THE ROLE OF CORTICOSTEROIDS IN COPD

Abour Author: Kesinath Kotha*1, Varun Raj Vemula2, Rupesh Kotte3
1. Department of Pharmacy Practice, St Peters institute of pharmaceutical sciences, Warangal, A.P
2. Department of Pharmaceutical Chemistry, Vikas College of Pharmacy, Warangal, A.P.
3. SRR college of pharmaceutical sciences, Karimnagar, A.P.

ABSTRACT
Chronic obstructive pulmonary disease (COPD) is chronic obstruction of the flow of air through the airways and out of the lungs, and the obstruction generally is permanent and may be progressive over time. According to WHO in India, a study collecting data without spirometry assessment suggested that 12 million people were affected by chronic obstructive pulmonary disease. Recent studies show a prevalence of respiratory symptoms in 6%–7% of non-smokers and up to 14% of smokers. In a recent study in southern India, the prevalence rate of COPD in adults was around 7%. COPD is the fourth leading cause of death in the U.S. and the economic burden of COPD in the U.S. in 2007 was $42.6 billion in health care costs and lost productivity.
In view of its importance, the use of corticosteroids in treatment & management of COPD in acute & chronic conditions has been discussed along with emphasis on recent research trends. Use of corticosteroids & different combination products in the treatment of COPD along with their uses and side effects are presented.

INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is comprised primarily of three related conditions - chronic bronchitis, chronic asthma, and emphysema. In each condition there is chronic obstruction of the flow of air through the airways and out of the lungs, and the obstruction generally is permanent and may be progressive over time.
While asthma features obstruction to the flow of air out of the lungs, usually, the obstruction is reversible. Between "attacks" of asthma the flow of air through the airways typically is normal. These patients do not have COPD. However, if asthma is left untreated, the chronic inflammation associated with this disease can cause the airway obstruction to become fixed. That is, between attacks, the asthmatic patient may then have abnormal air flow. This process is referred to as lung remodeling. These asthma patients with a fixed component of airway obstruction are also considered to have COPD.
Often patients with COPD are labeled by the symptoms they are having at the time of an exacerbation of their disease. For instance, if they present with mostly shortness of breath, they may be referred to as emphysema patients. While if they have mostly cough and mucus production, they are referred to as having chronic bronchitis. In reality, it is better to refer to these patients as having COPD since they can present with a variety of lung symptoms. There is frequent overlap among COPD patients. Thus, patients with emphysema may have some of the characteristics of chronic bronchitis and chronic asthma and vice a versa.
According to WHO in India, a study collecting data without spirometry assessment suggested that 12 million people were affected by COPD. Recent studies show a prevalence of respiratory symptoms in 6%–7% of non-smokers and up to 14% of smokers. In a recent study in southern India, the prevalence rate of COPD in adults was around 7%.
Worldwide, COPD ranked as the sixth leading cause of death in 1990. It is projected to be the fourth leading cause of death worldwide by 2030 due to an increase in smoking rates and demographic changes in many countries.[1] In England, an estimated 842,100 of 50 million people have a diagnosis of COPD; translating into approximately one person in 59 receiving a diagnosis of COPD at some point in their lives.[2] COPD is the fourth leading cause of death in the U.S. and the economic burden of COPD in the U.S. in 2007 was $42.6 billion in health care costs and lost productivity. [3]

DEFINITIONS:
Chronic bronchitis:
Chronic bronchitis involves inflammation and swelling of the lining of the airways that leads to narrowing and obstruction of the airways. The inflammation also stimulates production of mucous (sputum), which can cause further obstruction of the airways. Obstruction of the airways, especially with mucus, increases the likelihood of bacterial lung infections. Chronic bronchitis usually is defined clinically as a daily cough with production of sputum for three months, two years in a row. This definition was developed primarily for research so that like patients could be compared. [4-6]

