Antimuscarinic Bronchodilator Research Articles

The Design of and Rationale for the Effect of Perioperative Inhaled Tiotropium for Patients with Chronic Obstructive Pulmonary Disease in Esophageal Cancer Surgery (EPITOPE): an Open-Label, Randomized, Parallel-Group Study

Introduction: Pneumonia is one of the most frequently occurring complications after esophagectomy and is associated with increased operative mortality. Chronic obstructive pulmonary disease (COPD) is known to be a risk factor for pulmonary complications and operative mortality. However, in COPD patients preparing for esophagectomy, preventive measures against postoperative pneumonia have not yet been discovered. In this study, we evaluate the effect of perioperative inhaled tiotropium, a long-acting, antimuscarinic bronchodilator used in the management of COPD, on patients with COPD who undergo esophageal cancer surgery. Methods/Design: This study investigates the effect of perioperative inhaled tiotropium on patients with COPD who undergo esophagectomy. It is an open-label, randomized controlled trial conducted in a single center (EPITOPE study). A total of 32 enrolled patients are randomly assigned in a 1:1 ratio to either conventional management or inhalation of tiotropium in addition to the conventional management. Patients included in the intervention group receive tiotropium Respimat 5 μg (two inhalations of 2.5 μg) for at least 2 weeks before the esophagectomy. Following the esophagectomy, tiotropium is re-delivered, starting as early as possible and continuing until the postoperative evaluation (between 30 and 44 days after the operation). The primary outcome is the incidence of pneumonia within 30 days after esophagectomy. Secondary outcomes are the incidence of cardiovascular complications within 30 days after esophagectomy, the incidence of any postoperative complications within 30 days after esophagectomy, pulmonary function (preintervention, preoperative, and postoperative), walking distance in the incremental shuttle walking test (preintervention, preoperative, and postoperative), the incidence of adverse events, and mortality within 30 days after esophagectomy. Discussion: The EPITOPE study is the first pilot study on the effects of perioperative inhaled tiotropium on patients with COPD undergoing esophagectomy. After completing this study, we will plan a multicenter RCT with the appropriate outcomes in the future.

Anticholinergics Linked to Increased Risk of Dementia

Anticholinergics Linked to Increased Risk of Dementia

Short-term benefit of smoking cessation along with glycopirronium on lung function and respiratory symptoms in mild COPD patients: a retrospective study

Introduction. Tobacco smoke is the leading cause of chronic obstructive pulmonary disease (COPD). Smoking cessation can change the natural history of COPD, as we know from the GOLD guidelines. Little is known about the short-term clinical and functional effects of smoking cessation treatment combined with anti-muscarinic bronchodilators. Objective. To determine whether quitting smoking, obtained by smoking cessation treatment combined with the use of a new long-acting muscarinic antagonist bronchodilator (LAMA), can improve lung function tests and respiratory symptoms more than the use of LAMA alone. Methods. We evaluated, in a retrospective analysis, the functional and clinical data, collected in one year, of 120 patients who were current smokers affected by mild COPD and who quit smoking using smoking cessation treatment combined with glycopirronium. We compared them with a group of 80 patients with mild COPD undergoing the same treatment but who did not quit smoking. All patients underwent functional and clinical tests at baseline and at a third-month check. Measurements and main results. The two groups were homogeneous in terms of demographic data without significant differences. All patients used varenicline for smoking cessation. They all performed the following tests: a spirometry with detection of resistances, the 6 min walking test, haemogasanalysis, the exhaled CO test, the COPD assessment test (CAT) and finally the modified Medical Research Council test (mMRC). A significant improvement in the functional tests at the third-month check was found in both groups—quitters and non-quitters. However, a notable increase in the examined parameters was registered in the group of patients who quit smoking, in particular, we observed a significant increase at the third-month check of the parameter forced expiratory volume in 1 s (FEV1) of more than 200 ml with p < 0.001. A comparison between quitters and non-quitters revealed a major benefit derived from smoking cessation in terms of functional changes and symptom relief. In particular, not only FEV1 but also forced expiratory flow at 25%–75% of vital capacity (FEF 25–75) (p < 0.01) and CAT (p < 0.001) were found to be significantly improved in patients who quit than in patients who did not at the check time point. Conclusions. Smoking cessation treatment obtained by varenicline was confirmed as a crucial therapeutic option, especially when combined with bronchodilator in mild COPD. Patients who quit smoking could already benefit from both treatments in the short term, improving lung function and respiratory symptoms and therefore improving their quality of life.

