Login to your account

Username *
Password *
Remember Me

Blog With Right Sidebar

    Vous êtes ici :  
  1. Accueil
  2. Blog With Right Sidebar

Advancing asthma care: The glass is only half full!

Over the past 20 years, there has been a concerted effort in the United States to reduce morbidity related to chronic disease, including asthma. Attention was initially directed toward asthma in response to the recognition that asthma mortality was increasing and that the burden of disease was significant.

These efforts to address asthma mortality led to many new initiatives to develop clinical practice guidelines, implement the asthma guidelines into clinical practice, conduct research to fill the gaps in the guidelines, and continuously revise the asthma guidelines as more information became available. An assessment of our progress shows significant accomplishments in relation to reducing asthma mortality and hospitalizations. Consequently, we are now at a crossroads in asthma care. Although we have recognized some remarkable accomplishments in reducing asthma mortality and morbidity, the availability of new tools to monitor disease activity, including biomarkers and epigenetic markers, along with information technology systems to monitor asthma control hold some promise in identifying gaps in disease management. These advances should prompt the evolution of new strategies and new treatments to further reduce disease burden.

It now becomes imperative to continue a focus on ways to further reduce the burden of asthma and prevent its onset.

Pathophysiology of asthma: What has our current understanding taught us about new therapeutic approaches?

Current asthma therapy is based on the use of adrenergic bronchodilator and anti-inflammatory drugs the specificity, efficacy, duration of action, and safety of which have been derived through classical pharmacology and medicinal chemistry. That asthma is a TH2-type inflammatory disorder frequently associated with atopy and allergic comorbidities has led to a concentrated effort to find treatments that act selectively on this pathway.

A systematic literature review was undertaken, as well as a review of the Web site Clinicaltrials.gov for ongoing trials. Targets have included T cells themselves and their associated cytokines, chemokines, and receptors mostly targeted with biological agents. With the exception of anti-human IgE, none of these have met the expectations predicted from animal models and human in vitro tests. For most of these new therapies, only a very small subpopulation appears to respond. A case is made for a different approach to drug discovery based on acquiring a greater understanding of asthma stratification, the relevant pathways involved, and the development of appropriate diagnostic tests enabling the targeting of selective treatments to those asthmatic phenotypes most likely to respond. The recognition that asthma is more than allergy mandates improved predictive animal models and an appreciation that many of the environmental insults that initiate, consolidate, and exacerbate asthma operate through an epithelium functioning in a disorderly fashion.

An integrated model that places the epithelium at the forefront of asthma pathogenesis suggests that greater emphasis should be placed on therapeutics that increase the airways’ resistance against the inhaled environment rather than focusing only on suppression of inflammation.

Defective function at the epithelial junction: A novel therapeutic frontier in asthma?

The airway epithelium forms a highly regulated physical barrier that normally prevents invasion of inhaled pathogens and allergens from the airway lumen. Beyond being a simple physical barrier, the airway epithelium is now known to be a prominent regulator of the immune response to environmental triggers. Epithelial barrier function is maintained by apposed cell-cell contacts consisting of tight junctions (TJs), gap junctions, adherens junctions, and desmosomes.

As far back as the early 1990s, ultrastructure studies demonstrated that the airway epithelium of the asthmatic patient has fewer intercellular adhesion junction complexes compared with that of the nonasthmatic patient, but the molecular mechanisms underlying these structural differences were not described. Recent studies have now identified that the asthmatic epithelium displays reduced and altered expression of the adhesion proteins E-cadherin and zonula occludens 1 (ZO-1). This phenomenon is not only confined to the lower airways because disrupted desmosome formation has also been shown in nasal polyps from asthmatic children. The proposed mechanism for this epithelial barrier damage was originally thought to occur because of downregulation of junctional proteins indirectly through inflammatory mediator release or directly through cleavage by allergens.

The presumed consequences of this disrupted epithelial barrier function would be increased access of inhaled allergens to antigen-presenting cells in the submucosa and spasmogenic agonists reaching the smooth muscle.

The future of chronic obstructive pulmonary disease treatment—difficulties of and barriers to drug development

Although chronic obstructive pulmonary disease (COPD) is a major global health problem with a rising incidence and morbidity, few pharmacotherapeutic advances have been made over the past several decades.

The challenges of development of such agents are multifactorial and include rudimentary understanding of the biological genesis of human disease, inadequate in-vitro and in-vivo models, unvalidated biomarkers, inefficient physiological and clinical endpoints, and variable regulatory review worldwide.

Controversies in treatment of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a chronic disorder with substantial comorbidity and major effects attributable to the high morbidity and mortality rates. Despite an increasing evidence base, some important controversies in COPD management still exist.

The classic way to define COPD has been based on spirometric criteria, but more relevant diagnostic methods are needed that can be used to describe COPD severity and comorbidity. Initiation of interventions earlier in the natural history of the disease to slow disease progression is debatable, there are many controversies about the role of inhaled corticosteroids in the management of COPD, and long-term antibiotics for prevention of exacerbation have had a resurgence in interest.

Search

Search