Drugs For Chronic Obstructive Pulmonary Disease Research Articles

Symptom variability in COPD: a narrative review.

Chronic obstructive pulmonary disease (COPD) has traditionally been considered an inexorably progressive disease, associated with a constant increase of symptoms that occur as the forced expiratory volume in 1 second (FEV1) worsens, only intermittently interrupted by exacerbations. However, this paradigm has been challenged in recent decades by the available evidence. Recent studies have pointed out that COPD-related symptoms are not consistently perceived by patients in the same way, showing not only seasonal variation, but also changes in symptom perception during a week or even within a single day. According to the available data, patients experience the biggest increase in respiratory symptoms during the first hours of the early morning, followed by the nighttime. This variation over time is of considerable importance, since it impacts on daily life activities and health-related quality of life, as measured by a recently developed ad hoc questionnaire. Additionally, recent clinical trials have suggested that the use of rapid-onset long-acting bronchodilators may have an impact on morning symptoms, despite their current use as maintenance treatment for a determined period. Although this hypothesis is to be validated in future long-term clinical trials comparing fast-onset versus slow-onset inhaled drugs in COPD, it may bring forward a new concept of long-term bronchodilator therapy. At the present time, the two available long-acting, fast-onset bronchodilators used in the treatment of COPD are formoterol and the recently marketed indacaterol. Newer drugs have also been shown to have a rapid onset of action in preclinical studies. Health care professionals caring for COPD patients should consider this variation in the perception of symptoms during their clinical interview as a potential new target in the long-term treatment plan.

The future of combining inhaled drugs for COPD

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality globally, and its prevalence is projected to continue to increase owing to trends in smoking. Treatment of COPD has evolved from the initial adaptations of drugs and treatment strategies successfully used in asthma into more specific pharmacological strategies following global guidelines. Bronchodilating anticholinergic and beta-2-stimulating agents and anti-inflammatory corticosteroid drugs delivered by inhalators are the mainstay of COPD treatment. Despite significant progress, current pharmacotherapies neither fully alleviate the airway obstruction in COPD, nor reverse the progressive nature of the disease. This review discusses inhalation therapies which have recently become clinically available or are being developed, with focus on combination therapies. There is accumulating evidence that the combination of two or all three drug classes, triple therapy, is superior to single drug therapy. Several fixed combinations of both currently available and novel molecules will be launched for clinical use within the next few years. Also, improved understanding of subgroups within the clinical spectrum of COPD, is likely to offer new potentials to improve COPD care.

Use of nonprescription medicines by patients with COPD: A survey in Chongqing Municipality, China

To study the impact of self-administration of nonprescription medicines (NPMs) on patients with chronic obstructive pulmonary disease (COPD), in Chongqing Municipality, China. A total of 85 patients who had used NPM were assigned to the NPM group. Another 83 patients who had only used prescription medicines (PMs) were assigned to the PM group. Their income, educational levels, health status, public health insurance coverage, the expense of drugs during exacerbation, and the numbers of acute exacerbations during the past year were surveyed, and the approved drugs for COPD were evaluated. The contents of corticosterone in various types of NPMs were determined by high-performance liquid chromatography. The proportion of use of NPM in hospitalized patients with COPD was 12.96%. The percentage of illiteracy and low income was significantly higher in COPD patients in the NPM group than those in the PM group. The cost of drugs per day and the quality of life in the NPM group were lower than those in the PM group. Further analysis revealed that 15 of 21 NPMs contained corticosteroids. More importantly, medical advice from doctors and nurses appeared to be effective. Some Chinese patients with COPD living in the Chongqing area of China used NPMs that contained corticosteroids. Health education and advisement can effectively limit the use of NPMs.