Predicting the response to a bronchodilator in patients with airflow obstruction and lung cancer

BackgroundThe aim of the present study was to clarify the predictors of the response of patients with resectable lung cancer and untreated airflow obstruction to tiotropium, an antimuscarinic bronchodilator. MethodsTiotropium was administered to 29 preoperative patients with untreated airflow obstruction. The forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were measured before and after the introduction of tiotropium. The response to tiotropium was determined based on the percentage gain in the FEV1. The volume of the total lung area (TLV) and the low-attenuation area (LAA) was measured by deep inspiratory computed tomography based on the predefined thresholds for attenuation values. ResultsThe introduction of tiotropium resulted in a 15% gain in the FEV1 (P < 0.001). A univariate regression analysis revealed that the FVC/TLV was the best predictor of the gain in FEV1, followed by the FEV1/FVC. Based on the results of a multiple regression analysis, a regression equation to predict a gain in the FEV1 was generated using the FVC, TLV, and LAA. A receiver operating characteristic curve analysis revealed that this equation led to the highest area under the curve for predicting a major response to tiotropium, followed by the FVC/TLV and FEV1/FVC. Postoperatively, six of the 20 minor responders experienced a progression of dyspnea. In contrast, none of the major responders experienced a progression of dyspnea (P < 0.05). ConclusionsWe developed an equation for predicting the response to tiotropium using parameters obtained from spirometry and quantitative computed tomography. A large-scale study to validate the usefulness of this equation is warranted.

Pharmacokinetics of tiotropium administered by Respimat® in asthma patients: Analysis of pooled data from Phase II and III clinical trials

Tiotropium is a long-acting inhaled antimuscarinic bronchodilator that has recently received marketing authorization for the indication of asthma with dose delivery via the Respimat® inhaler, in addition to its widely established role in the management of chronic obstructive pulmonary disease (COPD). This report presents a combined analysis of tiotropium plasma and urine pharmacokinetics at steady state from 8 Phase II/III clinical trials in asthma and delineates the effects of patient characteristics on systemic exposure based on the parameters fe0-24,ss (fraction of dose excreted unchanged in urine over 24 h post-dose at steady-state) and dose-normalized AUCtau,ss and Cmax,ss. Pharmacokinetics were also compared between asthma and COPD, incorporating data from 3 COPD Phase II/III clinical trials. Tiotropium pharmacokinetics in asthma were dose-proportional up to 5 μg dosed once daily. The following factors showed no statistically significant effects on tiotropium systemic exposure in asthma based on analysis of geometric mean ratios and 90% confidence intervals: age, asthma severity, lung function, reversibility testing, allergy status, smoking history, geographical region, and posology (5 μg once daily or 2.5 μg twice daily via Respimat®). Asian patients showed a moderately but significantly higher systemic exposure compared to White or Black patients. However, no differences in safety by race were observed. Total systemic exposure (AUCtau,ss) was similar between asthma and COPD, but Cmax,ss was 52% lower in asthma patients compared to COPD. It is concluded that in asthma, patient characteristics have no relevant effect on tiotropium systemic exposure. Since systemic exposure to inhaled drugs is an indicator of safety, the lower Cmax,ss compared to COPD is not considered a concern for tiotropium therapy of asthma.

Long-acting medications for chronic obstructive pulmonary disease

This article explores the role of anticholinergic medications for the treatment of chronic obstructive pulmonary disease (COPD). It provides an overview of COPD and outlines the current long-activing anti-muscarinic bronchodilators available. It also looks at issues such as side-effects, adherence, and how these treatments compare with other long-acting drug therapies for COPD.

Role of anticholinergics in asthma management: recent evidence and future needs.

