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Mario Cazzola - One of the best experts on this subject based on the ideXlab platform.
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assessing the clinical value of fast onset and sustained duration of action of long acting Bronchodilators for copd
Pulmonary Pharmacology & Therapeutics, 2015Co-Authors: Mario Cazzola, Kai M Beeh, David Price, Nicolas RocheAbstract:The long-acting inhaled Bronchodilators available for use in chronic obstructive pulmonary disease (COPD) vary in their pharmacological class (β2-adrenergic agonist or antimuscarinic/anticholinergic, alone or combined), durations of action and speed of onset of bronchodilator effect. In the early stages of development of a maintenance bronchodilator, the goals are to identify a molecule with the theoretically 'ideal' profile of fast onset and prolonged duration of action in comparison with existing agents, while minimizing non-specific activity at organs outside the lungs. The move towards increasing duration of bronchodilator action is generally paralleled by improved effects on clinical outcomes, and the advent of more potent agents seems likely to provide an opportunity to reduce overreliance on the use of inhaled corticosteroids in treating COPD. In terms of onset of action, an immediately perceived benefit in reducing dyspnea, although not definitively demonstrated, might prove useful in increasing adherence, which is very poor among patients with COPD. Once-daily administration may also be helpful in this respect. Shared decision-making between patient and physician in the choice of treatment is important in optimizing adherence and, thus, treatment effectiveness.
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long acting Bronchodilators in copd where are we now and where are we going
Breathe, 2014Co-Authors: Mario Cazzola, Clive P PageAbstract:Educational aims To discuss fundamental questions relating to the use of Bronchodilators that can lead to an optimisation of their utilisation. To describe new Bronchodilators that have recently been approved in some countries or are currently undergoing clinical development Summary Bronchodilators are central to the treatment of chronic obstructive pulmonary disease (COPD) because they alleviate bronchial obstruction and airflow limitation, reduce hyperinflation, and improve emptying of the lung and exercise performance. For this reason, all guidelines highlight that inhaled Bronchodilators are the mainstay of the current management of all stages of COPD. However, there are still fundamental questions regarding their use that require clarification to optimise utilisation of these drugs. It is crucial to address the following questions. Is it appropriate to treat all COPD patients with long-acting Bronchodilators? Is it better to start treatment with a β2-agonist or with an anti-muscarinic agent in patients with stable mild/moderate COPD? Is it useful to use a bronchodilator with rapid onset of action? Is it preferable to administer a bronchodilator on a once- or twice-daily basis? Can a second bronchodilator can be introduced for patients with stable COPD (“dual” bronchodilator therapy), and if so when? Are inhaled corticosteroids (ICSs) really useful in COPD patients without chronic bronchitis, since long-lasting Bronchodilators may prevent exacerbations even in the absence of an ICS in frequent exacerbators? Finally, is combined therapy really useful in non-frequent exacerbators? Due to the the central role of Bronchodilators in the treatment of COPD, there is still considerable interest in finding novel classes of bronchodilator drugs. However, new classes of Bronchodilators have proved difficult to develop because either new emerging targets are not really important and/or it is difficult to find substances capable of interacting with them. As a consequence, many research groups have sought to improve the existing classes of Bronchodilators.
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new developments in the combination treatment of copd focus on umeclidinium vilanterol
Drug Design Development and Therapy, 2013Co-Authors: Mario Cazzola, Andrea Segreti, Maria Gabriella MateraAbstract:An increasing body of evidence suggests that the long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination appears to play an important role in maximizing bronchodilation, with studies to date indicating that combining different classes of Bronchodilators may result in significantly greater improvements in lung function compared to the use of a single drug, and that these combinations are well tolerated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). An inhaled, fixed-dose combination of two 24-hour Bronchodilators, the LAMA umeclidinium and the LABA vilanterol, is under development as a once-daily treatment for COPD. The efficacy of both mono-components has already been demonstrated. The information currently available suggests that umeclidinium/vilanterol is an effective once-daily dual bronchodilator fixed-dose combination in the treatment of COPD. However, it remains to be seen if it compares favorably with current therapies. Moreover, the question remains whether umeclidinium/vilanterol fixed-dose combination, which significantly improves FEV1, is also associated with improvements in other outcome measures that are important to COPD patients.
