Long-acting Anticholinergic Tiotropium Research Articles

Anticholinergics for asthma: a long history.

To provide a fast overview about the introduction and development of anticholinergic drugs in Western medicine to their current indications particularly in asthma. Although short-acting muscarinic antagonists have been positioned in the last 15 years for the treatment of adults and children with moderate-to-severe acute asthma in the emergency setting (reducing the risk of hospital admissions and improving lung function), a growing body of evidence has recently emerged that positions the long-acting muscarinic anticholinergic tiotropium bromide as add-on therapy to at least inhaled corticosteroids (ICS) maintenance therapy in adults, adolescents, and children with symptomatic asthma. Thus, the addition of tiotropium bromide to ICS alone or ICS and another controller was associated with significant improvements in spirometric measures and asthma control, and a significantly decrease in the rate of asthma exacerbations. Short-acting muscarinic antagonists and tiotropium bromide have a well established role in the treatment of different phases of asthma. Further data are needed to provide more evidence on other selective long-acting muscarinic antagonists in addition to tiotropium as potential treatment options.

Efficacy and safety of tiotropium in school-age children with moderate-to-severe symptomatic asthma: A systematic review.

Recently published data support the benefits and safety of the once-daily (OD) long-acting anticholinergic tiotropium bromide bronchodilator for the treatment of uncontrolled moderate-to-severe asthma in adults and adolescents. However, its role for the treatment of school-age asthmatics has not yet been clearly defined. The aim of this systematic review was to assess the efficacy and safety of tiotropium Respimat® in children aged 6-11years with moderate-to-severe symptomatic asthma. Randomized, placebo-controlled trials were included. Primary outcomes were peak forced expiratory volume in 1s measured within 3h post-dosing) [FEV1 (0-3h) ] and trough FEV1 measured at the end of the dosing interval. Three studies (more than 900 patients) were selected. Tiotropium was associated with significant improvements in FEV1 peak (mean change from baseline) by 102mL (P<.0001) and trough by 82mL (P<.0001) compared with placebo. Tiotropium 5μg dose presented a trend (statistically non-significant) toward a greater bronchodilation in comparison with 2.5μg dose. Tiotropium significantly increased the rate of the Asthma Control Questionnaire (ACQ-7) responders compared with placebo (82.2% vs 75.4%, number needed to treat for benefit [NNTB]=15) and significantly decreased the number of patients with at least one exacerbation in comparison with placebo (29.1% vs. 39.8%, with a NNTB of 10). There were no significant differences in rescue medication use, withdrawals, and adverse events. OD tiotropium Respimat® is efficacious and well tolerated as an add-on to inhaled corticosteroids plus one or more controller medications in school-age symptomatic asthmatics.

Tiotropium for the treatment of asthma in adolescents

ABSTRACTIntroduction: Asthma is a prevalent disease affecting millions of individuals. Despite receiving guideline therapy with inhaled corticosteroids (ICS) with or without a long-acting β2-agonist (LABA), a proportion of patients remain symptomatic or have suboptimal lung function. There is therefore an unmet need for additional therapies to improve asthma control. The long-acting anticholinergic tiotropium, delivered via the Respimat inhaler, is approved for the treatment of asthma in the EU, the USA, and other countries. Phase III investigation in adults has demonstrated that tiotropium improves lung function and asthma control, with a safety profile comparable with that of placebo.Areas covered: Clinical trials in adolescent patients (aged 12–17 years) with moderate or severe symptomatic asthma have shown that tiotropium Respimat as add-on to ICS, with or without other maintenance therapies, is a well-tolerated and efficacious bronchodilator showing trends toward improved asthma control, similar to data in adult patients.Expert opinion: Tiotropium Respimat may be of benefit as add-on maintenance therapy to medium- or high-dose ICS with or without LABA; however, further data are needed to directly compare the efficacy of ICS plus tiotropium versus ICS plus LABA in adolescents with symptomatic asthma, and to establish the long-term effects on airway modeling.

A systematic review of comparative studies of tiotropium Respimat® and tiotropium HandiHaler® in patients with chronic obstructive pulmonary disease: does inhaler choice matter?

