Exploring Inflammation in Asthma: From Suspension to Solution

This program was supported by an unrestricted educational grant from Forest Pharmaceuticals.

Faculty disclosures for this summary are provided on page 8 of this publication.

Pathophysiologic Solution: Exploring the Small Airway in Asthma

When looking at the pathophysiology of asthma, there are many clinical questions to be answered. Is there supporting anatomic evidence that distal airways are involved in asthma to a different extent than central airways?

Carroll and colleagues completed postmortem studies of airways of normal individuals, asthmatics that had died of other causes, and those who died from their asthma. The first parameter was inner wall thickness, which was further divided into larger (2 to 4 mm in size) and smaller (<2 mm) passages. In both sizes, both sets of asthmatics had a thicker inner wall than controls. However, only the outer wall area of the smaller airways was significantly increased in the asthma group compared to controls (Carroll N, et al. Am Rev Respir Dis. 1993;147: 405).

“No matter what caused their deaths, asthma patients still had a remodeled airway,” said Richard Martin, MD, Head, Pulmonary Division and Vice Chair of the Department of Medicine at the National Jewish Medical and Research Center in Denver.

Dr. Bruce Rubin looked at three patients postmortem, stripped away the lung’s parenchyma and bronchogramed the airway. In the individual who died from nonpulmonary causes, the branching of the airway was very fine and the alveolar flush of dye got into the alveolar units. In the person who had, by history, well controlled asthma and died from other causes, the broncho-gram showed branching airways cutoff in the distal area with no alveolar flushing. The fatal asthmatic had mucous plugging that cut off the large airway, not allowing gas exchange to occur (personal communication).

“There is supporting physiologic and clinical evidence that the central and distal airways are different in asthma,” said Dr. Martin.

Wagner and colleagues wedged a bronchoscope into the airway. Through one port they measured pressure and another they gave increasing flow rates. Having flow and pressure changes, peripheral airway resistance (PAR) can be measured (Wagner EM, et al. Am Rev Respir Dis. 1990;141:584).

Despite normal spirometry, PAR was markedly elevated in the asthma group compared to controls. This disparity continued after administering a bronchodilator. In those with mild asthma, as flow rates increased so did the pressure. PAR was markedly increased.

The investigators tried to link this to bronchial hyper-responsiveness using metacholine. After removing an outlier from consideration, there was an r-value of .8 between hyper-responsiveness and PAR.

A study from the Netherlands looked for physiological variables that could link or disassociate two groups with mild asthma (FEV1 approximately 95% of predicted). The number of exacerbations during the previous year differentiated the two cohorts. There was a significant increase in closing volume in the unstable group suggesting that early closure of the airways may make them more susceptible to exacerbation (Veen JC, et al. Am J Respir Crit Care Med. 2000;161:1902).

Martin and colleagues studied the coupling-uncoupling of lung parenchyma to the airway using a horizontal body plethysmograph during nighttime sleep. After assessing the volume-resistant relationship while awake as well as in the upright and supine position and finding these to be normal, the researchers allowed the subjects to sleep.

Approximately 90 minutes later the researchers increased volume and saw a slight change in resistance, indicating uncoupling was beginning. Other studies found that inflammation and bronchial hyper-responsiveness are greater during sleep. This study demonstrated that by four hours after falling asleep, there was an almost complete physiological uncoupling, i.e. minimal to no change in resistance as lung volumes increased (Irvin CG, et al. Am J Resp Crit Care Med. 2000;161:50).

“The physiology demonstrates that distal units in our asthmatics are involved,” said Dr. Martin. “That also leads us to wonder if a difference in proximal versus distal inflammation supports nocturnal uncoupling.”

Transbronchial biopsies were obtained at 4:00 p.m. and 4:00 a.m. in patients with and without nocturnal asthma. There were no differences in the volume of eosinophils in the afternoon between the groups. At 4:00 a.m., eosinophil infiltration into the alveolar tissue area was markedly increased in those with nocturnal asthma, less in controls (Kraft M, et al. Am J Respir Crit Care Med. 1996;154:1505).

The researchers found that the overnight fall in the FEV1 was correlated with the increase in the number of distal lung eosinophils. They also found relationships in the distribution of CD 4-positive T-lymphocytes, a controller cell for eosinophils, to the number of eosinophils in the distal lung. There was a very poor correlation for the EG2 marker for eosinophils compared to immunohistochemical stains for T-lymphocytes in larger airways (Kraft M, et al. Am J Respir Crit Care Med. 1999;159: 228).

Hamid and others found that in the small airway of asthmatic patients, there was a marked staining for eosinophils. Similar findings were seen in the more distal airways, at the alveolar level and along alveolar attachments (Hamid Q, et al. J Allergy Clin Immunol. 1997;100: 44).

Goldin and colleagues looked at how particle size of inhaled medications impacts on distal air trapping. Using HFA beclomethasone as a small particle inhaled steroid and CFC beclomethasone as their large particle medication, they found that the smaller particle was able to penetrate the distal lung. Using CAT scanning methods, there was a significant decrease in the amount of air trapping with the smaller particle steroid following four weeks of treatment (Goldin JG, et al. J Allergy Clin Imm-unol. 1999;104:S258).

