Respiratory system, inhalation therapy

The search for useful inhaled antibiotics has been driven, in part, by a concern about the adequacy of systemic antimicrobial therapy for respiratory infections. Some agents, including aminoglycoside antibiotics, exhibit limited penetration into respiratory tract secretions. In fact, aminoglycosides may achieve sputum concentrations that are 12% of related serum concentrations. In addition, cystic fibrosis patients are often colonized with mucoid strains of Pseudomonas aeruginosa. This phenotype is associated with a further reduction in penetration of antibiotics. 

For inhalation treatment of respiratory diseases, a pharmaceutical DNase I aerosol is on the market. Pulmozyme is a sterile solution for respiratory use at a concentration of 1000 Genentech Units/mL [22]. It contains 1 mg/mL rhDNase, sodium chloride as a tonicity modifier, calcium chloride as a stabilizer, and water for injection. Since deamidation is rapid at high pH and aggregation occurs at low pH, a nearly neutral solution (pH 6.3) is required. It is administered by means of a compressed air-driven nebulizer. Each 2.5-mL single-unit ampule will deliver 2.5 mg of rhDNase to the nebulizer chamber. The efficacy of DNase inhalation therapy largely depends on the aerosol quality and characteristics, which determine the respirable fraction. Significant differences were found between the different aerosol drug-delivery systems [68,81]. 

Routine modern therapy of severe exacerbations of asthma includes oxygen in addition to frequent inhalation of p -selective bronchodilators and. frequently, systemic corticosteroids. Therapy of status asthmaticus is more complicated, requiring intubation and respiratory assistance, sedation, parenteral corticosteroids, and bronchodilators. 

Pulmonary administration of medicines currently has the primary objective to achieve local effects in the respiratory tract of patients with chronic diseases like asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). For half a century, inhalation therapy has been the cornerstone in the management of these diseases and the often life-time therapies aim to suppress inflammatory processes and bacterial infection in order to reduce hospitalisations and to improve the patient s quality of life. They also give relief to the patient in moments of bronchoconstriction. The advantages of pulmonary administration of medicines for local treatment are well known. The active substances are delivered directly to the site of action which leads to a faster response than via the systemic route. It may also result in higher local active substance concentrations and this could reduce the total dose by as much as a factor 10 compared to oral or intravenous administration. This has the advantage that systemic side effects are reduced and in combination with being a non-invasive method of administration, inhalation therapy may lead to better patient compliance. 

The AEGL-1 concentration was based on a 1-hour (h) no-effect concentration of 8,000 parts per million (ppm) in healthy human subjects (Emmen et al. 2000). This concentration was without effects on pulmonary function, respiratory parameters, the eyes (irritation), or the cardiovascular system. Because this concentration is considerably below that causing any adverse effect in animal studies, an intraspecies uncertainty factor (UF) of 1 was applied. The intraspecies UF of 1 is supported by the absence of adverse effects in therapy tests with patients with severe chronic obstructive pulmonary disease and adult and pediatric asthmatics who were tested with metered-dose inhalers containing HFC-134a as the propellant. Because blood concentrations in this study approached equilibrium following 55 minutes (min) of exposure and effects are determined by blood concentrations, the value of 8,000 ppm was made equivalent across all time periods. The AEGL-1 of 8,000 ppm is supported by the absence of adverse effects in experimental animals that inhaled considerably higher concentrations. No adverse effects were observed in rats exposed at 81,000 ppm for 4 h (Silber and Kennedy 1979) or in rats exposed... 

Infections Localized fungal infections with Candida albicans or Aspergillus niger have occurred in the mouth, pharynx, and occasionally in the larynx. The incidence of clinically apparent infection is low, and may require treatment with appropriate antifungal therapy or discontinuance of aerosol steroid treatment. Use inhaled corticosteroids with caution, if at all, in patients with active or quiescent tuberculous infection of the respiratory tract, untreated systemic fungal, bacterial, parasitic or... 

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