BackgroundIn many countries worldwide, the long-acting anticholinergic drug tiotropium is available as a dry powder formulation delivered by means of the HandiHaler® inhalation device and as an aqueous solution delivered via the Respimat® Soft Mist™ Inhaler. Tiotropium HandiHaler® is a single-dose, dry powder, breath-actuated inhaler that provides delivered doses and lung deposition of tiotropium that are, over a wide range, not influenced by the severity of chronic obstructive pulmonary disease (COPD). Tiotropium Respimat® is a propellant-free, multi-dose inhaler that delivers a metered dose of medication as a fine, slow-moving, long-lasting soft mist, independently of patient inspiratory effort. The high fine-particle fraction of droplets produced by the Respimat® inhaler optimizes the efficiency of drug delivery to the lungs.MethodsTo help inform the choice of tiotropium inhaler for prescribers and patients, this systematic review summarizes the available pharmacokinetic, efficacy and safety data from comparative studies of tiotropium Respimat® and tiotropium HandiHaler® in COPD, focusing on the licensed once-daily doses of 5 and 18 μg, respectively. Data sources reviewed include publications and abstracts identified from database searches.ResultsPublished evidence from comparative studies suggests that tiotropium Respimat® 5 μg and tiotropium HandiHaler® 18 μg provide similar clinical outcomes in patients with COPD.ConclusionsThe findings indicate that physicians can base their decision about an inhaler for tiotropium on factors other than efficacy or safety. These could be patient preference for a particular inhaler, ease of use and the efficiency of drug delivery, with the aim of optimizing adherence and clinical outcomes with long-term tiotropium maintenance therapy. Video (MP4 314368 kb) Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-016-0291-4) contains supplementary material, which is available to authorized users.

Tiotropium in the add-on treatment of asthma in adults: clinical trial evidence and experience

Asthma is a chronic inflammatory airway disease, and its treatment is frequently challenging despite detailed national and international guidelines. While basic anti-inflammatory therapy usually consists of inhaled corticosteroids in doses adapted to the asthma severity, add-on treatment with bronchodilators is essential in more severe asthma. Only recently, the long-acting anticholinergic tiotropium was introduced into the GINA guidelines. This review reports on the studies that have been performed with tiotropium in adult asthmatic patients. Following early proof-of-concept studies, several studies with tiotropium as an add-on therapy to inhaled corticosteroids (ICS), with or without a long-acting beta agonist (LABA), demonstrated convincing clinical benefit for patients. Important lung function parameters and quality of life scores significantly improved shortly after onset of the add-on therapy with tiotropium, and some studies even demonstrated non-inferiority against salmeterol. All studies reported an excellent safety profile of tiotropium. The still growing body of tiotropium studies, both in adults and children, will help to identify the position of tiotropium in future asthma guidelines and might also indicate which patients benefit most from an add-on therapy with tiotropium.

Impact of tiotropium + olodaterol on physical functioning in COPD: results of an open-label observational study.

BackgroundMaintaining and improving physical functioning is key to mitigating the cycle of deconditioning associated with chronic obstructive pulmonary disease (COPD). We evaluated the impact of free combination of the long-acting anticholinergic tiotropium plus the long-acting β2-agonist olodaterol on physical functioning in a real-world clinical setting.MethodsIn this open-label noninterventional study, Global initiative for chronic Obstructive Lung Disease (GOLD) B–D patients with COPD aged ≥40 years were treated for 4–6 weeks with either tiotropium 5 μg + olodaterol 5 μg (both via Respimat® inhaler) or tiotropium 18 μg (HandiHaler®) + olodaterol 5 μg (Respimat®) once daily. Physical functioning was assessed by the self-reported 10-item Physical Functioning Questionnaire (PF-10). The primary end point was the percentage of patients achieving therapeutic success, defined as a 10-point increase in the PF-10 between baseline (visit 1) and weeks 4–6 (visit 2). Secondary end points included absolute PF-10 scores, Physicians’ Global Evaluation, satisfaction with Respimat® and adverse events.ResultsA total of 1,858 patients were treated: 1,298 (69.9%) with tiotropium 5 μg + olodaterol 5 μg and 560 (30.1%) with tiotropium 18 μg + olodaterol 5 μg. At study end, 1,683 (92.6%) and 1,556 patients (85.6%) continued using tiotropium and olodaterol, respectively; 48.9% (95% confidence interval: 46.5, 51.3) achieved the primary end point. Therapeutic success rates were significantly higher for maintenance-naïve patients compared to those who had received prior therapy (59.1% vs 44.5%; P<0.0001), largely driven by maintenance-treatment-naïve GOLD B (59.8%) and C (63.0%) patients. Absolute physical functioning scores increased from an average baseline of 44.0 (standard deviation: 25.2) to 54.2 (standard deviation: 26.9) at visit 2. Patients’ general condition improved from baseline to visit 2, and patients were largely satisfied with the Respimat® inhaler. Adverse events were reported by 7.5% of patients; the most common were respiratory in nature.ConclusionTiotropium + olodaterol improved physical functioning within 4–6 weeks in patients with moderate-to-very severe COPD. GOLD B and C patients with no prior maintenance treatment demonstrated the greatest benefit.

