Treatments in Respiratory Medicine

Introduction: Asthma and COPD are known to have significant health and economic consequences. Little is known about the costs of the latter in the UK. In this study we report the results of a comparison of the direct medical costs associated with COPD and asthma, where diagnoses are based on a robust prevalence study of a random sample of the Northern Ireland population. Methods: A two-stage survey was used to identify individuals with COPD and asthma. The diagnoses of asthma and COPD were based on patient history and lung function. Patients completed a detailed questionnaire covering healthcare utilization over the past 12 months, socioeconomic characteristics, impact of the disease on quality of life, and activities of daily living. Results: Forty-nine patients were diagnosed with COPD and 57 with asthma. Three asthma patients were excluded from the main analysis because they were thought to have atypical inpatient stays or other resource use. The mean direct healthcare cost for each COPD patient was estimated at £171.69 ($US309; year 2000 value) per annum, significantly less than the average cost of asthma among the 54 analyzed of £544.54 ($US980) [p < 0.05]. A correlation analysis revealed that among COPD patients, disease severity, defined by lung function, was a significant predictor of costs. Conclusion: Community-based costs for asthma are greater than those for COPD; this may relate in part to a relative under-diagnosis of COPD (73.5% COPD vs 15.8% asthma). As anticipated, the cost of COPD increases as FEV1 decreases. Further analysis will enable modeling of the cost consequences of both increased diagnosis and better management of COPD.

International guidelines on the management of asthma support the early introduction of corticosteroids to control symptoms and to improve lung function by reducing airway inflammation. However, not all individuals respond to corticosteroids to the same extent and it would be an advantage to be able to predict the response to corticosteroid treatment. Several biomarkers have been assessed following treatment with corticosteroids including measures of lung function, peripheral blood and sputum indices of inflammation, exhaled gases and breath condensates. The most widely examined measures in predicting a response to corticosteroids are airway hyperresponsiveness, exhaled nitric oxide (eNO) and induced sputum. Of these, sputum eosinophilia has been demonstrated to be the best predictor of a short-term response to corticosteroids. More importantly, directing treatment at normalizing the sputum eosinophil count can substantially reduce severe exacerbations. The widespread utilization of sputum induction is hampered because the procedure is relatively labor intensive. The measurement of eNO is simpler, but incorporating the assessment of NO in an asthma management strategy has not led to a reduction in exacerbation rates. The challenge now is to either simplify the measurement of a sputum eosinophilia or to identify another inflammatory marker with a similar efficacy as the sputum eosinophil count in predicting both the short- and long-term responses to corticosteroids.

Histamine is an important mediator in airway inflammation. It is elevated in the airways of asthmatic patients and is responsible for many of the pathophysiological features in asthma. Antihistamines block the actions of histamine and also have effects on inflammation which is independent of histamine-H1-receptor antagonism. Antihistamines have been shown to have bronchodilatory effects, effects on allergen-, exercise-, and adenosine- monophosphate-challenge testing, and also to prevent allergen-induced nonspecific airways hyperresponsiveness. Clinical studies have shown mixed results, and some studies have reported beneficial effects of azelastine, cetirizine, desloratadine, and fexofenadine on asthma symptoms or physiological measures in patients with asthma. The combination of an antihistamine and a leukotriene receptor antagonist has been shown to have additive effects in certain studies. Antihistamines have also been shown to delay or prevent the development of asthma in a subgroup of atopic children. These data suggest that antihistamines may have beneficial effects in the management of asthma.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal pulmonary disease for which there are no proven drug therapies. Anti-inflammatory and immunosuppressive agents have been largely ineffective. The precise relationship of IPF to other idiopathic interstitial pneumonias (IIPs) is not known, despite the observation that different histopathologic patterns of IIP may coexist in the same patient. We propose that these different histopathologic ‘reaction’ patterns may be determined by complex interactions between host and environmental factors that alter the local alveolar milieu. Recent paradigms in IPF pathogenesis have focused on dysregulated epithelial-mesenchymal interactions, an imbalance in TH1/TH2 cytokine profile and potential roles for aberrant angiogenesis. In this review, we discuss these evolving concepts in disease pathogenesis and emerging therapies designed to target pro-fibrogenic pathways in IPF.

