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The purpose of this review is to summarize essential pharmacological, pharmaceutical, and clinical aspects in the field of orally inhaled therapies that may help scientists seeking to develop new products. After general comments on the rationale for inhaled therapies for respiratory disease, the focus is on products approved approximately over the last half a century. The organization of these sections reflects the key pharmacological categories. Products for asthma and chronic obstructive pulmonary disease include β -2 receptor agonists, muscarinic acetylcholine receptor antagonists, glucocorticosteroids, and cromones as well as their combinations. The antiviral and antibacterial inhaled products to treat respiratory tract infections are then presented. Two "mucoactive" products-dornase α and mannitol, which are both approved for patients with cystic fibrosis-are reviewed. These are followed by sections on inhaled prostacyclins for pulmonary arterial hypertension and the challenging field of aerosol surfactant inhalation delivery, especially for prematurely born infants on ventilation support. The approved products for systemic delivery via the lungs for diseases of the central nervous system and insulin for diabetes are also discussed. New technologies for drug delivery by inhalation are analyzed, with the emphasis on those that would likely yield significant improvements over the technologies in current use or would expand the range of drugs and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of approved orally inhaled drug products for a variety of respiratory diseases and for systemic administration should be helpful in making judicious decisions about the development of new or improved inhaled drugs. These aspects include the choices of the active ingredients, formulations, delivery systems suitable for the target patient populations, and, to some extent, meaningful safety and efficacy endpoints in clinical trials., (Copyright © 2022 by The Author(s).)

Background: Methacholine challenges have been used in clinical trials to assess therapeutic effects and potential adverse reactions of interventions on pulmonary function in a sensitive population, such as in subjects with asthma. Here, we evaluate the variability of the methacholine challenge recovery model, and compare the results obtained for both incremental and bolus challenge methods., Methods: The extent, time course and variability of change in forced expiratory volume in 1 s (FEV 1 ) following repeated methacholine challenges in subjects with mild asthma were investigated in an open-label, four-period, fixed-sequence, two-method, replicate crossover study. At Visits 1 and 2, subjects underwent an incremental challenge using doubling doses of methacholine until a ≥20% decrease in FEV 1 was observed; at Visits 3 and 4, subjects underwent a bolus challenge, inhaling a single dose of methacholine calculated from the cumulative dose established during Visit 1., Results: A total of 19 subjects were included in the study. Both the mean FEV 1 area under the curve (FEV 1 AUC 0-tz ) and mean maximum reductions in FEV 1 (absolute and relative) 120 min post-challenge values were higher for the incremental challenges than the bolus challenges, with no reported difference between repetitions of the same methodology. FEV 1 AUC 0-tz decrease 120 min post challenge demonstrated an intra-subject coefficient of variation (CV) of 47.2% (incremental) and 78.3% (bolus), suggesting considerable between-visit variability. The mean absolute, and similarly relative, maximum reductions in FEV 1 compared with post-diluent baseline values demonstrated lower intra-subject variability (incremental 21.16%, bolus 40.67%) than the FEV 1 AUC 0-tz -based endpoint. There was a trend towards faster recovery following the bolus challenge than with the incremental challenge. The provocative dose of methacholine inducing a ≥20% decrease in FEV 1 resulted in a between-group mean difference of 27.20% in the incremental challenge periods, with a high intra-subject CV of 80.64%, demonstrating considerable variability., Conclusion: Maximum reduction in FEV 1 had the lowest variability. There was little difference between repetitions of the same methodology, as indicated by overlapping confidence intervals. There was a trend towards faster recovery following bolus challenge than with the incremental challenge. The results of this trial could be of value when designing future clinical trials using the methacholine challenge methodology., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The WISDOM study (NCT00975195) reported a change in lung function following withdrawal of fluticasone propionate in patients with severe to very severe COPD treated with tiotropium and salmeterol. However, little is known about the validity of home-based spirometry measurements of lung function in COPD. Therefore, as part of this study, following suitable training, patients recorded daily home-based spirometry measurements in addition to undergoing periodic in-clinic spirometric testing throughout the study duration. We subsequently determined the validity of home-based spirometry for detecting changes in lung function by comparing in-clinic and home-based forced expiratory volume in 1 second in patients who underwent stepwise fluticasone propionate withdrawal over 12 weeks versus patients remaining on fluticasone propionate for 52 weeks. Bland-Altman analysis of these data confirmed good agreement between in-clinic and home-based measurements, both across all visits and at the individual visits at study weeks 6, 12, 18, and 52. There was a measurable difference between the forced expiratory volume in 1 second values recorded at home and in the clinic (mean difference of -0.05 L), which may be due to suboptimal patient effort in performing unsupervised recordings. However, this difference remained consistent over time. Overall, these data demonstrate that home-based and in-clinic spirometric measurements were equally valid and reliable for assessing lung function in patients with COPD, and suggest that home-based spirometry may be a useful tool to facilitate analysis of changes in lung function on a day-to-day basis.

