Treatments in Respiratory Medicine

Neonatal chronic lung disease (CLD) is the major long-term pulmonary complication of preterm birth affecting about 20% of infants who need mechanical ventilation. CLD is the result of abnormal repair processes following inflammatory lung injury that lead to remodeling of the lung. Inflammation may be initiated by a variety of stimuli including mechanical ventilation, oxygen toxicity and infection. The resultant neutrophil chemotaxis and degranulation leads to the release of enzymes such as matrix metalloproteinases that can cause proteolysis of the lung extracellular matrix. Abnormal healing with remodeling leads to poorly compliant lungs with reduced capacity for gas exchange. Drugs can influence the normal process of lung modeling or remodeling. Fetal lung development can be influenced by glucocorticosteroids and inflammation. Both can cause abnormal lung modeling with fewer, larger alveoli and accelerated lung maturation, which confers benefits in terms of reduced morbidity and mortality from respiratory distress syndrome but potentially increases the risk of subsequent lung injury. Antioxidants, such as retinol (vitamin A), administered post-natally may reduce the effects of oxidative stress leading to a modest reduction in CLD but they require repeated intramuscular injections. Postnatal glucocorticosteroid therapy can modify the lung inflammatory response and reduce CLD but it can also have detrimental effects on the developing brain and lung, thereby creating a clinical dilemma for neonatologists. Proteinase inhibitors may be a rational therapy but more research is needed before they can be accepted as a treatment for preterm neonates. ‘Modeling’ is defined as planning or forming that follows a set pattern. The term is used to describe the normal process of lung growth and development that culminates in mature branching alveolar air spaces surrounded by a network of capillaries. Normal lung modeling occurs under a variety of genetic and hormonal influences that can be altered, leading to abnormal patterns of growth. ‘Remodeling’ is defined as altering the structure of or re-making and, in the case of the lung, is used to describe the abnormal patterns of lung growth that occur after lung injury. Modeling and remodeling of the lungs occur to an extent throughout life but never more rapidly than during the fetal and early neonatal periods, and factors that influence this process may lead to development of neonatal CLD. Some of the factors involved in normal and abnormal lung modeling and inflammation and glucocorticosteroid-induced remodeling in the perinatal period, in the context of neonatal CLD, are reviewed with considerations of how various drugs may influence these processes.

Chronic inflammation and oxidative stress are important features in the pathogenesis of COPD. The increased oxidative stress in patients with COPD is the result of an increased burden of inhaled oxidants, as well as increased amounts of reactive oxygen species (ROS) generated by various inflammatory, immune and epithelial cells of the airways. Oxidative stress has important implications on several events of lung physiology and for the pathogenesis of COPD. These include oxidative inactivation of antiproteases and surfactants, mucus hypersecretion, membrane lipid peroxidation, mitochondrial respiration, alveolar epithelial injury, remodeling of extracellular matrix, and apoptosis. An increased level of ROS produced in the airways is reflected by increased markers of oxidative stress in the airspaces, sputum, breath, lungs, and blood in patients with COPD. The biomarkers of oxidative stress such as H2O2, F2-isoprostanes, malondialdehyde and 4-hydroxy-2-nonenal have been successfully measured in breath condensate. ROS and aldehydes play a key role in enhancing the inflammation through the activation of mitogen-activated protein kinases and redox-sensitive transcription factors such as nuclear factor kappa B and activator protein-1. Oxidative stress also alters nuclear histone acetylation and deacetylation leading to increased gene expression of pro-inflammatory mediators in the lung. Oxidative stress may play a role in the poor clinical efficacy of corticosteroids in the treatment of COPD. Since a variety of oxidants, free radicals, and aldehydes are implicated in the pathogenesis of COPD it is likely that a combination of antioxidants may be effective in the treatment of COPD. Antioxidant compounds may also be of therapeutic value in monitoring oxidative biomarkers indicating disease progression. Various approaches to enhance the lung antioxidant screen and the clinical effectiveness of antioxidant compounds in the treatment of COPD are discussed.

