Biomedical subjects

Thomas G O'Riordan

Publications and source records attributed to Thomas G O'Riordan.

7 recordsLinked to original sources

PubMed2006

Assessing the effects of racemic and single-enantiomer albuterol on airway secretions in long-term intubated patients.

OBJECTIVE: In vitro data suggest that the S-enantiomer of albuterol can induce mucociliary dysfunction. This clinical study assesses the clinical significance of standard doses of the S-enantiomer on airway secretions in long-term intubated patients by comparing a racemic formulation of albuterol, an R-enantiomer formulation, and normal saline solution. DESIGN: A placebo-controlled crossover study. PATIENTS: Fourteen stable intubated patients with a median duration of intubation of 21 months and a median age of 72 years. SETTING: Long-term ventilator unit in skilled nursing facility. INTERVENTIONS: Following a 2-week washout period during which regularly scheduled beta2-agonists were discontinued, tracheal aspirates were collected for 4 h/d for a 5-day period to establish baseline values, and the patients were then randomized in crossover manner to each of three nebulized treatments: normal saline solution, racemic albuterol, and R-albuterol. Each treatment was administered three times daily for 5 days, followed by a 2-day washout. MEASUREMENTS: Tracheal aspirates were analyzed for volume, sodium, chloride, bicarbonate, interleukin (IL)-8, IL-1beta, soluble intercellular adhesion molecule, and tumor necrosis factor-alpha. RESULTS: There were no consistent significant differences among the three treatment periods either in terms of volume of secretions or in the concentrations of the electrolytes or the inflammatory indexes. However, all three treatments, including saline solution, were associated with increased secretion volume after the first dose, but this effect was not apparent on subsequent doses. CONCLUSION: There were no significant differences between racemic albuterol and R-albuterol observed in this study for any of the parameters studied, suggesting that the S-enantiomer does not adversely affect airway secretions at recommended doses. In addition, the routine administration of nebulized beta(2)-sympathomimetic agonists to stable patients undergoing prolonged intubation, for the sole purpose of changing the volume and composition of secretions of airway secretions, is not supported by the results of this study.

Administration, Inhalation↗

PubMed2005

Antiprotease function of airway secretions in purulent tracheobronchitis.

STUDY OBJECTIVES: Unopposed activity of the serine protease, human leukocyte elastase (HLE), is detectable in the airways of patients with purulent tracheobronchitis. The aim of this study was to assess the compartmentalization of HLE activity in the liquid sol phase and the solid gel phase of airway secretions. DESIGN: Seventy samples of tracheobrochial aspirates were obtained from patients who had hypersecretion and were receiving mechanical ventilation. METHODS: Samples were separated into sol and gel ("mucous pellet") phases, and HLE activity was measured using chromogenic substrate degradation. HLE was eluted from the mucous pellet using hypertonic saline solution, 1 mol/L, or bovine pancreatic deoxyribonuclease (DNase), 16 micromol/L. RESULTS: HLE activity partitioned between the sol and gel phases of the secretions, with most of the activity present in the gel phase (32:1 ratio of gel to sol HLE activity). The activity of HLE was 95% inhibited when bound to the gel phase, but activity appeared to be largely restored after elution from the gel phase. The gel phase was capable of binding additional exogenous HLE, and its binding capacity for exogenous HLE was not saturated by concentrations that exceeded the highest clinically relevant HLE levels (1.1 mg/mL). Hypertonic saline solution and DNase I efficiently liberated endogenous and exogenous gel phase-bound HLE activity, suggesting that electrostatic bonds and DNA, respectively, play important roles in binding HLE to the gel phase. CONCLUSIONS: The solid phase of airway secretions is a more important modulator of elastase-antielastase balance than has been previously recognized.

Bronchitis↗

PubMed2005

Aerosol delivery devices and obstructive airway disease.

Two obstructive lung diseases, asthma and chronic obstructive pulmonary disease, account for the vast majority of prescriptions for aerosolized medications and devices . Asthma is an immunologically mediated condition characterized by episodic reversible airway obstructions that occur in all age groups. In contrast, chronic obstructive pulmonary disease is a condition characterized by relatively irreversible obstruction that is seen in middle-aged and elderly cigarette smokers. Nevertheless, there is sufficient overlap in terms of airway physiology and therapeutics to allow a review of the challenge of aerosol delivery in both conditions in the same article. This review will concentrate on issues related to aerosol delivery.

Administration, Inhalation↗

PubMed2004

Potential role of inhibitors of neutrophil elastase in treating diseases of the airway.

