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Biomedical subjects

Duncan F Rogers

Publications and source records attributed to Duncan F Rogers.

14 recordsLinked to original sources
PubMed2006

Treatment of airway mucus hypersecretion.

Airway mucus hypersecretion is now recognized as a key pathophysiological feature in many patients with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapies, including anticholinergics, ss2-adrenoceptor agonists, corticosteroids, mucolytics and macrolide antibiotics, have variable efficacy in inhibiting airway mucus hypersecretion, and are less effective in COPD than in asthma. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity (e.g. large conductance calcium-activated potassium, BKCa, channel activators), tachykinin receptor antagonists, epoxygenase inducers (e.g. benzafibrate), inhibitors of mucin exocytosis (e.g. anti-myristoylated alanine-rich C kinase substrate (MARCKS), peptide and Munc-18B blockers), inhibitors of mucin synthesis and goblet cell hyperplasia (e.g. epidermal growth factor (EGF), receptor tyrosine kinase inhibitors, p38 mitogen-activated protein (MAP), kinase inhibitors, MAP kinase kinase/extracellular signal-regulated kinase (MEK/ERK), inhibitors, human calcium-activated chloride (hCACL2), channel blockers and retinoic acid receptor-a antagonists), inducers of goblet cell apoptosis (e.g. Bax inducers or Bcl-2 inhibitors), and purinoceptor P(2Y2) antagonists to inhibit mucin secretion or P(2Y2) agonists to hydrate secretions. However, real and theoretical differences delineate the mucus hypersecretory phenotype in asthma from that in COPD. More information is required on these differences to identify specific therapeutic targets which, in turn, should lead to rational design of anti-hypersecretory drugs for treatment of airway mucus hypersecretion in asthma and COPD.

Anti-Asthmatic Agents↗
PubMed2005

Mucociliary dysfunction in COPD: effect of current pharmacotherapeutic options.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. COPD comprises multiple components which, as well as a systemic component, include pulmonary inflammation, airway remodelling and mucociliary dysfunction. The latter features contribute to the development of chronic, progressive airflow limitation. The mucociliary dysfunction component of COPD is due to mucus hypersecretion coupled with a decrease in mucus transport, and represents an important pathophysiological feature requiring appropriate treatment. Current international guidelines do not recommend the use of mucolytics in the treatment of stable COPD. In contrast, bronchodilators are central to symptomatic management of COPD, and include beta(2)-adrenoceptor agonists, anti-cholinergics and methylxanthines. Interestingly, long-acting beta(2)-agonists (LABAs), rather than short-acting beta(2)-agonists, have the potential to improve the mucociliary component of COPD, in addition to providing symptomatic treatment by their bronchodilator action. Combination therapy with a LABA and an inhaled corticosteroid has the potential to more fully address the multicomponent nature of COPD by providing important anti-inflammatory activity, which may indirectly further improve mucociliary clearance. Theoretically, anti-cholinergics are likely to have mixed effects on mucociliary function, but clinically these effects have been difficult to demonstrate. Finally, a number of novel targets for the treatment of airway mucociliary dysfunction have been identified, and targeting agents are currently in development.

Adrenergic beta-Agonists↗
PubMed2005

The role of airway secretions in COPD: pathophysiology, epidemiology and pharmacotherapeutic options.

Often considered an aggravating but otherwise benign component of chronic obstructive pulmonary disease (COPD), airway mucus hypersecretion is now recognised as a potential risk factor for an accelerated loss of lung function in COPD and is a key pathophysiological feature in many patients, particularly those prone to respiratory tract infection. Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapy including anticholinergics, beta2-adrenoceoptor agonists, alone or in combination with corticosteroids, mucolytics and macrolide antibiotics are not entirely or consistently effective in inhibiting airway mucus hypersecretion in COPD. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity (e.g., BK(Ca) channel activators), tachykinin receptor antagonists, epoxygenase inducers (e.g., benzafibrate), inhibitors of mucin exocytosis (e.g., anti-MARCKS peptide and Munc-18B blockers), inhibitors of mucin synthesis and goblet cell hyperplasia (e.g., EGF receptor tyrosine kinase inhibitors, p38 MAP kinase inhibitors, MEK/ERK inhibitors, hCACL2 blockers and retinoic acid receptor-alpha antagonists), inducers of goblet cell apoptosis (e.g., Bax inducers or Bcl-2 inhibitors), and purinoceptor P(2Y2) antagonists to inhibit mucin secretion or P(2Y2) agonists to hydrate secretions. However, real and theoretical differences delineate the mucus hypersecretory phenotype in COPD from that in other hypersecretory diseases of the airways. More information is required on these differences to identify therapeutic targets pertinent to COPD which, in turn, should lead to rational design of anti-hypersecretory drugs for specific treatment of airway mucus hypersecretion in COPD.