Background: Blood eosinophil counts might predict response to inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. We used data from the WISDOM trial to assess whether patients with COPD with higher blood eosinophil counts would be more likely to have exacerbations if ICS treatment was withdrawn., Methods: WISDOM was a 12-month, randomised, parallel-group trial in which patients received 18 μg tiotropium, 100 μg salmeterol, and 1000 μg fluticasone propionate daily for 6 weeks and were then randomly assigned (1:1) electronically to receive either continued or reduced ICS over 12 weeks. We did a post-hoc analysis after complete ICS withdrawal (months 3-12) to compare rate of exacerbations and time to exacerbation outcomes on the basis of blood eosinophil subgroups of increasing cutoff levels. The WISDOM trial is registered at ClinicalTrials.gov, number NCT00975195., Findings: In the 2296 patients receiving treatment after ICS withdrawal, moderate or severe exacerbation rate was higher in the ICS-withdrawal group versus the ICS-continuation group in patients with eosinophil counts (out of total white blood cell count) of 2% or greater (rate ratio 1·22 [95% CI 1·02-1·48]), 4% or greater (1·63 [1·19-2·24]), and 5% or greater (1·82 [1·20-2·76]). The increase in exacerbation rate became more pronounced as the eosinophil cutoff level rose, with significant treatment-by-subgroup interaction reached for 4% and 5% only. Similar results were seen with eosinophil cutoffs of 300 cells per μL and 400 cells per μL, and mutually exclusive subgroups., Interpretation: Blood eosinophil counts at screening were related to the exacerbation rate after complete ICS withdrawal in patients with severe to very severe COPD and a history of exacerbations. Our data suggest that counts of 4% or greater or 300 cells per μL or more might identify a deleterious effect of ICS withdrawal, an effect not seen in most patients with eosinophil counts below these thresholds., Funding: Boehringer Ingelheim., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long-acting bronchodilators has not been fully explored., Methods: In this 12-month, double-blind, parallel-group study, 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary end point was the time to the first moderate or severe COPD exacerbation. Spirometric findings, health status, and dyspnea were also monitored., Results: As compared with continued glucocorticoid use, glucocorticoid withdrawal met the prespecified noninferiority criterion of 1.20 for the upper limit of the 95% confidence interval (CI) with respect to the first moderate or severe COPD exacerbation (hazard ratio, 1.06; 95% CI, 0.94 to 1.19). At week 18, when glucocorticoid withdrawal was complete, the adjusted mean reduction from baseline in the trough forced expiratory volume in 1 second was 38 ml greater in the glucocorticoid-withdrawal group than in the glucocorticoid-continuation group (P<0.001); a similar between-group difference (43 ml) was seen at week 52 (P=0.001). No change in dyspnea and minor changes in health status occurred in the glucocorticoid-withdrawal group., Conclusions: In patients with severe COPD receiving tiotropium plus salmeterol, the risk of moderate or severe exacerbations was similar among those who discontinued inhaled glucocorticoids and those who continued glucocorticoid therapy. However, there was a greater decrease in lung function during the final step of glucocorticoid withdrawal. (Funded by Boehringer Ingelheim Pharma; WISDOM ClinicalTrials.gov number, NCT00975195.).