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novel Bronchodilators for the treatment of chronic obstructive pulmonary disease
Trends in Pharmacological Sciences, 2011Co-Authors: Maria Gabriella Matera, Clive P Page, Mario CazzolaAbstract:Because of the central role of Bronchodilators in the treatment of respiratory diseases, there is still considerable interest in finding novel classes of broncholytic drugs. It can be hypothesized that a longer duration of bronchodilation with a once-daily agent might be associated with superior and more consistent efficacy over a range of endpoints than is achieved with a twice-daily agent. Several novel β(2)-adrenoceptor (AR) agonists, antimuscarinic agents, new combination platforms such as dual-acting muscarinic antagonist-β(2)-AR agonist Bronchodilators, xanthine drugs and phosphodiesterase inhibitors, and their combination with another bronchodilator class, or an inhaled corticosteroid are currently under development with the aim of achieving once-daily dosing and, therefore, increasing the likelihood of compliance with therapy. This review paper mainly focuses on recent results of preclinical studies that have used human tissue and clinical trials of new Bronchodilators in patients with chronic obstructive pulmonary disease.
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emerging inhaled Bronchodilators an update
European Respiratory Journal, 2009Co-Authors: Mario Cazzola, Maria Gabriella MateraAbstract:Bronchodilators remain central to the symptomatic management of chronic obstructive pulmonary disease and asthma, and, for this reason and also because the patent protection of many Bronchodilators has expired, several companies have reinitiated research into the field. The only limits set for the development of a long-lasting bronchodilator with a new product profile are medical needs and marketing opportunities. The incorporation of once-daily dose administration is an important strategy for improving adherence and is a regimen preferred by most patients. A variety of beta(2)-agonists and antimuscarinic agents with longer half-lives and inhalers containing a combination of several classes of long-acting bronchodilator are currently under development. The present article reviews all of the most important compounds under development, describing what has been done and discussing their genuine advantage.
Dave Singh - One of the best experts on this subject based on the ideXlab platform.
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the short term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor rpl554 in copd
European Respiratory Journal, 2018Co-Authors: Dave Singh, Katharine Abbottbanner, Thomas Bengtsson, Kenneth NewmanAbstract:Introduction: We investigated the short term bronchodilator effects of RPL554 (an inhaled dual phosphodiesterase 3 and 4 inhibitor) combined with other Bronchodilators in COPD patients with reversibility (>150 mL to short acting Bronchodilators). Methods: Study 1: six way placebo controlled crossover study (n=36) with single doses of RPL554 (6 mg), salbutamol (200 µg), ipratropium (40 µg), RPL554+salbutamol, RPL554+ipratropium and placebo. Study 2: three way crossover study (n=30) of tiotropium (18 µg) combined with RPL554 (1.5 mg or 6 mg) or placebo for 3 days. FEV 1 , lung volumes and sGaw were measured. Results: Study 1; Peak FEV 1 change compared to placebo was similar with RPL554, ipratropium and salbutamol (means 223, 199 and 187 mL respectively). The peak FEV 1 was higher for RPL554+ipratropium versus ipratropium (mean difference 94 mL, p versus salbutamol (mean difference 108 mL; p 1 effects than placebo. The average FEV 1 (0–12h) increase was greater with RPL554 6 mg only versus placebo (mean difference 65 mL p=0.0009). In both studies, lung volumes and sGaw showed greater RPL554 combination treatment effects versus monotherapy. Conclusion: RPL554 combined with standard Bronchodilators caused additional bronchodilation and hyperinflation reduction.
