Deposition and Fate of Aerosolized Drugs

Deposition and Fate of Aerosolized Drugs Michael T. Newhouse, M.D., and Richard E. Ruffin, M.B.

Aerosols are airborne suspensions of particulate

matter and, as aerosolized drugs, have long been used in respiratory medicine for the management of a number of obstructive airway diseases. Commonly used aerosols have included water or saline droplets in an attempt to "liquefy" sputum; various betas adrenergic agonists for bronchodilatation and augmentation of mucociliary transport; and sodium cromoglycate and steroid aerosols for the topical prophylactic therapy of asthma. There is a need for a greatly improved understanding of the deposition site of inhaled aerosols, as well as the location of the receptors for the various drug effects, in order to "tailor" particle size, delivery systems and breathing maneuvers to individual needs and maximum benefit. .AEROSOL DEPOSmON

Depositing aerosols in the lung is not a simple matter, since the upper respiratory tract, laryngeal region and branching system of airways provide an extremely efficient aerodynamic filter, which pre- , vents an assortment of naturally-occurring biologic and non biologic particulates from penetrating deeply into the lung and acts as an important pulmonary defense mechanism. 1 It is this same mechanism that makes it relatively difficult to achieve drug deposition in the airway. The factors determining aerosol deposition sites in the lung have recently been reviewed in detail by Morrow.s These include particle-related factors such as size (and changes in size due to evaporation and hygroscopicity), shape, and density, and airwayrelated factors such as flow rate, tidal volume, respiratory frequency and airway caliber. The size, shape, and density of naturally occurring aerosols varies greatly. Furthermore, naturally occurring and most therapeutic aerosols are heterodisperse (contain a range of particle sizes). For the comparison of aerosols and the prediction of their deposition sites in the airways the concept of aerodynamic mass median diameter (AMMD) is useful. The AMMD is a measure of the settling velocity of a given aerosol due to gravitational forces expressed in terms of a Reprint requests: Dr. Newhouse, St. Joseph's Hospital. Hamilton. Ontario, Canada

938 NEWHOUSE, RUFFIN

spherical particle of unit density having the identical settling velocity in air. The physical principles determining deposition site are related chiefly to aerodynamic particle size and are primarily impaction; sedimentation, and Brownian motion. 1 In addition, a small role is also played by convective diffusionS particle charge,"

Impaction From the therapeutic point of view, only particles with an AMMD less than 10 pm are of particular interest, since particles larger than this are readily removed in the upper respiratory tract and do not enter the lower airways in significant amounts. With nasal breathing, the majority of particles in the 5-10 pm range are deposited by impaction on the turbinates while, during mouth breathing the tonsillar area of the pharynx and larynx as well as the initial five or six bronchial bifurcations are the sites of greatest inertial impaction. Deposition results from the relatively high inertia of these particles which makes it difficult for them to follow the airstream as it changes direction. Smaller aerosol particles (5-0.6 p.m) remain airborne to penetrate beyond the 10th bronchial division and are deposited mainly by sedimentation. Because of aerosol losses in the generator, tubing, valves and mouthpiece and the efficiency of aerodynamic filtration in the upper respiratory tract, and because much of the mass of an aerosol resides in the larger particles, less than 10 percent of the dose from most aerosol generators producing particles in the 110 pm range actually enters the lower respiratory tract," When metered dose inhalers ( MD I) are used, the losses before the mouth are greatly decreased, but because the particles are rapidly ejected, their greater inertia increases the likelihood of oropharyngeal deposition (unpublished observations ). The importance of the inspiratory flow rate in determining deposition by impaction should be stressed, since the aerodynamic size of the particles deposited by impaction is greatly affected by flow rate. A higher flow rate effectively increases the aerodynamic size because of the greater inertia of the particles, resulting in increased deposition in proximal airways.

