrutiny for their safety and efficacy (4)(5)(6). As a result, new therapeutic strategies are sorely needed.…”

mentioning

confidence: 99%

“…However, there is legitimate concern that the therapeutic use of GABA A R modulators to alleviate bronchoconstriction may activate CNS GABA A Rs, leading to undesirable CNS side effects. GABA A Rs are pentamers made up of a combination of 19 possible subunits (a [1][2][3][4][5][6], b [1][2][3], g [1][2][3], d, e, u, p, and r [1][2][3]). Most commonly, these receptors contain two a subunits, two b subunits, and one "tertiary" subunit (g, d, e, u, or p), although other arrangements occur (9,10).…”

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confidence: 99%

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Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Yocum

Gallos

Zhang

et al. 2016

Am J Respir Cell Mol Biol

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We previously demonstrated that airway smooth muscle (ASM) cells express g-aminobutyric acid A receptors (GABA A Rs), and that GABA A R agonists acutely relax ASM. Among the GABA A R a subunits, human ASM cells express only a4 and a5, providing the opportunity for selective pharmacologic targeting. Novel GABA A R-positive allosteric modulators designed for enhanced a4/a6 subunit selectivity were synthesized using iterative computational analyses (CMD-45 and XHe-III-74). Studies using oocyte heterologous expression systems confirmed that CMD-45 and XHe-III-74 led to significantly greater augmentation of currents induced by a 3% maximal effective concentration (EC 3 ) of GABA [EC 3 ]-induced currents in oocytes expressing a4 or a6 subunits (along with b3 and g2) compared with other a subunits. CMD-45 and XHe-III-74 also led to greater ex vivo relaxation of contracted wild-type mouse tracheal rings compared with tracheal rings from GABA A R a4 subunit (Gabra4) knockout mice. Furthermore, CMD-45 and XHe-III-74 significantly relaxed precontracted human ASM ex vivo, and, at a low concentration, both ligands led to a significant leftward shift in albuterolmediated ASM relaxation. In vivo, inhaled XHe-III-74 reduced respiratory system resistance in an asthmatic mouse model. Pretreatment of human ASM cells with CMD-45 and XHe-III-74 inhibited histamine-induced increases in intracellular calcium concentrations in vitro, an effect that was lost when calcium was omitted from the extracellular buffer, suggesting that inhibition of calcium influx due to alterations in plasma membrane potential may play a role in the mechanism of ASM relaxation. Selective targeting of the GABA A R a4 subunit with inhaled ligands may be a novel therapeutic pathway to treat bronchoconstriction, while avoiding sedative central nervous system effects, which are largely mediated by a1-3 subunit-containing GABA A Rs in the brain.

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Section: Oocyte Electrophysiological Studiesmentioning

confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Yocum

Gallos

Zhang

et al. 2016

Am J Respir Cell Mol Biol

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“…Lingering concerns have led the US Food and Drug Administration (FDA) to require that manufacturers of LABA conduct randomised controlled trials (RCT) on the safety of the concomitant use of LABA and inhaled corticosteroids (ICS) versus ICS alone 1 3. The primary outcome of such trials is the composite event of asthma-related death, hospitalisation, or intubation, though it is already speculated that the results will be mainly driven by hospitalisation 3 13. The results of such RCTs will not be available for at least the next 5 years.…”

Section: Introductionmentioning

confidence: 99%

Dispensation of long-acting agonists with or without inhaled corticosteroids, and risk of asthma-related hospitalisation: a population-based study

Sadatsafavi

Lynd

Marra

2013

Thorax

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“…Whether this extensive programme of studies will provide definitive resolution remains uncertain (26). If 7 deaths are seen with ICS-LABA versus 1 with ICS in the 46,800 patients enrolled across these trials (a plausible if pessimistic estimate) that will still fail to exclude the possibility that the true difference is zero since the 95% confidence interval will straddle unity (relative risk 7.0; 95% confidence interval (CI), 0.9-56.9) (26).…”

Section: Main Textmentioning

confidence: 99%

Safety of β2-Agonists in Asthma: Linking Mechanisms, Meta-Analyses and Regulatory Practice

Dissanayake

2015

AAPS J

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Abstract. An epidemic of asthma fatalities in the 1970s prompted a series of case-control studies which indicated that short acting β-agonists increased the risk of death. Subsequent mechanistic and pharmacodynamic studies have suggested that β-agonist monotherapy facilitates airway inflammation, although when co-administered with inhaled corticosteroids (ICSs), similar evidence is lacking. The Salmeterol Multicenter Asthma Research Trial, which revealed a fourfold increase in asthma-related deaths in salmeterol-treated patients, prompted a paradigm shift in the evidential assessment of β-agonist safety. The FDA's meta-analysis of over 60,000 patients ultimately concluded that long-acting β-agonist (LABA) therapy increased the risk of serious asthma-related events. However, this meta-analysis itself raised questions given a large body of omitted data and a limited emphasis on the risk of ICS-LABA coadministration. Subsequently, the FDA mandated the conduct of five large studies to definitively ascertain whether ICS-LABAs increase asthma-related risk. Whether this ambitious programme will provide certainty remains to be seen given issues of multiplicity, the very low frequency of fatal and nearfatal asthma, and the administration of a free combination of ICS and LABA in one trial. The FDA's de facto use of FEV1 as a safety parameter, based on findings from the Foradil NDA, is a further topical issue: subsequent clinical study data, considerations relating to regional pulmonary drug deposition and pharmacological differences between different β-agonists suggest that FEV1 may be a suboptimal safety metric. Models evaluating airway inflammation and bronchial reactivity may be more appropriate to assess the relative risk of asthma-related events.

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US Food and Drug Administration-Mandated Trials of Long-Acting β-Agonists Safety in Asthma

Cited by 16 publications

References 13 publications

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

Dispensation of long-acting agonists with or without inhaled corticosteroids, and risk of asthma-related hospitalisation: a population-based study

Safety of β2-Agonists in Asthma: Linking Mechanisms, Meta-Analyses and Regulatory Practice

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