| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
Professor and Chief, Division of Pulmonary and Critical Care Medicine.
Correspondence to: Donald P. Tashkin, MD, FCCP, Division of Pulmonary and Critical Care Medicine, UCLA School of Medicine, 10833 LeConte Ave, Los Angeles, CA 90095-1690; e-mail: dtashkin@med1.medsch.ucla.edu
To comply with the mandatory phase-out of chlorofluorocarbons (CFCs) that destroy ozone in the stratosphere and allow excessive ultraviolet radiation to reach the earth's atmosphere,1 CFC-based metered-dose therapeutic aerosols are in the process of being reformulated with more environmentally friendly alternative propellants, such as hydrofluoroalkanes (HFAs). This process has created formidable technical challenges as well as new opportunities for potentially improved aerosol delivery. Beclomethasone dipropionate (BDP), the oldest inhaled corticosteroid molecule with high topical-to-systemic activity, has been used in asthma therapy for over two decades. Reformulation of BDP with HFA-134a results in a solution preparation that delivers an aerosol with a much smaller mean particle size (mass median aerodynamic diameter [MMAD] 1.1 µm) than that of aerosols generated by conventional CFC-based metered-dose inhalers of BDP (MMAD, 3.5 to 4 µm).2 Mathematical models that relate particle size to the site of deposition in the respiratory tract predict that extra-fine particles with an MMAD of approximately 1 µm would deposit to a greater extent in the lung periphery than less fine particles with an MMAD of 4 to 5 µm, which would tend to deposit more centrally, as well as in the oropharynx.3 Since this theoretical model does not take into account a number of other factors that influence aerosol particle deposition in vivo, such as variations in inhalation technique (inspiratory flow, breath-holding time) and airway morphology (narrowing or occlusion caused by disease),4 in vivo studies are required to ascertain actual sites of aerosol deposition in both healthy subjects and patients with airways disease. Using an optimized method of metered-dose inhaler use and lung imaging techniques incorporating procedures validated to ensure consistency of drug radiolabeling in the different ranges of particle size, Leach2 demonstrated that a large proportion of HFA-BDP (51 to 56%) was delivered uniformly throughout the lungs (ie, presumably to peripheral, as well as large- and medium-sized airways) of both normal volunteers and patients with mild asthma with relatively little oropharyngeal deposition (28 to 30%), in contrast to CFC-BDP that deposited mainly in the oropharynx (94%) and large central airways with little peripheral penetration.
The above data predict that patients with moderate asthma who are still symptomatic with low doses of CFC-BDP (up to 400 µg) might have their asthma well controlled with an equally low actuated dose of HFA-BDP, owing to a more efficient delivery of the latter to the lower respiratory tract. Essentially, this prediction has been borne out by the results of a randomized, placebo-controlled study published in this issue of CHEST (see page 343), in which a 400-µg dose of HFA-134a BDP was shown to produce significant benefits (compared with placebo) that were equivalent to those produced by double the dose of CFC-BDP in oral-steroid-responsive patients with moderate asthma whose asthma had not been adequately controlled with 0 to 400 µg/d of inhaled corticosteroids in conventional formulations. Moreover, the HFA preparation was tolerated at least as well as the CFC formulation of BDP with comparably negligible effects on morning serum cortisol level.
