Dose-effect relationship of the beta-agonists fenoterol and salbutamol in patients with asthma.

QUESTION: What is the relative per microgram potency and side effect profile of the beta-agonists salbutamol and fenoterol? METHOD: The relative bronchodilator (delta FEV1, V25, V50) potency and side effect profile (delta tremor, heart rate, breathlessness, BP) of nebulized salbutamol and fenoterol were evaluated by means of a randomized, double-blind, crossover, cumulative (50 to 2,500 micrograms) dose-response study. Both beta-agonists were administered to 12 patients with stable asthma over age 18 years with baseline FEV1 between 35 to 70 percent predicted. RESULTS: (1) Salbutamol and fenoterol both provided significant bronchodilatation compared with baseline. (2) There was no dose-effect difference between the two beta-agonists with respect to bronchodilator response. (3) Overall there was no significant difference between the side effect profiles of the two beta-agonists, although at the highest dose of fenoterol, there was marginally greater tremor when measured by accelerometry. (4) There was no difference in the vital signs or subjective patient evaluations of tremor, palpitations, or breathlessness as estimated by a visual analogue scale. (5) No significant adverse reactions occurred. SUMMARY AND CONCLUSION: Equivalent bronchodilatation and similar side effect profiles were measured in a group of patients with stable asthma after treatment with nebulized salbutamol or fenoterol in the dose range 50 to 1,250 micrograms (cumulative, 2,500 micrograms). This indicates that both beta-agonists have similar per microgram potency and side effect profiles. Observed clinical differences in response or side effects associated with fenoterol metered-dose inhaler administration may be a result of its higher dose per puff metered-dose inhaler formulation.

Efficiency of bronchodilator aerosol delivery to the lungs from the metered dose inhaler in mechanically ventilated patients. A study comparing four different actuator devices.

STUDY OBJECTIVE: To compare aerosol delivery to the lungs in ventilated patients from two devices with holding chamber and two devices without holding chamber. DESIGN: A controlled clinical trial with randomization to one of four delivery devices. SETTING: An academic university-affiliated Canadian ICU. PATIENTS: Forty-eight patients undergoing mechanically assisted ventilation for a variety of clinical reasons and each judged to require inhaled bronchodilator therapy by the attending physician. INTERVENTIONS: Patients received 4 puffs of fenoterol labeled with technetium 99m pertechnetate delivered by metered-dose inhaler via 1 of the following: A, a 167-ml chamber device; B, a 700-ml chamber device; C, a nonchamber device (A, B, and C, all in the ventilator inspiratory line); and D, a nonchamber device on the end of the endotracheal tube. MEASUREMENTS AND RESULTS: One-minute images of the thorax were made by a portable gamma camera at the bedside. Deposition of radioactivity in the lungs (uncorrected for tissue absorption and calculated as a percentage of the radioactivity delivered from 4 puffs) was 5.53 +/- 0.72 (mean +/- 1 SEM), 6.33 +/- 1.16, 1.67 +/- 0.43, and 3.89 +/- 0.52 percent for devices A, B, C, and D, respectively (p = 0.004). Subgroup analysis showed a statistically significant difference in delivery between devices A and C and between devices B and C only. CONCLUSION: There were statistically significant differences between delivery from both chamber devices and the inline nonchamber device, but not between delivery from other devices. Further work will be necessary to determine the effect of device position in the ventilator circuit on aerosol delivery.

Ciliary function, cell viability, and in vitro effect of ribavirin on nasal epithelial cells in acute rhinorrhea.