Emphysema:
There is permanent enlargement of the alveoli due to the destruction of the walls between alveoli in emphysema. The destruction of the alveolar walls reduces the elasticity of the lung overall. Loss of elasticity leads to the collapse of the bronchioles obstructing airflow out of the alveoli. Air becomes "trapped" in the alveoli and reduces the ability of the lung to shrink during exhalation. This trapped air takes up space and results in a reduced amount of air that can be taken in during the next breath. As a result, less air gets to the alveoli for the exchange of gasses. This trapped air also can compress adjacent less damaged lung tissue, preventing it from functioning to its fullest capacity. The exchange of carbon dioxide and oxygen between air and the blood in the capillaries takes place across the thin walls of the alveoli. Destruction of the alveolar walls decreases the number of capillaries available for gas exchange. This adds to the decrease in the ability to exchange gases. [7]

Role of inflammation in COPD:
In contrast to the eosinophil, which is the most prominent inflammatory cell in persons with asthma, the cellular composition of the airway inflammation in COPD is predominantly mediated by the neutrophils. Cigarette smoking induces macrophages to release neutrophil chemotactic factors and elastases, thus unleashing tissue destruction. Severity of airflow obstruction has correlated with greater induced sputum neutrophilia that is also more prevalent in patients with chronic cough and sputum production and is associated with an accelerated decline in lung function. [8-10]

Macrophages also play an important role through macrophage-derived matrix metalloproteinases (MMPs). Cigarette smoke causes neutrophil influx and is required for the secretion of MMPs, therefore suggesting that both neutrophils and macrophages are required for the development of emphysema. Studies have also shown that T lymphocytes, particularly CD8+, in addition to the macrophages, play an important role in the pathogenesis of smoking-induced airflow limitation. To support the inflammation hypothesis further, a stepwise increase in alveolar inflammation occurs in surgical specimens from patients without COPD versus patients with mild or severe emphysema.

SYMPTOMS OF COPD:
COPD symptoms from smoking
Typically, after smoking 20 or more cigarettes a day for more than twenty years, patients with COPD develop a chronic cough, shortness of breath (dyspnea), and frequent respiratory infections.

Emphysema symptoms of COPD
In patients affected predominantly by emphysema, shortness of breath may be the major symptom. Dyspnea usually is most noticeable during increased physical activity, but as emphysema progresses, dyspnea occurs at rest.

Chronic bronchitis and bronchiectasis symptoms of COPD
In patients with chronic bronchitis as well as bronchiectasis, chronic cough and sputum production are the major symptoms. The sputum is usually clear and thick. Periodic chest infections can cause fever, dyspnea, coughing, production of purulent (cloudy and discolored) sputum and wheezing. (Wheezing is a high pitched noise produced in the lungs during exhalation when mucous, bronchospasm, or loss of lung elasticity obstructs airways.) Infections occur more frequently as bronchitis and bronchiectasis progress. [11-13]

Advanced COPD symptoms
In advanced COPD, patients may develop cyanosis (bluish discoloration of the lips and nail beds) due to a lack of oxygen in blood. They also may develop morning headaches due to an inability to remove carbon dioxide from the blood. Weight loss occurs in some patients, primarily (another possibility is reduced intake of food) because of the additional energy that is required to breathe. In advanced COPD, small blood vessels in the lungs are destroyed, and this blocks the flow of blood through the lungs. As a result, the heart must pump with increased force and pressure to get blood to flow through the lungs. Patients with COPD may cough up blood (hemoptysis). Usually hemoptysis is due to damage to the inner lining of the airways and the airways' blood vessels; however, occasionally, hemoptysis may signal the development of lung cancer. [14-16]

DIAGNOSIS:
COPD usually is first diagnosed on the basis of a medical history which discloses many of the symptoms of COPD and a physical examination which discloses signs of COPD. The diagnosis of COPD should be considered in anyone who has dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease such as regular tobacco smoking. No single symptom or sign can adequately confirm or exclude the diagnosis of COPD although COPD is uncommon under the age of 40 years.