Purpose: In the absence of head-to-head clinical trials comparing the once-daily, long-acting beta2-agonists olodaterol and indacaterol for the treatment of chronic obstructive pulmonary disease (COPD), an indirect treatment comparison by systematic review and synthesis of the available clinical evidence was conducted., Methods: A systematic literature review of randomized, controlled clinical trials in patients with COPD was performed to evaluate the efficacy and safety of olodaterol and indacaterol. Network meta-analysis and adjusted indirect comparison methods were employed to evaluate treatment efficacy, using outcomes based on trough forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index, St George's Respiratory Questionnaire total score and response, rescue medication use, and proportion of patients with exacerbations., Results: Eighteen trials were identified for meta-analysis (eight, olodaterol; ten, indacaterol). Olodaterol trials included patients of all severities, whilst indacaterol trials excluded patients with very severe COPD. Concomitant maintenance bronchodilator use was allowed in most olodaterol trials, but not in indacaterol trials. When similarly designed trials/data were analyzed for change from baseline in trough FEV1 (liters), the following mean differences (95% confidence interval) were observed: trials excluding concomitant bronchodilator: indacaterol 75 mcg versus olodaterol 5 mcg, -0.005 (-0.077 to 0.067), and indacaterol 150 mcg versus olodaterol 5 mcg, 0.020 (-0.036 to 0.077); trials with concomitant tiotropium: indacaterol 150 mcg versus olodaterol 5 mcg, 0.000 (-0.043 to 0.042). In sensitivity analyses of the full network, results for change from baseline in trough FEV1 favored indacaterol, but this dataset suffered from trial design heterogeneity. For the other endpoints investigated, no statistically significant differences were found when analyzed in the full network., Conclusion: When compared under similar trial conditions, olodaterol and indacaterol have similar efficacy in patients with COPD. This research highlights the importance of considering the concomitant COPD medication when evaluating treatment effects in COPD.

Background: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis., Methods: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period., Results: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2., Conclusions: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.).

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD., (© 2013 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Long-acting bronchodilators in combination with inhaled corticosteroids (ICS) are recommended to decrease the risk of recurrent exacerbations in patients with Global initiative for chronic Obstructive Lung Disease (GOLD) stage 3-4 chronic obstructive pulmonary disease (COPD). There is increasing concern about the clinical benefit and long-term safety of ICS use in COPD patients. The WISDOM (Withdrawal of Inhaled Steroids During Optimised bronchodilator Management) study (NCT00975195) aims to evaluate the need for ICS use via stepwise withdrawal of ICS in COPD patients (GOLD 3-4 with a history of at least one exacerbation during the 12-month period prior to screening) receiving dual bronchodilation. During the 6-week run-in period, 2456 patients receive tiotropium 18 μg once daily, salmeterol 50 μg twice daily and fluticasone 500 μg twice daily. In a randomized, double-blind, parallel-group, active-controlled fashion, one group of patients continues to receive tiotropium, salmeterol and fluticasone, while the second group initiates stepwise withdrawal of fluticasone. The primary end point is time to first moderate or severe exacerbation following randomized treatment over 52 weeks. Lung function, symptoms and safety are also assessed. A sub-study aims to identify sub-populations and markers of steroid need. This study will determine the benefit of continued ICS therapy in combination with dual long-acting bronchodilators in COPD., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo., Methods: In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 μg or 5 μg, as compared with tiotropium HandiHaler at a once-daily dose of 18 μg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 μg or 2.5 μg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 μg vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease., Results: During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 μg vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups., Conclusions: Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 μg in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR ClinicalTrials.gov number, NCT01126437.).