Comorbidities of chronic obstructive pulmonary disease

Defining the nature of the association between chronic obstructive pulmonary disease (COPD) and other chronic conditions is of primary importance to improve the health status of COPD patients through the optimal care of comorbidities. We aimed at providing a reasoned guide to understand, recognize and treat comorbidity of COPD with the perspective of shifting from comorbidity to multimorbidity. Select comorbidities, such as atherosclerotic disease, depression, chronic kidney disease, cognitive impairment, obstructive sleep apnea syndrome, lung cancer, osteoporosis, diabetes, heart failure, sarcopenia, aortic aneurysm, arrhythmias and pulmonary embolism are highly prevalent among older COPD patients. Several concerns may affect the management of older COPD patients with comorbidity (e.g. the use of β-blockers in patients with COPD and cardiovascular diseases or concerns about the cardiovascular safety of inhaled COPD drugs). Evidence suggests that systemic inflammation may be the link between COPD and comorbidities, but this issue is still debated. Whatever the mechanism underlying comorbidities in COPD may be, it has an important clinical, prognostic and therapeutic impact. Nevertheless, clinical practice guidelines do not take into account comorbidities in their recommendations. Additionally, clinical trials investigating COPD treatment in the context of multimorbidity and considering geriatric outcomes are also distinctly lacking.

Biomarkers of Therapeutic Response in Patients with Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality across the world. Unfortunately, none of the current therapies, except for smoking cessation and supplemental domiciliary oxygen for hypoxaemic patients, can modify its natural course or alter survival. The pipeline for new compounds is not very promising owing to repeated failures, and many large pharmaceutical companies have abandoned COPD drug discovery altogether. One major barrier to new drug discovery is the lack of modifiable biomarkers that can be used as surrogates of clinical outcomes such as exacerbation and mortality. The only accepted marker in COPD is forced expiratory volume in 1 second (FEV(1)). However, by definition, COPD is a non-reversible or poorly reversible condition with respect to FEV(1). Thus, very few drugs except for bronchodilators have been able to address this endpoint. Of many candidate molecules, sputum neutrophil counts, exhaled corrected alveolar nitric oxide and proline-glycine-proline (PGP) and N-α-PGP, which are breakdown products of collagen, are promising lung-based biomarkers. However, their clinical utility has not been validated in large clinical trials. Promising blood biomarkers include surfactant protein D, and pulmonary- and activation-regulated chemokine (PARC/CCL-18). However, the clinical data have been inconsistent. Non-specific inflammatory biomarkers such as C-reactive protein and interleukin-6 lack specificity for COPD and thus are of limited clinical usefulness.

The role of sphingolipids in respiratory disease

Sphingolipids form a broad class of lipids with diverse functions ranging from membrane constituents to intracellular second messengers and extracellular mediators. They can be rapidly generated or converted into each other and they play pivotal roles in various cellular processes, many of which are broadly associated with inflammation and apoptosis. Among the numerous sphingolipids, ceramide and sphingosine-1-phosphate (S1P) have received the greatest attention. Ceramide is a hydrophobic molecule that is increased in the lungs of patients with cystic fibrosis and chronic obstructive pulmonary disease (COPD). Ceramide is the eponym for ceramide-rich membrane platforms. that need to form as a prerequisite to the uptake of several microorganisms including Pseudomonas aeruginosa, and as a prerequisite to many signaling processes including apoptosis and increased vascular permeability. Accordingly, abnormal amounts of enzymes involved in the synthesis of ceramide, such as neutral or acid sphingomyelinase, are found in emphysematic smokers and in patients with severe sepsis, and are considered as novel pharmacological targets. S1P acts as an extracellular mediator that opposes several actions of ceramide and acts by binding to G-protein coupled S1P receptors (S1P(1)-S1P(5)). Of particular interest are S1P(1) receptors that enhance vascular barrier functions and are antiapoptotic. Therefore, S1P(1)-receptor ligands are suggested as novel drugs for COPD and acute lung injury. S1P is a potent chemotaxin for many leukocytes, it organizes lymphocyte trafficking and is involved in several key symptoms of asthma such as airway hyperresponsiveness and pulmonary eosinophil sequestration. S1P is formed by sphingosine kinases that have been identified as possible drug targets for the treatment of asthma. Based on these findings, several new drugs have recently been developed to specifically target sphingomyelinases, sphingosine kinases and S1P receptors for the treatment of COPD, cystic fibrosis, asthma and acute lung injury.

A Kinder Side of Red Tides?

A Kinder Side of Red Tides?