Anticholinergic antimuscarinic bronchodilators play a major role in the treatment of chronic obstructive pulmonary disease, but their role in asthma has long been limited to acute management. More recently, the role of long-acting antimuscarinic bronchodilators (LAMAs) in chronic asthma management has been explored. This review will examine the pharmacological rationale for use of inhaled anticholinergics in the treatment of asthma, and provide an overview of the current literature supporting this use, as well as describe future research needs in this area. Short-acting anticholinergic bronchodilators have a role as add-on agents in the treatment of acute asthma. Preliminary clinical studies suggest that inhaled LAMAs may be comparable to long-acting beta2-agonists (LABAs) as an add-on therapy in patients not controlled by inhaled corticosteroids (ICS) alone, and may also have added benefit in patients not controlled on combined ICS-LABA. Mechanistic studies suggest that apart from their bronchodilator activity, LAMAs may have anti-inflammatory and antiremodeling influences on the airways. Further research is needed to clarify the clinical relevance of these experimental observations. Accumulating evidence supports the use of inhaled LAMAs as an add-on therapy in patients with asthma, who remain symptomatic despite guideline-based therapy with ICS with or without LABAs. Further studies are warranted to help define mechanisms of action of LAMAs, apart from their role as bronchodilators, and determine how these other actions impact asthma outcomes over time. Furthermore, future studies need to examine the long-term efficacy and safety of LAMAs in asthma and identify a subgroup of patients who would benefit from such therapies to facilitate early, personalized therapy.

Tiotropium Bromide in Chronic Obstructive Pulmonary Disease and Bronchial Asthma.

Inhaled bronchodilators are the mainstay of pharmacological treatment for stable chronic obstructive pulmonary disease (COPD), including β2-agonists and muscarinic antagonists. Tiotropium bromide, a long-acting antimuscarinic bronchodilator (LAMA), is a treatment choice for moderate-to-severe COPD; its efficacy and safety have been demonstrated in recent trials. Studies also point to a beneficial role of tiotropium in the treatment of difficult-to-control asthma and a potential function in the asthma-COPD overlap syndrome (ACOS). Combination of different bronchodilator molecules and addition of inhaled corticosteroids are viable therapeutic alternatives. A condensation of the latest trials and the rationale behind these therapies will be presented in this article.

Current treatments for chronic obstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a common and growing problem worldwide. Although frequently linked with poverty and poor living conditions, there is strong genetic basis to the disease and chronic exposure to environmental toxins and irritants, such as cigarette smoking. Inhaled beta-agonists and anti-muscarinic bronchodilators form the basis of both acute and chronic therapeutic treatment, with inhaled corticosteroids to boost their effectiveness and reduce the chronic inflammation. Smoking is the most important preventable risk factor for exacerbation and continued pulmonary deterioration. Patients should be biochemically tested to verify their self-reported smoking status and given in-house and specialist smoking cessation advice and counselling. This should be part of the rehabilitation process, which includes exercise training, education, nutritional intervention, and psychosocial support to improve the efficacy of pharmaceutical treatment and to enhance physical and mental wellbeing.

The lungs need to be deflated: effects of glycopyrronium on lung hyperinflation in COPD patients.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation caused by bronchial alterations, small airways disease and parenchymal destruction. In patients with COPD the structural and functional lung alterations can progress more or less rapidly from the initial small airways disease to an overt COPD where a severe expiratory flow limitation takes place. In these conditions, lung hyperinflation develops characterized by increase in functional residual capacity (FRC) and decrease in inspiratory capacity (IC). Thus, IC is an easy and reliable index to monitor lung hyperinflation and to assess the efficacy of bronchodilator drugs. When FRC increases, tidal volume (VT) is located in a more flatted upper part of the P –V curve of the respiratory system and respiratory muscles must sustain a greater elastic workload. Furthermore, due to inadequate time for expiration, there is a positive alveolar pressure at the end of expiration (PEEPi). This represents a further elastic workload for the inspiratory muscles. This impairment of ventilatory mechanics generates dyspnea that in most severely compromised patients occurs also for small efforts causing activity limitation and worst health-related quality of life (HRQoL). Due to these respiratory alterations, bronchodilators are the cornerstone of the long-term treatment of COPD in order to decrease airways resistances, lung hyperinflation and exacerbation rate, and improve patient’s symptoms, exercise tolerance and health status. Long-acting antimuscarinic bronchodilators (LAMAs) have proven to be very useful in terms of lung deflation and exercise tolerance. Recently, new LAMAs with several positive characteristics have been introduced into clinical use among which glycopyrronium bromide has shown to be particularly effective. Glycopyrronium has a longer-lasting effect compared to other anticholinergic drugs, therefore it allows a single daily administration and facilitates the therapy of a disease that needs a chronic bronchodilation by decreasing the mechanic stress of the airways determined by repeated bronchoconstriction and increasing patient’s adherence to treatment plan with better clinical results. Several studies demonstrated that glycopyrronium is able to positively and significantly decrease lung hyperinflation, symptoms, and improve psycho-physical status of COPD patients, with a low rate of adverse events, similar to that of placebo.