Tiotropium bromide (Spiriva®) is a long-acting anticholinergic bronchodilator that maintains bronchodilation for at least 24 hours, allowing once-daily administration. The active moiety is the tiotropium cation (tiotropium); tiotropium bromide 22.5µg is equivalent to 18µg of tiotropium cation. Greater improvements in lung function from baseline (primary endpoint mean trough FEV1) were observed with inhaled tiotropium 18µg once daily than with placebo in 6-month and 1-year randomized, double-blind trials in patients with COPD. Tiotropium improved lung function (trough FEV1 response) more effectively than ipratropium bromide (ipratropium) 40µg four times daily in 1-year clinical trials, and was at least as effective as salmeterol 50µg 12-hourly in 6-month trials. Preliminary data suggest that tiotropium alone or in combination with once-daily formoterol has a greater bronchodilator effect than twice-daily formoterol in patients with COPD. Improvements in patients’ perception of health-related quality of life (HR-QOL) or dyspnea were greater with tiotropium than with placebo or ipratropium, and were similar to those with salmeterol. Reductions in the frequency and severity of acute exacerbations and in the use of rescue medication were also greater with tiotropium than with ipratropium or placebo. There was no evidence of tachyphylaxis with tiotropium during 1-year clinical trials. Inhaled tiotropium was generally well tolerated in clinical trials. Apart from dry mouth, the type and incidence of adverse events with tiotropium were similar to those with ipratropium, salmeterol or placebo in patients with COPD. In conclusion, inhaled tiotropium 18µg once daily improved lung function, dyspnea, and HR-QOL, and decreased the incidence of acute COPD exacerbations and the use of rescue medication relative to placebo or ipratropium in clinical trials in patients with COPD. Tiotropium was at least as effective as salmeterol in terms of bronchodilator efficacy and improvements in dyspnea or HR-QOL. With the exception of dry mouth, the tolerability profile of tiotropium was similar to that with placebo, ipratropium, or salmeterol. Consequently, inhaled tiotropium is likely to be a valuable option for first-line, long-term maintenance therapy in the management of bronchoconstriction in patients with symptomatic COPD. Tiotropium bromide has a quaternary ammonium structure and acts as an anticholinergic bronchodilator; the active moiety is the tiotropium cation (tiotropium). A 22.5µg dose of tiotropium bromide provides 18µg of tiotropium. Orally inhaled tiotropium bromide antagonizes the muscarinic M1, M2, and M3 receptors located in airway smooth muscle, reversing vagally mediated bronchoconstriction. Receptor binding assays and in vitro tests indicate that tiotropium bromide is kinetically selective for M1 and M3 receptors over the M2 receptor, unlike ipratropium bromide, which is nonselective. Animal and in vitro studies showed that tiotropium bromide was more potent (≈20-fold) than ipratropium bromide in displacing [3H]N-methylscopolamine (NMS) from muscarinic receptors, and had a more sustained protective effect (>70% inhibition) against NMS binding. Tiotropium bromide was a more potent inhibitor of bronchial contraction than atropine (≈ 23-fold), and had a slower onset and markedly longer duration of action than atropine or an equipotent dose of ipratropium bromide. Aerosol particle penetration is improved with tiotropium, without delaying mucus clearance from the lungs. Tiotropium 4.5–36µg once daily for 4 weeks increased mean trough and average FEV1 and FVC and mean PEFR values from baseline compared with placebo, with no evidence of tachyphylaxis. Improvements in trough FEV1 from baseline with tiotropium 4.5–36µg were not dose dependent. Based on a lack of dose response, the optimal once-daily tiotropium dosage is 18µg. Steady-state trough FEV1 values are achieved within 48 hours of commencing tiotropium. Sustained bronchodilation (for ≥24 hours) and an attenuation of the nocturnal decline in FEV1 that were unaffected by timing of the daily tiotropium dose