Intended for healthcare professionals

Practice ABC of chronic obstructive pulmonary disease

Future treatments

BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.333.7561.246 (Published 27 July 2006) Cite this as: BMJ 2006;333:246
  1. Peter J Barnes, professor of respiratory medicine
  1. National Heart and Lung Institute, Imperial College London.

    Current treatment used in the management of chronic obstructive pulmonary disease (COPD) is often poorly effective and fails to halt the relentless decline in lung function that leads to increasing symptoms, disability, and exacerbations. This has stimulated clinicians, scientists, and drug companies to seek more effective ways to control the underlying disease process.

    Figure1

    Additive effects of once daily formoterol and tiotropium on forced expiratory volume in 1 second (FEV1) in patients with severe COPD after six weeks' treatment

    The challenge of drug development

    Only recently has there been much research into the molecular and cell biology of COPD in order to identify new therapeutic targets. There are several reasons why drug development in COPD is fraught with difficultly, but significant progress is being been made, and several new therapeutic strategies are now in the preclinical and clinical stages of development.

    Problems encountered in developing new drugs for treating COPD

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    New bronchodilators

    The mainstay of current drug therapy in COPD consists of long acting bronchodilators—β2 agonists (salmeterol and formoterol) and anticholinergics (tiotropium). They are the preferred first line treatment for symptomatic patients with established disease. Several new long acting anticholinergics and once daily (“ultra-long acting”) β2 agonists are in development for treating COPD. Although novel classes of bronchodilators, such as potassium channel openers, have been investigated, these have proved to be less effective than established bronchodilators and have more adverse effects.

    Current and future long acting bronchodilators for treating COPD

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    Fixed combination inhalers—which contain an inhaled corticosteroid plus long acting β2 agonist—are now commonly prescribed for patients with COPD. Both salmeterol-fluticasone (Seretide) and formoterol-budesonide (Symbicort) are more effective than their separate constituents as monotherapy and are indicated in patients with moderate to severe airflow obstruction (forced expiratory volume in one second (FEV1) < 50% predicted) who have frequent exacerbations (> 2 per year). Fixed combination inhalers containing a long acting corticosteroid and long acting β2 agonist are now in development and may be suitable for once daily treatment.

    Current and future drug treatments for smoking cessation

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    When used on a once daily basis, the addition of formoterol to tiotropium has an additive effect on lung function. This is likely to pave the way for a fixed combination inhaler containing both long acting anticholinergic plus long acting β2 agonist.

    Effective smoking cessation strategies

    Cigarette smoking is the main cause of COPD, and quitting at most stages of the disease reduces progression. Smoking cessation is therefore an important part of management, although current cessation strategies have only limited long term success. One of the most effective drug treatments currently available is bupropion. However, in patients with COPD, an annual quit rate of around 15% indicates that more effective smoking cessation therapies are urgently required.

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    Several new classes of non-nicotinic drugs for smoking cessation are now in development. Some of these are based on altering neurotransmitter systems in the brain stem that are involved in “reward,” but the prospects for long term efficacy seem limited as their action stops on withdrawal of treatment in animal models. However, rimonabant, a cannabinoid CB1 antagonist currently in phase III trials, and varenicline, a partial nicotine agonist that targets the α4β2 nicotinic acetylcholine receptor, seem to be promising in clinical trials.

    Figure2

    Inflammatory process in COPD. Inhaled irritants stimulate macrophages in the respiratory tract to release neutrophil chemotactic factors such as interleukin 8 and leucotriene B4. These cells release proteases that break down connective tissue in lung parenchyma, leading to emphysema, and stimulate mucus hypersecretion. Cytotoxic (CD8) T cells may also be involved in alveolar wall destruction. White boxes show potential agents to inhibit stages in this process

    An approach that may have longer term benefits is the development of a vaccine against nicotine. This stimulates the production of antibodies that bind nicotine, preventing it from entering the brain.

    Figure3

    Broad spectrum of inhibitory effects of phosphodiesterase 4 (PDE4) inhibitors on inflammatory and structural cells in airways of patients with COPD

    Treating inflammation in COPD

    COPD is characterised by chronic inflammation, particularly of the small airways and lung parenchyma. With a predominance of macrophages, neutrophils, and cytotoxic T lymphocytes and inflammatory mediators, this inflammation has a different pattern from that of asthma, and, in sharp contrast, it is largely resistant to the anti-inflammatory effects of corticosteroids, prompting the search for alternative treatments. Better understanding of the underlying mechanisms in COPD has revealed several potential targets for non-steroidal anti-inflammatory agents.