Albuterol and levalbuterol use and spending in medicare beneficiaries with chronic obstructive pulmonary disease

Background: The evidence for the benefits of branded levalbuterol over generic albuterol in patients with chronic obstructive pulmonary disease (COPD) is inconclusive. However, there are significant cost differences between these products. Objectives: This study examined use and spending on albuterol and levalbuterol in a nationally representative sample of Medicare beneficiaries with COPD enrolled in Part D in 2006. It also examined differences in patient characteristics and use of other COPD drugs among recipients of these 2 short-acting β-agonists. Methods: Data were obtained from the 5% Medicare files for 2005–2006 linked to the 2006 Medicare Part D files. The sample consisted of all fee-for-service beneficiaries with COPD enrolled in stand-alone Part D plans in 2006. Patient characteristics and other COPD medication use were compared across albuterol-only users, levalbuterolonly users, and users of both albuterol and levalbuterol. Multinomial logistic regressions were used to identify factors independently associated with levalbuterol use. Results: There were 5.5 times more albuterol users than levalbuterol users in 2006; however, mean annual spending on levalbuterol was 18.6 times higher per user in 2006 than spending on albuterol ($1876 vs $101 per user, respectively). Levalbuterol-only users were more likely to be older than albuterol-only users (mean age: 71.5 vs 68.7 years; P < 0.05), as well as sicker (mean prescription drug hierarchical condition category score: 1.72 vs 1.55; P < 0.05) and residing in the South (67.9% vs 41.6%; P < 0.05). Levalbuterol-only users were more likely to use nebulizer forms covered under Part B than inhaler forms covered under Part D (78.6% vs 26.8%, respectively; P < 0.05), whereas albuterol-only users were more likely to use inhaler forms covered under Part D than nebulizer forms covered under Part B (82.2% vs 33.0%, respectively; P < 0.05). Conclusions: In this sample of Medicare beneficiaries with COPD enrolled in Part D, mean annual spending in 2006 was significantly higher for levalbuterol than for albuterol. The differences between levalbuterol and albuterol users in terms of patient characteristics, geographic region, and drug formulation/device type, coupled with the inconclusive evidence for efficacy differences in the literature, highlight the need for further comparative clinical and cost-effectiveness studies of these agents.

Sustained 24-h efficacy of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients

NVA237 is a once-daily inhaled long-acting muscarinic antagonist in development for the treatment of COPD. This randomized, double-blind, placebo-controlled, four-period, incomplete block crossover study, with open-label active comparator (tiotropium), assessed the efficacy and safety of NVA237. Patients (>or=40 years; smoking history >or=10 pack-years) with stable moderate-to-severe COPD (post-bronchodilator FEV(1) >or= 30% and <80% predicted, FEV(1)/FVC < 0.7) received NVA237 12.5, 25, 50 or 100 microg, placebo, or tiotropium 18 microg once-daily for 7 days. The primary endpoint was mean trough (23-24 h post-dose) FEV(1) on Day 7. Secondary endpoints included mean trough FEV(1) on Day 1, and FEV(1) and FVC at individual time points post-dose on Days 1 and 7. 83 patients (mean age 64.4 years; male 83.1%; mean COPD duration 6.7 years; mean post-bronchodilator FEV(1) 1.5 L/52.7% predicted) were randomized; 78 completed. Mean trough FEV(1) on Day 7 and Day 1 was significantly higher with all active treatments versus placebo (p < 0.05). NVA237 50 microg, 100 microg and tiotropium showed clinically relevant improvements versus placebo on Day 7 (differences of 131, 142 and 127 mL, respectively; p < 0.0001) and 1 (differences of 121, 135 and 112 mL, respectively; p < 0.0001). On Day 1, but not Day 7, FEV(1) was significantly higher (p < 0.05) with NVA237 50 and 100 microg versus tiotropium from 5 min up to 2 and 4 h post-dose, respectively. All doses of NVA237 and tiotropium were well tolerated. NVA237 once-daily was effective and well tolerated versus placebo, and demonstrated rapid and sustained 24-h bronchodilation. (ClinicalTrials.gov Identifier: NCT00501852).

