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Gary T Ferguson - One of the best experts on this subject based on the ideXlab platform.

  • Benefits of Tiotropium/Olodaterol Compared with Tiotropium in Patients with COPD Receiving only LAMA at Baseline: Pooled Analysis of the TONADO^® and OTEMTO^® Studies
    Advances in Therapy, 2020
    Co-Authors: Roland Buhl, Dave Singh, Gary T Ferguson
    Abstract:

    Introduction The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (LAMA) or long-acting β_2-agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted. Methods TONADO^® 1&2 and OTEMTO^® 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with LAMA monotherapy at baseline who were randomised to receive either 5 µg tiotropium (LAMA) or 5/5 µg tiotropium/Olodaterol (LAMA/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV_1), St. George’s Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI). Results Overall, 151 patients received tiotropium; 148 received tiotropium/Olodaterol. Mean differences from baseline with tiotropium/Olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P  = 0.0004) for trough FEV_1, − 2.675 (95% CI − 5.060, − 0.291; P  = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P  = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/Olodaterol versus tiotropium for trough FEV_1 (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P  

  • Efficacy of Tiotropium/Olodaterol Compared with Tiotropium as a First-Line Maintenance Treatment in Patients with COPD Who Are Naïve to LAMA, LABA and ICS: Pooled Analysis of Four Clinical Trials
    Advances in Therapy, 2020
    Co-Authors: Roland Buhl, Dave Singh, Gary T Ferguson
    Abstract:

    People with chronic obstructive pulmonary disease (COPD) often have problems breathing, which can make it difficult to carry out daily physical tasks. Bronchodilators are a type of medication that relax the muscles in the lungs and widen airways, making it easier to breathe. Evidence suggests that using a combination of two different bronchodilators is more effective than using one bronchodilator on its own. In this article, we look at four large studies that compared the effects of at least 12 weeks of treatment with two bronchodilators (tiotropium/Olodaterol) with tiotropium on its own in people who had not received any previous medication for their COPD. The results suggest that people who were treated with tiotropium and Olodaterol together had significantly better improvements in lung function, quality of life and breathlessness after 12 weeks than those taking tiotropium alone, without compromising safety. Overall, people treated with tiotropium/Olodaterol were 60% more likely to experience a meaningful improvement in at least one of these areas compared with those on tiotropium alone. These results support the use of tiotropium and Olodaterol together as a first medication for COPD. Introduction The efficacy of tiotropium/Olodaterol compared with tiotropium in patients with chronic obstructive pulmonary disease (COPD) has been demonstrated in a large clinical programme. Currently, randomised controlled trial (RCT) data on dual bronchodilation as first-line maintenance therapy are limited. In this post hoc analysis of pooled data from four RCTs, we compared the efficacy of tiotropium/Olodaterol versus tiotropium as maintenance therapy in patients with COPD who were not receiving maintenance treatment with long-acting muscarinic antagonists (LAMAs), long-acting β_2-agonists (LABAs) or inhaled corticosteroids (ICS) (“maintenance naïve”) at study entry. Methods TONADO^® 1/2 (52 weeks) and OTEMTO^® 1/2 (12 weeks) were phase III RCTs in patients with COPD. TONADO 1/2 and OTEMTO 1/2 enrolled patients with post-bronchodilator forced expiratory volume in 1 s (FEV_1) 

  • Benefits of Tiotropium/Olodaterol Compared with Tiotropium in Patients with COPD Receiving only LAMA at Baseline: Pooled Analysis of the TONADO® and OTEMTO® Studies.
    Advances in therapy, 2020
    Co-Authors: Roland Buhl, Dave Singh, Gary T Ferguson
    Abstract:

    The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (LAMA) or long-acting β2-agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted. TONADO® 1&2 and OTEMTO® 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with LAMA monotherapy at baseline who were randomised to receive either 5 µg tiotropium (LAMA) or 5/5 µg tiotropium/Olodaterol (LAMA/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV1), St. George's Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI). Overall, 151 patients received tiotropium; 148 received tiotropium/Olodaterol. Mean differences from baseline with tiotropium/Olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P = 0.0004) for trough FEV1, - 2.675 (95% CI - 5.060, - 0.291; P = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/Olodaterol versus tiotropium for trough FEV1 (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P < 0.0001), SGRQ (OR 1.49, 95% CI 0.93, 2.40; P = 0.0980) and TDI (OR 2.81, 95% CI 1.71, 4.60; P < 0.0001). Minimum clinically important difference from baseline in any of the analysed outcomes (FEV1 ≥ 0.1 l, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) was more likely in patients treated with tiotropium/Olodaterol versus tiotropium (OR 2.43, 95% CI 1.32, 4.51; P = 0.0046). In patients with COPD receiving only LAMA monotherapy, treatment escalation to tiotropium/Olodaterol resulted in statistically significant and clinically relevant improvements in lung function, health status and breathlessness. These results support early therapy optimisation to dual bronchodilation with tiotropium/Olodaterol in patients receiving tiotropium alone. TONADO® 1 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431274). TONADO® 2 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431287). OTEMTO® 1 was registered in the US National Library of Medicine on 17 October 2013 (Clinicaltrials.gov: NCT01964352). OTEMTO® 2 was registered in the US National Library of Medicine on 10 December 2013 (Clinicaltrials.gov: NCT02006732).

  • benefits of tiotropium Olodaterol compared with tiotropium in patients with copd receiving only lama at baseline pooled analysis of the tonado and otemto studies
    Advances in Therapy, 2020
    Co-Authors: R Buhl, Dave Singh, Gary T Ferguson
    Abstract:

    INTRODUCTION The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (LAMA) or long-acting β2-agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted. METHODS TONADO® 1&2 and OTEMTO® 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with LAMA monotherapy at baseline who were randomised to receive either 5 µg tiotropium (LAMA) or 5/5 µg tiotropium/Olodaterol (LAMA/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV1), St. George's Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI). RESULTS Overall, 151 patients received tiotropium; 148 received tiotropium/Olodaterol. Mean differences from baseline with tiotropium/Olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P = 0.0004) for trough FEV1, - 2.675 (95% CI - 5.060, - 0.291; P = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/Olodaterol versus tiotropium for trough FEV1 (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P < 0.0001), SGRQ (OR 1.49, 95% CI 0.93, 2.40; P = 0.0980) and TDI (OR 2.81, 95% CI 1.71, 4.60; P < 0.0001). Minimum clinically important difference from baseline in any of the analysed outcomes (FEV1 ≥ 0.1 l, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) was more likely in patients treated with tiotropium/Olodaterol versus tiotropium (OR 2.43, 95% CI 1.32, 4.51; P = 0.0046). CONCLUSION In patients with COPD receiving only LAMA monotherapy, treatment escalation to tiotropium/Olodaterol resulted in statistically significant and clinically relevant improvements in lung function, health status and breathlessness. These results support early therapy optimisation to dual bronchodilation with tiotropium/Olodaterol in patients receiving tiotropium alone. TRIAL REGISTRATION TONADO® 1 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431274). TONADO® 2 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431287). OTEMTO® 1 was registered in the US National Library of Medicine on 17 October 2013 (Clinicaltrials.gov: NCT01964352). OTEMTO® 2 was registered in the US National Library of Medicine on 10 December 2013 (Clinicaltrials.gov: NCT02006732).

  • Safety of tiotropium/Olodaterol in chronic obstructive pulmonary disease: pooled analysis of three large, 52-week, randomized clinical trials.
    Respiratory Medicine, 2018
    Co-Authors: Gary T Ferguson, Ulrich Bothner, Roland Buhl, Antonio Anzueto, Florian Voß, Peter M A Calverley
    Abstract:

    Abstract Background An extensive clinical trial program supports the efficacy and safety of tiotropium/Olodaterol in chronic obstructive pulmonary disease (COPD). We examined the safety of tiotropium/Olodaterol compared with tiotropium in a large population of patients, focusing on cardiovascular and respiratory events. Methods Patients (n = 9942) who received once-daily tiotropium/Olodaterol 5/5 μg or tiotropium 5 μg (via Respimat®) in TONADO 1 & 2 and DYNAGITO were included. The number of patients and exposure-adjusted rate of events are presented for adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, and cardiovascular and respiratory events. Findings Fewer patients discontinued due to AEs with tiotropium/Olodaterol (5.9%) versus tiotropium (7.9%; rate ratio [RR] 0.72; 95% confidence interval [CI] 0.62–0.84). There was no significant difference in the incidence of AEs, SAEs, cardiovascular AEs or central nervous system vascular AEs between treatments. Incidences of major adverse cardiovascular events (MACE) were 2.11 per 100 patient-years with tiotropium/Olodaterol and 2.22 with tiotropium (RR 0.95; 95% CI 0.72–1.25), and incidences of fatal MACE (including death with undetermined cause) were 0.91 and 1.00 per 100 patient-years with tiotropium/Olodaterol and tiotropium, respectively (RR 0.91; 95% CI 0.60–1.37). Respiratory AEs were generally balanced between treatment groups. Conclusions These results provide robust evidence that the benefits of tiotropium/Olodaterol versus tiotropium are not at the expense of an increased risk of safety events. The combination is a suitable option for patients with COPD, even in the presence of cardiovascular risk factors. Clinical trials registration clinicaltrials. gov (TONADO 1 and 2: NCT01431274, NCT01431287; DYNAGITO: NCT02296138).

Roland Buhl - One of the best experts on this subject based on the ideXlab platform.

  • Benefits of Tiotropium/Olodaterol Compared with Tiotropium in Patients with COPD Receiving only LAMA at Baseline: Pooled Analysis of the TONADO^® and OTEMTO^® Studies
    Advances in Therapy, 2020
    Co-Authors: Roland Buhl, Dave Singh, Gary T Ferguson
    Abstract:

    Introduction The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (LAMA) or long-acting β_2-agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted. Methods TONADO^® 1&2 and OTEMTO^® 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with LAMA monotherapy at baseline who were randomised to receive either 5 µg tiotropium (LAMA) or 5/5 µg tiotropium/Olodaterol (LAMA/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV_1), St. George’s Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI). Results Overall, 151 patients received tiotropium; 148 received tiotropium/Olodaterol. Mean differences from baseline with tiotropium/Olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P  = 0.0004) for trough FEV_1, − 2.675 (95% CI − 5.060, − 0.291; P  = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P  = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/Olodaterol versus tiotropium for trough FEV_1 (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P  

  • Efficacy of Tiotropium/Olodaterol Compared with Tiotropium as a First-Line Maintenance Treatment in Patients with COPD Who Are Naïve to LAMA, LABA and ICS: Pooled Analysis of Four Clinical Trials
    Advances in Therapy, 2020
    Co-Authors: Roland Buhl, Dave Singh, Gary T Ferguson
    Abstract:

    People with chronic obstructive pulmonary disease (COPD) often have problems breathing, which can make it difficult to carry out daily physical tasks. Bronchodilators are a type of medication that relax the muscles in the lungs and widen airways, making it easier to breathe. Evidence suggests that using a combination of two different bronchodilators is more effective than using one bronchodilator on its own. In this article, we look at four large studies that compared the effects of at least 12 weeks of treatment with two bronchodilators (tiotropium/Olodaterol) with tiotropium on its own in people who had not received any previous medication for their COPD. The results suggest that people who were treated with tiotropium and Olodaterol together had significantly better improvements in lung function, quality of life and breathlessness after 12 weeks than those taking tiotropium alone, without compromising safety. Overall, people treated with tiotropium/Olodaterol were 60% more likely to experience a meaningful improvement in at least one of these areas compared with those on tiotropium alone. These results support the use of tiotropium and Olodaterol together as a first medication for COPD. Introduction The efficacy of tiotropium/Olodaterol compared with tiotropium in patients with chronic obstructive pulmonary disease (COPD) has been demonstrated in a large clinical programme. Currently, randomised controlled trial (RCT) data on dual bronchodilation as first-line maintenance therapy are limited. In this post hoc analysis of pooled data from four RCTs, we compared the efficacy of tiotropium/Olodaterol versus tiotropium as maintenance therapy in patients with COPD who were not receiving maintenance treatment with long-acting muscarinic antagonists (LAMAs), long-acting β_2-agonists (LABAs) or inhaled corticosteroids (ICS) (“maintenance naïve”) at study entry. Methods TONADO^® 1/2 (52 weeks) and OTEMTO^® 1/2 (12 weeks) were phase III RCTs in patients with COPD. TONADO 1/2 and OTEMTO 1/2 enrolled patients with post-bronchodilator forced expiratory volume in 1 s (FEV_1) 