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anti inflammatory effect of a novel inhaled dual pde3 4 inhibitor rpl554 in man a unique first in class drug for the treatment of copd asthma
European Respiratory Journal, 2013Co-Authors: Dave Singh, Fred Reid, Lui Franciosi, Michael J A Walker, Clive P PageAbstract:Background: Current Bronchodilators have limited efficacy in severe COPD & asthma & the neutrophilic inflammation is not well treated. RPL554 is a novel, well tolerated dual PDE 3/4 inhibitor with significant bronchodilator properties in COPD & asthma, bronchoprotective effects in asthmatics & is anti-inflammatory pre-clinically. Aim: To evaluate the effect of RPL554 on inhaled lipopolysaccharide (LPS)-induced neutrophilia in sputum. Methods: In a randomised, double-blind, placebo (PBO)-controlled crossover study in 21 healthy subjects, RPL554 (0.018mg/kg)was inhaled using a jet nebuliser via an oro-nasal mask o.d for 6 days. On day 6 an inhaled LPS challenge was performed 1h post RPL554 or PBO using a Mefar dosimeter. Sputum was induced 6 & 24h post-LPS & cells/g sputum calculated. Results: RPL554 statistically significantly reduced total & individual cells, 6h post LPS vs PBO (Table 1). RPL554 was well-tolerated with AE’s being generally mild, transient & not different from PBO. RPL554’s PK properties were reproducible over 6 days. View this table: Table 1. Cells/g sputum Conclusions: RPL554 produced significant airway anti-inflammatory effects, including reducing neutrophil infiltration & is the first drug demonstrating bronchodilator & anti-inflammatory properties in one molecule. RPL554 is thus a promising “bifunctional” first in class treatment for patients with COPD or asthma and not well controlled on existing treatment.
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aclidinium bromide for the treatment of chronic obstructive pulmonary disease
Expert Review of Respiratory Medicine, 2012Co-Authors: Vandana Gupta, Dave SinghAbstract:Chronic obstructive pulmonary disease is characterized by poorly reversible airflow obstruction. Long-acting Bronchodilators improve lung function and relieve dyspnea. Aclidinium bromide is a novel long-acting antimuscarinic bronchodilator; Phase III clinical trials have demonstrated that administration of this drug twice per day improves lung function, dyspnea and health-related quality of life. Aclidinium bromide is delivered using the Genuair® device, which is an easy to use multidose dry powder inhaler. Aclidinium bromide is rapidly metabolized in the plasma, so there is low systemic exposure that minimizes the anticholinergic side effects. This new long-acting bronchodilator provides effective bronchodilation with minimal side effects.
Charlotte Suppli Ulrik - One of the best experts on this subject based on the ideXlab platform.
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clinical benefit of fixed dose dual bronchodilation with glycopyrronium and indacaterol once daily in patients with chronic obstructive pulmonary disease a systematic review
International Journal of Chronic Obstructive Pulmonary Disease, 2014Co-Authors: Charlotte Suppli UlrikAbstract:Background and aim Long-acting Bronchodilators are the preferred option for maintenance therapy of patients with chronic obstructive pulmonary disease (COPD). The aim of this review is to provide an overview of the clinical studies evaluating the clinical efficacy of the once-daily fixed-dose dual bronchodilator combination of indacaterol and glycopyrronium bromide in patients suffering from COPD.
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aclidinium bromide clinical benefit in patients with moderate to severe copd
The Open Respiratory Medicine Journal, 2012Co-Authors: Charlotte Suppli UlrikAbstract:Background and Aim: Long-acting Bronchodilators are the mainstay of pharmacological treatment for patients with chronic obstructive pulmonary disease (COPD). The aim of this review is to provide an overview of the clinical studies evaluating the safety and efficacy of inhaled aclidinium bromide, a novel long-acting anticholinergic bronchodilator, for the treatment of COPD.
James F. Donohue - One of the best experts on this subject based on the ideXlab platform.