Health, treatment and health care resources consumption profile among Spanish adults with diabetes and chronic obstructive pulmonary disease

Aims To describe the health, treatment and health care resources consumption profile among Spanish adults with diabetes and chronic obstructive pulmonary disease (COPD), and compare it with that of non-diabetic COPD patients. Patients and methods An observational and descriptive epidemiological study (EPIDEPOC study). The study included patients with stable COPD and aged ≥40 years, evaluated in primary care. Data were collected relating to sociodemographic variables, health profile, quality of life (SF-12), treatment and health care resources consumption. The results corresponding to diabetic and non-diabetic patients were compared. Results A total of 10,711 patients (75.6% males) with COPD were evaluated. The prevalence of diabetes was 16.9%. The diabetic patients were significantly older, with a larger percentage of women, and a lesser educational level compared with the non-diabetic patients. In addition, the diabetics were more sedentary, smoked less, and presented a higher percentage of obesity (33.6% versus 19.7%) than the non-diabetic patients. The severity of airways obstruction was greater among the diabetics than in the non-diabetic patients (54.57 ± 13.37% versus 57.92 ± 13.39%, respectively, p < 0.05). As to co-morbidity, the diabetics showed a greater frequency of arterial hypertension, hypercholesterolemia, heart disease, depression and anxiety. Both the physical and the mental component as measured by the SF-12 yielded significantly poorer results among the diabetics. On the other hand, the diabetic subjects showed a higher consumption of drugs for COPD. In addition, they consumed significantly more health care (and thus economical) resources than the non-diabetic patients. The results of the multivariate logistic regression analysis showed that the variables that were independently associated to COPD among diabetic patients were: higher age, higher BMI, concomitant chronic heart disease, use of inhaled corticoids, SF-12 mental component, SF-12 physical component and total cost of COPD. Conclusions The presence of diabetes in patients with COPD shows in the bivariate analysis a more severe lung disease, greater co-morbidity, poorer quality of life, and a greater consumption of resources, as well as a less favorable course in the previous year. However, the multivariate logistic regression shows that the variables that are independently associated to COPD among diabetic patients are higher age, higher BMI, concomitant chronic heart disease, use of inhaled corticoids, physical and mental component of quality of life questionnaire and total cost of COPD.

Seretide withdrawal increases airway inflammation in moderate COPD patients

IntroductionInhaledcorticosteroids(ICS)arewidelyusedtotreatpatients with chronic obstructive pulmonary disease(COPD), either alone or in combination with a long-actingbeta agonist (LABA) [ 1]. Clinical trials of the effects ofthese drugs in COPD usually allow patients to be recruitedirrespective of their previous ICS and/or LABA use [ 2]. Inthe subset of patients who are using ICS/LABA treatments,these are withdrawn at the start of the run-in period prior torandomisation to ensure that all patients in the study are at asimilar baseline point [ 3]. However, it is probable that thewithdrawal of medication in some patients causes clinicaldeterioration, which may continue if they are assigned tothe placebo arm of the study. This is not clinicallyjustifiable in some patients with severe or very severeCOPD [Global Initiative for Chronic Obstructive LungDisease (GOLD) stage III –IV) [ 1]. However, in stablemoderate COPD patients (GOLD stage II), ICS / LABAwithdrawal is likely to be better tolerated, as these patientshave better lung function. Nevertheless, it is possible that asignificant clinical deterioration could occur, even inmoderate COPD patients.We hypothesised that ICS/LABA withdrawal wouldcause significant deterioration in clinical status andincrease airway inflammation even in stable, moderateGOLD stage-II COPD patients. We conducted a pilotstudy in 14 COPD patients using an open, parallel groupdesign. Patients were randomised at a ratio of 3:2,stratified according to cu rrent smoking status, toeither withdrawal or continuation of inhaled fluticasonepropionate/salmeterol (SFC) for 6 weeks. Patients per-formed spirometry and sputum induction at random-isation (V0) and at 2-week intervals up to 6 weeks (V1,V2, V3). Inclusion criteria at screening were postbron-chodilator forced expiratory volume in 1 s (FEV

New treatments for chronic obstructive pulmonary disease and viable formulation/device options for inhalation therapy

