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Chronic obstructive disease (COPD) is a disease characterised by the limitation of airflow and airway inflammation which result in chronic bronchitis and emphysema. The multi-component disease is mainly caused smoking, and the patients suffer from an irreversible shortness of breath due to the obstruction of air flow in the airways and a progressive degeneration of the lungs. (Srivastava et al, 2007). Currently there is no cure for COPD, but there are several pharmacological treatments which include bronchodilators and corticosteroids, and non-pharmacological treatments which include smoking cessation, long-term oxygen therapy (LOT), nasal positive pressure ventilation (nPPV) and Lung volume-reduction surgery (LVRS). (Hanania et al, 2005). Currently, there are studies being done and drugs which are under clinical development to produce more efficient COPD treatment for the near future.
Smoking has been determined as the main cause of COPD and Srivastava et al (2007) state that, about 80% of COPD cases are observed in patients with a history of tobacco smoking. Rang et al 2007, explains that smoking cessation is the only mechanism which decreases the progressive deterioration of COPD and Gillisen A (2008) says that smoking cessation is the only mechanism that has been shown to reduce mortality very effectively. Therefore smoking cessation seems to be the most important treatment in the management of diagnosed COPD. Strassmann et al, (2009) have also conducted studies on the effectiveness of smoking cessation and have found that the use of smoking cessation counselling (SCC) and nicotine replacement therapy (NRT) relieves symptoms greatly. Combination therapies of SCC and NRT have been found to be the most effective, followed by the combination of SCC and antidepressants.
The main current treatment for COPD is the bronchodilators which are categorised into short acting and long acting. These bronchodilators are delivered by inhalation into the lungs where they cause airway muscles relaxation and bronchodilation to prevent or treat wheeze and prevent bronchospasms at night or during exercise (Hanania and Sharafkhaneh, 2007). Rang et al (2007), explains that these inhaled bronchodilators can be used to partially treat, but not cure the disease in patients with reversible COPD. Short-acting bronchodilators include the β2-agonist salbutamol and terbutaline, and the anticholinergic ipratropium and they are recommended for symptoms in mild disease (Hanania and Sharafkhaneh, 2007). The long-bronchodilators acting bronchodilators include the β2-agonist salmeterol and formoterol, and the anticholinergic tiotropium and theophylline. (Hanania et al, 2005). These are recommended for maintenance therapy of daily symptoms. (Hanania and Sharafkhaneh, 2007).
β2 adrenoceptor agonists act by binding directly on to the β2 adrenoceptors on the smooth muscles, thereby inhibiting the effect of bronchoconstictors. (Rang et al, 2007).This results in the relaxation of bronchial muscles which helps alleviate the breathlessness experienced by the COPD sufferers. According to Rang et al (2007), the short acting bronchodilators salbutamol and terbutaline last for about 3 to 5 hours, of which their maximum effect occurs within 30 minutes of delivery. The longer acting bronchodilators have a mechanism of action which last for 8 to 12 hours. (Barnes et al, 2008) states that the anticholinergic tiotropium, is the one which has shown to have the most bronchodilating efficacy amongst the bronchodilator family. Rang et al (2007), explains that theophylline can also have respiratory stimulant effects to patients who have a tendency of retaining carbon dioxide, but these benefits also are not guaranteed.
The β2-adrenoceptors are mostly expressed in the smooth muscles of the small airways whereby their activation causes Gs protein- mediated adenyl cyclase activation which increases the cyclic AMP concentration and cyclic AMP-dependent protein kinase activity. As a result, cytosolic Ca2+ concentration decreases due to the efflux of Ca2+ and, or as a result of Ca2+ influx, leading to the inhibition of myosin phosphorylation by myosin light chain kinase (MLCK) and consequently leading to myosin dephosphorylation. Therefore this causes a relaxation of the airways smooth muscle, helping the COPD sufferers who suffer breathlessness as shown in figure 1. (Rang et al, 2007).
Β2- Bronchodilator mechanism in smooth muscles
Figure 1, shows how the β2- agonist such as salmeterol binds to the 7 Transmembrane β2-adrenoceptors activating the Gs- activated adenyl cyclase. This causes inhibition of the mysosin light chain kinase and subsequent muscle relaxation.
Hanania et al (2005) also shows that the use of combination therapies is more effective than the use of single therapeutic agents. The combination of the long acting bronchodilators salmeterol and theophylline, and the combination of the short-acting salbutamol and ipratropium bromide, have been shown to be more potent and effective minimising adverse reactions compared to single therapies. The combination of a long-acting β2- agonist bronchodilator such as salmeterol, can also be used in combination with a short-acting anticholinergic bronchodilator such as ipratropium to produce an effective therapy compared to the use of bronchodilators alone. Hanania et al (2005), also report that bronchodilators such as theophylline can also have non-bronchodilatory effects such as anti-inflammatory effects.