Clinical use of aclidinium in patients with COPD.

Chronic obstructive pulmonary disease (COPD) is the sixth-leading cause of death in the US. The Global initiative for Chronic Obstructive Lung Disease (GOLD) guidelines provide evidence-based recommendations for the clinical management of chronic COPD. Long-acting inhaled bronchodilators continue to be the mainstay of current management. Aclidinium bromide (Tudorza™ Pressair™) joins tiotropium as a long-acting inhaled antimuscarinic bronchodilator approved by the US Food and Drug Administration for the maintenance treatment of COPD. Early studies demonstrated aclidinium’s significant bronchodilatory effects supporting once-daily dosing; however, two Phase III studies, Aclidinium Clinical Trial Assessing Efficacy and Safety in Moderate to Severe COPD Patients (ACCLAIM/COPD) I and ACCLAIM/COPD II, in which patients were randomized to receive aclidinium 200 μg daily, failed to achieve the minimal clinically important difference in improvement of trough forced expiratory volume in 1 second (FEV1), suggesting the need for higher doses or more frequent dosing. Additional studies – Aclidinium to Treat Airway Obstruction in COPD Patients (ATTAIN) and Aclidinium in Chronic Obstructive Respiratory Disease (ACCORD) I – were undertaken to compare 200 and 400 μg twice-daily dosing. The mean improvements from baseline in trough FEV1 in the 400 μg groups were +129 mL over 24 weeks and +124 mL over 12 weeks in ATTAIN and ACCORD I, respectively. Aclidinium also had beneficial effects on health-related quality of life and other endpoints, such as rescue medication use and rates of exacerbations. Aclidinium bromide inhalation powder is generally well tolerated in patients with COPD, with headache, cough, diarrhea, and rhinosinusitis among the most commonly reported adverse events. Cardiovascular side effects were rarely reported. Patient satisfaction studies found that patients using the aclidinium delivery device had fewer errors affecting drug delivery than those using the tiotropium device and, overall, the aclidinium device was preferred to the tiotropium device. In conclusion, aclidinium bromide is approved for use in the US at a dose of 400 μg twice daily and is a promising alternative to tiotropium.

The lungs need to be deflated: effects of glycopyrronium on lung hyperinflation in COPD patients