Chronic obstructive pulmonary disease (COPD) is an increasingly important cause of morbidity and mortality, pathological features of which are pulmonary inflammation and irreversible airflow obstruction. Current therapies for COPD are aimed at improvement of clinical symptoms and reduction of inflammation in the respiratory systems. There is a pressing need for the development of new COPD medication, particularly as no existing treatment has been shown to reduce disease progression. In spite of a better understanding of the underlying disease process, there have been limited advances in the drug therapy of COPD, in contrast to the enormous advances in asthma management. Several new therapeutic targets and strategies have been proposed, and new drug candidates, including bronchodilators, protease inhibitors anti-inflammatory drugs and mediator antagonists, are now in clinical development for COPD treatment. New dry powder inhaler (DPI) systems for inhaled COPD therapy have also been developed to maximize drug concentrations in the airway systems, while minimizing systemic exposure and associated toxicity. This article aims to review recent developments in COPD drugs and the delivery systems for inhalation therapy, with particular emphasis on device options and formulations of DPI systems.

Drugs (including oxygen) in severe COPD

Access to comprehensive guidelines on the management of chronic obstructive pulmonary disease (COPD) is now available, and several treatment goals of therapy have been identified from these guidelines, which have since been studied in clinical trials. Drug therapy is a key component of an individual patient's management plan, particularly in more severe disease. During the past few years, a number of new drug treatments have become available, although these are not always appropriately prescribed; this is particularly the case for oxygen. For patients with a history of exacerbations, there is good evidence for the use of inhaled long-acting anticholinergic agents or combined inhaled steroids and long-acting beta-agonists. Evidence for prophylactic antibiotics and antioxidant agents is lacking. Nutritional and calorie supplementation have not been shown to improve exercise capacity. Statins may improve outcomes in COPD, but prospective trials are needed to confirm this. The evidence for the use of long-term oxygen therapy in hypoxaemic patients is robust. Ambulatory oxygen improves exercise capacity, but whether it is used appropriately is in doubt. Overall, short burst oxygen therapy does not offer a benefit and therefore cannot be recommended.

Enhanced persistence with tiotropium compared with other respiratory drugs in COPD

Tiotropium is a once-daily inhaled anticholinergic maintenance treatment with demonstrated effectiveness in chronic obstructive pulmonary disease (COPD). To compare persistence of tiotropium-use with other inhaled respiratory drugs in COPD in current clinical practice. The PHARMO database includes, among others, drug-dispensing and hospital discharge records for 2> or = million subjects in the Netherlands. All probable COPD-patients were identified by new respiratory drug use (age >54 years) or COPD-hospitalisations. New users of tiotropium, ipratropium, long-acting beta-agonists (LABAs), or fixed combination of LABA and inhaled corticosteroids (LABA+ICS), in 1998-2003, were included in the study. Persistence was assessed quarterly during the first year of follow-up. Patients with a proportion of days covered (PDC) > or =80% were considered persistent. Persistence was analysed using generalised estimating equations model. About 37% of new users of tiotropium continued treatment for 1 year, compared with 14% for ipratropium, 13% for LABA, and 17% for LABA+ICS. Multivariate analyses showed that tiotropium-users were 2-3 times more persistent with their therapy than patients using ipratropium (relative risk [RR]: 2.0; 95% confidence interval [CI]: 1.8-2.3), LABA (RR: 2.9; 95% CI: 2.4-3.6), or LABA+ICS (RR: 2.4; 95% CI: 2.1-2.8), respectively. Sub-analyses in patients with a prior hospitalisation for COPD showed that 1-year persistence rates were increased for all treatments (varying from 33% for patients using LABA+ICS to 61% for patients using tiotropium), while persistence with tiotropium was again 2-3 times higher compared with other treatments. Persistence with tiotropium was higher compared to other inhaled respiratory drugs in COPD in clinical practice.

Drug Prescription for Chronic Obstructive Pulmonary Disease and Asthma by Primary Care Physicians in the Spanish Autonomous Community of Madrid, 1996-2002