Combination therapy of tiotropium and ciclesonide attenuates airway inflammation and remodeling in a guinea pig model of chronic asthma.

BackgroundThe long-acting anticholinergic tiotropium has recently been registered for the treatment of asthma, and its use is associated with a reduction in exacerbation frequency. Anti-inflammatory and anti-remodeling effects of tiotropium have been demonstrated in in vitro and in vivo models. Because tiotropium treatment is used in combination with inhaled corticosteroids, potential additive effects between the two would be clinically relevant. Therefore, the aim of this study was to investigate additive effects between tiotropium and ciclesonide on airway inflammation and remodeling in guinea pig models of asthma.MethodsGuinea pigs (n = 3–8/group) were sensitized and challenged with ovalbumin in an acute (single challenge) and a chronic model (12 weekly challenges) of allergic asthma. Animals were treated with vehicle, nebulized tiotropium (0.01–0.3 mM) and/or intranasally instilled ciclesonide (0.001–1 mg/kg) before each challenge. Bronchoalveolar lavage fluid and lungs were collected for analysis of airway inflammation and remodeling.ResultsTiotropium and ciclesonide treatment, alone or in combination, did not inhibit airway inflammation in the acute asthma model. In a dose-finding study, low doses of tiotropium and ciclesonide inhibited airway eosinophilia and airway smooth muscle thickening in the chronic asthma model. Threshold doses of 0.01 mM tiotropium (nebulizer concentration) and 0.01 mg/kg ciclesonide were selected to investigate potential additive effects between both drugs. At these doses, tiotropium and ciclesonide did not inhibit airway eosinophilia or airway smooth muscle thickening when administered alone, but significantly inhibited these allergen-induced responses when administered in combination.ConclusionsCombined treatment with low doses of tiotropium and ciclesonide inhibits airway inflammation and remodeling in a guinea pig model of chronic asthma, suggesting that combined treatment with anticholinergics and corticosteroids may have anti-inflammatory and anti-remodeling activity in allergic airway diseases. Since tiotropium is registered as a therapy for asthma added on to corticosteroid treatment, these beneficial effects of the combination therapy may be clinically relevant.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0327-6) contains supplementary material, which is available to authorized users.

Practical guidance on the recognition of uncontrolled asthma and its management.

To highlight the significance of asthma in primary care and offer a practitioner-friendly interpretation of the asthma guidelines for the busy provider, while introducing new treatment options currently in clinical trials, such as the once-daily long-acting anticholinergic bronchodilator tiotropium Respimat. Articles with relevant adult data published between 2004 and 2015 were identified via PubMed. Additional references were obtained by reviewing bibliographies from selected articles. In the United States, uncontrolled or symptomatic asthma is common, with rates of 46%-78% in primary care. Uncontrolled asthma has a substantial impact on patients' quality of life and represents a significant healthcare burden. Nurse practitioners can improve patients' asthma control through education, monitoring, assessment, and treatment. Although asthma management guidelines are readily available, the authors recognize that nurse practitioners see patients with multiple comorbidities, all of which have treatment guidelines of their own. Nurse practitioners have a compelling opportunity as frontline caregivers and patient educators to recognize and assess uncontrolled asthma, along with determining the steps necessary to help patients gain and maintain symptom control.

Tiotropium Respimat(®) Soft Mist™ inhaler: a review of its use in chronic obstructive pulmonary disease.