&#x0D; &#x0D; &#x0D; &#x0D; Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation caused by bronchial alterations, small airways disease and parenchymal destruction. In patients with COPD the structural and functional lung alterations can progress more or less rapidly from the initial small airways disease to an overt COPD where a severe expiratory flow limitation takes place. In these conditions, lung hyperinflation develops characterized by increase in functional residual capacity (FRC) and decrease in inspiratory capacity (IC). Thus, IC is an easy and reliable index to monitor lung hyperinflation and to assess the efficacy of bronchodilator drugs. When FRC increases, tidal volume (VT) is located in a more flatted upper part of the P –V curve of the respiratory system and respiratory muscles must sustain a greater elastic workload. Furthermore, due to inadequate time for expiration, there is a positive alveolar pressure at the end of expiration (PEEPi). This represents a further elastic workload for the inspiratory muscles. This impairment of ventilatory mechanics generates dyspnea that in most severely compromised patients occurs also for small efforts causing activity limitation and worst health-related quality of life (HRQoL). Due&#x0D; to these respiratory alterations, bronchodilators are the cornerstone of the long-term treatment of COPD in order to decrease airways resistances, lung hyperinflation and exacerbation rate, and improve patient’s symptoms, exercise tolerance and health status. Long-acting antimuscarinic bronchodilators (LAMAs) have proven to be very useful in terms of lung deflation and exercise tolerance. Recently, new LAMAs with several positive characteristics have been introduced into clinical use among which glycopyrronium bromide has shown to be particularly effective. Glycopyrronium has a longer-lasting effect compared to other anticholinergic drugs, therefore it allows a single daily administration and facilitates the therapy of a disease that needs a chronic bronchodilation by decreasing the mechanic stress of the airways determined by repeated bronchoconstriction and increasing patient’s adherence to treatment plan with better clinical results. Several studies demonstrated that glycopyrronium is able to positively and significantly decrease lung hyperinflation, symptoms, and improve psycho-physical status of COPD patients, with a low rate of adverse events, similar to that of placebo.&#x0D; &#x0D; &#x0D; &#x0D;

Priming of beta-2 agonist and antimuscarinic induced physiological responses induced by 1200 mg/day NAC in moderate to severe COPD patients: A pilot study

This study evaluated antioxidant modulations of lung physiological-responses to beta-2-agonist and antimuscarinic bronchodilators with 1200mg/day n-acetyl-cysteine (NAC) in a placebo-controlled, randomised, double-blind, parallel-group study, in moderate-very severe COPD patients. Methods15 COPD patients received NAC treatment, while 9 COPD patients received placebo treatment, for 15 days. Pre-and-post salbutamol and ipratopium-bromide lung-physiology responses were measured using body-plethysmography, impulse-oscillometry (IOS) and spirometry before-and-after study treatments. ResultsCompared to pre-treatment, the NAC-treatment significantly enhanced the potential of ipratopium-bromide to reduce functional-residual-capacity (FRC) by nearly 3-folds (mean% FRC-response: pre-NAC: −5.51%±10.42% versus post-NAC: −17.89%±12.94%, p=0.02; mean-absolute FRC-response: pre-NAC: −300ml±450ml versus post-NAC: −770ml±550ml, p=0.02), which was superior to placebo-treatment. The increase in total-lung-capacity response to ipratopium-bromide, although insignificant, was superior with post-NAC treatment versus post-placebo treatment (p=0.049). The salbutamol-response remained unaltered with either treatment. ConclusionThe treatment with 1200mg/day NAC has potential to enhance the bronchodilator ability of antimuscarinic-agents but not beta-2-agonist. However, its clinical application has to be established in large sample-size studies for longer-duration.

Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study

We evaluated the effect of dual, longacting inhaled bronchodilator treatment on exacerbations in patients with severe and very severe chronic obstructive pulmonary disease (COPD). In this parallel-group study, 2224 patients (aged ≥40 years, Global Initiative for Chronic Obstructive Lung Disease stages III-IV, and one or more moderate COPD exacerbation in the past year) were randomly assigned (1:1:1; via interactive voice response or web system; stratified for smoking status) to once-daily QVA149 (fixed-dose combination of indacaterol 110 μg and glycopyrronium 50 μg), glycopyrronium 50 μg, or tiotropium 18 μg for 64 weeks. Assignment to QVA149 and glycopyrronium was double-blind; tiotropium was open-label. Efficacy was assessed in all patients randomly assigned to treatment groups who received at least one dose of study drug; safety was assessed in all patients who received at least one dose whether or not they were assigned to a group. The primary objective was to show superiority of QVA149 versus glycopyrronium for rate of moderate to severe COPD exacerbations (defined by worsening symptoms and categorised by treatment requirements) during treatment. This completed trial is registered at ClinicalTrials.gov, NCT01120691. Between April 27, 2010, and July 11, 2012, 741 patients were randomly assigned to receive QVA149, 741 to receive glycopyrronium, and 742 to receive tiotropium (729, 739, and 737 patients, respectively, analysed for efficacy). QVA149 significantly reduced the rate of moderate to severe exacerbations versus glycopyrronium by 12% (annualised rate of exacerbations 0·84 [95% CI 0·75-0·94] vs 0·95 [0·85-1·06]; rate ratio 0·88, 95% CI 0·77-0·99, p=0·038). Adverse events (including exacerbations) were reported for 678 (93%) of 729 patients on QVA149, 694 (94%) of 740 on glycopyrronium, and 686 (93%) of 737 on tiotropium. Incidence of serious adverse events was similar between groups (167 [23%] patients on QVA149, 179 [24%] on glycopyrronium, and 165 [22%] on tiotropium); COPD worsening was the most frequent serious adverse event (107 [15%] patients on QVA149, 116 [16%] on glycopyrronium, 87 [12%] on tiotropium). The dual bronchodilator QVA149 was superior in preventing moderate to severe COPD exacerbations compared with the single longacting antimuscarinic bronchodilator glycopyrronium, with concomitant improvements in lung function and health status. These results indicate the potential of dual bronchodilation as a treatment option for patients with severe and very severe COPD. Novartis Pharma AG.