To identify trends in the drug prescription used to treat chronic obstructive pulmonary disease (COPD) and asthma at the primary care level in Madrid between 1996 and 2002, and to assess the repercussion of new treatments. We analyzed information on primary care general practitioners' and pediatricians drug prescription from the R03 group (drugs for obstructive airway diseases) of the Anatomical Therapeutic Chemical Classification System. Drug consumption was measured by recording the number of packages charged to the Spanish National Health Service and dispensed in pharmacies in the Spanish autonomous community of Madrid between 1999 and 2002. Consumption was expressed as defined daily dose per 1000 inhabitants per day. Drug use expressed as defined daily dose per 1000 inhabitants per day for COPD and asthma in Madrid increased by 18.48% between 1996 and 2002. The use of inhalants increased by 33.5% over the same period. The most marked differences were the increase in the number of patients treated with selective beta2 adrenergic agonists, anticholinergics, and combinations of fixed doses of long acting beta2 agonists with corticosteroids. The most-used drugs in 2002 were selective beta2 adrenergic agonist inhalants (37.7%), anticholinergics (22.5%), corticosteroids (19.5%), combinations of fixed doses of long acting beta2 adrenergic agonists with corticosteroids (10.5%) band xanthines (5.03%). In 2002, the prescription of 5 new treatments amounted to 15.76% of total use of COPD and asthma drugs (R03 group). Drug use for obstructive diseases of the airways showed a sharp increase between 1996 and 2002. Changes in patterns of use were observed, new treatments being quickly adopted, modifying the profile of drug prescription for the management of COPD and asthma.

Retrospective incremental cost analysis of a hospital-based COPD Disease Management Programme in Sweden

This paper reports on a retrospective analysis of hospital-based healthcare costs associated with the management of chronic obstructive pulmonary disease (COPD). During the second half of 2001, Simrishamn Hospital, Sweden, implemented a structured Disease Management Programme (DMP) for COPD and a total of 784 patients with COPD, enrolled in the DMP, were included in the analysis. The goal was to reduce the number of clinical events, such as severe exacerbations by early intervention, aggressive drug treatment, specialists easy available for advice, improved support for smoking cessation, increased number of scheduled follow-ups and closer tracking of high-risk COPD patients. The hospital administrative system provided data on resource consumption, such as outpatient care, inpatient care and drugs and unit cost, used in the economic analysis. The total cost of COPD drugs doubled (from €14,133 to €30,855 per year) as did the total number of outpatient visits (from 580 to 996 visits per year). The number of hospitalizations for acute COPD exacerbations and COPD with acute lower respiratory infection decreased from 67 to 25 per year. Total COPD-related healthcare costs decreased. The results presented here support the hypothesis that a COPD DMP can offer substantial overall direct cost savings.

ABS58: Investigation of factors influencing family physician adherence to chronic obstructive pulmonary disease treatment guideline recommendations

Family physicians do not prescribe antihypertensive medication for the treatment of chronic obstructive pulmonary disease (COPD) according to current guidelines. This study investigates possible reasons for this. The objectives were to measure the knowledge, attitude and stated practice of family physicians to the initiation of pharmacotherapy for uncomplicated COPD and to explore the reasons why clinical practice differs from guideline recommendations. A cross-sectional postal survey conducted between April and November 2005. Telephone and facsimile contact was made to non-responders. The survey instrument included respondent characteristics, preference for initiation of drug therapy for COPD and their opinion of efficacy, adverse effects and long-term safety, as well as knowledge of guidelines. Participants: Family physicians in the Kharkov region, Ukraine. Ranked preference of drugs for uncomplicated COPD. Opinion of drug efficacy, adverse effects, safety and cost. Knowledge of guidelines for first-line COPD drugs. Older agents are preferred to newer agents in the initiation of drug therapy contrary to current guideline recommendations. Newer agents were not thought to be more efficacious, have better short- and long-term adverse effect profiles and be more expensive than older agents. Older doctors most often held these attitudes. Guidelines influenced decision making but were not the most important factor. There is a demonstrable need for governments to invest in the promotion of accurate information on drugs through continuing education of prescribers and facilitating the production of standardized paper and web-based clinical guidelines. A program of targeted investment in clinical trials that examine the justification for different classes of agents should also be considered in appropriate circumstances. Conflict of interest and funding No conflicts of interest declared. The work was funded by Kharkov Medical Academy of Postgraduate education.