The long-acting anticholinergic agent tiotropium bromide (Spiriva(®)) is available as a solution for inhalation via Respimat(®) Soft Mist™ Inhaler in the EU and various other countries for the treatment of chronic obstructive pulmonary disease (COPD). With the Respimat(®) Soft Mist™ Inhaler there is improved lung deposition of drug (allowing a reduced dosage compared with tiotropium HandiHaler(®)), the delivered drug dose is independent of inspiratory effort and the prolonged duration of the aerosol cloud should make the co-ordination of actuation and inhalation easier. In patients with COPD, tiotropium Respimat(®) improved lung function, COPD exacerbations, health-related quality of life and dyspnoea and was at least as effective as tiotropium HandiHaler(®). Tiotropium Respimat(®) was generally well tolerated in patients with COPD, with anticholinergic adverse events among the most commonly reported adverse events. In the TIOSPIR trial, tiotropium Respimat(®) was noninferior to tiotropium HandiHaler(®) in terms of all-cause mortality, and the risk of cardiovascular mortality or major adverse cardiovascular events did not significantly differ between the two treatment groups. In conclusion, tiotropium Respimat(®) Soft Mist™ Inhaler is a useful option for the treatment of patients with COPD.

Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma?

Despite current guidelines and the range of available treatments, over a half of patients with asthma continue to suffer from poor symptomatic control and remain at risk of future worsening. Although a number of non-pharmacological measures are crucial for good clinical management of asthma, new therapeutic controller medications will have a role in the future management of the disease. Several long-acting anticholinergic bronchodilators are under investigation or are available for the treatment of respiratory diseases, including tiotropium bromide, aclidinium bromide, glycopyrronium bromide, glycopyrrolate and umeclidinium bromide, although none is yet licensed for the treatment of asthma. A recent Phase III investigation demonstrated that the once-daily long-acting anticholinergic bronchodilator tiotropium bromide improves lung function and reduces the risk of exacerbation in patients with symptomatic asthma, despite the use of inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs). This has prompted the question of what the rationale is for long-acting anticholinergic bronchodilators in asthma. Bronchial smooth muscle contraction is the primary cause of reversible airway narrowing in asthma, and the baseline level of contraction is predominantly set by the level of ‘cholinergic tone’. Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, possibly as a result of elevated cholinergic activity, which anticholinergic compounds are known to reduce. Further, anticholinergic compounds may also have anti-inflammatory properties. Thus, evidence suggests that long-acting anticholinergic bronchodilators might offer benefits for the maintenance of asthma control, such as in patients failing to gain control on ICS and a LABA, or those with frequent exacerbations.

Tiotropium in the treatment of patients with asthma.

Asthma is a chronic disease with a significant disease burden, and many patients fail to achieve disease control despite recommended medical therapy. Recent evidence suggests that there may be benefits to the use of the long-acting anticholinergic agent tiotropium in patients with asthma. We performed a systematic review of the literature to determine the role of tiotropium in management of adult patients with asthma. In six studies, 1773 patients were randomized and 1057 received tiotropium as an intervention. The mean prebronchodilator forced expiratory volume in 1 second was 60.1%. All six studies reported a small but statistically significant improvement in spirometry when using tiotropium as compared with the control. Improvement was reported in patients with both moderate and severe asthma, patients uncontrolled on previous regimens, patients treated with low- to high-dose inhaled corticosteroids regimens, and patients treated with and without long-acting β-agonist therapy. Five studies evaluated clinical outcomes with tiotropium with variable success rates. Although a large randomized trial demonstrated a reduction in the frequency of severe asthma exacerbation with tiotropium, there is insufficient evidence to support the argument that tiotropium therapy leads to improvements in asthma symptom measures, asthma control days, asthma-related quality-of-life-scores, or rescue inhaler use. There is strong evidence supporting improvement in spirometry and asthma exacerbations with tiotropium in patients with moderate and severe asthma; therefore, tiotropium may be an effective intervention in patients with asthma.

Tiotropium as add-on to inhaled corticosteroids significantly improves asthma control as reflected by the ACQ responder rate

Background: Despite current medications, there remains an unmet need for asthma control in patients with moderate asthma receiving at least ICS. We analysed ACQ (asthma control questionnaire) data in patients treated with once-daily long-acting anticholinergic bronchodilator tiotropium who had symptomatic asthma despite treatment with medium-dose ICS (400 – 800 µg budesonide equivalent).