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Sedimentation Particles of AMMO 1-5 #£Ill, which include most aerosolized drugs, are chiefly deposited by sedimentation as a result of gravitational forces. This occurs mainly from the 5th bronchial division to terminal lung units. However, approximately 15 to 20 percent of 3 #£Ill particles are deposited in the larger, more proximal airways as a result of impaetion.8.1 Although of no immediate relevance to aerosol therapy, the importance of particle shape is indicated by the fact that asbestos fibers up to ~ pm in length may be found in peripheral airways and lung parenchyma. This is because their approximately 0.5 #£Ill width allows them to act more like particles having an AMMD of approximately 1 I'ID. Despite their aerodynamic size, such fibers are also fairly efficiently deposited in larger airways as a result of interception, a mechanism by which asbestos fibers that have lodged across an airway act as a filter to remove other asbestos fibers from the airstream," The greatest collection efficiency for particles in the 1-31'1D range occurs beyond the 10th bronchial division and is maximal at the 15th to 17th bronchial division.8,II Indeed, when radioactively tagged 3 #£Ill (ag 1.6) albumin particles were inhaled by nine normal subjects and their -removal quantified topographically using a scintillation camera and appropriate data handling equipment, it was found that approximately 15 percent of the inhaled lung burden was cleared from the central airways with a half-time of 30+12 minutes, indicating proximal airway deposition, while 80 percent was removed with much slower clearance half-times of the order of 1224 hours. Approximately 50 percent was still present in the lung after 24 hours, suggesting deposition on nonciliated airways distal to the terminal bronchiole," By contrast, nonbronchitic smokers and patients with marked airways obstruction, breathing particles of similar size at similar flow rates, showed aerosol penetration into the airways which was inversely proportional to the degree of airways obstruction and the overall removal of the inhaled lung burden of aerosol was more rapid." For particles deposited by sedimentation, the deposition efficiency and penetration into the airways will be determined not only by particle size (AMMD)2 and airway caliber," but also by lung volumes (expiratory reserve volume and tidal volume) and the respiratory frequency,":" which determines the residence time of particles in the airways. By taking advantage of the relatively high deposition efficiency of particles in the range of 2-4 #£Ill in the smaller airways in the region of the junction of

CHEST 73: 6, JUNE, 1978 SUPPLEMENT

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F1cURE 1. Comparison of scintigrams representing pulmonary distribution of lUXe gas and deposition of an AMMD 3,.m (~g 1.6) aerosol in a normal subject, smoker and patient with severe alpha l antitrypsin deficiency emphysema.

ciliated and nonciliated airways, and by maintaining all of the variables determining.deposition relatively constant, it has been possible to quantify "airway caliber" in aerodynamic terms. Scintigrams (Fig 1). from three typical subjects representing normal subjects, asymptomatic young smokers and patients with severe chronic obstructive airways disease (COLD), illustrate this point. In the scintigrams from normal subjects, aerosol deposition is fairly uniform and similar to the 135Xe gas equilibration, whereas in the COLD scintigrams there is marked disparity between the distribution of 13l1Xe and the 3 #£Ill aerosol, indicating poor distribution of the particles to the peripheries. The asymptomatic smoker with normal 1 sec forced expired volume (FEV I) and maximum midexpiratory 80w rate ( MMFR) shows an intermediate abnormality of aerosol deposition indicating poor aerosol penetrance presumably related to small airway narrowing. These data can be quantified in terms of an aerosol penetrance index (AeP) (Fig 2) which takes into account both the initial topographic aerosol deposition and the radioactivity remaining in the lung after completion of the mucociliary transport phase of removal. When the AeP was related to the

DEPOSITION AND FATE OF AOOSOUlED DRUGS 937

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MMFR in groups of normal subjects, nonbronchitic smokers, and patients with severe airways obstruction, the AeP was significantly more sensitive than the MMFR. The AeP was able to discriminate small airways obstruction relatively "early" in young smokers without symptoms or signs of pulmonary disease and with little or no measurable physiologic abnormality of pulmonary function (Fig 3) .10 The corollary with respect to aerosol drug therapy is that if aerosols are to be efficiently deposited in peripheral airways in patients with airways obstruc-

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5. Particle size and respiratory deposition. The deposition probabilities of particles of different aerodynamic size are indicated for the upper respiratory tract (URT) and the lower respiratory tract (LRT), the demarcation of the two divisions being the epiglottis. These curves can be considered useful for associating the approximate deposition pattern and amount deposited within the human respiratory system during spontaneous respiration through the nose. (From Morrow 2 , by permission) FIGURE

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938 NEWHOUSE, RUmN

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tion, smaller particles than those commonly used should be produced. Using such techniques under controlled conditions, it has been possible to demonstrate that positive pressure breathing of aerosols in patients with airways obstruction failed to produce a more uniform or more peripheral distribution of aerosols than quiet breathing (Fig 4) .