were seen in randomized, double-blind, placebo-controlled studies in patients with stable COPD. The drug improved static and dynamic lung hyperinflation (evidenced by reduced trapped air volume and increased tidal volume and end-of-exercise inspiratory capacity), and improved exertional dyspnea (during activities of daily living and exertion) and exercise tolerance compared with placebo in randomized, double-blind studies. In patients with stable COPD, improved sleep-related oxygen desaturation that was unaffected by the timing of the daily dose was seen with tiotropium but not with placebo. Clinically significant treatment-related disorders of conduction or rhythm, or changes in heart rate were not observed with tiotropium in this patient group. Mean maximal plasma concentrations (Cmax) were observed within 5 minutes of inhalation of a single dose of tiotropium 18µg in patients with COPD. Plasma drug levels declined to minimum concentrations (Cmin) within 1 hour of treatment in healthy volunteers. Mean steady-state Cmax concentrations (16 ng/L) were achieved after 2–3 weeks of once-daily inhaled tiotropium 18µg in elderly patients with COPD; tiotropium does not appear to accumulate once steady-state has been achieved. The estimated absolute bioavailability of tiotropium at steady state in healthy volunteers was approximately 20–25%, and approximately 72% of the drug is bound to plasma proteins. Excretion of tiotropium is predominantly renal (through active secretion by the kidneys), although in vitro studies suggest that cytochrome P450 (CYP) oxidation (possibly involving CYP2D6 and CYP3A4 enzymes) may have a minor role. In patients with COPD, renal excretion of the unchanged drug at 24 hours (Ae24) was approximately 7%. The mean plasma elimination half-life after single or multiple doses in healthy volunteers and elderly patients with COPD was approximately 5–6 days. The renal clearance and urinary excretion of tiotropium decrease with increasing age; however, these changes are not considered to be clinically significant. Because of altered steady-state Cmax, Cmin, area under the concentration-time curve, and Ae24 values, caution is required with tiotropium administration in patients with moderate-to-severe renal impairment. The pharmacokinetics of tiotropium in patients with severe renal or hepatic impairment have not been studied. Tiotropium does not interact with drugs such as cimetidine or ranitidine, which are also eliminated by active renal secretion. Orally inhaled tiotropium bromide has been evaluated as a bronchodilator for the management of patients with COPD in randomized, double-blind 6-month and 1-year trials, and in several shorter studies. In clinical trials, COPD was diagnosed according to the American Thoracic Society guidelines. The bronchodilator effect was expressed as the trough FEV1 response (the mean change in FEV1 from baseline measured 1 hour prior to and immediately before a scheduled dose), and was the primary endpoint in all but two clinical trials. The bronchodilator effect with tiotropium 18µg once daily was superior to that with placebo in several well designed trials in patients with COPD. Moreover, greater improvements in mean peak and average FEV1 responses occurred with tiotropium but not with placebo. Mean trough, peak, and average FVC responses, and weekly mean morning and evening PEFR values were also improved to a greater extent with tiotropium than with placebo. Tiotropium demonstrated a greater bronchodilator effect than ipratropium bromide (hereafter referred to as ipratropium when used at approved dosages) 40µg four times daily in two 1-year trials in patients with COPD. Mean peak and average FEV1, mean trough FVC responses, and weekly mean morning and evening PEFR values were also increased to a greater extent with tiotropium than with ipratropium. In one of the two 6-month trials that compared the efficacy of tiotropium with that of inhaled salmeterol 50µg twice daily, greater improvements from baseline in mean trough, peak, and average FEV1 and FVC responses were seen with tiotropium than with