Humans↗
PubMed2004

Airway mucus hypersecretion in asthma: an undervalued pathology?

Airway mucus hypersecretion is a feature of many patients with asthma. It is indicative of poor asthma control and contributes to morbidity and mortality. Excess mucus not only obstructs airways but also contributes to airway hyperresponsiveness. Furthermore, asthma might have a specific mucus hypersecretory phenotype. Goblet cell hyperplasia and submucosal gland hypertrophy are shared with other hypersecretory diseases, such as chronic obstructive pulmonary disease; however, some features are different, including mucus plugging, mucus "tethering" to goblet cells, plasma exudation, and increased amounts of a low charge glycoform of mucin (MUC)5B and the presence of MUC2 in secretions. Experimentally, most of the inflammatory mediators and neural mechanisms implicated in the pathophysiology of asthma impact upon the mucus hypersecretory phenotype. There is currently huge research interest in identifying targets involved in inducing mucus abnormalities, which should lead to the rational design of anti-hypersecretory drugs for treatment of airway mucus hypersecretion in asthma.

Airway Obstruction↗
PubMed2003

Pulmonary mucus: Pediatric perspective.

Airway mucus hypersecretion is a clinical feature of a number of childhood diseases, including asthma and bronchitis-associated conditions. However, compared with adults, there is relatively scarce information concerning mucus pathophysiology in respiratory diseases in children. The available evidence indicates many similarities between adult and childhood respiratory hypersecretory conditions, including goblet-cell hyperplasia and submucosal gland hypertrophy, and airway mucus plugging in asthma. Consequently, it is likely that treatments that are effective in adults would be effective in children. Numerous therapeutic targets are linked to the pathophysiology of airway mucus hypersecretion in experimental models and adults with respiratory disease. Whether or not these same targets are relevant in children is for the most part unclear. These targets include the inflammatory cells mediating the inflammatory response that generates the hypersecretory phenotype, and highly specific cellular elements such as epidermal growth factor receptor tyrosine kinase and calcium-activated chloride (CACL) channels. Identification of these factors is linked with the development of different classes of pharmacotherapeutic molecules directed at these targets. Compounds with a broader spectrum of anti-inflammatory activity are likely to be more effective than compounds with restricted activity. However, certain highly specific targets, such as human CACL1 channels, appear to be strongly associated with the development of an airway hypersecretory phenotype. Data from current clinical trials in adults with blockers of these specific targets are awaited with great interest. The hope is that, if effective, pediatric trials with these compounds could be initiated with a view to alleviation of the clinical impact of airway mucus hypersecretion in children. A significant challenge to the therapeutic progression of these new compounds is effective delivery to the airways in children, with the research effort into development of new compounds matched by advances in inhaler design.

Adult↗
PubMed2003

Airway hypersecretion in allergic rhinitis and asthma: new pharmacotherapy.

Mucus hypersecretion is a prominent feature of allergic rhinitis and asthma. Biologic targets for suppression of hypersecretion range from the inflammatory cells that initiate airway inflammation, to specific cellular elements such as calcium-activated chloride (CLCA) channels, epidermal growth factor receptor tyrosine kinase, and antiapoptotic factors (eg, Bcl-2). Identification of these targets is driving development of new pharmacotherapeutic compounds. Aside from specific instances in which a single mediator has a major impact on hypersecretion--for example, histamine in rhinitis--it is likely that compounds with broad-spectrum anti-inflammatory activity are more effective than compounds with restricted activity. However, certain highly specific targets, such as CLCA channels, seem to be intimately associated with development of a hypersecretory phenotype. Data from clinical trials with blockers of these targets are awaited with great interest, not only for disease management but also to determine the clinical benefit of selective inhibition of airway hypersecretion.

Asthma↗
PubMed2003

The airway goblet cell.