▲ Lucinactant, formerly known as KL4 surfactant, is a novel synthetic lung surfactant containing phospholipids and an engineered peptide, sinapultide, which is designed to mimic the actions of human surfactant protein B. It has been developed for use in the prevention or treatment of respiratory distress syndrome (RDS), a common problem in premature infants, which results from a deficiency or degradation of pulmonary surfactant. Lucinactant is administered intratracheally soon after birth as a replacement surfactant. ▲ In the pivotal randomized, double-blind, prophylaxis trial in premature infants, the incidence of RDS at 24 hours after birth was significantly lower in lucinactant recipients than in recipients of colfosceril palmitate, a synthetic non-protein-containing surfactant. RDS-related mortality at 14 days was significantly lower in lucinactant recipients than in recipients of colfosceril palmitate or beractant, a bovine-derived surfactant. ▲ In another randomized, double-blind, prophylaxis trial in premature infants, the rate of survival without bronchopulmonary dysplasia at 28 days of age in lucinactant recipients was not inferior to that in recipients of poractant alfa, a porcine-derived surfactant. ▲ Lucinactant was generally well tolerated. Adverse events were transient and related to the administration procedure. There were no differences in the incidences of complications of prematurity between lucinactant and the other surfactants.

▴ Ipratropium bromide is a nonselective antagonist of the muscarinic receptors located on airway smooth muscle, and is delivered via a metered-dose inhaler (MDI). ▴ Because of the requirement to phase out chlorofluorocarbon (CFC)-propelled MDIs, the ipratropium bromide inhalation aerosol MDI has been redesigned with a hydrofluoroalkane as the propellant (ipratropium bromide HFA). Ipratropium bromide HFA has recently been approved in the US for the maintenance treatment of bronchospasm associated with COPD. ▴ Ipratropium bromide HFA 42μg four times daily (one dose [42μg] is delivered via two puffs of the inhaler) demonstrated comparable efficacy to that of ipratropium bromide CFC 42μg four times daily, as measured by spirometric testing, in a large, randomized, double-blind, placebo-controlled, 12-week trial in patients with stable COPD. ▴ Similarly, four-times-daily ipratropium bromide HFA 42μg and ipratropium bromide CFC 42μg provided a comparable degree of bronchodilation in patients with stable COPD during a 1-year, open-label study primarily designed to assess safety. ▴ In both studies, the tolerability profiles of ipratropium bromide HFA and ipratropium bromide CFC were comparable. The most common adverse events were related to respiratory system disorders. During the 1-year study, dry mouth was reported by 1.3% and 0.7% of patients in the ipratropium bromide HFA or ipratropium bromide CFC groups.

Leukocyte infiltration of the lung is a characteristic feature of allergic asthma and it is thought that these cells are selectively recruited by chemokines. Extensive research has confirmed that chemokine receptors are expressed on the main cell types involved in asthma, including eosinophils, T helper type 2 cells, mast cells and even neutrophils. Moreover, animal experiments have outlined a functional role for these receptors and their ligands. Chemokines signal via seven-transmembrane spanning G-protein coupled receptors, which are favored targets of the pharmaceutical industry due to the possibility of designing small-molecule inhibitors. In fact, this family represents the first group of cytokines where small-molecule inhibitors have been designed. However, the search for efficient antagonists of chemokine/chemokine receptors has not been easy; a particular feature of the chemokine system is the number of molecules with overlapping functions and binding specificities, as well as the difficulty in reconciling the in vivo biologic functional validation of chemokines in rodent models with the development of antagonists which bind the human receptor, because of the lack of species cross-reactivity. The chemokines and their receptors that are active during allergic reactions are reviewed. Possible points of interaction that may be a target for development of new therapies, as well as the progress to date in developing inhibitors of key chemokine receptors for asthma therapy, are also discussed.