  • Benefits of Tiotropium/Olodaterol Compared with Tiotropium in Patients with COPD Receiving only LAMA at Baseline: Pooled Analysis of the TONADO® and OTEMTO® Studies.
    Advances in therapy, 2020
    Co-Authors: Roland Buhl, Dave Singh, Gary T Ferguson
    Abstract:

    The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report recommends long-acting muscarinic antagonists (LAMA) or long-acting β2-agonists (LABA) as first-line treatment for chronic obstructive pulmonary disease (COPD), but many patients remain symptomatic on monotherapy and escalation to dual-bronchodilator therapy may be warranted. TONADO® 1&2 and OTEMTO® 1&2 assessed lung function and patient-reported outcomes in patients with moderate-to-severe (OTEMTO) or moderate-to-very-severe (TONADO) COPD. This pooled post hoc analysis included patients treated with LAMA monotherapy at baseline who were randomised to receive either 5 µg tiotropium (LAMA) or 5/5 µg tiotropium/Olodaterol (LAMA/LABA). We assessed changes from baseline and responder rates for trough forced expiratory volume in 1 s (FEV1), St. George's Respiratory Questionnaire (SGRQ) and the Transition Dyspnoea Index (TDI). Overall, 151 patients received tiotropium; 148 received tiotropium/Olodaterol. Mean differences from baseline with tiotropium/Olodaterol versus tiotropium were + 0.074 l (95% confidence interval [CI] 0.033, 0.115; P = 0.0004) for trough FEV1, - 2.675 (95% CI - 5.060, - 0.291; P = 0.0280) for SGRQ and 1.148 (95% CI 0.564, 1.732; P = 0.0001) for TDI. Patients were more likely to respond when treated with tiotropium/Olodaterol versus tiotropium for trough FEV1 (odds ratio [OR] 3.14, 95% CI 1.94, 5.06; P < 0.0001), SGRQ (OR 1.49, 95% CI 0.93, 2.40; P = 0.0980) and TDI (OR 2.81, 95% CI 1.71, 4.60; P < 0.0001). Minimum clinically important difference from baseline in any of the analysed outcomes (FEV1 ≥ 0.1 l, SGRQ ≥ 4.0 points or TDI ≥ 1.0 point) was more likely in patients treated with tiotropium/Olodaterol versus tiotropium (OR 2.43, 95% CI 1.32, 4.51; P = 0.0046). In patients with COPD receiving only LAMA monotherapy, treatment escalation to tiotropium/Olodaterol resulted in statistically significant and clinically relevant improvements in lung function, health status and breathlessness. These results support early therapy optimisation to dual bronchodilation with tiotropium/Olodaterol in patients receiving tiotropium alone. TONADO® 1 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431274). TONADO® 2 was registered in the US National Library of Medicine on 9 September 2011 (Clinicaltrials.gov: NCT01431287). OTEMTO® 1 was registered in the US National Library of Medicine on 17 October 2013 (Clinicaltrials.gov: NCT01964352). OTEMTO® 2 was registered in the US National Library of Medicine on 10 December 2013 (Clinicaltrials.gov: NCT02006732).