Aclidinium bromide for the treatment of chronic obstructive pulmonary disease

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.

Chronic cough and Holmes-Adie syndrome

In April, 2006, a 45-year-old white man—a lifelong nonsmoker—was referred to the Royal Brompton Hospital Cough Clinic. In October, 2002, he had presented to his general practitioner with a persistent dry cough. The cough had started in March, 2002, after a bout of pneumonia. In addition, he claimed to have night sweats but no systemic symptoms. Auscultation of his chest, and a chest radiograph were normal, and he had a negative (grade 1) tuberculin skin test. In January, 2003, he was referred to his local chest clinic, where further inves tigations including lung function and CT of the chest were normal. He was reassured and discharged. In June, 2004, he presented to his local eye clinic complaining of blurred vision. Anisocoria was noted with an enlarged tonic left pupil (fi gure) and near light dissociation. Ankle tendon arefl exia was present on the right and elicited on the left only with reinforcement. He was diagnosed with Holmes-Adie syndrome—a condition of unknown cause characterised by tonic pupillary reactions and absent tendon refl exes. In August 2004, he was re-referred back to his local chest clinic because his dry cough persisted. Empirical treatment with omeprazole 20 mg daily was started and he underwent a normal barium swallow. Over the course of the following year, with no improvement in symptoms, he was prescribed an inhaled antimuscarinic bronchodilator (oxitropium bromide), an oral H1-anti histamine (loratadine), and he was given a trial of an H2-receptor antagonist (ranitidine) for 1 month, with no eff ect. When seen by us in April, 2006, his cough had persisted and he reported that during one coughing paroxysm he had experienced syncope. Direct questioning revealed truncal and right arm hyperhydrosis with excessive sweating in the right armpit. Respiratory, nasopharyngeal, and cardiovascular examinations were unremarkable. In particular, the patient had no evidence of dry eyes, dry mouth, or skin changes that might suggest a diagnosis of Sjogren’s syndrome. VDRL, autoantibody screen, and fasting blood sugar were negative. CT of the chest, full lung function (including histamine challenge, nitric oxide, and reversibility testing), nasolaryngo scopy, cinevideo fl uoroscopy, and 24-hour oesophageal pH monitoring were all normal. The patient declined fi breoptic bronchoscopy and capsaicin cough challenge. Treatment with high-dose inhaled corticosteroid (fl uticasone propionate 1000 μg daily) delivered from a pressurised metered-dose inhaler and spacer attachment, induced paroxysms of cough. Two separate courses of high dose oral steroids provided no improvement in either symptomatology or diurnal peak expiratory fl ow rate measurements. The addition of a non-selective oral H1-antihistamine treatment (chlorphenamine maleate 4 mg four times a day) was of no additional benefi t. As of September, 2006, the patient is still symptomatic and awaiting neurological consultation including cardiovascular autonomic testing. Kimber and colleagues, have reported an association between Holmes-Adie syndrome and chronic cough. Our patient showed early signs of autonomic neuropathy as his cough developed, including anisocoria, hyperhydrosis and syncope. The mechanism behind the cough is poorly understood, but it has been proposed that selective loss of thinly myelinated aff erent nerves in the lung, trachea, and larynx leads to denervation hypersensitivity of secondary neurons in the nucleus solitarius. Although the patient undoubtedly had a trigger episode precipitating his chronic cough (the original episode of pneumonia), the presence of an autonomic neuropathy may well explain the persistence of his symptoms. This case also highlights the diffi culty in treating patients with no apparent cause for their cough. Although chronic idiopathic cough and Holmes-Adie syndrome are both of unknown cause, recognition of this association has led to a more accurate diagnosis and, in this case, an appropriate tertiary specialist opinion.