Spirometry:
The diagnosis of COPD is confirmed by spirometry, a test that measures breathing. Spirometry measures the forced expiratory volume in one second (FEV1) which is the greatest volume of air that can be breathed out in the first second of a large breath. Spirometry also measures the forced vital capacity (FVC) which is the greatest volume of air that can be breathed out in a whole large breath. Normally at least 70% of the FVC comes out in the first second (i.e. the FEV1/FVC ratio is >70%). A ratio of less than normal defines the patient as having COPD. More specifically, the diagnosis of COPD is made when the FEV1/FVC ratio is <70%. The severity of COPD also depends on the severity of dyspnea and exercise limitation. The GOLD criteria also require that values are after bronchodilator medication has been given to make the diagnosis, and the NICE criteria also requires FEV1%. The FEV1 (measured post-bronchodilator) is expressed as a percent of a predicted "normal" value based on a person's age, gender, height and weight. [17-20]

TREATMENT FOR COPD:
The goals of COPD treatment are:
1. To prevent further deterioration in lung function;
2. To alleviate symptoms;
3. To improve performance of daily activities and quality of life.

The treatment strategies include:
1. Quitting cigarette smoking;
2. Taking medications to dilate airways (bronchodilators) and decrease airway inflammation;
3. Vaccination against flu influenza and pneumonia;
4. Regular oxygen supplementation; and
5. Pulmonary rehabilitation.

Smoking Cessation:
Smoking cessation is one of the most important factors in slowing down the progression of COPD. Once COPD has been diagnosed, stopping smoking slows down the rate of progression of the disease. Even at a late stage of the disease it can significantly reduce the rate of deterioration in lung function and delay the onset of disability and death. It is the only standard intervention that can improve the rate of progression of COPD. [21]
Smoking cessation starts with an individual decision to stop smoking that leads to an attempt at quitting. Often several attempts are required before long-term smoking cessation is achieved. Some smokers can achieve long-term smoking cessation through "willpower" alone. However smoking is highly addictive and many smokers need further support to quit. The chance of successfully stopping smoking can be greatly improved through social support, engagement in a smoking cessation programme and the use of drugs such as nicotine replacement therapy, bupropion and varenicline. [22-24]

Bronchodilators:
Bronchodilators are medicines that relax smooth muscle around the airways, increasing the caliber of the airways and improving air flow. They can reduce the symptoms of shortness of breath, wheeze and exercise limitation, resulting in an improved quality of life for people with COPD. They do not slow down the rate of progression of the underlying disease. Bronchodilators are usually administered with an inhaler or via a nebulizer. There are two major types of bronchodilator, β2 agonists and anticholinergics. Anticholinergics appear to be superior to β2 agonists in COPD. Anticholinergics reduce respiratory deaths while β2 agonists have no effect on respiratory deaths. Each type may be either long-acting (with an effect lasting 12 hours or more) or short-acting (with a rapid onset of effect that does not last as long). [25]

CORTICOSTEROIDS IN COPD:
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.
• Glucocorticoids such as cortisol control carbohydrate, fat and protein metabolism and are anti-inflammatory by preventing phospholipids release, decreasing eosinophil action and a number of other mechanisms.
• Mineral corticoids such as aldosterone control electrolyte and water levels, mainly by promoting sodium retention in the kidney.
In cases of COPD and Asthma, inflammation tends to be chronic and severe. Therefore oral glucocorticosteroids are often prescribed for these types of conditions due to their powerful ability to decrease inflammation in the body. [26-28]

GLUCOCORTICOSTEROIDS:
The effects of oral and inhaled glucocorticosteroids in COPD are much less dramatic than in asthma, and their role in the management of stable COPD is limited to specific indications.
Oral Glucocorticosteroids:
Short-term: Many existing COPD guidelines recommend the use of a short course (two weeks) of oral glucocorticosteroids to identify COPD patients who might benefit from long-term treatment with oral or inhaled glucocorticosteroids. This recommendation is based on evidence that short-term effects predict long-term effects of oral glucocorticosteroids on FEV1, and evidence that asthma patients with airflow limitation might not respond acutely to an inhaled bronchodilator but do show significant bronchodilation after a short course of oral glucocorticosteroids. There is mounting evidence, however, that a short course of oral glucocorticosteroids is a poor predictor of the long-term response to inhaled glucocorticosteroids in COPD. For this reason, there appears to be insufficient evidence to recommend a therapeutic trial with oral glucocorticosteroids in patients with Stage II: Moderate COPD, Stage III: Severe COPD, or Stage IV: Very Severe COPD and poor response to an inhaled bronchodilator.