Chronic bronchitis results from the chronic inflammation of the bronchi in the lungs due to the increase and accumulation of the inflammatory mediators such as neutrophils, macrophages and T lymphocytes. Corticosteroids are used in the treatment of COPD mainly to target inflammation in the airways and can be administered by inhalation, intravenously in the form of hydrocortisone or orally in the form of prednisolone. Rang et al (2007), explains that corticosteroids do not affect the progressive deterioration of the lungs but however they have shown to reduce exacerbations and increase the quality of life for the people suffering from stable and severe COPD (Heidjra, 2007) (Rang et al, 2007) .
Inflammatory genes are activated by the acetylation of nuclear histones where DNA is wound resulting in the opening of chromatin structure. When the chromatin structure opens, this gives access to the transcription machinery leading to the synthesis of inflammatory proteins. Therefore corticosteroids act by recruiting a molecule called HDAC which switches off gene transcription and inhibit the synthesis of pro-inflammatory cytokines. (Barnes et al, 2008). Though with this kind of mechanism, corticosteroids have been very ineffective and have been found to have no effect in disease progression. Ito et al, (2005) have suggested that this might be caused by oxidative stress mainly from smoking, inhibiting the activity of HDAC.
Gillesen A (2008) mentioned that the use of inhaled corticosteroids (ICS) is recommended when used in a combination with long- acting β2 agonist (LABA) such as formoterol. To support this mechanism of treatment, Miller-Larsson and Selroos (2006), state that two ICS and LABA combination therapies budesonide/formoterol (Symbicort) and salmeterol/fluticasone propionate (Seretide) are already available and are being used in the treatment of COPD treatment by inhalation. Daniels et al, (2010) have recently shown that the combination of antiobiotics such as doxycycline with corticosteroids greatly improves symptoms in COPD patients. The airways of COPD sufferers are often colonised with bacteria and therefore the use of antibiotics such as crufoxime can also help alleviate symptoms. Although reducing symptoms, the antiobiotic-corticostroid combination has been found to have no overall effect on inflammation and progressive lung deterioration.
Long-term oxygen therapy (LTOT) is mainly used in the treatment of people with severe COPD. Hanania et al, (2005) report that patients with oxygen pressure (PaO2) of less than 7.3kPa should be given oxygen supplements even if the disease becomes stable. Those with a PaO2 between 7.3 and 7.8 kPa can be treated with LTOT only if they exhibit erythrocytosis, pulmonary hypertension, impaired mental state and oedema from heart failure on the right side. Rang et al (2007), explains that patients exhibiting the acute exacerbations of COPD are initially given inhaled oxygen with a concentration of at least 24% oxygen, which is just above the atmospheric oxygen concentration of 20%. This is done to avoid carbon dioxide retention in the lungs by precipitation and the subsequent inhibition of hypoxic drive to respiration. LTOT is mainly used to treat people who become hypoxaemic (O2 saturation <90%) during exercising and those who suffer from oxygen desaturation during sleep (Hanania et al, 2005). Rang et al (2007), state that LTOT increases the life expectancy in people suffering from severe COPD and hypoxaemia.
Non-invasive respiratory methods such as the nasal positive pressure ventilation (nPPV) improve the efficiency of gaseous exchange by increasing the rate of inspiration. nPPV takes over from the spontaneous respiration of the individual suffering from acute respiratory failure, helping them to breathe. This mechanism of treatment has been observed to be effective in relieving symptoms in patients with severe stable COPD and chronic hypercapnia. nPPV treatment is also of benefit as it is thought to act by resting the respiratory muscles and reset the central respiratory drive (Hanania et al, 2005). Contrary to these findings, Strumpf et al, (1991) could not find any improvement in physiological outcomes and Gay et al (1996) did not observe any significant changes in inspiratory and expiratory flow rates after the use of nPPV in COPD patients. Therefore, nPPV treatment effectiveness depends on the patient and disease stage.
In cases of severe hyperinflation of the lungs, lung volume reduction surgery (LVRS) is an alternative which can be used to remove about 25-30% of the emphysematous lung tissue on both the sides of the lungs. The primary aim of this surgery is to improve the function of the lung by decreasing the lung volume and increasing the forced expiration volume (FEV1). (Hanania et al, 2005). Rang et al (2007), explains that currently there are no licensed treatments which inhibit the inflammation in the bronchi and alveoli or which can decrease the progression of the disease. Therefore main current efforts are being put to develop therapies which can target the initiation and progression of inflammation, and with success these might be used to treat COPD in ten years time.
The main hindrance to effective COPD treatment is the underlying chronic inflammation which characterises the disease as outlined in figure 2. Current efforts are being put into targeting the inflammatory pathway in order to develop better drugs for COPD. In the initiation of inflammation, pro-inflammatory molecules such as neutrophils, monocytes and cytotoxic T-cells are recruited to the surface of epithelial cells of the airways and to the endothelial cells of the bronchi through adhesion molecules. (Antoniu et al, 2006). According to studies by Chez H et al (2008), adhesion molecules circulating intercellular molecule-1 (cICAM-1), and circulating E-selectin (c-E-selectin) were found be increased in serum of patients with COPD compared to those without. They also described the recruitment of leukocytes to the vascular endothelium via the selectin mediated pathway as a key process in the early development and initiation of the pro-inflammatory response in the airways. Therefore targeting the adhesion molecules seems to be a viable target in the fight against inflammation. Several inhibitors of adhesion molecules such as Bimosiamose which is a selectin inhibitor are currently under development.