Bronchoprotection by Olodaterol Is Synergistically Enhanced by Tiotropium in a Guinea Pig Model of Allergic Asthma

The novel once-daily β₂-agonist bronchodilator drug olodaterol has recently been shown to be effective in patients with allergic asthma for >24 hours. An increased cholinergic tone common to these patients may decrease the effectiveness of β₂-agonists. This could provide a rationale for combination therapy with olodaterol and the long-acting anticholinergic tiotropium to aim for a once-daily treatment regimen. In guinea pigs, we evaluated the protective effects of olodaterol, alone and in combination with tiotropium, on airway responsiveness to histamine, which is partially mediated by a cholinergic reflex mechanism. In addition, using a guinea pig model of acute allergic asthma, we examined the cooperative effects of these bronchodilators on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyper-responsiveness (AHR) to histamine, and airway inflammation. It was demonstrated that the protective effect of olodaterol against histamine-induced bronchoconstriction was synergistically enhanced and prolonged in the presence of tiotropium. In addition, tiotropium synergistically augmented both the reversal of and the protection against the allergen-induced AHR after the EAR by olodaterol. Olodaterol and tiotropium were highly effective in inhibiting the magnitude of the allergen-induced EAR and LAR, and both reactions were fully inhibited by the combination of these drugs. It is remarkable that these effects were not associated with an effect on inflammatory cell infiltration in the airways. In conclusion, the results indicate that combination therapy with olodaterol and tiotropium may be highly effective in the treatment of allergen-induced asthmatic reactions and AHR.

The Emerging Role of Tiotropium for Patients with Asthma

To review clinical data on the use of the long-acting anticholinergic agent tiotropium in patients with asthma. A literature search was performed via EMBASE and MEDLINE (1966-November 2012). The search was limited to human data published in the English language. Search terms included asthma, tiotropium, and long-acting anticholinergics. Relevant information related to the use of tiotropium in patients with asthma was reviewed. Randomized controlled trials and open-label trials were included. The references of published articles identified in the search were also examined for additional studies appropriate to include in the review. Data were prioritized if they originated from human studies, especially if derived from randomized, placebo-controlled trials. Trials and case reports involving the use of long-acting anticholinergic tiotropium in asthma patients were included; conversely, trials involving ipratropium were not. Two large randomized controlled trials support the safety and efficacy of adding tiotropium to the treatment regimen of select patients with poorly controlled asthma already receiving combination high-dose glucocorticosteroid/long-acting β-agonist (LABA) therapy. Pharmacogenomic studies have shown that patients with polymorphisms of the β2-adrenoreceptor (ADRB2; 16 Arg/Arg and 16 Arg/Gly) are particularly responsive to treatment with tiotropium. Smaller studies indicate that the advantages may be most pronounced in patients with a predominance of sputum neutrophils and that tiotropium can assist with decreasing the inhaled corticosteroid (ICS) dose. An increased risk of cardiovascular events was not identified. Tiotropium should be considered in patients with asthma who remain symptomatic while receiving high-dose ICS and LABA therapy. Specifically, patients with high sputum neutrophil levels or with 16 Arg/Arg or 16 Arg/Gly polymorphism of the ADRB2 gene appear to respond best.

Chronic obstructive pulmonary disease: a slowly progressive cardiovascular disease masked by its pulmonary effects?

Chronic obstructive pulmonary disease: a slowly progressive cardiovascular disease masked by its pulmonary effects?

Inhibitory effects of tiotropium on rhinovirus infection in human airway epithelial cells

Infection by rhinoviruses (RVs) causes exacerbations of chronic obstructive pulmonary disease (COPD). The long-acting anti-cholinergic agent tiotropium reduces the frequency of COPD exacerbations, but the inhibitory effects of tiotropium on the COPD exacerbations induced by RVs are unclear. Likewise, the effects of tiotropium on RVs infection remain to be studied. To examine the effects of tiotropium on RV infection and RV infection-induced airway inflammation, human tracheal epithelial cells were infected with a major group RV, type 14 RV (RV14). RV14 infection increased the viral titre and the amount of pro-inflammatory cytokines, including interleukin (IL)-1β and -6, in supernatant fluids and the amount of RV14 RNA in cells. Tiotropium reduced RV14 titres, RNA and cytokine concentrations, and susceptibility to RV14 infection. Tiotropium reduced the expression of intercellular adhesion molecule (ICAM)-1, the receptor for RV14, and the number of cellular acidic endosomes, which allow RV14 RNA to enter the cytoplasm. Tiotropium inhibited the activation of nuclear factor-(κ)B proteins, including p50 and p65, in the nuclear extracts, and it increased the cytosolic amount of inhibitory κB-α. Tiotropium may inhibit RV14 infection by reducing the levels of ICAM-1 and acidic endosomes and may also modulate airway inflammation in rhinovirus infection.