Nasal epithelial (NE) cells were collected from the nasopharynx of 25 individuals with symptomatic colds and 27 healthy volunteers (controls), and ciliary beat frequency (CBF) was assessed by microscopy employing video motion analysis techniques. Baseline CBF was statistically significantly elevated in the group with colds compared to the control group (14.6 +/- 1.5 Hz [mean +/- SD] vs 13.8 +/- 0.9 Hz; p = 0.02). After four days of incubation in culture, there was a significant decrease in the CBF in both groups, with a change from baseline of 1.9 Hz for the cold group, compared to 1.0 Hz for the control group (p = 0.0001). The in vitro addition of ribavirin at 500 micrograms/ml to NE cells from individuals with colds preserved the viability of the cells and maintained the CBF at baseline values. Twenty-four (96 percent) of 25 ribavirin-treated specimens from the cold group survived for four days in culture, compared with 17 (68 percent) of 25 untreated cold specimens. In addition, the ribavirin-treated cells had a mean CBF of 14.2 +/- 1.3 Hz, compared with 12.7 +/- 1.9 Hz for the untreated cell samples (p = 0.0005). Ribavirin had no effect on NE cells from the control group. These results suggest that ribavirin in a concentration of 500 micrograms/ml may have some benefit in the treatment of acute rhinorrhea.

The preferential deposition of inhaled isoproterenol and propranolol in asthmatic patients.

This study describes the use of central and diffuse airway deposition patterns of isoproterenol and radiotracer aerosol alone, and in the presence of centrally deposited propranolol and radiotracer aerosol, to investigate the distribution of beta 2 adrenoreceptors in six asthmatic patients. The central deposition technique was only partially successful. No definite beta 2 receptor distribution pattern could be interpreted from the airway function responses. It was noted that 3-10 micrograms of isoproterenol in the airways was able to produce 50 percent of the maximum possible flow rate response. Centrally deposited propranolol was an effective antagonist of isoproterenol.

Aerosol therapy with Sch 1000. Short-term mucociliary clearance in normal and bronchitic subjects and toxicology in normal subjects.

The anticholinergic bronchodilator drug, Sch 1000, was administered as an aerosol by a metered-dose inhaler (200 microgram) to six normal and six bronchitic subjects. The short-term effect on mucociliary clearance was assessed and compared to a placebo (propellant and dispersal agent) in a double-blind crossover study. Mucociliary clearance in the normal group was significantly faster with administration of Sch 1000 than with placebo (P less than 0.01). There was no significant difference between the effects of administration of Sch 1000 and placebo on mucociliary clearance in the bronchitic group. Pulmonary function was significantly increased by therapy with Sch 1000 (as compared to administration of placebo) in the bronchitic group for two hours (P less than 0.05) and in the normal group for one hour (P less than 0.05). In another study, 12 normal subjects inhaled aerosols containing 40 microgram of placebo or 400 microgram of Sch 1000 from metered-dose inhalers on separate days in a randomized double-blind fashion. A significant sustained improvement in pulmonary function (P less than 0.05) and a transient fall in diastolic blood pressure were observed after administration of Sch 1000.

Reliable salbutamol administration in 6- to 36-month-old children by means of a metered dose inhaler and Aerochamber with mask.

A double-blind study was performed to demonstrate that bronchodilator can be administered reliably to infants and children under 3 years of age from a metered-dose inhaler (MDI) by means of an economical valved aerosol-holding chamber device (Aerochamber) fitted with a mask. Symptoms of cough and breathlessness were compared for two 1-week crossover periods with the child either taking active drug or placebo. The MDI and Aerochamber with mask is an effective delivery system for respiratory therapy in these young children.

Nicotine microaerosol inhaler.

OBJECTIVE: To measure the droplet size distribution of a nicotine pressurized metered-dose inhaler using a nicotine in ethanol solution formulation with hydrofluoroalkane as propellant. MATERIALS AND METHODS: Sizing was performed at room temperature by multistage liquid impinger and quartz crystal impactor. RESULTS: The mass median aerodynamic diameter of the nicotine aerosol produced was measured at 1.6 mm by multistage liquid impinger and 1.5 mm by quartz crystal impactor. CONCLUSIONS: The inhaler formulation used produces a microaerosol of sufficiently fine droplet size that mimics the puff-by-puff pulmonary arterial bolus nicotine delivery of tobacco smoke. The absence of combustion products such as heat, carcinogens and carbon monoxide permits safer nicotine delivery via the inhaler than is possible via smoked tobacco.

Measuring total and regional lung deposition using inhaled radiotracers.