Background: Tiotropium bromide is an effective therapy for COPD patients. Comparing across programs tiotropium Respimat Soft Mist inhaler was at least as efficacious as tiotropium HandiHaler, however, concerns have been raised about tiotropium's safety when given via Respimat., Methods: The TIOSPIR trial (NCT01126437) compares the safety and efficacy of tiotropium Respimat 5 μg once daily (marketed) and 2.5 μg once daily (investigational) with tiotropium HandiHaler 18 μ once daily (marketed). The hypotheses to be tested are 1). that tiotropium Respimat 5 μg once daily and Respimat 2.5 μg once daily are non-inferior to HandiHaler in terms of all-cause mortality, and 2). that tiotropium Respimat 5 μg once daily is superior to HandiHaler in terms of time to first exacerbation. A spirometry substudy evaluates the bronchodilator efficacy. The trial is a randomized, double-blind, double dummy, event-driven, parallel group study. Participants can use any background treatment for COPD except inhaled anticholinergic agents. The study encompasses a wide range of COPD patients, e.g. patients with stable cardiac diseases including arrhythmia can be included. Clinical sites are international and include both primary care as well as specialists., Results: To date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2-3 years., Conclusion: TIOSPIR will provide precise estimates of the relative safety and efficacy of the Respimat and HandiHaler formulations of tiotropium, assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort.

Background: Some patients with severe asthma remain symptomatic and obstructed despite maximal recommended treatment. Tiotropium, a long-acting inhaled anticholinergic agent, might be an effective bronchodilator in such patients., Objective: We sought to compare the efficacy and safety of 2 doses of tiotropium (5 and 10 μg daily) administered through the Respimat inhaler with placebo as add-on therapy in patients with uncontrolled severe asthma (Asthma Control Questionnaire score, ≥ 1.5; postbronchodilator FEV₁, ≤ 80% of predicted value) despite maintenance treatment with at least a high-dose inhaled corticosteroid plus a long-acting β₂-agonist., Methods: This was a randomized, double-blind, crossover study with three 8-week treatment periods. The primary end point was peak FEV₁ at the end of each treatment period., Results: Of 107 randomized patients (54% female patients; mean, 55 years of age; postbronchodilator FEV₁, 65% of predicted value), 100 completed all periods. Peak FEV₁ was significantly higher with 5 μg (difference, 139 mL; 95% CI, 96-181 mL) and 10 μg (difference, 170 mL; 95% CI, 128-213 mL) of tiotropium than with placebo (both P < .0001). There was no significant difference between the active doses. Trough FEV₁ at the end of the dosing interval was higher with tiotropium (5 μg: 86 mL [95% CI, 41-132 mL]; 10 μg: 113 mL [95% CI, 67-159 mL]; both P < .0004). Daily home peak expiratory flow measurements were higher with both tiotropium doses. There were no significant differences in asthma-related health status or symptoms. Adverse events were balanced across groups except for dry mouth, which was more common on 10 μg of tiotropium., Conclusion: The addition of once-daily tiotropium to asthma treatment, including a high-dose inhaled corticosteroid plus a long-acting β₂-agonist, significantly improves lung function over 24 hours in patients with inadequately controlled, severe, persistent asthma., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Two 1-year studies evaluated the long-term efficacy and safety of tiotropium 5 or 10 microg versus placebo, inhaled via the Respimat Soft Mist Inhaler (SMI). The two studies were combined and had 4 co-primary endpoints (trough FEV(1) response, Mahler Transition Dyspnea Index [TDI] and St George's Respiratory Questionnaire scores all at week 48, and COPD exacerbations per patient-year). A total of 1990 patients with COPD participated (mean FEV(1): 1.09 L). The mean trough FEV(1) response of tiotropium 5 or 10 microg relative to placebo was 127 or 150 mL, respectively (both P < 0.0001). The COPD exacerbation rate was significantly lower with tiotropium 5 microg (RR = 0.78; P = 0.002) and tiotropium 10 microg (RR = 0.73; P = 0.0008); the health-related quality of life and Mahler TDI co-primary endpoints were significantly improved with both doses (both P < 0.0001). Adverse events were generally balanced except anticholinergic class effects, which were more frequent with active treatment. Fatal events occurred in 2.4% (5 microg), 2.7% (10 microg), and 1.6% (placebo) of patients; these differences were not significant. Tiotropium Respimat SMI 5 microg demonstrated sustained improvements in patients with COPD relative to placebo and similar to the 10 microg dose but with a lower frequency of anticholinergic adverse events.

