<p>Ultra Long-Acting β-Agonists in Chronic Obstructive Pulmonary Disease</p>

Abstract

Introduction Inhaled β-agonists have been foundational medications for maintenance COPD management for decades. Through activation of cyclic adenosine monophosphate pathways, these agents relax airway smooth muscle and improve expiratory airflow by relieving bronchospasm and alleviating air trapping and dynamic hyperinflation improving breathlessness, exertional capabilities, and quality of life. β-agonist drug development has discovered drugs with increasing longer durations of action: short acting (SABA) (4–6 h), long acting (LABA) (6–12 h), and ultra-long acting (ULABA) (24 h). Three ULABAs, indacaterol, olodaterol, and vilanterol, are approved for clinical treatment of COPD. Purpose This article reviews both clinically approved ULABAs and ULABAs in development. Conclusion Indacaterol and olodaterol were originally approved for clinical use as monotherapies for COPD. Vilanterol is the first ULABA to be approved only in combination with other respiratory medications. Although there are many other ULABA’s in various stages of development, most clinical testing of these novel agents is suspended or proceeding slowly. The three approved ULABAs are being combined with antimuscarinic agents and corticosteroids as dual and triple agent treatments that are being tested for clinical use and efficacy. Increasingly, these clinical trials are using specific COPD clinical characteristics to define study populations and to begin to develop therapies that are trait-specific.

In Silico Drug Repurposing Framework Predicts Repaglinide, Agomelatine and Protokylol as TRPV1 Modulators with Analgesic Activity

“…Protokylol, a β2-adrenergic agonist used as a bronchodilator [57] emerged as a compound with the second highest probability of exerting agonist activity on TRPV1. Two different, overlapping binding sites were observed for protokylol, one specific to vanilloids and competitive antagonists and another for phosphoinositides [59].…”

“…Bronchodilator protokylol [57] showed the second highest estimated probability for acting as a TRPV1 agonist. Protokylol had an average activity score of 2.76, its molecule containing the 5-(5-cyclohexylpentyl)-octahydro-1H-indene BM skeleton (BM-126), represented by the benzene (PR-1) and benzodioxole (PR-44) plain rings, these structural features being also present among TRPV1 agonists.…”

Double broncholytic combination of umeclidnium/ vilanterol in COPD therapy: issues of efficacy and safety

“…Вилантерол обладает высокой селективностью к β 2 -адренорецепторам. По данным исследований, его селективность выше, чем у сальбутамола, формотерола, индакатерола, и сходна с салметеролом [25][26][27]. В исследованиях показано, что после ингаляции вилантерола средняя C max достигалась через 5-15 мин, абсолютная биодоступность ингаляционного вилантерола составляла около 27%.…”

“…В исследованиях показано, что после ингаляции вилантерола средняя C max достигалась через 5-15 мин, абсолютная биодоступность ингаляционного вилантерола составляла около 27%. In vitrocвязывание с белками плазмы крови человека в среднем составляет 94% [26]. В клинических исследованиях применение вилантерола в дозе 25 мкг у пациентов с ХОБЛ в первый день приема уже через 6 мин увеличивало ОФВ 1 на > 100 мл от исходного [28].…”

The mechanobiology of airway narrowing in asthma

“…Numerous ULABA drugs have been developed and studied in clinical trials, some which show promising bronchoprotective effects, however, others have been shown to adversely affect the heart 275 . Long acting muscarinic antagonists (LAMAs) are also used as bronchodilators in asthmatics, as they block cholinergic signaling from nerves and reduce airway tone 276 , but studies have demonstrated that they can impair ciliary beating, increasing infection and mucus plugs 277 .…”