Virus-induced wheezing is a relatively benign entity that is usually transient in early childhood but is responsible for much health care utilization. The condition, seen traditionally as a subset of those children diagnosed as having frequent episodic asthma, is often treated with inhaled corticosteroids, despite their lack of efficacy. However, there remains some confusion differentiating atopic asthma from virus-induced wheezing in young children and their respective treatment strategies. The demonstration of cysteinyl leukotrienes in the nasopharyngeal secretions of infants and young children who wheeze prompted investigation of the role of leukotriene receptor antagonists in the treatment of virus-induced wheezing for young children with bronchiolitis and virus-induced wheezing. Montelukast, the only leukotriene receptor antagonist studied in young children, has been proven useful in increasing the number of symptom-free days and delaying the recurrence of wheeze in the month following a diagnosis of respiratory syncytial virus-induced wheezing in children aged 3–36 months. Subsequently, in children aged 2–5 years with frequent episodic asthma, primarily involving viral induced attacks in this age group, regular therapy with daily montelukast for 12 months reduced the rate of asthma exacerbations by 31% over placebo, delayed the time to the first exacerbation by 2 months, and lowered the need to prescribe inhaled corticosteroids as preventative therapy. Additionally, montelukast has been demonstrated to be efficacious as an acute episode modifier in children aged 2–14 years (85% children <6 years) with virus-induced wheezing where it was prescribed at the onset of a viral infection in children with an established pattern of viral induced episodes of wheeze in the preceding year. In this study, emergency department visits were reduced by 45%, visits to all health care practitioners were reduced by 23%, and time of preschool/school and parental time off work was reduced by 33% for children who took montelukast for a median of 10 days. At present, there is good evidence to support the use of bronchodilators in the acute treatment of virus-induced wheezing, and increasing evidence to support the use of leukotriene receptor antagonists, in particular montelukast, in the management of children with virus-induced wheezing.

Inflammation of the distal lung, which consists of the small airways (internal diameter <2mm) and alveolar tissue, is an important feature of the asthma clinical syndrome comprising airway inflammation, airway hyperresponsiveness and bronchodilator-responsive expiratory airflow limitation. Support for this assertion is derived from histologic studies which have demonstrated evidence of inflammation in this anatomic compartment, along with additional studies, which have elucidated the radiologic and physiologic correlates of distal lung inflammation. Delivering inhaled drugs to this area is challenging and is dependent on a number of drug-and delivery device-related factors, as well as on a patient’s inhaler technique and bronchial anatomy. Newer chlorofluorocarbon-free formulations of inhaled corticosteroids such as hydrofluoroalkane propelled metered-dose inhalers and dry powder inhalers appear to have certain advantages with regard to drug delivery that facilitate improved drug delivery to the distal lung. Mounting evidence indicates that recognition and treatment of distal lung inflammation may be key components of appropriate asthma pharmacotherapy.

Since the 1960s, corticosteroids have been used in the treatment of laryngotracheobronchitis, commonly called croup. Initially, their use for croup was controversial and highly debated in the literature. The evidence over the last 2 decades has strongly favored corticosteroid use in croup management. It has now become the standard of care to use corticosteroids in moderate-to-severe croup. Corticosteroid use in these patients has been shown to reduce hospitalizations, length of illness, and subsequent treatments when compared with placebo. By extrapolation, corticosteroids may even play a role in patients with milder croup presenting for medical assessment. The current recommendation is to treat patients with moderate-to-severe croup with oral dexamethasone in a dose of 0.6 mg/kg (maximum 10–12mg) because of its ease of administration, easy availability, and low cost. Intramuscular dexamethasone is reserved for patients who are vomiting or who are in severe respiratory distress and unable to tolerate oral medication. Nebulized budesonide, used commonly in some geographic locations, has been found to be effective, but is often not used in favor of the oral corticosteroids. Controversy still exists over the use of corticosteroids in mild and potentially self-limiting disease. Some evidence exists for treating these patients; some clinicians use corticosteroids for all patients with croup who seek care regardless of the severity of the illness. Patients with mild disease may be candidates for lower doses of dexamethasone such as 0.15–0.3 mg/kg. Corticosteroid-induced complications in croup are rare. Overall, corticosteroids have gained universal acceptance for the treatment of croup and have been found to be effective, well tolerated, and inexpensive.