This study compared the bronchodilator effects of tiotropium, formoterol and both combined in chronic obstructive pulmonary disease (COPD). A total of 71 COPD patients (mean forced expiratory volume in one second (FEV1) 37% predicted) participated in a randomised, double-blind, three-way, crossover study and received tiotropium 18 microg q.d., formoterol 12 microg b.i.d. or both combined q.d. for three 6-week periods. The end-points were 24-h spirometry (FEV1, forced vital capacity (FVC)) at the end of each treatment, rescue salbutamol and safety. Compared with baseline (FEV1 prior to the first dose in the first period), tiotropium produced a significantly greater improvement in average daytime FEV1 (0-12 h) than formoterol (127 versus 86 mL), while average night-time FEV1 (12-24 h) was not different (tiotropium 43 mL, formoterol 38 mL). The most pronounced effects were provided by combination therapy (daytime 234 mL, night-time 86 mL); both differed significantly from single-agent therapies. Changes in FVC mirrored the FEV1 results. Compared with both single agents, daytime salbutamol use was significantly lower during combination therapy (tiotropium plus formoterol 1.81 puffs.day(-1), tiotropium 2.41 puffs x day(-1), formoterol 2.37 puffs x day(-1)). All treatments were well tolerated. In conclusion, in chronic obstructive pulmonary disease patients, tiotropium q.d. achieved a greater improvement in daytime and comparable improvement in night-time lung function compared with formoterol b.i.d. A combination of both drugs q.d. was most effective and provided an additive effect throughout the 24-h dosing interval.

In the past mucoactive drugs in airway diseases have been identified and profiled in symptom-based animal experiments and in clinical trials along related lines (cough and expectoration). Presently available drugs of this class are not generally accepted by licensing authorities worldwide and no new molecule clinically profiled as a mucoactive drug has been brought to regulatory approval in the past 20 years. Among regulatory guidelines only the CPMP 1999 'points to consider' on drug development in chronic obstructive pulmonary disease (COPD) advises for mucoactive drug development by suggesting that an indication for symptomatic treatment may be established on the basis of a symptom-related primary endpoint that should be justified as for its importance and supported by a co-primary lung function endpoint. Quality and safety of the new drug must be documented in long-term studies and the indication and use clearly described based on established or adequately profiled new primary endpoints in two pivotal studies. Published trials on mucoactive drugs have used a variety of endpoints. These include mucus hypersecretion-related symptoms by questionnaire, expectorated volume and dry weight, and mucus viscosity, elasticity and transportability. Most methods and endpoints are not validated and a positive standard of treatment is not established. New surrogate markers of efficacy for shorter term trials, e.g. induced or spontaneous sputum based assays (cellularity, mucus antigens), exhaled breath (NO), breath condensate (eicosanoids) or airway biopsy are only partially validated and the risk of false positive or negative phase II results is appreciably high. On the other hand, lung function measurements including airway hyper-reactivity assessment and typical phase III (long-term) endpoints like dyspnoea ratings, health status assessments, incidence of exacerbations and lung function decline over time are validated endpoints and offer a high likelihood of regulatory acceptance. Proof for no depression of lung mucociliary clearance is an important safety endpoint.