salmeterol. Increases in weekly mean evening, but not morning, PEFR values were generally greater with tiotropium than salmeterol. In the second trial, improvement in the primary endpoint (mean trough FEV1 response from baseline) with tiotropium or salmeterol was similar, although peak and average responses were superior with tiotropium. Preliminary results from a 6-week crossover study in patients with COPD suggested that tiotropium alone or in combination with once-daily formoterol improved mean trough and average FEV1 and trough FVC values from baseline to a greater extent than twice-daily formoterol. More patients achieved a clinically important improvement (increase of ≥1 unit) in the transitional dyspnea index focal score (a measure of dyspnea-related impairment) with tiotropium than with placebo in the 1-year trials. Tiotropium was superior to ipratropium in 1-year trials, and was at least as effective as salmeterol in 6-month trials, in achieving a clinically important improvement in focal scores. Tiotropium recipients experienced fewer COPD exacerbations than placebo or ipratropium recipients and had fewer and shorter COPD-related hospitalizations compared with placebo recipients. Unlike salmeterol, tiotropium lengthened the time to onset of the first exacerbation and decreased the number of exacerbations compared with placebo in two 6-month trials. Similar proportions of tiotropium, salmeterol, and placebo recipients required COPD-related hospitalizations. According to the St George’s Respiratory Questionnaire, more patients achieved a clinically meaningful improvement (a reduction of ≥4 units from baseline) in heath-related quality of life with tiotropium than with placebo, ipratropium, or salmeterol in 6-month or 1-year trials. Results from the Short Form 36 questionnaire confirmed that greater improvements in physical domains occurred with tiotropium than with placebo or ipratropium. The need for rescue treatment with albuterol (salbutamol) was reduced with tiotropium compared with placebo or ipratropium, but was similar to that with salmeterol. The increased cost of treatment with tiotropium over 1 year compared with ipratropium in patients with COPD was €180 per patient per year. The higher acquisition cost of tiotropium was partially offset by reduced healthcare utilization costs. Inhaled tiotropium was generally well tolerated in all clinical trials. Similar percentages of tiotropium, ipratropium, salmeterol, or placebo recipients reported at least one adverse event in studies of up to 1 year. Apart from dry mouth, tiotropium appears to have a similar tolerability profile to that of placebo, ipratropium, or salmeterol. Dry mouth (an event likely to be related to the pharmacologic activity of tiotropium) occurred more frequently with tiotropium than with placebo (6-fold increase; p < 0.05), ipratropium (2-fold increase; p = 0.03) or salmeterol (4-fold increase; p-value not reported). Dry mouth, constipation, and urinary tract infections were reported more frequently with increasing age with tiotropium than with ipratropium in 1-year trials. Similar percentages of tiotropium, ipratropium, or placebo recipients experienced serious adverse events or adverse events leading to withdrawal in the 1-year trials. However, significantly (p < 0.01) fewer tiotropium than salmeterol or placebo recipients withdrew because of adverse events in the 6-month trials. Tiotropium was not associated with any clinically significant changes in ECG recordings, vital signs or laboratory values in 6-month and 1-year trials. Heart rate or rhythm disorders were uncommon with tiotropium (4%), placebo (2%) or ipratropium (5%) in 1-year trials. Inhaled tiotropium bromide is a bronchodilator indicated for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD. It is approved in >40 countries worldwide, including the US and those in the EU. The recommended dosage is a once-daily inhalation of tiotropium 18µg via a dry powder capsule inhaler, the HandiHaler®, at the same time each day. Tiotropium should not be used as an initial treatment for episodes of acute bronchospasm.