Side Effects:
1) Osteoporosis (bone weakening), which is common. Destruction of bone from loss of blood supply is rare.
2) Weight gain and fluid retention
3) Recurrent infections.
4) A cloudy area in the lens of the eye (cataracts).
5) Thin, fragile skin that bruises easily.
6) Increased risk for sores in the stomach (ulcers).

Examples (Oral):

Fig:2

Side effect of long-term treatment with systemic glucocorticosteroids is steroid myopathy, which contributes to muscle weakness, decreased functionality, and respiratory failure in subjects with advanced COPD.
In view of the well-known toxicity of long-term treatment with oral glucocorticosteroids, prospective studies on the long-term effects of these drugs in COPD are limited. [29] Therefore, based on the lack of evidence of benefit, and the large body of evidence on side effects, long-term treatment with oral glucocorticosteroids is not recommended in COPD. [30]

Inhaled Glucocorticosteroids:
Regular treatment with inhaled glucocorticosteroids does not modify the long-term decline of FEV1 in patients with COPD. However, regular treatment with inhaled glucocorticosteroids is appropriate for symptomatic COPD patients with an FEV1 < 50% predicted (Stage III: Severe COPD and Stage IV: Very Severe COPD) and repeated exacerbations (for example, 3 in the last 3 years). This treatment has been shown to reduce the frequency of exacerbations and thus improve health status, and withdrawal from treatment with inhaled glucocorticosteroids can lead to exacerbations in some patients. Re-analysis of pooled data from several longer studies of inhaled glucocorticosteroids in COPD suggests that this treatment reduces all-cause mortality, but this conclusion requires confirmation in prospective studies before leading to a change in current treatment recommendations. [31-33]
The possibility of side effects increases as the dose of the medicine increases. Side effects are less likely to occur when you use the inhaled form of the medicine.

Side Effects:
1. Sore mouth or sore throat.
2. Voice changes, such as hoarseness.
3. Heavy growth of a fungus in the mouth, throat, or esophagus (thrush).

Examples (Inhaled):

Fig:3 Inhaled corticosteroids are usually delivered using a metered-dose inhaler (MDI) but are also often available for dry powder inhalers (DPI). [34] Corticosteroid and beta2-agonist combination:
An inhaled glucocorticosteroid combined with a long-acting beta2-agonist is more effective than the individual components. Examples (Combined form):

Fig:4

The U.S. Food and Drug Administration (FDA) have reported that salmeterol may make breathing more difficult. If wheezing gets worse after taking this medicine (Advair), call doctor right away.
Using a device called a spacer with your metered-dose inhaler and rinsing mouth with water and spitting the water out after inhaling should reduce these side effects. Dry powder inhalers are not used with a spacer. [35]

Advantages:
1. Oral corticosteroids may be used to treat chronic obstructive pulmonary disease (COPD) when symptoms rapidly get worse (COPD exacerbation), especially when there is increased mucus production.
2. Inhaled corticosteroids may be used to treat stable symptoms of COPD or symptoms that are slowly getting worse.
3. Inhaled corticosteroids may decrease the number of COPD exacerbations in people with severe COPD, particularly those with chronic bronchitis and frequent exacerbations.
4. Corticosteroids may be useful for people who have asthma as a component of their disease.
5. They improve lung function, reduce the amount of time in the hospital, and reduce the incidence of treatment failure (return to the hospital, death, or the need for a tube inserted through the mouth or nose and into the chest to deliver oxygen [endotracheal intubation]).
6. Suggests that for some people they reduce the frequency of COPD exacerbations compared to a placebo.
7. Studies report that combining an inhaled corticosteroid with a long-acting beta2-agonist resulted in-Improved lung function and improved shortness of breath and less use of relief medicine compared to a placebo and compared to either medicine used alone.
8. Fewer COPD exacerbations compared to a placebo.
9. Combining a corticosteroid with a beta2-agonist and an anti cholinergic improved. [36]

