Advances in inhaled corticosteroid pharmacology.

Inhaled corticosteroids have been the backbone of asthma therapy for the past 20 plus years. Although they have, for the most part, been effective in controlling asthma symptoms and preventing exacerbations, not all patients are universally responsive to their beneficial effects. In addition, several recent studies have failed to demonstrate a disease-modifying effect of inhaled corticosteroids, with clinically indicated doses failing to prevent long term deterioration in lung function and potential airway "remodeling". Furthermore, it is apparent that possible side effects are still a concern with currently available formulations. Steroid characteristics, which might improve the therapeutic index of this class of medicine by enhancing efficacy while minimizing side effects, are explored, with special emphasis on the molecule, ciclesonide.

Optimal management of community-acquired acute bacterial rhinosinusitis: the allergist's perspective.

OBJECTIVES: To characterize the antibiotic resistance seen in community-acquired respiratory tract infections (RTIs) and determine which characteristics to look for in an antibiotic to improve clinical outcomes and decrease the potential for development of resistance. DATA SOURCES: Using MEDLINE, we performed a search of articles published from 1966 to 2004 to evaluate the current literature on the subject of antibiotic resistance and strategies to overcome it. Additional cited references, such as abstracts, were also identified. STUDY SELECTION: Relevant original research articles, reviews, and published abstracts were selected for inclusion in this review. RESULTS: Several factors were identified that should be considered when choosing empiric antibiotic therapy for community-acquired RTIs with the goal of improving clinical outcomes while minimizing the risk of resistance. These factors include spectrum of activity, bactericidal vs bacteriostatic activity, chemical structure, elimination half-life, and potency. CONCLUSIONS: The results of these studies support the use of targeted antibiotic agents that, based on structural and chemical properties, are optimized to have a low potential to induce resistance. This approach to antimicrobial therapy appears to be the most suitable for patients with acute bacterial rhinosinusitis and other community-acquired RTIs.

Properties of the ideal corticosteroid therapy.

Currently, inhaled corticosteroids (ICSs) are the most effective long-term control therapy for persistent asthma. However, patients show a variable response to ICSs and some exhibit glucocorticoid resistance. At recommended doses, there is little evidence to suggest that ICSs can either prevent or reverse the chronic airflow limitation that develops in some asthma patients. Could an improvement in the therapeutic index and greater accessibility of the drug to peripheral airways improve patient outcomes? Can a more potent ICS overcome glucocorticoid resistance or prevent airway remodeling? An optimal response could be achieved by modifying the drug's pharmacokinetic and pharmacodynamic profile, thus maximizing potency while minimizing adverse effects, creating the "ideal" ICS. Increasing lung deposition by modifying the drug formulation, increasing the fraction of respirable particles and receptor binding affinity, and heightening lipophilicity to facilitate passage of the drug into airway cells all play a role in improving efficacy. Could a drug that undergoes lipid conjugation increase the time the drug remains in the lungs, potentially allowing for once-daily dosing? Improvements in drug safety can be achieved by optimizing half-life and plasma clearance, limiting oropharyngeal deposition by on-site activation in the lungs, and increasing plasma protein binding to reduce the amount of free drug in systemic circulation. Ciclesonide, a novel ICS currently being developed for the treatment of persistent asthma, achieves many of these positive properties. The delivery of this relatively high-potency drug to strategic areas of inflammation, without the development of significant adverse effects, ideally will lead to improved asthma outcomes.

The role of nonsedating antihistamines in asthma therapy.

There is well-established evidence that histamine plays a significant role as a chemical mediator in asthma. However, although antihistamines are commonly used for the treatment of allergic rhinitis, their use in asthma has been somewhat controversial. Mechanistically, their application for asthma appears logical. In addition to their effects at the histamine receptor, antihistamines, in a dose-dependent fashion, inhibit the release of preformed mediators such as histamine and mediators synthesized de novo including the metabolities of arachidonic acid from mast cells and basophils. Antihistamines also show, in a concentration-dependent manner, anti-inflammatory and immunomodulatory activity through their effects on epithelial cells, endothelial cells, macrophages, eosinophils, and T lymphocytes. Clinically, there appears to be a link between allergic rhinitis and asthma such that treatment of the upper airway has been shown to benefit lower airway disease. Of interest is that although antihistamines have been shown to reduce asthma symptoms and improve quality of life, generally, they have not, at doses sufficient to control rhinitis, improved objective measures of lung function. This could potentially be achieved, in a fashion similar to that observed in concentration-dependent in vitro studies, by using higher medication levels. However, most antihistamines, both first- and second-generation, cannot be used above recommended doses without causing unacceptable side effects including sedation and psychomotor function impairment. As newer antihistamines with improved therapeutic indices have been developed, asthma studies can and must be conducted to evaluate high-dose therapy with the potential of reaping the anti-inflammatory and immunomodulatory effects of these drugs.