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32

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0.1 Jilll and below and currently has no therapeutic significance. Such submicron particles are deposited as the result of bombardment by air molecules with an efficiency of up to 15 percent in the nose and in the alveolar region with an efficiency approaching 50 percent when particles of the order of 0.01 f'ID are inhaled. 3 •13 These data are well summarized in a diagram (Fig 5) taken from Morrow. 2 Note the unique position of particles of 0.5-0.2pm which are too small to be significantly affected by gravitational forces and too large to be influenced by Brownian forces. As a result, these particles remain airborne, are deposited in the lung with an efficiency of less than 20 percent under normal breathing conditions and are most suitable for studying mass flow of gas in the airways, since particles of this size act like a nondiffusible gas. 14 It has been stressed by Morrow that particles of less than 0.1 f'ID may have a significance out of proportion to their very small mass since thev have an excellent airborne persistence. Even if their deposition probability is low (of the order of 5 to 10 percent) they can be of major concern because of the large numbers and availability for inhalation. Thus, despite their low mass, such particles might be of potential value in patients with a degree of reversibility in peripheral airways associated with a major fixed obstructive component Fate

from the alveolar regions." This accounts for the systemic effects such as tremor and tachycardia commonly noted within about 30 seconds of inhalation of beta adrenergic agonists such as isoproterenol. 16 With respect to the betas adrenergic bronchodilator action, the receptor site in man is not certain, but in cats the betas effect appears to reside both in proximal and peripheral airways." In attempting to determine the site of action of histamine in human airways, we have made use of techniques arising out of an improved understanding of the physical principles determining aerosol deposition. By adjusting particle size, inspiratory flow rate, and the timing of delivery in the inspiratory cycle of a tagged aerosol, central and diffuse deposition patterns in human airways have been obtained, as shown in Figure 6. By means of dose response curves using as an end point of the study a 20 percent reduction in FEV I, it was shown that much less histamine was required when deposited selectively in central airways compared with diffuse airways deposition of a much larger dose to achieve the same reduction in FEV1 (Fig 7). While this SUBJECT 5

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of Inhaled Aerosols

The fate of the inhaled aerosol burden is influenced by the deposition site, physical, chemical and biological characteristics of the particles, efficiency of the mucociliary transport system, and the response of macrophages and other cellular and humoral mechanisms. Soluble particles such as drugs will be readily absorbed into the bloodstream wherever they are deposited, absorption being somewhat more rapid

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DEPOSInON AND FATE OF AEROSOUlED DRUGS 939

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may indicate that the receptors mediating the histamine effect are chiefly in central airways, without additional data regarding peripheral airway response, it is impossible to be sure of the site of action. Other possible explanations are submaximal stimulation of possible peripheral receptors by diffusely deposited histamine or failure to appreciate changes in small airway caliber because the FEV 1 is relatively insensitive. When a betas adrenergic agonist (salbutamol) was deposited selectively prior to central histamine delivery, a similar protective effect for FEV 1 was noted whether the salbutamol was deposited mainly centrally or peripherally (Fig 8). However, when salbutamol was deposited mainly peripherally, a relatively greater beneficial effect on V211 is evident (Fig 9). Since salbutamol deposited at different sites has a relatively different protective effect on FEV 1 and V23 responses in histamine induced bronchoconstriction, it is likely that this effect is on receptors at different sites in the airway, and suggests that the betas receptors in man, like those in the cat, may be present diffusely throughout the airways. It should be emphasized that in the case of soluble particles such as aerosolized drugs, particle size is an important determinant of the delivered dose. This is because the volume is proportional to the cube of the radius, so that the dose of drug in a single 3 pm particle is nine times greater than that contained in

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deposited drug (solid bar) on histamine bronchoconstriction as determined by expiratory flow at 25 percent of vital capacity (V 2.) in one subject.