Research studies on the role of corticosteroids in COPD:
1. People using fluticasone combined with a beta2-agonist were more likely to get pneumonia.
2. The addition of an inhaled corticosteroid but not an inhaled anticholinergic agent to maintenance treatment with a beta-agonist (trebutaline) substantially reduced morbidity, hyperresponsiveness, and airways obstruction in patients with a spectrum of obstructive airways disease.
3. Studies on cost-effectiveness of tiotropium versus salmeterol in the treatment of chronic obstructive pulmonary disease in patients with moderate COPD, tiotropium is more cost-effective than salmeterol and no treatment.
4. The cost of hospitalization in patients with acute exacerbations of COPD continues to have both significant economic burden and high mortality rate.
5. In Lung Health Study, an effect was seen on the exacerbations, both hospitalization and unscheduled outpatient visits were reduced by approximately 50% in the triamcinolone group.
6. Studies suggest that particle interaction between inhaled Beclomethasone-hydrofluoralkane (BDP-HFA) pMDI and environmental tobacco smoke (ETS) takes place in the first few seconds after drug delivery, with a decrease in smaller particles and a concurrent increase of larger particles. The resulting changes in aerosol particle profile might modify regional drug deposition with potential detriment to drug efficacy, and represent a new element of steroid resistance in smokers.
7. During an exacerbation-free period, a trial of corticosteroids, 0.4–0.6 mg•kg-1 for 2–4 weeks, may be used to test reversibility of the airflow limitation. About 10% of patients with stable COPD will achieve an improvement in FEV1.
8. Methylprednisolone in combination with conventional medical therapy not only improved lung function values but also mean nocturnal oxyhemoglobin saturation and sleep duration in clinically stabilized COPD patients who experience nocturnal oxyhemoglobin desaturation.
9. Discontinuation of chronic systemic corticosteroid treatment in steroid-dependent COPD patients did not cause a significant increase in COPD exacerbations, but did reduce total systemic corticosteroid use and body weight. [37-40]

FUTURE DIRECTIONS IN COPD:
There is significant evidence that COPD is an inflammatory process just as is bronchial asthma, however, it seems that there are different patterns of lung inflammation in these patients. The mechanisms of baseline inflammation in COPD and inflammation during exacerbation of the disease need to be investigated. There is minimal or no information on the molecular mechanisms of inflammation in stable COPD patients. This latter issue becomes important particularly in the area of treatments. Currently, there are numerous clinical trials looking to intervene at the various inflammatory pathways. A newer class of medications that work to reduce this inflammation is being developed. They are referred to as PDE4 inhibitors. Drugs under clinical development include Rolipram, Piclamilast, Cilomilast, and Roflumilast. These inhibitors reduce the number and the activity of the different types of inflammatory cells and inflammatory substances seen in COPD. [41-43]
The concept of attempting to reduce hyperinflation is intriguing. Less invasive procedures than LVRS are being developed to reduce this air trapping. Investigational devices such as Spiration and Emphasys are being studied that are valve-like and are placed directly in the airways by bronchoscope. The effectiveness of these devices is unknown. Another area of interest is the genetic mechanisms of why only a fraction of smokers develop emphysema. A third area of research interest is the role of nerve receptors in the lungs, which is currently the focus of final clinical trials. Finally, methods for early detection of COPD need to be refined. [44]

CONCLUSION
Inhaled corticosteroids are preferred to oral corticosteroids for long-term treatment of COPD because they cause fewer side effects. But low-dose inhaled steroids do not always work as well as high-dose oral steroids. Long-term treatment with oral corticosteroids is not recommended. Although long-term treatment with inhaled corticosteroids reduces the frequency of COPD exacerbations in some people, the long-term risks and whether the benefit is worth the risks of long-term treatment is not known. [45] Therefore, many doctors use oral corticosteroids as the treatment of last resort. When oral corticosteroids are used, they are prescribed at the lowest possible doses for the shortest period of time to minimize side effects. When it is necessary to use long term oral steroids, medications are often prescribed to help reduce the development of the side effects. It is not possible to predict who will improve with corticosteroid therapy. Lung function tests (spirometry) can be done before and after using the medicine, to learn if it has helped. Most doctors recommend that everyone using an inhaler also use a spacer. Use of a spacer is especially important when using an inhaler containing a steroid medicine. But you should not use a dry powder inhaler (DPI) with a spacer. [46]