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bronchodilator reversibility in copd
Chest, 2011Co-Authors: Nicola A. Hanania, Bartolome R Celli, James F. Donohue, Ubaldo J. MartinAbstract:COPD is a preventable and treatable disease characterized by airflow limitation that is not fully reversible. The diagnosis of COPD is based on spirometric evidence of airways obstruction following bronchodilator administration. Although it used to be commonly believed that patients with COPD have largely irreversible airflow obstruction, evidence now suggests that a considerable proportion of patients exhibit clinically significant bronchodilator reversibility. The complexity and inherent variability of a patient's acute response to a bronchodilator and the lack of a standardized procedure for assessing bronchodilator reversibility have led to significant confusion surrounding this concept. Although bronchodilator reversibility commonly is defined based on thresholds for improvement in FEV1, lung volume-based measures of pulmonary function may be of particular importance in patients with severe COPD. The usefulness of acute reversibility to short-acting Bronchodilators in predicting a patient's long-term response to bronchodilator maintenance therapy is also unclear, although most studies suggest that a lack of acute response to short-acting Bronchodilators does not preclude a beneficial long-term response to maintenance bronchodilator treatment. This review outlines recent findings about the prevalence and usefulness of bronchodilator reversibility in patients with COPD based on the available literature and proposes areas of future research.
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mono and combination therapy of long acting Bronchodilators and inhaled corticosteroids in advanced copd
Seminars in Respiratory and Critical Care Medicine, 2010Co-Authors: Jill A Ohar, James F. DonohueAbstract:Beta-2 adrenergic agonists are sympathomimetic agents that stimulate bronchodilation by activation of adenyl cyclase to produce cyclic 3'5' adenosine monophosphate (AMP). Short-acting beta-agonists (SABAs) have a 3- to 6-hour duration of action, and the duration of action of long-acting beta-agonists (LABAs) exceeds 12 hours. Because of their rapid onset of action, SABAs are effective for rescue from symptoms of chronic obstructive pulmonary disease (COPD). LABAs-salmeterol and formoterol-have been shown to significantly improve lung function, health status, and symptom reduction, compared with ipratropium. Despite safety concerns over the use of LABAs as monotherapy in asthma the use of these medications in COPD has generally been described as safe. Novel Bronchodilators for COPD in late-stage development include the beta-agonists indacterol and carmoterol. Parasympathetic activity in the large and medium-size airways is mediated through the muscarinic receptors and results in airway smooth-muscle contraction, mucus secretion, and possibly increased ciliary activity. Although short-acting ipratropium has been used as monotherapy or in combination with albuterol the use of long-acting antimuscarinics is superior in improving health outcomes. The use of tiotropium results in improved health status, dyspnea, and exercise capacity, and reduced hyperinflation and COPD exacerbation rate in patients with moderate to severe COPD. Analysis of prospective clinical trial data shows a mortality reduction in subjects treated with tiotropium, despite retrospective review of insurance claims that show an enhanced mortality. Theophylline is a nonselective phosphodiesterase inhibitor that acts as both a weak bronchodilator and a respiratory stimulant. Novel approaches include using the inhalation route to reduce side effects and combination with inhaled corticosteroids (ICS). However, because of its potential adverse effects and narrow therapeutic index, it should only be used when symptoms persist despite optimal bronchodilator therapy. Current guidelines highlight that for COPD patients uncontrolled by bronchodilator monotherapy, combination therapy is recommended. These include LABA/ICS and LAMA/LABA combinations. Bronchodilators and their combination with ICS are central to the management of COPD. The choice of agents is based primarily on disease stage, individual response, cost, side effect profile, and availability.