The two principal features of airway goblet cells are rapid secretion of mucin onto the airway surface and increase in number (hyperplasia) with chronic inhaled 'insult'. The first is associated with homeostasis, the latter with pathophysiology. Myristoylated alanine-rich C kinase (MARCKS) is a key molecule regulating mucin exocytosis, a process also involving cooperative interaction between protein kinase (PK) C and PKG. The epidermal growth factor (EGF) cascade and calcium activated chloride channels (CLCA) are key signalling molecules involved in development of goblet cell hyperplasia, with Bcl-2, an inhibitor of apoptosis, involved in maintenance of hyperplasia. Goblet cell hyperplasia and associated mucus hypersecretion is a pathophysiological feature of asthma and chronic obstructive pulmonary disease (COPD). Novel therapeutic strategies to prevent or reverse goblet cell hyperplasia include inhibitors of EGF receptor tyrosine kinase and CLCA, of which viable pharmaceutical molecules are now available for clinical trial in hypersecretory conditions of the airways.

Animals↗
PubMed2003

Therapy for chronic obstructive pulmonary disease in the 21st century.

Chronic obstructive pulmonary disease (COPD) is a common, smoking-related, severe respiratory condition characterised by progressive, irreversible airflow limitation. Current treatment of COPD is symptomatic, with no drugs capable of halting the relentless progression of airflow obstruction. Better understanding of the airway inflammation, oxidative stress and alveolar destruction that characterise COPD has delineated new disease targets, with consequent identification of novel compounds with therapeutic potential. These new drugs include aids to smoking cessation (e.g. bupropion) and improvements to existing therapies, for example long-acting rather than short-acting bronchodilators, as well as combination therapy. New antiproteases include acyl-enzyme and transition state inhibitors of neutrophil elastase (e.g. sivelestat and ONO-6818), matrix metalloprotease inhibitors (e.g. batimastat), cathepsin inhibitors and peptide protease inhibitors (e.g. DX-890 [EPI-HNE-4] and trappin-2). New antioxidants include superoxide dismutase mimetics (e.g. AEOL-10113) and spin trap compounds (e.g. N-tert-butyl-alpha-phenylnitrone). New anti-inflammatory interventions include phosphodiesterase-4 inhibitors (e.g. cilomilast), inhibitors of tumour necrosis factor-alpha (e.g. humanised monoclonal antibodies), adenosine A(2a) receptor agonists (e.g. CGS-21680), adhesion molecule inhibitors (e.g. bimosiamose [TBC1269]), inhibitors of nuclear factor-kappaB (e.g. the naturally occurring compounds hypoestoxide and (-)-epigallocatechin-3-gallate) and activators of histone deacetylase (e.g. theophylline). There are also selective inhibitors of specific extracellular mediators such as chemokines (e.g. CXCR2 and CCR2 antagonists) and leukotriene B(4) (e.g. SB201146), and of intracellular signal transduction molecules such as p38 mitogen activated protein kinase (e.g. RWJ67657) and phosphoinositide 3-kinase. Retinoids may be one of the few potential treatments capable of reversing alveolar destruction in COPD, and a number of compounds are in clinical trial (e.g. all-trans-retinoic acid). Talniflumate (MSI-1995), an inhibitor of human calcium-activated chloride channels, has been developed to treat mucous hypersecretion. In addition, the purinoceptor P2Y(2) receptor agonist diquafosol (INS365) is undergoing clinical trials to increase mucus clearance. The challenge to transferral of these new compounds from preclinical research to disease management is the design of effective clinical trials. The current scarcity of well characterised surrogate markers predicts that long-term studies in large numbers of patients will be needed to monitor changes in disease progression.

Clinical Trials as Topic↗
PubMed2002

Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is characterized by inflammation of the respiratory tract in which macrophages are the predominant inflammatory cell and for which the efficacy of treatment with corticosteroids is controversial. We investigated the effect of dexamethasone on basal and interleukin (IL)-1beta or cigarette smoke media (CSM)-stimulated release of IL-8 and granulocyte macrophage-colony stimulating factor (GM-CSF) by bronchoalveolar lavage macrophages from cigarette smokers and patients with COPD (n = 15). Basal release of IL-8 was approximately fivefold greater in patients with COPD than smokers, whereas GM-CSF was similar for each group. IL-1beta and CSM increased IL-8 and GM-CSF release by macrophages from both smokers and patients with COPD. Dexamethasone did not inhibit basal or stimulated IL-8 release from macrophages from patients with COPD but inhibited release in smokers. In contrast, basal and IL-1beta-stimulated GM-CSF release, but not CSM-stimulated release, was inhibited by dexamethasone. We conclude that the lack of efficacy of corticosteroids in COPD might be due to the relative steroid insensitivity of macrophages in the respiratory tract.