REFERENCES
1. Mathers CD, Loncar D (November 2006). "Projections of global mortality and burden of disease from 2002 to 2030". PLoS Med. 2002; 3 (11): 442.
2. Simpson CR, Hippisley-Cox J, Sheikh A. "Trends in the epidemiology of chronic obstructive pulmonary disease in England: a national study of 51804 patients". Brit J Gen Pract. 2010; 60 (576): 483–488.
3. Young RP, Hopkins RJ, Christmas T, Black PN, Metcalf P, Gamble GD., "COPD prevalence is increased in lung cancer, independent of age, sex and smoking history". Eur. Respir. J. 2009; 34(2): 380–386.
4. Devereux, Graham. "ABC of chronic obstructive pulmonary disease. Definition, epidemiology, and risk factors". BMJ. 2006; 332 (7550): 1142–4.
5. Hnizdo E, Vallyathan "Chronic obstructive pulmonary disease due to occupational exposure to silica dust: a review of epidemiological and pathological evidence". Occup Environ Med. 2003; 60(4): 237–43.
6. Loscalzo, Joseph; Fauci, Anthony S.; Braunwald, Eugene; Dennis L. Kasper; Hauser, Stephen L; Longo, Dan L. Harrison's Principles of Internal Medicine. McGraw-Hill Professional. 2008; 17: 1142-44  
7. Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. "Global burden of COPD: systematic review and meta-analysis". Eur. Respir. J. 2006; 28 (3): 523–32.
8. Kennedy SM, Chambers R, Du W, Dimich-Ward H. "Environmental and occupational exposures: do they affect chronic obstructive pulmonary disease differently in women and men". Proceedings of the American Thoracic Society 2007; 4 (8): 692–4.
9. Silverman EK, Chapman HA, Drazen JM, et al. "Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease. Risk to relatives for airflow obstruction and chronic bronchitis". Am. J. Respir. Crit. Care Med. 1988; 157: 1770–8.
10. Agustí A, MacNee W, Donaldson K, Cosio M.. "Hypothesis: does COPD have an autoimmune component". Thorax 2003; 58 (10): 832–4.
11. Rutgers, Steven R.; Postma, Dirkje S.; Ten Hacken, Nick H.T.; Kauffman, Henk F.;van der Mark,Thomas W; Koeter, Gerard H.; Timens,. "Ongoing airway inflammation in patients with COPD who do not currently smoke". Thorax 2000; 55 (1): 12–18.
12. Calverley PM, Koulouris NG. "Flow limitation and dynamic hyperinflation: key concepts in modern respiratory physiology". Eur Respir J. 2005; 25 (1): 186–199.
13. O'Donnell DE. "Hyperinflation, Dyspnea, and Exercise Intolerance in Chronic Obstructive Pulmonary Disease". The Proceedings of the American Thoracic Society 2006; (2): 180–4.
14. Rana GS, York TP, Edmiston JS, Zedler BK, et al. "Proteomic biomarkers in plasma that differentiate rapid and slow decline in lung function in adult cigarette smokers with chronic obstructive pulmonary disease (COPD)". Anal Bioanal Chem. 2010; 397(5): 1809–19.
15. Morissette MC, Vachon-Beaudoin G, Parent J, Chakir J, Milot J. Increased p53 level, Bax/Bcl-(L) ratio, and TRAIL receptor expression in human emphysema. Am J Respir Crit Care Med. 2008; 178(3):240-7.
16. Hodge S, Hodge G, Jersmann H, et al. Azithromycin improves macrophage phagocytic function and expression of mannose receptor in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008; 178(2):139-48.
17. Badgett RG, Tanaka DJ, Hunt DK, et al. "The clinical evaluation for diagnosing obstructive airways disease in high-risk patients". Chest. 1994; 106 (5): 1427–31.
18. Drummond MB, Dasenbrook, Murphy DJ, Fan E. "Inhaled corticosteroids in patients with stable chronic obstructive pulmonary disease: a systematic review and meta-analysis". JAMA. 2008; (20): 2407–16.
19. Liesker JJ, Wijkstra PJ, Ten Hacken NH, Koëter GH, Postma DS, Kerstjens HA. "A systematic review of the effects of bronchodilators on exercise capacity in patients with COPD". Chest. 2002; 121(2): 597–608.
20. Salpeter SR, Buckley NS, Salpeter EE. "Meta-analysis: anticholinergics, but not beta-agonists, reduce severe exacerbations and respiratory mortality in COPD". J Gen Intern Med 2006; 21 (10): 1011–9.