940 NEWHOUSE, RUffiN

FIGURE 10. Distribution of fnhaled aerosolized fenoterol in the human respiratory and gastrointestinal tract within five minutes of inhalation. Quantification allows precise determination of drug dose at each site.

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three 1 J4ID particles. In the past, aerosol bronchodilator response has been studied using dose response relationships of the generated aerosol without consideration of the amount or distribution of drug in the airways. By delivering a betas adrenergic agonist (fenoterol) together with radioactive label in the nebulized solution it is possible to determine precisely how much drug enters the lower respiratory tract (Fig 10). When 12 asthmatic subjects were studied in this way, it was possible to actually quantify the intrapulmonary dose and distribution using the Anger scintillation camera and an appropriate data han2' T IDA L DOSE ~

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dling system. The administered intrapulmonary dose was then related to the physiological response (Fig 11 ). These data emphasize the marked sensitivity of human pulmonary airways to very small topical doses of beta adrenergic agonists. It is important to establish the intrapulmonary dose of a given drug accurately to determine the lowest airway dose necessary to provide maximum bronchodilatation in order to minimize side-effects. Furthermore, for inhalation challenge studies, using histamine or methacholine, to be comparable it is surely useful to have information about the dose of the material actually administered to the airway. Studies illustrating the marked variation in deposition and dose of inhaled AMMD 3 J4ID particles in relation to various breathing patterns are shown in Figure 12. Comparison of three modes of breathing are shown in one subject. It is apparent that two vital capacity breaths at a flow rate of approximately 0.5 LIsec accomplished deposition of 55 percent of the intrapulmonary dose achieved during two minutes of tidal breathing. while two vital capacity breaths inhaled at about 2 LIsec deposited only 4 percent of the aerosol dose in the lower airway compared to the low flow rate study. Furthermore, inhalation of aerosol at the low flow rate resulted in a much more uniform deposition pattern than either of the other two maneuvers. Based on these findings in a pilot study, we are now undertaking a systematic investigation of the factors determining lung dose and distribution of aerosol inhaled from metered dose inhalers. These studies will attempt to determine the most efficient aerosol delivery method in patients with varying degrees of airways obstruction. We also hope to improve our understanding of aerosol deposition with respect to drug receptor sites in order to minimize treatment failures, particularly with those topically acting drugs such as betas adrenergic agonists, sodium cromoglycate, and aero2 SLOW

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I} O 2.03 1.59 3. FIClJRE 12. Scintigrams representing intrapulmonary dose and distribution of aerosolized drug delivered during two minutes of tidal breathing and two slow (0.5 LIsee) or two fast (2 Lisee) vital capacity breaths in an asthmatic subject. The marked differences in deposited total dose ( S) and inner to outer ratio (I/O) are shown.

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DEPOSmON AND FATE OF AEROSOUZED DRUGS 941

solized steroids, where it is presumably most important that the aerosols penetrate deeply into the lung. This point has already been emphasized by Godfrey et ailS in studies which demonstrated that 2 pm particles of sodium cromoglycate effectively reduced exercise induced asthma in a group of patients while 11.7 p.m particles of the drug did not, presumably because the larger particles, most of which would tend to impact in the upper airway, failed to penetrate sufficiently deeply into the lung. ACKNOWLEDGMENT: The authors are grateful to M. Dolovich, P. Eng., for assistance in the preparation of the manuscript and to Miss Chris Pogodzinski for the typescljpt. We appreciate the support of the Ontario and Canadian Thoracic Societies. MediCal Research Council of Canada and Boehringer Ingelheim Ltd. Dr. R. RuHin is a Boehringer Ingelheim Research Fellow.