Aged↗
PubMed2002

Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is characterized by a neutrophilic airway inflammation that can be demonstrated by examination of induced sputum. Theophylline has antiinflammatory effects in asthma, and in the present study we investigated whether a similar effect occurs in COPD patients treated with low doses of theophylline. Twenty-five patients with COPD were treated with theophylline (plasma level of 9-11 mg/L) for 4 weeks in a placebo-controlled, randomized, double-blind crossover study. Theophylline was well tolerated. Induced sputum inflammatory cells, neutrophils, interleukin-8, myeloperoxidase, and lactoferrin were all significantly reduced by about 22% by theophylline. Neutrophils from subjects treated with theophylline showed reduced chemotaxis to N-formyl-met-leu-phe (approximately 28%) and interleukin-8 (approximately 60%). Neutrophils from a healthy donor showed reduced chemotaxis (approximately 30%) to induced sputum samples obtained during theophylline treatment. These results suggest that theophylline has antiinflammatory properties that may be useful in the long-term treatment of COPD.

Aged↗
PubMed2002

Pharmacological regulation of the neuronal control of airway mucus secretion.

The dominant neural control of human airway mucus secretion is cholinergic. There is no adrenergic control and sensory-efferent control is equivocal. Recent advances have identified several mechanisms that inhibit neurogenic mucus secretion. Muscarinic M3 receptor antagonists and tachykinin NK1 receptor antagonists inhibit neurogenic secretion. Muscarinic M2 receptors, nitric oxide and vasoactive intestinal peptide are inhibitory and regulate the magnitude of neurogenic secretion. The opening of large-conductance calcium-activated potassium channels is a common endogenous inhibitory mechanism and may represent the best therapeutic target. None of these inhibitory options are currently being targeted specifically for therapy of airway hypersecretion.

Animals↗
PubMed2002

Comparison of the effects of salmeterol and formoterol in patients with severe asthma.

STUDY OBJECTIVE: Several studies have demonstrated the superiority of salmeterol and formoterol to either regular treatment with albuterol or placebo. However, to date there have been no trials comparing the efficacy of salmeterol and formoterol in patients with severe asthma. DESIGN: We undertook a randomized, placebo-controlled, crossover study to compare 4 weeks of treatment with inhaled formoterol (12 microg twice daily) or salmeterol (50 microg twice daily) in patients with severe asthma whose conditions were not being adequately controlled by therapy with high doses of inhaled corticosteroids (i.e., > or = 1,500 microg daily) or with regular oral corticosteroid treatment. Morning pretreatment peak expiratory flow (PEF) during the last 14 days of the treatment period was the primary outcome variable. Patients recorded morning and evening pretreatment PEF, daytime and nighttime symptom scores, and any use of rescue medication. Spirometry and bronchial reversibility were performed after each treatment. RESULTS: Forty-two nonsmoking patients (29 women; mean age, 45 +/- 2 years; mean [+/- SEM] FEV(1), 61.8 +/- 3.4% of predicted) took part in the trial, and 27 patients completed the trial. The mean morning PEF was greater in patients receiving formoterol (mean increase, 14.4 L/min; 95% confidence interval [CI]. 0.2 to 28.6) or salmeterol (mean increase, 14.8 L/min; 95% CI, 0.5 to 29.1) compared with those receiving placebo, but there was no difference between these treatments. There were no significant treatment effects for any of the secondary outcome variables (i.e., FEV(1,) FVC, mean evening PEF, mean daytime symptom score, or nighttime symptom score). CONCLUSION: We conclude that the long-acting beta(2)-agonists salmeterol and formoterol improve morning PEF in patients with severe asthma, but that there is no difference in efficacy between the two drugs.

Adrenergic beta-Agonists↗
PubMed2002

Mucoactive drugs for asthma and COPD: any place in therapy?

Airway mucus hypersecretion is a clinical and pathophysiological feature of a number of severe respiratory conditions, including asthma and chronic obstructive pulmonary disease (COPD). The importance of mucus hypersecretion to the morbidity and mortality of asthma is acknowledged, whereas in COPD it appears to affect only certain groups of patients, particularly the elderly and those prone to chest infections. Treatment with compounds that alter mucus is perceived as a therapeutic option, in particular in continental Europe, and numerous compounds have been developed and are available for clinical use worldwide. However, acceptance (or otherwise) of these drugs in guidelines for management of asthma or COPD has been hampered by lack of information from well designed clinical trials. In addition, the mechanism of action of most of these drugs is unknown and is it likely that any beneficial effects are due to activities other than, or in addition to, effects on mucus. Current information indicates that the most effective use of mucolytic drugs is long-term therapy for reduction of exacerbations of COPD. Cost-effective treatment would be in patients with poor lung function who have frequent or prolonged exacerbations or are repeatedly admitted to hospital.

Asthma↗