The delivery of an inhaled drug to the lungs can be measured by adding a gamma-emitting radiotracer to the formulation and using two-dimensional planar imaging or three-dimensional single photon emission computerized tomography (SPECT) to provide detailed information on lung deposition. The isotope most commonly used is the low energy (140 KeV) isotope, 99m technetium. Radiolabeling techniques have been successfully developed for use with nebulizers, pressurized metered dose inhalers (pMDIs), and dry powder inhaler formulations (DPI), and to investigate drug delivery to the respiratory tract for a variety of drug formulations and patient populations. However, for pMDIs and DPIs, the radiotracer is usually only physically associated with, rather than chemically bound, to the drug. Therefore, once deposited, the radiotracer may disassociate from the drug and cannot be used to track its subsequent fate; however, incorporation of a radiotracer directly into the drug molecule can overcome this. By using positron emitters such as 11carbon or 18fluorine it is possible to generate three-dimensional images of the drug in the lung using positron emission tomography (PET) scanning, which has a higher resolution and is more accurate than SPECT. Labeling drugs with PET emitters is more complex as the drug molecule must first be synthesized to contain the radioactive isotope before the drug is formulated for the inhaler. As with gamma-scintigraphy, PET scanning can be used to investigate physiological changes in the lung following therapeutic intervention, but as biological radiotracers are used, functional images (i.e., of the drug's uptake and metabolism) can also be obtained.

Aerosols and devices.

The success of aerosol therapy depends upon the delivery of ample amounts of the drug to appropriate sites in the lung with minimal side effects. Successful aerosol therapy delivery systems must provide sufficient respirable particles or droplets, with minimal loss of the drug. Ultimately, the patient must be able to use the device easily, maintain it, and derive clinical benefit from the drug delivered from the system.

Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications.

As the end organ for the treatment of local diseases or as the route of administration for systemic therapies, the lung is a very attractive target for drug delivery. It provides direct access to disease in the treatment of respiratory diseases, while providing an enormous surface area and a relatively low enzymatic, controlled environment for systemic absorption of medications. As a major port of entry, the lung has evolved to prevent the invasion of unwanted airborne particles from entering into the body. Airway geometry, humidity, mucociliary clearance and alveolar macrophages play a vital role in maintaining the sterility of the lung and consequently are barriers to the therapeutic effectiveness of inhaled medications. In addition, a drug's efficacy may be affected by where in the respiratory tract it is deposited, its delivered dose and the disease it may be trying to treat.

Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications.

Research in the area of pulmonary drug delivery has gathered momentum in the last several years, with increased interest in using the lung as a means of delivering drugs systemically. Advances in device technology have led to the development of more efficient delivery systems capable of delivering larger doses and finer particles into the lung. As more efficient pulmonary delivery devices and sophisticated formulations become available, physicians and health professionals will have a choice of a wide variety of device and formulation combinations that will target specific cells or regions of the lung, avoid the lung's clearance mechanisms and be retained within the lung for longer periods. It is now recognized that it is not enough just to have inhalation therapy available for prescribing; physicians and other healthcare providers need a basic understanding of aerosol science, inhaled formulations, delivery devices, and bioequivalence of products to prescribe these therapies optimally.

Methodologic considerations in mucociliary clearance and lung epithelial absorption measurements.

Measurements of mucociliary clearance and lung epithelial permeability are relatively simple to perform, with minimum discomfort to the subjects. Awareness of the factors influencing the outcome of these procedures will help to avoid errors and yield useful information about these two clearance mechanisms from both a physiological and a pathological point of view.

Optimization of a column liquid chromatographic procedure for the determination of plasma salbutamol concentration.

A reversed-phase column liquid chromatographic procedure with fluorescence detection for the determination of salbutamol in plasma is described. A l-ml aliquot of the sample, after the addition of bamethan as the internal standard, is passed through a Bond Elut silica extraction column. The column is selectively washed to remove neutral, acidic, and weakly basic compounds. The desired compounds are eluted with a l-ml aliquot of methanol. The eluate is evaporated under vacuum at ambient temperature and the residue is reconstituted in 40 microliters of the mobile phase which contains octanesulfonic acid as the ion-pairing reagent. The entire extract is injected onto a 150 x 4.6 mm I.D. column packed with 5-micron octylsilica particles. Peaks are detected with a fluorescence detector (excitation wavelength = 275 nm, emission wavelength = 310 nm). In the resulting chromatogram, salbutamol and the internal standard give sharp peaks that are well resolved from the extraneous peaks. The procedure allows the quantitation of salbutamol down to 0.2 ng/ml.