The potential therapeutic use of inhibitors of neutrophil elastase (NE) is reviewed with emphasis on diseases of the airway. In addition to its proteolytic properties, NE is a potent secretagogue and may be pro-inflammatory. The properties of natural occurring inhibitors of NE such as alpha-one antitrypsin and secretory leukoprotease inhibitor are reviewed. In addition, recombinant versions of naturally occurring inhibitors and synthetic small molecule inhibitors are potential therapies for respiratory diseases. For recombinant proteins, aerosol administration has been the preferred method of delivery. The inhaled mode of delivery can complicate the determination of dose responsiveness and thus the evaluation of safety and efficacy of these agents. In addition to the aerosolization issue, there remain other significant barriers to the successful deployment of these agents in clinical trials. These include the need for high standards for purification of recombinant proteins, the lack of understanding of interaction with airway secretions, the controversy over role of NE in the pathogenesis of nonhereditary COPD, and asthma, while the need for the safety of new classes of systemically delivered small molecules will need to be established.

Administration, Inhalation↗

PubMed2003

Inhaled corticosteroids in chronic obstructive pulmonary disease: new trials and old practices.

The practice of using inhaled steroids (ICS) in chronic obstructive pulmonary disease (COPD) is common but controversial. Four large randomized controlled trials provide an objective assessment of this practice. An examination of the design of these studies is useful to explaining some of the differences between their results but may also help to appropriately integrate the findings of these studies into clinical practice. All studies agree that the early introduction of the inhaled corticosteroids (ICS) does not appear to affect the rate of decline in FEV1. Thus, the routine prescription of these agents to asymptomatic patients with well-preserved lung function is not indicated. However, more selective use of ICS in patients with moderately severe disease (FEV1 < 50% predicted) may produce clinical benefit as measured by an increase in FEV1, reduced symptoms and fewer exacerbations. The effectiveness of ICS in patients with severe disease (FEV < 800 mL, or chronic respiratory failure) has not been studied due to practical difficulties of enrolling and maintaining such patients in clinical trials. Similarly patients with evidence of chronic bronchitis and emphysema who demonstrate high degrees of reversibility (>10% predicted FEV1) are usually excluded from both COPD and asthma trials, and the effectiveness of ICS in this population is also not known. Neither responsiveness to a single dose of beta(2)-agonist nor to a 14-day trial of systemic steroids has been shown to be a reliable predictor of response to ICS. For individual patients with moderate or severe symptomatic COPD, an 8-week therapeutic trial with ICS may be needed to assess clinical benefit.

Budesonide↗

PubMed2002

Optimizing delivery of inhaled corticosteroids: matching drugs with devices.

Over the past decade, the therapeutic options for delivering inhaled corticosteroids have greatly increased as newer compounds, formulations, and delivery systems have been developed. In the present article, some of the controversies surrounding inhaled steroid delivery systems will be reviewed, concentrating on differences in systemic bioavailability and emphasizing the need to match delivery systems with particular drugs and target populations. The strategies employed to minimize systemic exposure due to absorption of steroid from the gastrointestinal tract include increasing the first pass metabolism of the drug, the use of holding chambers with pressurized metered dose inhalers, and reformulation to create smaller, more respirable, particles. However, because the drugs and devices are not interchangeable, comparisons of the devices based on clinical studies will be confounded by differences in the pharmacology and pharmacokinetics of the drugs. In addition to the interaction of drugs and devices, the needs of different patient populations should influence design of delivery systems. For example, patients without airflow obstruction may have greater systemic exposure compared to those with obstruction, while young children need different delivery systems from adults. In conclusion, no delivery system can be considered to be intrinsically superior to all others. The delivery system should be judged instead by its ability to optimize the pharmacokinetic properties of the drug, most notably oral bioavailability, and by its suitability for the target subpopulation of asthmatics.

Administration, Inhalation↗

PubMed2002

Formulations and nebulizer performance.

To deliver a drug by nebulization, the drug must first be dispersed in a liquid (usually aqueous) medium. After application of a dispersing force (either a jet of gas or ultrasonic waves), the drug particles are contained within the aerosol droplets, which are then inhaled. Some drugs readily dissolve in water, whereas others need a cosolvent such as ethanol or propylene glycol. Some drugs are delivered as suspensions, and the efficiency of nebulizers can be different for solutions and suspensions. Solutions are delivered more efficiently with most devices. In general, conventional ultrasonic nebulizers should not be used to aerosolize suspensions, because of low efficiency. Newer strategies to improve the delivery of non-water-soluble drugs include the use of liposomes and the milling of the drug into very small "nanoparticles." In addition to the active therapeutic ingredient and solvents, drug formulations may include buffers (the solubility of some medications is influenced by pH), stabilizers, and, in the case of multi-dose preparations, antibacterial agents. Though formulations are designed to optimize drug solubility and stability, changes in formulation can also affect inhaled mass, particle size, and treatment time, though the differences between nebulizer brands probably have a greater impact than differences in formulation. Ultrasonic and jet nebulizers may damage protein and other complex agents through heat or shear stress. Additives to multi-dose formulations, especially antimicrobial and chelating agents, may cause adverse events, so there is a trend towards single-use, preservative-free vials.

Administration, Inhalation↗