    Mediator antagonists for potential use in COPD

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    Mediator antagonists

    Many mediators—including lipid mediators and cytokines—are implicated in the pathophysiology of COPD. Inhibiting specific mediators, by receptor antagonists or synthesis inhibitors, is relatively easy, but such an approach is unlikely to produce effective drugs, since so many mediators with similar effects are involved. As a result of specific mediators having been shown to be increased in COPD, several mediator antagonists are in clinical development. Antibodies to tumour necrosis factor are used to treat severe rheumatoid arthritis and inflammatory bowel disease, but their effect on COPD is disappointing. An antibody that blocks interleukin 8 also seems to be largely ineffective.

    Protease inhibitors for potential use in COPD

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    Oxidative stress is increased in COPD, particularly as the disease becomes more advanced and during exacerbations. Oxidative stress amplifies inflammation and may result in corticosteroid resistance, and is therefore an important target for future treatment. Currently available antioxidants are not effective, and more potent and stable antioxidants—such as analogues of superoxide dismutase—are now in development.

    Protease inhibitors

    Several proteases—such as elastases, which are implicated in alveolar destruction—might be targeted to treat patients with COPD who have marked emphysema. Proteases may be inhibited by giving the endogenous antiprotease, such as α1 antitrypsin, or by small molecule inhibitors. However, no clinical studies have yet shown these approaches to have any effect.

    New anti-inflammatory treatments

    The most promising new anti-inflammatory agents for use in COPD are phosphodiesterase 4 (PDE4) inhibitors. These orally active drugs increase cyclic AMP concentrations in inflammatory cells and exhibit a broad spectrum of anti-inflammatory effects.

    Although effective in animal models of COPD, PDE4 inhibitors (such as cilomilast and roflumilast) have so far proved disappointing in clinical trials. This is because the dose is limited by adverse effects—particularly nausea and gastrointestinal problems. However, in a large randomised, placebo controlled study of patients with COPD with a mean FEV1 of around 50%, treatment with roflumilast reduced exacerbations and improved lung function over a 24 week period. Diarrhoea was the most common adverse effect largely due to active treatment and occurred in roughly 5% of patients. More selective inhibitors (PDE4B inhibitors) or inhaled administration of drugs are being investigated as ways to circumvent the problem of adverse effects.

    Novel anti-inflammatory treatments for COPD

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    Several other broad spectrum anti-inflammatory agents are currently under investigation, although most of these are likely to be associated with adverse effects when given systemically, suggesting that inhaled administration may be required.

    Reversal of corticosteroid resistance in COPD

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    Corticosteroid resistance is one of the typical features of COPD. An alternative therapeutic strategy is therefore to reverse the molecular mechanism of this resistance, which seems to be due to a defect in the nuclear enzyme histone deacetylase 2 (HDAC-2). This can be achieved in vitro with theophylline, which is an HDAC activator, or by inhibiting oxidative or nitrative stress. As a consequence, novel HDAC2 activators are now being sought.

    Lung repair

    COPD is a largely irreversible disease process, but it is possible that enhanced repair of damage might restore lung function in the future. There has been particular interest in retinoic acid, which is able to reverse experimental emphysema in rats. However, this is unlikely to work in humans, whose lungs do not have the regenerative capacity of that found in rats. Another approach now actively being explored is the use of stem cells in an attempt to regenerate alveolar type 1 cells.

    Route of delivery

    Drugs for airway diseases are traditionally given by inhalation, although inhaler devices usually target larger airways that are predominantly involved in asthma. Moreover, many elderly patients or those with musculoskeletal problems may have difficulty in using conventional inhalers. With COPD, the inflammation occurs mainly in the small airways and lung parenchyma, suggesting that devices that deliver drugs more peripherally may be of greater benefit. A systemic approach facilitated by oral drug delivery is therefore an attractive option. Oral treatments could also have an impact on systemic complications that are a problem in patients with severe disease, but this obviously carries an increased risk of adverse effects. An alternative approach is targeted drug delivery by exploiting specific cell uptake mechanisms in target cells, such as macrophages.

    Footnotes

    • The ABC of chronic obstructive pulmonary disease is edited by Graeme P Currie, specialist registrar in the Respiratory Unit, Aberdeen Royal Infirmary, Aberdeen. The series will be published as a book by Blackwell Publishing in autumn 2006.

    • Competing interest PJB has received research funding, speaker's fees, and consulting fees from several drug companies involved in developing new drugs for COPD, including GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Mitsubishi, Millennium, and Scios. GPC has received funding for attending international conferences and honorariums for giving talks from GlaxoSmithKline, Pfizer, and AstraZeneca.

    • The figure showing the additive effects of formoterol and tiotropium is adapted from van Noord JA, et al. Eur Respir J 2005;26: 214-22. The figure of the inflammatory mechanisms in COPD and potential inhibitors and the figure of the effects of phosphodiesterase 4 inhibitors are adapted from Barnes PJ, Stockley RA. Eur Respir J 2005;25: 1084-106.

    References

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