Pressurized aerosol versus jet aerosol delivery to mechanically ventilated patients. Comparison of dose to the lungs.

The purpose of this study was to compare deposition of aerosol to the lung from a metered-dose inhaler (MDI) and aerosol holding chamber and from a jet nebulizer in ventilator-dependent patients. Twenty-one patients were entered into the study, all receiving assisted ventilation and inhaled bronchodilators because of airflow limitation. The average age was 68 yr; there were 10 men and 11 women. The patients were randomized to receive either 4 puffs (800 micrograms) of radiolabeled fenoterol by MDI of 1.75 ml (1,750 micrograms) of radiolabeled fenoterol solution by nebulizer. Imaging of lung fields was made by a portable scintillation camera at 5-min intervals during the study. Results showed that 20 patients completed the study, 9 receiving fenoterol by MDI, and 11 by jet nebulizer. Four were excluded from analysis because of previous pneumonectomy, two from each group. Lung deposition measured as a percent of given dose from either system was 5.65 +/- 1.09 (mean +/- SEM) for MDI plus extension chamber and 1.22 +/- 0.35 for jet nebulizer (p less than 0.001). Therefore, this trial shows significantly greater efficiency of aerosol deposition to the lung in ventilator-dependent patients when using an MDI plus aerosol holding chamber than when using a jet nebulizer.

Aerosol penetrance: a sensitive index of peripheral airways obstruction.

Early injury of the small airways has been demonstrated in asymptomatic smokers. Ventilatory tests including the maximum midexpiratory flow rate and closing volume have been useful in clinical detection of small airways disease in symptomatic subjects. In the present study, airway "obstruction" was assessed aerodynamically by gamma camera measurements of chest radioactivity following the inhalation of 131I-labeled aerosol (aerodynamic mass median diameter 3 mum). Studies were performed in normal subjects, asymptomatic smokers, and patients with chronic obstructive lung disease. An aerosol penetrance index (AeP) was devised from determinations which involved 1) an analysis of central (inner zone) and peripheral (outer zone) deposition of aerosol in the lung and 2) a ratio of initial counts to 24-h counts in the periphery (outer zone) of the lung. AeP values were 41.5 +/- 11.5 for the normal group, 20.9 +/- 7.6 for the smoker group, and 10.6 +/- 5.2 for the subjects with chronic obstructive airway disease. AeP was significantly reduced in the smokers indicating that the AeP is a sensitive index of early peripheral airways obstruction.

The effects of preferential deposition of histamine in the human airway.

Two inhalation techniques were performed to obtain airway and diffuse airway deposition of histamine aerosol. A radiotracer method was used to confirm the patterns of aerosol deposition and to measure the dose of histamine aerosol in the airways. In 5 subjects the effect of cumulative doses of histamine aerosol given either centrally or diffusely to the airways was measured. Histamine aerosol deposited predominantly in the large airways was more effective in increasing airway obstruction that was diffusely deposited histamine aerosol, suggesting that the receptors mediating the action of histamine reside mainly in the large airways.

Pulmonary aerosol deposition in chronic bronchitis: intermittent positive pressure breathing versus quiet breathing.

Quiet breathing by mouth of a 3-mum aerosol was compared with intermittent positive pressure delivery of the same aerosol to the lung in a group of bronchitics. The pattern of lung deposition and the total dose delivered to the lung were measured. The differences between quiet breathing and intermittent positive pressure breathing were found not to be significant (P greater than 0.5). In addition, during similar or greater total ventilation, intermittent positive pressure breathing delivered a mean of 32% less aerosol to the lung than did quiet breathing. These findings suggest that intermittent positive pressure breathing as currently used for aerosol delivery cannot be expected to enhance peripheral deposition of inhaled aerosols in patients with airway obstruction.