The prevalence of asthma has been increasing worldwide over the past 2 decades, especially the prevalence of childhood asthma. Currently, the prevalence of childhood asthma is around 3–20% in different countries based on the report from the International Study of Asthma and Allergies in Children (ISAAC). Asthma in childhood is predominantly an extrinsic asthma. In general, countries in the coastal, temperate, and subtropical zones have the highest prevalence of mite- and cockroach-sensitive asthma. Countries in the sub-arctic or semi-arid areas have a lower prevalence of childhood asthma, mostly associated with sensitization to pet dander, moulds, and pollens. Many genes have been linked to asthma in different ethnic populations. A global consensus for the management of asthma in adults and children >5 years of age has been made possible in the Global Initiative for Asthma (GINA) guidelines, where a step-wise management program using inhaled medication with and without oral anti-inflammatory drugs is recommended. The management of asthma in children <5 years of age remains inconclusive. Recent studies suggest that inherited susceptibility associated with risk factors from the prenatal and postnatal environment is likely to promote allergic sensitization and development of asthma. Consequently, early prevention of prenatal sensitization in utero and environmental control of early life exposure to various allergens may decrease the incidence of childhood asthma. In the management of moderate persistent asthma in infants and young children <5 years of age, airway resistance tests (FEV1 or PEF) are not of significance, but assessment of respiratory rate and skin pulse oximeter measurements of arterial oxygen saturation are helpful. Moreover, recent advances in pharmacogenetics and pharmacogenomics may provide better individualized care for early pharmacological prevention of childhood asthma via selective modulation of airway remodeling.

Asthma and COPD are chronic inflammatory conditions that affect hundreds of millions of patients worldwide. New therapeutics are desperately needed, especially those that target the underlying causes and prevent disease progression. Although asthma and COPD have distinct etiologies, both are associated with reduced airflow caused by excess infiltration of inflammatory cells into healthy lung tissues. As selectin-mediated adhesion of leukocytes to the vascular endothelium is a key early event in the initiation of the inflammatory response, selectin inhibition is thought to be a good target for therapeutic intervention. Three known selectins are expressed in distinct subsets of cells: P-selectin is presented on the surface of activated platelets and endothelial cells, L-selectin is constitutively expressed on leukocytes, and E-selectin synthesis is upregulated in activated endothelial cells. They mediate cell-cell adhesion in the shear flow of the bloodstream via specialized interactions with clusters of oligosaccharides presented on cell surface glycopeptide ligands. The role of selectin-ligand interactions in the inflammatory response has been demonstrated in various animal models, prompting considerable attention from the pharmaceutical industry. Drug discovery efforts have yielded many different classes of selectin inhibitors, including soluble protein ligands, antibodies, oligosaccharides and small molecules. Although many selectin inhibitors have shown activity in preclinical models, clinical progress of selectin-directed therapies has been slow. Early approaches employed carbohydrate-based inhibitors to mimic the natural ligand sialyl Lewis X; however, these compounds proved challenging to develop. Cytel’s CY 1503, a complex oligosaccharide, progressed to phase II/III trials for reperfusion injury, but further development was halted when it failed to demonstrate clinical efficacy. Two protein-based selectin inhibitors have reached phase II development. These included Wyeth’s recombinant soluble P-selectin ligand, TSI (PSGL-1), which was discontinued after disappointing results in myocardial infarction trials and Protein Design Labs’ humanized anti-L-selectin monoclonal antibody, which is currently in development for trauma. Bimosiamose, discovered by Encysive Pharmaceutical and presently being developed by Revotar Biopharmaceuticals, is an 863 g/mol molecular weight dimer with minimal carbohydrate content and is, to date, the leading selectin inhibitor in clinical development. This compound has shown promise in a phase Ha ‘proof of concept’ trial in patients with asthma, reducing airway recruitment of eosinophils after intravenous administration. Further clinical development of an inhaled formulation is underway. Despite a significant need for new therapeutics, selectin inhibitors have not yet been explored for the treatment of COPD. Bimosiamose represents an important proof of principle, and hopefully continued success will spark renewed interest in selectin-directed therapeutics for respiratory diseases.