Inhibition of granulocyte migration by tiotropium bromide.

Study objectivesNeutrophil influx into the airways is an important mechanism in the pathophysiology of the inflammatory process in the airways of patients with chronic obstructive pulmonary disease (COPD). Previously it was shown that anticholinergic drugs reduce the release of non-neuronal paracrine mediators, which modulate inflammation in the airways. On this basis, we investigated the ability of the long-acting anticholinergic tiotropium bromide to inhibit a) alveolar macrophage (AM)-mediated chemotaxis of neutrophils, and b) cellular release of reactive oxygen species (ROS).MethodAM and neutrophils were collected from 71 COPD patients. Nanomolar concentrations of tiotropium bromide were tested in AM cultured up to 20 h with LPS (1 μg/ml). AM supernatant was tested for TNFα, IL8, IL6, LTB4, GM-CSF, MIPα/β and ROS. It was further used in a 96-well chemotaxis chamber to stimulate the migration of fluorescence labelled neutrophils. Control stimulants consisted of acetylcholine (ACh), carbachol, muscarine or oxotremorine and in part PMA (phorbol myristate acetate, 0.1 μg/ml). Potential contribution of M1-3-receptors was ascertained by a) analysis of mRNA transcription by RT-PCR, and b) co-incubation with selective M-receptor inhibitors.ResultsSupernatant from AM stimulated with LPS induced neutrophilic migration which could be reduced by tiotropium in a dose dependent manner: 22.1 ± 10.2 (3 nM), 26.5 ± 18,4 (30 nM), and 37.8 ± 24.0 (300 nM, p < 0.001 compared to non-LPS activated AM). Concomitantly TNFα release of stimulated AM dropped by 19.2 ± 7.2% of control (p = 0.001). Tiotropium bromide did not affect cellular IL8, IL6, LTB4, GM-CSF and MIPα/β release in this setting. Tiotropium (30 nM) reduced ROS release of LPS stimulated AM by 36.1 ± 15.2% (p = 0.002) and in carbachol stimulated AM by 46.2 ± 30.2 (p < 0.001). M3R gene expression dominated over M2R and M1R. Chemotaxis inhibitory effect of tiotropium bromide was mainly driven by M3R inhibition.ConclusionOur data confirm that inhibiting muscarinic cholinergic receptors with tiotropium bromide reduces TNFα mediated chemotactic properties and ROS release of human AM, and thus may contribute to lessen cellular inflammation.

In Vitro Validation of a Respimat® Adapter for Delivery of Inhaled Bronchodilators During Mechanical Ventilation

Inhaled bronchodilators are frequently used in patients with chronic obstructive pulmonary disease (COPD). However, there has been no efficient way to administer the long-acting anticholinergic tiotropium to mechanically ventilated patients. The aim of this in vitro study was to compare the fine particle dose (FPD) output of a specifically designed adapter with other accessory devices for the delivery of bronchodilators using the Respimat® (RMT) inhaler by simulating the specific inhalation flow profiles of patients with COPD. Using characteristic flow profiles from COPD patients being weaned off mechanical ventilation, an in vitro study was performed analyzing the FPD achieved with different accessory devices (connectors, spacers, AeroTrachPlus valved holding chamber), which can be used to deliver drugs from pressurized metered dose inhalers (pMDI) and RMT inhalers to artificial airways. Fenoterol pMDI, tiotropium RMT, and a fixed-dose combination of salbutamol and ipratropium delivered by pMDI or RMT, were used as bronchodilators. Aerosols were collected by a next-generation impactor. The RMT inhaler, combined with a new in-line adapter, was superior to other inhaler device connector or spacer combinations in FPD delivery during simulated mechanical ventilation (p<0.01). The outcome with the RMT inhaler/RMT adapter combination during simulation of mechanical ventilation was comparable to the measurements with the RMT/AeroTrachPlus valved holding chamber during simulation of spontaneous breathing. The delivery rates of the RMT adapter were not significantly affected by the administered bronchodilators or by the type of artificial airway (endotracheal or tracheostomy tube) employed. The RMT inhaler combined with the prototype in-line adapter was better than the other accessory device combinations in fine particle deposition of inhaled bronchodilators during mechanical ventilation. Further research is required to determine the clinical relevance of these in vitro findings.