Anticholinergic therapy for chronic asthma in children over two years of age.

In the intrinsic system of controlling airway calibre, the cholinergic (muscarinic) sympathetic nervous system has an important role. Anticholinergic, anti muscarinic bronchodilators such as ipratropium bromide are frequently used in the management of childhood airway disease. In asthma, ipratropium is a less potent bronchodilator than beta-2 adrenergic agents but it is known to be a useful adjunct to other therapies, particularly in status asthmaticus. What remains unclear is the role of anticholinergic drugs in the maintenance treatment of chronic asthma. To determine the effectiveness of anticholinergic drugs in chronic asthma in children over the age of 2 years. The Cochrane Airways Group trials register and reference lists of articles were searched in January 2002. Randomised controlled trials in which anticholinergic drugs were given for chronic asthma in children over 2 years of age were included. Studies including comparison of: anticholinergics with placebo, and anticholinergics with any other drug were included. Eligibility for inclusion and quality of trials were assessed independently by two reviewers. Eight studies met the inclusion criteria.Three papers compared the effects of anticholinergic drugs with placebo, and a meta-analysis of these results demonstrated no statistically significant benefit of the use of anticholinergic drugs over placebo in any of the outcome measures used. The results of one of these trials could not be included in the meta-analysis but the authors did report significantly lower symptom scores with inhaled anticholinergics compared with placebo. However, there was no significant difference between ipratropium bromide and placebo in the percentage of symptom-free nights or days. Two trials studied the effects of anticholinergics on bronchial hyper responsiveness to histamine, by measuring the provocation dose of histamine needed to cause a fall of 20 % in FEV1 (PD 20). One study (comparing anticholinergics with placebo) reported a statistically significant increase in PD 20 but this was not found in another study (comparing anticholinergics with a beta-2 agonist). Both trials also examined the effect of anticholinergic drugs on diurnal variation in peak expiratory flow rate (PEFR) and reported no significant effect. Two studies compared the addition of an anticholinergic drug to a beta-2 agonist with the beta-2 agonist alone. Both trials failed to show any significant benefit from the long term use of combined anticholinergics with beta-2 agonists compared with beta-2 agonists alone. One trial compared the effects of oral and inhaled anticholinergic drugs with placebo. No statistically significant differences were found in any of the outcome measures except for a higher FEV1 / VC ratio and RV / TLC ratio with oral anticholinergic therapy when compared with placebo. The present review summarises the best evidence available to date. Although there were some small beneficial findings in favour of anticholinergic therapy, there is insufficient data to support the use of anticholinergic drugs in the maintenance treatment of chronic asthma in children.

Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Dutch Study Group

The objective of the present study was to investigate the dose-dependent bronchodilator efficacy and duration of action of the newly developed antimuscarinic agent tiotropium bromide in patients with chronic obstructive pulmonary disease (COPD). In a randomized, double-blind, placebo-controlled, crossover design, patients inhaled single doses of 10-80 micrograms tiotropium bromide and placebo, formulated in lactose powder capsules. The washout period between test doses was 72 h. Thirty five patients were enrolled in the trial (32 males and 3 females; mean age 64 yrs). Baseline forced expiratory volume in one second (FEV1) (mean 1.34 L) was less than 65% of predicted and was < 70% of forced vital capacity (FVC). All subjects had a smoking history of more than 10 pack-years. The mean reversibility of FEV1 after inhalation of 40 micrograms ipratropium bromide was 28%. Pulmonary function testing was performed before and at regular time intervals for up to 32 h after test drug administration. Compared to placebo, tiotropium bromide produced significant improvements in FEV1, FVC, peak expiratory flow rate (PEFR) and forced mid-expiratory flow (FEF25-75%). The bronchodilator response was almost immediate; peak improvement in FEV1 was reached 1-4 h after test drug inhalation, and the duration of action extended to 32 h after the 20, 40 and 80 micrograms doses. A clear dose-response relationship was seen for peak FEV1 and for the average FEV1 over differing time periods during the 32 h observation period, 80 micrograms of test drug being superior to the 10 micrograms dose. Peak improvement in FEV1 ranged 19-26% of test-day baseline for tiotropium bromide doses compared to 16% for placebo. The large improvement for placebo is probably due to carry-over effect which was significant. After excluding carry-over effect, the peak response to placebo decreased to 11%, whilst for tiotropium bromide doses it ranged 20-25%; standard error for mean difference was about 4%. There was no evidence of systemic anticholinergic effects. In this population of patients with COPD, tiotropium bromide was found to be a safe and long-acting bronchodilator, demonstrating a clear dose-response relationship following single dose administration.

The Combination of Ipratropium and Albuterol Is More Effective Than Either Agent Alone

Anticholinergic bronchodilators have been used since the beginning of recorded time. The datura genus of plants that contains anticholinergic alkaloids, including atropine, has been used by man for several thousand years for “recreational and various nefarious purposes” 1 Gross N Skorodin MS Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis. 1984; 129: 856-870 Crossref PubMed Scopus (232) Google Scholar The anticholinergics have been used as bronchodilators for at least 300 years. 2 Gandevia B Historical review of the use of parasympatholytic agents in the treatment of respiratory disorders. Postgrad Med I. 1975; 51: 7:13-20 Google Scholar Stramonium powders, burned and inhaled, are still used worldwide, often in underdeveloped countries. 3 Weiner N Atropine, scopolamine and related antimuscarinic drugs. in: Gilman AG Goodman LS Gilman A The pharmacologic basis of therapeutics. 6th. MacMillan, New York1980: 135 Google Scholar , 4 Beakley JF Bresnick E Levinson L et al. Evaluation of therapeutic substances employed for the relief of bronchospasms: III. Anticholinergic agents. Ann Allergy. 1949; 7: 113-121 Google Scholar Several anticholinergics are regularly prescribed by physicians worldwide, including atropine, ipratropium bromide, thiazinamium, oxitropium, and glycopyrrolate. Only ipratropium bromide is licensed for use in the United States.

Ba 679 BR, A novel long-acting anticholinergic bronchodilator

The use of anticholinergics in antiobstructive therapy is well established in pulmonary medicine. We sought to improve the duration of action of inhaled antimuscarinics. A newly developed compound, Ba 679 BR (abbreviated Ba 679) proved to be a highly potent muscarinic antagonist in guinea pig tracheal rings. Its binding to human receptors (Hm1, Hm2, Hm3) was characterized by K D-values in the 10 −10 M concentration range. Assessment of the dissociation rate of complexes of labelled Ba 679 and human muscarinic receptors revealed very slow dissociation in comparison to ipratropium. The half-lives in hours were: Ba 679-Hm3: 34.7, -Hm1: 14.6, -Hm2: 3.6; ipratropium-Hm3: 0.26, -Hm1: 0.11, -Hm2: 0.035. The duration of action in vivo was determined by means of acetylcholine-induced bronchospasms in dogs following inhalation of the drugs. Ba 679 demonstrated a significantly longer duration of protection than an equipotent dose of ipratropium. The plasma levels following inhalation in dogs declined rapidly and are unlikely to reflect the duration of the pharmacological activity. In summary, Ba 679 represents a novel type of antimuscarinic bronchodilator with a long duration of action, most likely due to its slow dissociation from Hm3-receptors. In addition, the drug showed “kinetic receptor subtype selectivity” by having a more rapid dissociation from Hm2 than from Hm1 and Hm3 receptors.