Potential future therapeutic targets in treating COPD
Figure 2, outlines some of the pathways which can be targeted to treat COPD by inhibition of chronic inflammation which is characterised in both chronic bronchitis and emphysema.
The p38 mitogen-activated protein kinase (p38 MAPK) is crucial in development of chronic inflammation by the Mitogen Activated Protein Kinase (MAPK) pathway, whereby it triggers a cascade of events which result in the increased expression of pro-inflammatory signals. Cellular stress is responsible for activating the p38 MAPK pathway which leads to the expression of inflammatory cytokines such as TNF-α, IL-8 and matrix metalloproteinases (MMPs). (Chez et al, 2008), (Trifilieff et al, (2005). Underwood et al, (2000) conducted experiments using rats and have shown a compound called SB239063 to be effective in decreasing neutrophil infiltration, IL-6 and MMP9 in the bronchoalveolar lavage fluid of the rats. This compound is now in the clinical trials and one of the potential future therapeutic agents for COPD.
Cell signalling is also a target in the treatment of COPD as transcription factors such as NFkB are involved in the production of pro-inflammatory cytokines such as TNF-α and chemokines. NFkB is a transcription regulator of inflammatory pathways and has been found to be highly expressed in the macrophages and epithelial cells of patients with COPD. Therefore therapeutic agents which target the effects of the transcription factor NFkB can be potentially useful in the treatment of COPD. Other molecules involved in signalling are phosphodiesterase -4 (PDE4) are enzymes, which act by decreasing cAMP leading to the inhibition of the inflammatory response. (Chez et al, 2008), (Wagner et al 2007). Roflumilast and Cilomast are PDE-4 selective inhibitors which are currently under Phase III clinical trials and have been shown to greatly reduce inflammatory cells such as CD8+, decrease frequency of exacerbations and improve quality of life. (Tatlicouglu T, 2008).
Chemokines antagonists are some of the new several treatments that are in the clinical development. As described by Chez et al (2008), the lungs of COPD patients have been observed to have increased amounts of chemokines such as interleukins and tumour necrosis factor (TNF-α) which are released from the alveoli and pulmonary epithelial cells. These chemokines recruit pro-inflammatory cells such as macrophages, neutrophils, monocytes and CD8+ cytotoxic cells T-cells. Targeting chemokines receptors such as the CXCR1 andCXCR2 found on neutrophils and monocytes has been observed through animal studies to be potentially useful in combating inflammation. Animal studies using CXCR2 antagonists have been observed to decrease the amount of neutrophil upon exposure to pro-inflammatory agents. Hanania et al (2005) describes LTB4 as another important neutrophil chemoattractant which is involved in airway inflammation. This inflammatory mediator has been targeted by two LTB4 receptor antagonists, Ly29311 and SB201146 which have been observed to greatly reduce COPD symptoms. (Chez et al, 2008). These two types of antagonists are currently under clinical development and can be used as future treatment for COPD.
One of the more specific approaches being currently explored in the treatment of COPD is the development of antioxidants. Oxidants have been shown to greatly increase oxidative stress and decrease the major cellular antioxidant enzymes such as glutaredoxin and catalase. As explained by (Srivastava et al, (2007) cigarette smoke is concentrated and heavily rich in oxidants. These oxidative stress agents have been shown through mice studies to initiate the activation of transcription of the genes responsible for stimulating severe airway inflammation and development of emphysema. (Chez et al 2008). Therefore giving antioxidants to increase the cellular antioxidant capacity has been observed to be another potential therapeutic advancement in treating COPD.
Several antioxidant compounds such as selenium-based drugs and superoxide dismutase mimics are currently in development for potential future use. Moretti M (2009) has also shown that Erdosteine which is a thiol compound with antioxidant activity, can also exhibit mucolytic, antibacterial and anti-inflammatory activities. This antioxidant has been shown to improve COPD symptoms when used in combination with standard treatment and also to reduce acute exacerbations and improve quality of life in patients with severe COPD exacerbations (Chez et al, 2008). Therefore if developed this antioxidant can be used to treat COPD in the near future.
Although COPD which is characterised by emphysema and chronic bronchitis cannot be cured as yet, there are pharmacological treatments and non-pharmacological treatments which are being currently used to relieve symptoms, reduce exacerbations and improve the quality of life of COPD suffers. Of all the current treatments, LTOT is the only one to have been shown to prolong life of patients. The noxious particles which attack the airways cause chronic inflammation, and it is this chronic inflammation which makes COPD difficult to treat. Therefore current studies are focusing different combinations of drugs, and drugs which can target inflammation as potential future therapy. There are several drugs such as Roflumilast which are under different stages of clinical development and can be used to treat COPD in ten years time.
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