The results of this study imply some advantages of the extra-fine aerosol generated by HFA-134a BDP over the coarser aerosol produced by CFC-BDP. The most obvious advantage is a savings in cost (at least to the manufacturer), since only half the amount of HFA-based medication compared with CFC-based medication would be required to produce the same therapeutic benefit. However, a clinically more meaningful advantage would occur only if the lower dose of HFA-BDP yielded a higher ratio of therapeutic efficacy to side effects. Relatively lower effective doses and substantially reduced oropharyngeal deposition of the HFA preparation should translate into less frequent local side effects (dysphonia, candidiasis) than would occur with CFC-BDP, particularly if high doses of the latter were required, although an add-on spacer device could serve a similar purpose. Of greater importance is the potential for reduced systemic side effects of the extra-fine corticosteroid aerosol (hypothalamic-pituitary-adrenal axis suppression, purpura, osteopenia, ocular effects) as a result of both (1) reduced throat deposition and thus less GI absorption from swallowed BDP (which undergoes incomplete first-pass metabolism by the liver) and (2) the lower total ex-actuator doses needed to achieve comparable efficacy. However, while the total ex-actuator HFA dose may be reduced, the relative amount delivered to the lower respiratory tract appears increased compared with equivalently effective CFC doses.2 This enhanced lower respiratory deposition could result in an actual increase in systemic bioavailability of the BDP from the HFA preparation owing to greater absorption from the lung, as suggested by data from pharmacokinetic studies5 that imply the potential for equivalent or even increased systemic side effects from half doses of HFA-BDP compared with CFC-BDP. In contrast, results of a 12-week clinical trial in patients with moderately severe asthma point to a tendency to relatively greater effects on adrenal function from 1,500 µg CFC-BDP than 800 µg HFA-134a BDP in the face of comparable overall efficacy,6 suggesting a slightly more favorable therapeutic ratio for the HFA preparation. The apparent discrepancy between the latter clinical findings and results of deposition and pharmacokinetic studies might be due to differences in metabolism of BDP absorbed from different sites in the lung and from the gut, possibly leading to differences in the ratio of adrenally active metabolites to unchanged BDP and its nonactive metabolites. Further investigation of the latter possibility is warranted.
Another potential advantage of extra-fine corticosteroid aerosols is
their apparently greater accessibility to peripheral airways (
2 mm in
diameter), which appear to be poorly penetrated by conventional
CFC-based aerosols. On the basis of indirect physiologic studies, small
airways were initially believed to be less affected in asthma than
larger airways.7
However, more recent data indicate that
airway inflammation is present in both large and small
airways,8
as well as alveolar tissue,9
and
that airway wall remodeling10
,11
occurs in small airways,
probably accounting for the marked increases in peripheral airways
resistance that have been detected by direct measurements in even
asymptomatic asthmatics with normal results of spirometry and
plethysmographic airway resistance.12
The clinical
significance of small airways involvement in asthma, its contribution
to fatal asthma or to the accelerated rate of decline in lung function
with age that occurs in asthma,13
and the consequences of
treating (or not treating) the small airways component are as yet
unclear. Now that it appears possible to deliver topical
anti-inflammatory medication directly to the small peripheral, as well
as to the larger more central, airways using extra-fine corticosteroid
aerosols, we have an opportunity to assess the potential benefits of
this new form of aerosol therapy, in comparison to more conventional
coarser aerosols. Ideally, several different methods of assessment
might be employed. These include the following: (1) conventional
measures of asthma control (symptom scores, rescue medication use,
morning peak flow and peak flow variability, airways responsiveness,
exacerbation rate); (2) prospectively assessed longitudinal changes in
FEV1 (as a reflection of the natural history of asthma);
(3) indirect measures of small airways function (extent of regional air
trapping as assessed by novel CT imaging techniques, including helical
thin-section CT14
or single photon emission CT
following inhalation of a bolus of technetium-labeled ultra-fine
carbon particles15
; (4) bronchial and alveolar
inflammation (assessed by BAL); and (5) possibly small airways
histopathology (evaluated via transbronchial biopsy
specimen5). Results of such studies should
provide valuable additional information concerning the clinical
significance of small airways involvement in asthma and the impact of
anti-inflammatory treatment partially targeted to these airways on the
long-term course of the disease.
References
This article has been cited by other articles:
|
|
 |
|
  N. L. Dean, G. N. Gross, and D. P. Tashkin Extra Fine Hydrofluoroalkane-134A Beclomethasone Aerosols : Selecting an Optimal Inhaled Steroid for an Individual Patient Chest, September 1, 1999; 116(3): 841 - 842. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