  • Assessment of physical functioning and handling of tiotropium/Olodaterol Respimat® in patients with COPD in a real-world clinical setting.
    International Journal of Chronic Obstructive Pulmonary Disease, 2019
    Co-Authors: Karlotto Steinmetz, Birgit Abenhardt, Stefan Pabst, Michaela Hansel, A Kondla, Valentina Bayer, Roland Buhl
    Abstract:

    Background: Patients with chronic obstructive pulmonary disease (COPD) show signs of reduced physical activity from the early stages of the disease, impacting morbidity and mortality. Data suggest treatment with tiotropium, a long-acting muscarinic antagonist, and Olodaterol, a long-acting s2-agonist (LABA), as monotherapies and in combination, increases exercise capacity. This study assessed the effects of fixed-dose tiotropium/Olodaterol (delivered via Respimat®) on physical function in Global Initiative for Chronic Obstructive Lung Disease A-D patients requiring long-acting dual bronchodilation treatment in a real-world setting. Methods: This open-label, single arm, noninterventional study measured changes in physical function in COPD patients treated with tiotropium/Olodaterol 5/5 μg for approximately 6 weeks (between Visit 1 [baseline] and Visit 2). Primary end point was therapeutic success, defined as a minimum 10-point increase in Physical Functioning Questionnaire (PF-10) score. Secondary end points included change in PF-10 from Visit 1 to Visit 2, the patient's general condition (measured by Physician's Global Evaluation score) at Visit 1 and Visit 2, and patient satisfaction with treatment delivered via the Respimat® device (assessed by Patient Satisfaction Questionnaire) at study end. Results: Therapeutic success was observed in 51.5% of 1578 patients (95% confidence interval [CI] 49.0, 54.0) after approximately 6 weeks of treatment with tiotropium/Olodaterol. Mean change in PF-10 score between Visit 1 and Visit 2 was 11.6 points (95% CI 10.7, 12.6). Patient general condition improved as indicated by a general improvement in scores between visits. Most patients were very satisfied or satisfied with tiotropium/Olodaterol treatment (82.5%), inhalation (87.5%), and handling of Respimat® (85.2%). One percent of patients reported an investigator-defined drug-related adverse events (AE). Conclusion: Tiotropium/Olodaterol treatment improved physical functioning in COPD patients. An associated increase in patient general condition was observed. Most patients were very satisfied or satisfied with tiotropium/Olodaterol treatment, inhaling, and handling of the Respimat® device. No unexpected drug-related AE occurred.

  • safety of tiotropium Olodaterol in chronic obstructive pulmonary disease pooled analysis of three large 52 week randomized clinical trials
    Respiratory Medicine, 2018
    Co-Authors: Gary T Ferguson, Ulrich Bothner, Roland Buhl, Antonio Anzueto, Peter M A Calverley
    Abstract:

    Abstract Background An extensive clinical trial program supports the efficacy and safety of tiotropium/Olodaterol in chronic obstructive pulmonary disease (COPD). We examined the safety of tiotropium/Olodaterol compared with tiotropium in a large population of patients, focusing on cardiovascular and respiratory events. Methods Patients (n = 9942) who received once-daily tiotropium/Olodaterol 5/5 μg or tiotropium 5 μg (via Respimat®) in TONADO 1 & 2 and DYNAGITO were included. The number of patients and exposure-adjusted rate of events are presented for adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, and cardiovascular and respiratory events. Findings Fewer patients discontinued due to AEs with tiotropium/Olodaterol (5.9%) versus tiotropium (7.9%; rate ratio [RR] 0.72; 95% confidence interval [CI] 0.62–0.84). There was no significant difference in the incidence of AEs, SAEs, cardiovascular AEs or central nervous system vascular AEs between treatments. Incidences of major adverse cardiovascular events (MACE) were 2.11 per 100 patient-years with tiotropium/Olodaterol and 2.22 with tiotropium (RR 0.95; 95% CI 0.72–1.25), and incidences of fatal MACE (including death with undetermined cause) were 0.91 and 1.00 per 100 patient-years with tiotropium/Olodaterol and tiotropium, respectively (RR 0.91; 95% CI 0.60–1.37). Respiratory AEs were generally balanced between treatment groups. Conclusions These results provide robust evidence that the benefits of tiotropium/Olodaterol versus tiotropium are not at the expense of an increased risk of safety events. The combination is a suitable option for patients with COPD, even in the presence of cardiovascular risk factors. Clinical trials registration clinicaltrials. gov (TONADO 1 and 2: NCT01431274, NCT01431287; DYNAGITO: NCT02296138).

Alan Hamilton - One of the best experts on this subject based on the ideXlab platform.

