“…All patients inhaled aclidinium bromide 200 μg once daily over 3 days, followed by a second series of inhalations of aclidinium bromide 400 μg over 3 days after a washout period of 7 days. The results of this study showed that aclidinium bromide is rapidly degraded with no difference comparing young with elderly patients, and thereby confirmed the rapid degradation of aclidinium bromide, which had been reported by others 9,13,14,19. The plasma concentration of aclidinium bromide was not detectable at time points later than 3 hours after inhalation and this effect was independent of age.…”
Section: Clinical Benefits Of Rapid Aclidinium Bromide Metabolismsupporting
confidence: 89%
“…Aclidinium bromide is hydrolyzed by butyrylcholinesterase into either carboxylic acid or alcohol metabolites, and thus results in fewer systemic side effects than other muscarinic receptor inhibitors, including tiotropium 9,10. Based on preclinical and Phase I studies, it was concluded that aclidinium bromide would have fewer side effects than other muscarinic receptor antagonists, especially in the cardiovascular system 9–14…”
Chronic obstructive pulmonary disease (COPD) is increasing worldwide and is predicted to become the third most frequent cause of death by 2030. Muscarinic receptor antagonists, alone or in combination with long-acting β2-agonists, are frequently used for COPD therapy. Aclidinium bromide is a novel muscarinic receptor antagonist, and clinical studies indicate that its metabolism is more rapid than that of other muscarinic receptor inhibitors, so systemic side effects are expected to occur less frequently. Aclidinium bromide is well tolerated, and when compared with other muscarinic receptor antagonists, the drug achieves better control of lung function, especially night-time symptoms in COPD patients. This review summarizes the safety profile and side effects reported by recent clinical studies using aclidinium bromide alone.
“…All patients inhaled aclidinium bromide 200 μg once daily over 3 days, followed by a second series of inhalations of aclidinium bromide 400 μg over 3 days after a washout period of 7 days. The results of this study showed that aclidinium bromide is rapidly degraded with no difference comparing young with elderly patients, and thereby confirmed the rapid degradation of aclidinium bromide, which had been reported by others 9,13,14,19. The plasma concentration of aclidinium bromide was not detectable at time points later than 3 hours after inhalation and this effect was independent of age.…”
Section: Clinical Benefits Of Rapid Aclidinium Bromide Metabolismsupporting
confidence: 89%
“…Aclidinium bromide is hydrolyzed by butyrylcholinesterase into either carboxylic acid or alcohol metabolites, and thus results in fewer systemic side effects than other muscarinic receptor inhibitors, including tiotropium 9,10. Based on preclinical and Phase I studies, it was concluded that aclidinium bromide would have fewer side effects than other muscarinic receptor antagonists, especially in the cardiovascular system 9–14…”
Chronic obstructive pulmonary disease (COPD) is increasing worldwide and is predicted to become the third most frequent cause of death by 2030. Muscarinic receptor antagonists, alone or in combination with long-acting β2-agonists, are frequently used for COPD therapy. Aclidinium bromide is a novel muscarinic receptor antagonist, and clinical studies indicate that its metabolism is more rapid than that of other muscarinic receptor inhibitors, so systemic side effects are expected to occur less frequently. Aclidinium bromide is well tolerated, and when compared with other muscarinic receptor antagonists, the drug achieves better control of lung function, especially night-time symptoms in COPD patients. This review summarizes the safety profile and side effects reported by recent clinical studies using aclidinium bromide alone.
“…The activity of tiotropium on TRPV1 might be responsible, at least in part, for some of the clinical benefit associated with taking it and might suggest alternative applications for this compound outside of COPD in respiratory and nonrespiratory disorders in which cough is a major debilitating symptom. Several other LAMAs (eg, aclidinium bromide 46 ) are currently in clinical development, and it remains to be seen whether these compounds share the same beneficial properties.Key messagesRecent studies have suggested that the LAMA tiotropium, a drug widely prescribed for its bronchodilator activity in patients with COPD and asthma, improves symptoms and attenuates capsaicin-induced cough in preclinical and clinical challenge studies.For the first time, we have demonstrated that tiotropium inhibits TRPV1-mediated effects in sensory afferents through a mechanism unrelated to its anticholinergic activity.We suggest that some of the clinical benefit associated with taking tiotropium could be explained through this proposed mechanism of action.…”
BackgroundRecent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed.ObjectiveThe aim of this study was to investigate whether tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex.MethodsWe used a conscious cough model in guinea pigs, isolated vagal sensory nerve and isolated airway neuron tissue– and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques.ResultsInhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel–mediated responses. Complementary data were generated in airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes.ConclusionFor the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action.
“…There is little information available from studies of aclidinium plus formoterol; only initial results of preclinical cardiac safety in beagle dogs have been reported [80]. …”
Section: Combination Bronchodilation: Existing Evidence and Ongoing Smentioning
Chronic obstructive pulmonary disease (COPD) represents a significant cause of global morbidity and mortality, with a substantial economic impact. Recent changes in the Global initiative for chronic Obstructive Lung Disease (GOLD) guidance refined the classification of patients for treatment using a combination of spirometry, assessment of symptoms, and/or frequency of exacerbations. The aim of treatment remains to reduce existing symptoms while decreasing the risk of future adverse health events. Long-acting bronchodilators are the mainstay of therapy due to their proven efficacy. GOLD guidelines recommend combining long-acting bronchodilators with differing mechanisms of action if the control of COPD is insufficient with monotherapy, and recent years have seen growing interest in the additional benefits that combination of long-acting muscarinic antagonists (LAMAs), typified by tiotropium, with long-acting β2-agonists (LABAs), such as formoterol and salmeterol. Most studies have examined free combinations of currently available LAMAs and LABAs, broadly showing a benefit in terms of lung function and other patient-reported outcomes, although evidence is limited at present. Several once- or twice-daily fixed-dose LAMA/LABA combinations are under development, most involving newly developed monotherapy components. This review outlines the existing data for LAMA/LABA combinations in the treatment of COPD, summarizes the ongoing trials, and considers the evidence required to inform the role of LAMA/LABA combinations in treatment of this disease.
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