1 Newhouse M, Sanchis J, Bienenstock J: Lung defense mechanisms. N Eng! J Moo 295:990-998, 1976 2 Morrow PE: Aerosol characterization and deposition. Am Rev Respir Dis 110: (Part 2) :88-99, 1974 3 Owen PR: Turbulent flow and particle deposition in the trachea, circulatory and respiratory mass transport. (Wolstenholme GEW, Knight J, eds), Boston, Little, Brown and Company, 1969, pp 236-252 4 Wehner AP: Negatively charged aerosols: Effect on pulmonary clearances of inhaled 239~ in rats. Chest 60: 468-471, 1971 5 Dolovich MB. Rossman C, Wolff R. et al: Pulmonary aerosol deposition in chronic bronchitis: IPPB vs quiet breathing. Am Rev Respir Dis 115:397-402, 1977 6 Sanchis JM, Dolovich M, Chalmers R. et al: Quantitation of regional aerosol clearance in the normal human lung. J Appl Physiol33:757-762, 1972 7 Landahl HO: Removal of airborne droplets by the human respiratory tract. L The lung. Bull Math Biophys 12:43-

56,1950

8 Beeclcmans 1M: The deposition of asbestos particles in the human respiratory tract. Int 1 Environ Stud 1:31-34, 1970 9 Schroter, RC, Sudlow MF: Flow patterns in models of the human bronchial airways. Respir Physiol 7:341-355, 1989 10 Dolovich MB, Sanchis J, Rossman C, et al: Aerosol penetrance: A sensitive index of peripheral airways obstruction. J Appl Physiol40:468-471, 1976 11 Muir DCF, Davies CN: The deposition of 0.5 II- diameteraerosols in the lungs of man. Ann Occup Hyg 10:161-174, 1967 12 Davies CN, Heyder J, Subba Ramu MC: Breathing of half-micron aerosols. I. Experimental J Appl Physiol 32:591-600, 1972 13 Stuart BO: Deposition of inhaled aerosols. Arch Intern Med 131:60-73,1973 14 Heyder J, Davies CN: The breathing of half-micron aerosols. DI. Dispersion of particles in the respiratory tract. Aerosol Sci. 2:437-452, 1971 15 Yeates DB, Aspin N, Bryan AC et al: Regional clearance of ions from the airways of the lung. Am Rev Respir Dis 107:602-608, 1973 16 Patterson JW, Connolly ME, Davies OS, et aI: Isopre-

142 NEWHOUSE, RUmN

naline resistance and the use of pressurized aerosols in asthma. Lancet 11:426-429, 1968 17 Lubich KM, Mitchell HW, Sparrow MP, et al: The cat lung strip as an in vitro preparation of peripheral airways: A comparison of B-adrenoreceptor agonists, autacoids and anaphylactic challenge on the lung strip and trachea. Br J Pharmac 58:71-79, 1976 18 Godfrey S, Zeidifard E, Brown K, et al: The possible site of action of sodium cromoglycate assessed by exercise challenge. Clin Sci Molec Moo 46:265-272, 1974 DISCUSSION

Dr. FaUiers: I have seen some recent opimons, but unfortunately no data, that suggest that the optimal distance an aerosol device should be held from the mouth is determined by the pressure at the valve. For instance, it has been recommended that salbutamol should be held about 17 em from the mouth; steroid aerosols about 15 an, and some of the other mists about 11 em. Do you think we know enough to make these recommendations? Dr. Newhouse: I haven't seen the data on which that recommendation was based. However, I hope that in a year, perhaps, we will have some answers to these questions. Dr. Rosenthal: We have developed a metered dose aerosol generator, and from what you've told us today, I suspect that most of what we're delivering is deposited in the central airways. Several investigators at Walter Reed, using a similar device, have been unable to bloclc: histamine effects with atropine. This suggests to me that there are specific histamine receptors in the central airways as opposed to histamine acting on central airways only through vagal reflexes. Dr. Loudon: Is there any evidence that the particle size in any of the test aerosols that you were using was changing as a result of hygroscopic effects, humidity, or temperature? H so, I wonder if there is any way of controlling these effects. Dr. Newhouse: As you know, that's a loaded question and it's abnost unanswerable. Once aerosol particles leave the site at which they can still be measured, that is the mouth, I suppose some of them get bigger and some of them get smaller. This information is certainly important and it could probably be obtained with studies using an appropriate model. However, knowledge of the particle size itseH becomes less important if you actually know where the particles are deposited. Dr. Bernstein: I was wondering if you have any data or information concerning the effects of the fluorinated hydrocarbon propellants on deposition site. I think a number of people have demonstrated that freon propellants may cause an increase in airway resistance, and £rom your data, this should have an effect on particle deposition. Dr. Newhouse: There is, as you know, considerable disagreement about whether freon produces bronchoconstriction. Certainly, aerosolized particles themselves may produce reflex bronchoconstriction in some individuals and this may determine where particles go by impairing peripheral deposition. Under these circum-