Maria Gabriella Matera - One of the best experts on this subject based on the ideXlab platform.

  • Optimizing the Development Strategy of Combination Therapy in Respiratory Medicine: From Isolated Airways to Patients
    Advances in Therapy, 2019
    Co-Authors: Luigino Calzetta, Mario Cazzola, Maria Gabriella Matera, Paola Rogliani
    Abstract:

    The current recommendations for the treatment of chronic obstructive pulmonary disease (COPD) are pushing towards triple combination therapy based on the combination of an inhaled corticosteroid (ICS) associated with two bronchodilator agents. However, dual bronchodilation remains the cornerstone for the treatment of most COPD patients. Combining a long-acting β_2 adrenoceptor agonist (LABA) with a long-acting muscarinic antagonist (LAMA) induces appreciable synergistic bronchorelaxant effect in human airways, especially when the medications are combined at isoeffective concentrations. Thus, each LABA/LAMA combination is characterized by a specific range of concentration-ratio at which the drug mixture may induce sustained synergistic interaction. Results of a recent randomized controlled trial (RCT, NCT00696020) and evidences from pre-clinical studies in human isolated airways poses the question whether combining tiotropium 5 μg with Olodaterol 5 μg is the best combination option: tiotropium/Olodaterol 5/5 μg has the same efficacy profile of tiotropium/Olodaterol 5/2 μg, and it is less effective than tiotropium/Olodaterol 5/10 μg. Furthermore, tiotropium/Olodaterol 5/2 μg, 5/5 μg, and 5/10 μg combinations are generally characterized by the same safety profile. Indeed tiotropium/Olodaterol 5/5 μg is effective and safe in COPD, but a different development strategy based on solid data obtained from human isolated airways would have driven towards a better-balanced FDC to be tested in Phase III RCTs. Accurate bench-to-bedside plans are needed also in the development of triple combination therapies for asthma and COPD, in which the presence of an ICS in the formulation may further modulate the beneficial interaction between the LABA and the LAMA.

  • pharmacological characterization of the interaction between tiotropium bromide and Olodaterol on human bronchi and small airways
    Pulmonary Pharmacology & Therapeutics, 2019
    Co-Authors: Luigino Calzetta, Paola Rogliani, Clive P Page, Barbara Rinaldi, Mario Cazzola, Maria Gabriella Matera
    Abstract:

    : Combining a long-acting β2-agonist (LABA) with a long-acting muscarinic antagonist (LAMA) is the cornerstone to treat patients with chronic obstructive pulmonary disease (COPD). In this study we have characterized the interaction between the LAMA tiotropium bromide, and the LABA Olodaterol, on the contractile tone of human medium bronchi and small airways. The response to a combination of tiotropium bromide and Olodaterol was assessed at sub-maximal contractile tone induced by carbachol. The duration of action was studied in tissue contracted by transmural stimulation. Relaxation of bronchial tone was expressed as % of maximal response to papaverine. Drug interactions were analyzed by the Bliss Independence method and Unified Theory. Tiotropium bromide/Olodaterol combination induced a significant synergistic relaxant response (P < 0.05 vs. expected additive effect) in medium bronchi and small airways pre-contracted by carbachol, by enhancing relaxation +22.13 ± 4.42% and +26.31 ± 12.39%, respectively. The combination of tiotropium bromide and Olodaterol also reduced the airway smooth muscle contractility elicited by transmural stimulation by 73.60 ± 3.10%. The extent of synergy was strong to very strong, and was supported by the release of neuronal acetylcholine, cyclic adenosine monophosphate levels, and activation of iberiotoxin-sensitive KCa++ channels. Conversely, the interaction between tiotropium bromide and olodaterl was independent of the activity at M2 muscarinic receptors. These results indicate that tiotropium bromide/Olodaterol combination leads to a potent and durable synergistic relaxation of human medium bronchi and small airways. Further pharmacological studies are needed to confirm these results in clinical settings.