Tiotropium is non-inferior to salmeterol in maintaining improved lung function in b16-arg/arg patients with asthma

Background The efficacy and safety of inhaled long-acting beta-2 adrenergic agonists (LABA) in asthmatic patients with the B16-Arg/Arg genotype has been questioned, and the use of anti-muscarinics proposed as an alternative in patients not controlled on inhaled steroids (ICS). Objective We compare the efficacy and safety of the long-acting anticholinergic tiotropium with salmeterol and placebo added to ICS in B16-Arg/Arg patients with asthma not controlled by ICS alone. Methods In a double-blind, double-dummy, placebo-controlled trial, after a 4‑week run-in on 50μg b.i.d. MDI salmeterol, 388 asthma patients were randomised 1:1:1 to 16 weeks treatment with Respimat ® tiotropium 5μg q.d. evening, MDI salmeterol 50μg b.i.d., or placebo. Patients aged 18‑67 years demonstrated reversibility to bronchodilators and were uncontrolled on regular ICS (400‑1000 μg budesonide/equivalent). ICS regimes were maintained throughout the trial. Mean weekly morning PEF before randomisation was 358±115.7 L/min (range: 80.3‑733.0). Results Changes in weekly PEF from the last week of run-in to the last week of treatment (primary endpoint: ∆PEF) were -3.9±4.87 L/min (n=128) for tiotropium and ‑3.2±4.64 L/min (n=134) for salmeterol, and were superior to placebo (‑24.6±4.84 L/min; n=125; P<0.05). Tiotropium was non-inferior to salmeterol (estimated difference: −0.78 L/min; 95% CI: −13.096, 11.53; P=0.002, α level 0.025, 1‑sided, non-inferiority delta=20 L/min). Tiotropium and salmeterol were numerically superior to placebo in some patient-reported secondary outcomes. Adverse events were comparable across treatments. Conclusion Tiotropium was more effective than placebo and as effective as salmeterol in maintaining improved lung function in B16-Arg/Arg patients with moderate persistent asthma. Safety profiles were comparable.

Inhaled anticholinergic drugs and risk of acute urinary retention

Study Type--Harm (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Inhaled anticholinergic drugs have been associated with the risk of acute urinary retention (AUR), but this association was never studied under real life circumstances nor was this risk ever quantified. Use of inhaled anticholinergic drugs increases the risk of AUR by 40%. The risk of AUR is highest in recent starters, in patients with benign prostatic hyperplasia (BPH), and in patients receiving their anticholinergic drugs via nebulizer. It might be advisable to consider alternatives for inhaled anticholinergic drugs in COPD patients with BPH. • To investigate the association between the use of inhaled anticholinergic drugs and the risk of acute urinary retention (AUR) under real-life circumstances. • We conducted a nested case-control study within a cohort of patients with chronic obstructive pulmonary disease (COPD; as AUR has been associated with the use of inhaled anticholinergic drugs, which are used as first-line treatment for COPD) from the Integrated Primary Care Information (IPCI) database. • The cohort consisted of all patients with COPD aged ≥45 years, registered between 1996 and 2006, with ≥12 months of valid history. Cases were patients with a first diagnosis of AUR. • To each case, controls were selected matched for age, gender and index date. • Multivariate conditional logistic regression analysis was used to calculate adjusted odds ratios (OR(adj)) with 95% confidence intervals (95% CI). • Within the cohort of 22,579 patients with COPD, 209 cases were identified. • Current use of inhaled anticholinergic drugs was associated with a 40% increase in risk for AUR (OR(adj) 1.40; 95% CI 0.99-1.98) compared with non-users. • Among current users, the risk was highest for the recent starters (OR(adj) 3.11; 95% CI 1.21-7.98). The risk of long-acting anticholinergic drug tiotropium was not substantially different from that of the short-acting anticholinergic ipratropium. • The association was not dose-dependent, but changed by mode of administration, with nebulizers having the highest risk (OR(adj) 2.92; 95% CI 1.17-7.31). • In men with COPD and benign prostatic hyperplasia (BPH) the association was strongest (OR(adj) 4.67; 95% CI 1.56-14.0). • Current use of inhaled anticholinergic drugs increases the risk of AUR, especially in patients with BPH or if administered via a nebulizer.