Inhaled antimuscarinic drugs are the treatment of choice, recommended by guidelines, in chronic obstructive pulmonary disease (COPD). In long-term clinical studies ipratropium shows important effects beyond relaxation of airway smooth muscle, e.g. reduction of exacerbations of COPD. In phase III clinical trials the new generation antimuscarinic tiotropium, inhaled once daily, has provided more than 24 hours of stable bronchodilation, that was sustained over the one year treatment period. In addition, tiotropium in comparison to placebo and even ipratropium, has been shown to provide improvement in dyspnea, reduction of exacerbations of COPD, reduced hospital admissions for exacerbations, reduced duration of hospitalisations as well as improved health-related quality of life. Chronic effects, such as reduction of hospitalisations, are conventionally attributed to an anti-inflammatory action and not to symptomatic bronchodilation. The 24 hour stabilisation of airway patency, avoiding fluctuations of the diameter with occasional closure and consequent need for reopening, may explain the extended therapeutic profile of tiotropium. Inhibition by antimuscarinics of pro-inflammatory cholinergic effects may also occur, e.g. inhibition of 5-HETE release from epithelial cells and inhibition of release of neutrophil and eosinophil chemotactic activity from alveolar macrophages. Antimuscarinics have shown increasing value as a therapeutic approach in COPD. The elucidation of their anti-inflammatory potential constitutes an interesting target for future studies.

Inhaled antimuscarinics, often called anticholinergics in clinical medicine, are established as first line bronchodilators in COPD. Tiotropium has been developed as a new generation antimuscarinic following ipratropium. Tiotropium is a specific, highly potent antimuscarinic, demonstrating very slow dissociation from muscarinic receptors. Dissociation from M2-receptors is faster than from M3 or M1, which in functional in vitro studies, appeared as kinetic receptor subtype selectivity of M3 and M1 over M2. The high potency and slow receptor dissociation found its clinical correlate in significant and long lasting bronchodilatation and bronchoprotection in patients with COPD and asthma. In asthma, protection against methacholine challenge exceeded the study period of 48 hours. In COPD, bronchodilatation of about 80% of the plateau was demonstrated after the first dose. Following chronic once daily inhalation for 28 days, the improvement in pulmonary function was sustained and there was a further increase in peak effects, but more importantly a rising baseline, achieving steady state within 2 weeks. Tiotropium achieves very stable long lasting effects with comparatively low variation of bronchodilatation between peak and trough (the level before the next administration). Stable 24 hour effectiveness profiles the compound as the first once daily bronchodilator. Clinical correlates of kinetic receptor subtype selective blockade remain to be shown. Plasma levels of tiotropium at trough are in the low pg/ml range and are unlikely to explain the sustained effectiveness in the airways. Slow dissociation from muscarinic receptors is likely to be responsible for the long duration of action.

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 KD-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.

We investigated the influence of smoking on the cell count, proteins and phospholipids in the bronchoalveolar lavage fluid in 371 patients. In the case of smokers, the cell count and the content of N-acetylglucosaminidase-an enzyme involved in glycoprotein metabolism were elevated. In contrast, the concentrations of protein, alpha amylase and phospholipids were lower than in the nonsmokers. The figures for ex-smokers were, for the most part, similar to those of the non-smokers.

Twenty-two premature lambs (gestational age 124-125 days, term 144-160 days) were intubated and supported by infant ventilators immediately after delivery. Respiratory rate was 60/min, inspiratory time 0.4 s, peak inspiratory pressure (PIP) 35 cm H2O, positive endexpiratory pressure (PEEP) 2 cm H2O, FiO2 1.0. 15 min after delivery 10 lambs (group 1) were treated with 35 mg/kg body weight bovine surfactant (SF-RI 1), whereas 1 ml/kg body weight saline was instilled in 12 lambs as controls (group 2). Sequential measurements of blood gases and acid base status (every 30 min) as well as continuous registration of PIP, PEEP, respiratory rate and tidal volume (TV) were performed in all lambs for 300 min. PIP was varied between 20 and 40 cm H2O in order to attain paCO2 values between 35 and 50 mm Hg. Significantly improved oxygenation was observed in group 1 lambs with maximum differences 30 min after delivery for 2 h. Ventilation was likewise affected: paCO2 and PIP values were significantly lower in the surfactant-treated animals (group 1). Total lung-thorax compliances (calculated from TV and delta P, i.e. PIP-PEEP) per kg body weight also significantly reflected the improvement of pulmonary function in group 1 compared to group 2 lambs. Intratracheal instillation of SF-RI 1 improved gas exchange in premature lambs, whereas control animals exhibited severe respiratory failure characteristic of respiratory distress syndrome (RDS).