Control During Inhalation Of A Radiolabeled Aerosol And Subject Variables

Lung deposition varies with the drug and the formulation. In addition, many of the 2D deposition studies have been performed in normal, healthy volunteers rather than in the patient groups intended for the therapy. This option of using normals is chosen for several reasons. The subject with normal pulmonary function provides the best possible outcome or the "envelope" for the deposition value obtained. Patients with lung disease may have greater or lesser deposition compared to normals, depending upon the particle size characteristics of the test aerosol and the inspiratory volumes and flow rates used during aerosol inhalation. The regional distribution of the inhaled therapy within the lung would, however, be abnormal [11,93-96]. It is often easier to solicit normal healthy volunteers for deposition studies, and certainly there is not the inevitable rescheduling due to variability in baseline lung function or exacerbations of the disease that occurs when doing studies in patients. However, the drugs being tested are to be prescribed for the treatment of respiratory and other diseases. Therefore, knowing the lung deposition and distribution in the various patient groups is more relevant to the assessment of the drug and the delivery device.

When designing protocols to measure deposition, a number of clinical factors need to be considered and incorporated into the study design: subjects' age, sex, smoking history, and current drug regimens, presence of a viral infection, severity of disease, stability of pulmonary function, and other outcome measures that could affect the inhalation of the radioaerosol, the measurement of deposition, and the results. Some of these also apply when using healthy volunteers as subjects for deposition studies. For example, we allow a 4- to 6-week recovery period between repeat studies for subjects who have suffered an exacerbation of their asthma or developed a chest cold or infection after enrollment.

The particle size of therapeutic aerosols range from < 1-^m mass median aerodynamic diameter (MMAD) to 8 mm MMAD. However, the "effect" of particle size, once the inspiratory flowrate is taken into account, can be much greater, shifting the deposition pattern to more proximal airways, as does airway narrowing due to the presence of lung disease, effects demonstrated in a number of published deposition studies. Thus the inhalation variables—inspiratory flowrate, inspiratory volume, and time of breath hold—are important to control during the inhalation of the tracer aerosol [11,97,98]. This can be accomplished by either training the subject prior to the inhalation maneuver or using a monitoring system with or without visual feedback. While this level of control is rarely present during actual patient use of the inhaler, nonetheless it is important to the interpretation of deposition results if the objective is to determine delivery efficiency under optimal conditions of use. Small changes in particle size and/or inspiratory flowrate can influence the deposition measurement (Fig. 7, [99]). Control of these variables may contribute to a reduction in intersubject variability in deposition and, perhaps,

D ■ Oropharynx = 17,06 x Log(dJQ) ■ 43.97, r2 = 0.28

A * Oropharynx + Gut = 30,60 x Logfd'Q) -108.62, r! = 0,60

Figure 7 Deposition in the lung, the oropharynx, and the sum of the oropharynx and gut, expressed as the percent of nominal dose, plotted against the impaction parameter, d2Q, where d is particle size and Q is inspiratory flow rate [99]. With this particular inhaler, a fourfold difference in Q caused a marked shift in the distribution of drug between lung and oropharynx + gut. Variability in deposition seen between subjects may be reduced by controlling the particle size of the inhaled drug and the inspiratory flowrate during the inhalation maneuver.

response to the therapy. Similarly, when measuring deposition in patients, clinical classification of their disease must be documented, and an attempt should be made to study patients with similar severities or extent of airway narrowing.

Other technical factors influencing the delivery and measurement of the radioactivity must be well controlled. Some of these are

• Use of the same collimator for all studies.

• Position of the subject in front of the gamma camera and restriction of movement of the subject during imaging [100].

• Careful notation of image acquisition times and times of the in vitro emitted dose measurements prior to administration of the radiolabeled formulation in order that all data can be corrected for decay to a common time (time 0).

• Normalization of acquired counts for time to account for different imaging times between subjects. Images presented should have the same acquisition time because the scans can then be compared visually for differences in deposited radioactivity. This can be done, however, only if the nominal dose is similar between subjects. The use of color palettes can be misleading when presenting images of different subjects within a study, unless the scale relating count levels to color is kept the same for all images.

• Accurate measurement of the various calibration factors to be applied to both the in vivo data and any gamma camera images taken of inhalers and tubing. These latter calibration factors are different from those for the subject and need to be measured using sources or phantoms with known quantities of the same radioactivity as being inhaled.

• Ensuring a tight mouthpiece seal between the subject and the delivery system to avoid loss of aerosol inhaled and contamination of the room [101]. The use of a facemask is not recommended, except for infants.

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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