Reducing airways inflammation to prevent exacerbations in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is amajor cause of handicap, mortality and health careexpenses (1). Altered quality of life (QOL) is a hallmarkof the disease, and relates mainly to dyspnoea andexacerbations: both QOL at steady-state and its rate ofdecline over time correlate to the frequency of acuterespiratory events (2, 3). In parallel, hospitalizations forexacerbations in the most severe patients are importantdeterminants of health care costs (4). Thus, preventingexacerbations is a major goal of care for COPD patients,both from an individual and collective point of view.Inflammation and COPD exacerbationsIn most cases, COPD occurs in smokers and ex-smokers,in whom airflow limitation is the consequence of variousdegrees of emphysema, chronic bronchiolitis and mucusplugging (5). These components of the disease have beenlinked to inflammatory and remodelling processes in theairways and lung parenchyma, involved inflammatorycells being mainly neutrophils, B and T lymphocytes andmacrophages (5, 6). Airways inflammation is moreintense during exacerbations, as shown by increases inthe levels of (i) expression of neutrophil elastase, CXCL-5, CXCL-8 and CXCR1/2 in biopsies (7), (ii) exhaledLTB4 and 8-isoprostane in breath condensates (8), (iii)interleukin (IL)-8 and tumour necrosis factor (TNF)-a insputum (9).Infections are a leading cause of exacerbations andfurther amplify airway inflammation (10). However,about one half of exacerbations occur in the absence ofany detectable infective pathogen, which may not preventinflammation from increasing (11). Besides, higher levelsof inflammatory markers in the airways of patients atsteady-state are also associated with more frequentexacerbations (12). Studies of the East London COPDcohort even suggest the existence of a particular subgroupof COPD patients called frequent exacerbators, whoconsistently have more than 2–3 exacerbations per year(13). In these patients, QOL is more altered, forcedexpiratory volume at 1 s (FEV

Tiotropium: An inhaled anticholinergic for chronic obstructive pulmonary disease

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, dosage and administration, and formulary considerations of tiotropium are discussed. Tiotropium, a long-acting inhaled anticholinergic, recently received approval from the Food and Drug Administration for the management of chronic obstructive pulmonary disease (COPD). In patients with COPD, increased parasympathetic nervous system activity leads to bronchoconstriction and mucus secretion. Tiotropium induces relaxation of the airway smooth muscle, as does ipratropium, but differs in receptor association and dissociation rates, allowing for once-daily administration. After inhalation, tiotropium reaches maximal plasma concentrations within five minutes, but clinical improvements in forced expiratory volume in one second (FEV(1)) are maintained over 24 hours. Clinical trials of tiotropium with placebo, ipratropium, and salmeterol have demonstrated the efficacy of tiotropium in improving FEV(1) and forced vital capacity values and health-related quality of life. The most commonly observed adverse effect is dry mouth. No increase in adverse effects was observed when tiotropium was administered concomitantly with other drugs for COPD, including sympathomimetic bronchodilators and oral and inhaled corticosteroids. The combination of tiotropium and other anticholinergics has not been studied and is not recommended. The recommended dosage of tiotropium is the inhalation of an 18-mug capsule with a HandiHaler breath-actuated inhalation device once daily. Tiotropium appears to be at least as effective as currently available alternatives in the treatment of patients with COPD who require daily bronchodilator treatment. Its simplified dosing and tolerable adverse-effect profile can potentially lead to enhanced patient compliance.

Neurogenic mechanisms in bronchial inflammatory diseases.

Neurogenic inflammation encompasses the release of neuropeptides from airway nerves leading to inflammatory effects. This neurogenic inflammatory response of the airways can be initiated by exogenous irritants such as cigarette smoke or gases and is characterized by a bi-directional linkage between airway nerves and airway inflammation. The event of neurogenic inflammation may participate in the development and progression of chronic inflammatory airway diseases such as allergic asthma or chronic obstructive pulmonary disease (COPD). The molecular mechanisms underlying neurogenic inflammation are orchestrated by a large number of neuropeptides including tachykinins such as substance P and neurokinin A, or calcitonin gene-related peptide. Also, other biologically active peptides such as neuropeptide tyrosine, vasoactive intestinal polypeptide or endogenous opioids may modulate the inflammatory response and recently, novel tachykinins such as virokinin and hemokinins were identified. Whereas the different aspects of neurogenic inflammation have been studied in detail in laboratory animal models, only little is known about the role of airway neurogenic inflammation in human diseases. However, different functional properties of airway nerves may be used as targets for future therapeutic strategies and recent clinical data indicates that novel dual receptor antagonists may be relevant new drugs for bronchial asthma or COPD.