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pharmacologic interventions in chronic obstructive pulmonary disease Bronchodilators
Proceedings of the American Thoracic Society, 2007Co-Authors: Nicola A. Hanania, James F. DonohueAbstract:Chronic obstructive pulmonary disease (COPD) is a treatable disease characterized by progressive airflow limitation. Prevention of disease progression, improvement of symptoms, exercise tolerance, health status, and decrease in exacerbations and in mortality are the main goals of the management of COPD. Bronchodilators play a pivotal role in the treatment of symptomatic patients with COPD. Inhaled short-acting Bronchodilators are currently recommended for rescue of symptoms in patients with mild disease, whereas inhaled long-acting Bronchodilators are recommended as first-line agents for maintenance therapy in patients with moderate and severe disease and those with daily symptoms. Long-acting Bronchodilators improve symptoms, exercise tolerance, and health status, and reduce exacerbations in patients COPD. However, their effects on long-term decline in lung function and mortality are currently under investigation. When symptoms are not sufficiently controlled by the use of one bronchodilator, combining Bronchodilators of different classes may be a more effective approach. In fact, recent evidence supports the regular use of a combination of a long-acting beta2-adrenoceptor agonist and a long-acting anticholinergic agent in patients with severe COPD. Combining a long-acting beta2-adrenoceptor agonist with an inhaled corticosteroid has also been shown to be more effective than the use of either agent alone. The use of theophylline has declined in recent years because of its narrow therapeutic index, and should be reserved as a third-line option in patients with very severe disease. Several novel Bronchodilators are now in different stages of development for use alone or in combination with other agents.
Maria Gabriella Matera - One of the best experts on this subject based on the ideXlab platform.
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new developments in the combination treatment of copd focus on umeclidinium vilanterol
Drug Design Development and Therapy, 2013Co-Authors: Mario Cazzola, Andrea Segreti, Maria Gabriella MateraAbstract:An increasing body of evidence suggests that the long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination appears to play an important role in maximizing bronchodilation, with studies to date indicating that combining different classes of Bronchodilators may result in significantly greater improvements in lung function compared to the use of a single drug, and that these combinations are well tolerated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). An inhaled, fixed-dose combination of two 24-hour Bronchodilators, the LAMA umeclidinium and the LABA vilanterol, is under development as a once-daily treatment for COPD. The efficacy of both mono-components has already been demonstrated. The information currently available suggests that umeclidinium/vilanterol is an effective once-daily dual bronchodilator fixed-dose combination in the treatment of COPD. However, it remains to be seen if it compares favorably with current therapies. Moreover, the question remains whether umeclidinium/vilanterol fixed-dose combination, which significantly improves FEV1, is also associated with improvements in other outcome measures that are important to COPD patients.
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novel Bronchodilators for the treatment of chronic obstructive pulmonary disease
Trends in Pharmacological Sciences, 2011Co-Authors: Maria Gabriella Matera, Clive P Page, Mario CazzolaAbstract:Because of the central role of Bronchodilators in the treatment of respiratory diseases, there is still considerable interest in finding novel classes of broncholytic drugs. It can be hypothesized that a longer duration of bronchodilation with a once-daily agent might be associated with superior and more consistent efficacy over a range of endpoints than is achieved with a twice-daily agent. Several novel β(2)-adrenoceptor (AR) agonists, antimuscarinic agents, new combination platforms such as dual-acting muscarinic antagonist-β(2)-AR agonist Bronchodilators, xanthine drugs and phosphodiesterase inhibitors, and their combination with another bronchodilator class, or an inhaled corticosteroid are currently under development with the aim of achieving once-daily dosing and, therefore, increasing the likelihood of compliance with therapy. This review paper mainly focuses on recent results of preclinical studies that have used human tissue and clinical trials of new Bronchodilators in patients with chronic obstructive pulmonary disease.
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emerging inhaled Bronchodilators an update
European Respiratory Journal, 2009Co-Authors: Mario Cazzola, Maria Gabriella MateraAbstract:Bronchodilators remain central to the symptomatic management of chronic obstructive pulmonary disease and asthma, and, for this reason and also because the patent protection of many Bronchodilators has expired, several companies have reinitiated research into the field. The only limits set for the development of a long-lasting bronchodilator with a new product profile are medical needs and marketing opportunities. The incorporation of once-daily dose administration is an important strategy for improving adherence and is a regimen preferred by most patients. A variety of beta(2)-agonists and antimuscarinic agents with longer half-lives and inhalers containing a combination of several classes of long-acting bronchodilator are currently under development. The present article reviews all of the most important compounds under development, describing what has been done and discussing their genuine advantage.