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stances, one may have to use smaller particles. There may be some patients who do well with 3 micron particles, whereas other patients may require 1 or even 0.5 micron particles. This will depend very much on the way in which they react to an aerosol, as well as the structural changes that are already present. Dr. Marks: Have you done any work with any of the powdered aerosols such as cromolyn sodium? Dr. Newhouse: No. Unfortunately, you can't tag the cromolyn particle in a way that wiD allow you to detect: it with a scintillation camera. One would have to use a radioactive powder in such a way that the particles would be very similar to cromolyn and would leave the generator in the same way. However, some interesting studies that relate to this question have been done by Dr. Simon Godfrey. He has shown that patients using cromolyn of 2 micron particle size had fairly good control of exerciseinduced asthma. However, when they were switched to 11 micron particles, no protection was conferred. It's obviously an important issue, especially with medications like cromolyn, steroid aerosols, and of course, with the beta, adrenergic agonists as well. An understanding of the particle size and breathing maneuvers necessary to accomplish diffuse drug deposition is very important. Perhaps one of the most important things that is 0btained £rom these studies is the realization that we must spend much more time instructing patients in the use of these drugs so that we can determine whether treatment failure is failure to respond to a drug, as opposed to a failure in drug delivery. Dr. Haynes: Your data concerning the effect of histamine on FEV1 showed a smaller drop in FEV 1 with peripheral deposition than with central deposition of particles. This was interpreted to indicate that histamine receptors are located primarily in large airways. Isn't it also possible that there are an enormous number of histamine receptors in the small peripheral airways, but that a tremendous increase in resistance in the smaller airways is necessary to produce a drop in FEVI? Dr. Newhouse: That's a very good point, and to clearly

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establish that the effect is in small airways or large, we need to use additional tests of small airway function. Dr. RtJchelefsky: I wonder if you have any data comparing children with adults in terms of particle distribution, as a possible way of explaining why cromolyn sodium is more effective in children than in adults. Dr. Newhouse: We haven't done this. However, I suspect that it isn't related to particle size or distribution, but more likely related to the fact that more children are extrinisic asthmatics and this drug seems to work better in extrinsic asthma. It may also be related in part to the fact that children haven't had the disease as long and therefore, chronic inflammatory changes are not as advanced. Dr. McFadden: I would like to urge a note of caution in using the FEV1 vs flow in the mid-vital capacity when talking about large vs small airways obstruction. H you have a change in FEY1 without extensive evaluation using other techniques, it's not possible to tallc about where the site of obstruction is. Massive small airways obstruction will reduce the FEVr- In addition, it's not possible to talk about relative changes in flow rate in the mid-vital capacity as indicating small airway obstruction if the FEV1 is changing. Dr. Lyons: You demonstrated that some patients had very little aerosol deposition in the lung. Did any of those patients show a response or a reduction of resistance? H so, then I'd like to ask, do you think that the site of drug response could be located high in the respiratory tract? Dr. Newhouse: I don't think that question can be answered yet. Patients that had very small amounts of drug in the lung did respond. We haven't looked at this systematically to see what the dose response relationship is and obviously, that has to be done. We are planning to evaluate responses in terms of the anatomic site of drug deposition outside the lung, such as the buccal mucosa or under the tongue. Hopefully, with this information, we will be better prepared to answer your question.

DEPOSITION AND FATE OF AEROSOUZED DRUGS 143