21. Calverley PM, Anderson JA, Celli B, et al. "Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease". N. Engl. J. Med. 2007; 356(8): 775–89.
22. Tashkin DP, Celli B, Senn S, et al. "A 4-year trial of tiotropium in chronic obstructive pulmonary disease". N. Engl. J. Med. 2008; 359 (15): 1543–54.
23. O'Donnell DE, Flüge T, Gerken F, et al. "Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD". Eur Respir J 2004; 23(6): 832–40.
24. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA. Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study. Thorax. 2003; 58(8):654-8.
25. Pauwels RA, Lofdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N Engl J Med 1999; 340(25):1948-53.
26. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000; 320(7245):1297-303.
27. Spencer S, Calverley PM, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J 2004; 23(5):698-702.
28. Callahan CM, Dittus RS, Katz BP. Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease. A meta-analysis. Ann Intern Med 1991; 114(3):216-23.
29. Postma DS, Steenhuis EJ, van der Weele LT, Sluiter HJ. Severe chronic airflow obstruction: can corticosteroids slow down progression. Eur J Respir Dis 1985; 67(1): 56-64.
30. Decramer M, de Bock V, Dom R. Functional and histologic picture of steroid-induced myopathy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 153: 1958-64.
31. Decramer M, Stas KJ. Corticosteroid-induced myopathy involving respiratory muscles in patients with chronic obstructive pulmonary disease or asthma. Am Rev Respir Dis 1992; 146(3): 800-2.
32. Rice KL, Rubins JB, Lebahn F, Parenti CM, Duane PG, Kuskowski M, et al. Withdrawal of chronic systemic cortico-steroids in patients with COPD: a randomized trial. Am J Respir Crit Care Med 2000; 162(1):174-8.
33. Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer T, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002; 166(8):1084-91.
34. Jones PW, Willits LR, Burge PS, Calverley PM. Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations. Eur Respir J 2003; 21(1): 68-73.
35. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2003; 361(9356): 449-456.
36. Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, et al. Efficacy and safety of budesonide/ formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003; 21(1): 74-81.
37. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C. Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care Med 2002; 166(10): 1358-63.
38. Sin DD, Wu L, Anderson JA, Anthonisen NR, Buist AS, Burge PS, et al. Inhaled corticosteroids and mortality in COPD. Thorax 2005; 60(12): 992-7.
39. Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, et al. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. Chest 2003; 124(3) :834-43.
40. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003; 22(6): 912-9.
41. Johnell O, Pauwels R, Lofdahl CG, Laitinen LA, Postma DS, Pride NB, et al. Bone mineral density in patients with chronic obstructive pulmonary disease treated with budesonide Turbuhaler. Eur Respir J 2002; 19(6): 1058-63.
42. Singh JM, et al. Corticosteroid therapy for patients with acute exacerbations of chronic obstructive pulmonary disease. Archives of Internal Medicine, 2002; 162: 2527–2536.
43. Highland KB, et al. Long-term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease. Annals of Internal Medicine, 2003; 138: 969–973.
44. Calverley P, et al. combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: A randomised controlled trial. Lancet, 2003; 361: 449–456.
45. Aaron SD, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease. Annals of Internal Medicine, 2007; 146(8): 545–555.
46. Callahan C, Dittus RS, Katz BP. Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease: a meta-analysis. Ann Intern Med 1991; 114: 216–223.

Reference ID: PHARMATUTOR-ART-1045

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