  • Pharmacological characterization of the interaction between tiotropium bromide and Olodaterol on human bronchi and small airways
    Pulmonary Pharmacology & Therapeutics, 2019
    Co-Authors: Luigino Calzetta, Paola Rogliani, Clive P Page, Barbara Rinaldi, Mario Cazzola, Maria Gabriella Matera
    Abstract:

    : Combining a long-acting β2-agonist (LABA) with a long-acting muscarinic antagonist (LAMA) is the cornerstone to treat patients with chronic obstructive pulmonary disease (COPD). In this study we have characterized the interaction between the LAMA tiotropium bromide, and the LABA Olodaterol, on the contractile tone of human medium bronchi and small airways. The response to a combination of tiotropium bromide and Olodaterol was assessed at sub-maximal contractile tone induced by carbachol. The duration of action was studied in tissue contracted by transmural stimulation. Relaxation of bronchial tone was expressed as % of maximal response to papaverine. Drug interactions were analyzed by the Bliss Independence method and Unified Theory. Tiotropium bromide/Olodaterol combination induced a significant synergistic relaxant response (P 

  • interaction between tiotropium bromide and Olodaterol in small human airways
    European Respiratory Journal, 2017
    Co-Authors: Luigino Calzetta, Paola Rogliani, Maria Gabriella Matera, Francesco Facciolo, Mario Cazzola
    Abstract:

    Background: Combining a long-acting β2-agonist (LABA) with a long-acting muscarinic antagonist (LAMA) may improve chronic obstructive pulmonary disease therapy. Aim: We investigated the pharmacological interaction of tiotropium bromide (LAMA) and Olodaterol (LABA) in small human bronchi. Methods: Precision cut lung slices (PCLSs) were incubated in Krebs-Henseleit solution (37°C) aerated with O2/CO2 (95:5%). The concentration response to tiotropium bromide and Olodaterol, administered alone and in combination at isoeffective concentrations, was assessed at sub-maximal contraction (70% maximum, EC70) induced by carbachol (CCh). PCLS relaxation was expressed as % of maximal response (lumen area enhancement) induced by papaverine (Emax) and potency as the negative logarithm of IC50 or EC50 (pEC50). Drug mixture effects were analyzed by Bliss Independence theory. Values (n=4) are mean±SEM. Results: Tiotropium bromide and Olodaterol induced potent concentration-dependent relaxation of PCLSs (overall pEC50 8.2±0.4). Both drugs abolished the CCh-induced bronchiolar contraction (overall Emax: 105.5±10.1%). Tiotropium bromide plus Olodaterol induced a significant synergistic relaxant response on PCLSs by enhancing relaxation +32.7±5.4%, compared with the expected response (P Low concentrations (EC30) of tiotropium bromide with Olodaterol induced significant (p Conclusions: Tiotropium bromide and Olodaterol had a synergistic interaction on the lumen area enhancement of human bronchioles. Funding: This study was supported by Boehringer Ingelheim International GmbH, Germany.

  • pharmacological characterization of the interaction between tiotropium and Olodaterol administered at 5 5 concentration ratio in equine bronchi
    COPD: Journal of Chronic Obstructive Pulmonary Disease, 2017
    Co-Authors: Luigino Calzetta, Paola Rogliani, Mario Cazzola, Maurizio Mattei, Pietro Alfonsi, Giuseppe Cito, Elena Pistocchini, Maria Gabriella Matera
    Abstract:

    ABSTRACTEquine airways represent a suitable ex vivo model to study the functional impact of pharmacological treatments on human chronic obstructive pulmonary disorders, such as asthma and chronic obstructive pulmonary disease (COPD). We aimed to characterize the pharmacological interaction between the long-acting muscarinic antagonist (LAMA) tiotropium and the long-acting β2-agonist (LABA) Olodaterol in equine airways. The effect of tiotropium and Olodaterol, administered alone and in combination at the ratio of concentrations reproducing ex vivo the concentration-ratio delivered by the currently available fixed-dose combination (FDC) (5:5), was investigated on the cholinergic contractile tone induced by the parasympathetic activation of equine isolated airways. The drug interaction was analysed by using the Bliss Independence and Unified Theory models. Both tiotropium and Olodaterol induced a sub-maximal concentration-dependent inhibition of bronchial contractility (Emax: tiotropium 83.6 ± 14.8%, olodate...

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