“It is a proof of concept that there is inflammatory response in the very distal lung and perhaps with different kinds of medications we can alter this,” said Dr. Martin.

From Suspension to Solution: Targeting the Distal Lung

Three strategies were approved by regulators for transitioning corticosteroids inhalation medications from chlorofluorocarbons (CFC) to hydrofluoro- alkanes propellants (HFA). The first kept the same formulation and only changed the propellants. The second, changing the formulation, was used only for steroids because it was possible to dissolve them in the propellant and produce a solution. The third was to change both the formulation and delivery system.

“There are some differences that patients will notice when using the HFA formulations such as taste and the sound of the spray as it is released from the canister,” said Myrna Dolovich, P. Eng., Associate Clinical Professor Medicine and Radiology, McMaster University, Hamilton Ontario Canada. “An important change resulting from the reformulation is reduction of the particle size making a difference in how medication is deposited in the lung.”

Cumulative mass distribution looks at the size of the droplets in the aerosol. From measurements of particle size for Beclovent suspension aerosol and Qvar solution aerosol of beclomethasone dipropionate, the median diameter of the particles was determined to be about 1 micron for the solution (Dolovich M. Can Resp Journal. 1999;6:290).

The other statistic of interest is percentage of particles less than 5 microns. For the suspension, it is around 75% vs. 95% for the solution, a 20% difference in the availability of fine particles for depositing in the lower respiratory tract.

“I want to stress that while the median diameter is very different, there are still large particles in both types of aerosols,” said Prof. Dolovich. “It is important to know the percentage of particles greater than 5 microns as they deposit mainly in the oropharynx, larynx, and on the larger airways.”

From physics, it is known that 1 micron particles behave like a gas. They have a minimum sedimentation rate, which determines how quickly these particles will settle onto the airway epithelium and a minimum diffusion rate for transport into the alveoli.

Steroid receptors line the airways and increase in density as you go toward the periphery. To fight inflammation, steroids have to get into the distal lung.

Prof. Dolovich and her group compared deposition of Beclovent to Qvar using radioactive formulations of the two drugs. The Qvar 2-D imaging scans appeared fuller and indicated that slightly more aerosol was deposited peripherally. With Beclovent, the airways were more obvious in both the anterior and posterior deposition image and there was more radioactivity (drug) in the oropharynx. For the group as a whole, the deposition of Beclovent, ex-acuator, was about 17% compared to 53% for Qvar (Dolovich MB, et al. AJRCCM. 2000; 161:A33).

HFA flunisolide delivers a nominal dose of 145 micrograms, about half of its CFC formulation. The spacer collects 58 micrograms, leaving about 85 micrograms for inhalation. Of this amount, 58 micrograms was deposited in the lung, 21 in the oropharynx and 6 was exhaled. The latter figure is typical of HFAs and about three times as much as seen for CFC formulations.

Twelve normal subjects using a radioactive formulation of flunisolide were compared to four normal subjects using CFC flunisolide. There was a 10-fold decrease in the oropharyngeal deposition of medication. With HFAs, there was an increase in the amount deposited in the lungs, 68% ex-spacer versus 20% ex-acuator resulting in a 10 microgram difference in lung deposition (Richards J, et al. J Aerosol Med. 2001; 14:197).

“It is important that we translate the percentages into micrograms because you get a different picture of the amount of drug deposited than if interpreted only from the percentages,” said Prof. Dolovich. “This also allows, in my view, for a clearer interpretation of the clinical findings. It is important to use these formulations with a spacer, particularly with children, both to improve patient coordination and also if you are concerned about total body independent of their aerosol properties. This is particularly true if you are concerned about total body dose of steroid.”

In normal subjects using Qvar without a spacer, 51% of the medication was deposited in the lung and about 29% in the oropharynx. After adding a valved spacer, the lung dose was unchanged but the oropharynx dose was reduced five-fold. Similar differences were seen using flunisolide with and without a spacer.

Prof. Dolovich and colleagues measured deposition in specific regions of the lung using Qvar and Beclovent. There was an increase in the total dose of Qvar of three- to four-fold throughout the lung. When the lung was divide into regions, there was also a three- to four-fold difference in drug deposited between the two formulations.

In micrograms of beclomethasone delivered per acuation, HFA deposited 5 in the outer zone, 7 in the mid zone, and 12 in the inner zone. These are approximately three times more than from the CFC product in each zone. Thus the ratio, inner to outer, is unchanged as there is an increased quantity overall.
The same results were seen for flunisolide comparing HFA vs. CFC. There is little difference in the peripheral to central ratio of the drug (Richards J, et al. J Aerosol Med. 2001;14:197).

Forest Pharmaceuticals organized a 3-D tomography study using Single-Photon Tomography (SPET) to compare their HFA and CFC formulations of flunisolide. From the mid-transaxial slice, the concentration of aerosol was seen to be much greater in the HFA image. The total dose showed a three- to four-fold increase in the amount of radioactivity (Newman SP, et al. J Allergy Clin Immunol. 2003;111:S216).

“When they analyzed the regional differences, there was more radioactivity in the outer zone with HFA and less in the inner zone,” said Prof. Dolovich. “This suggested that a greater amount of the finer aerosol reached the distal lung.”

Therapeutic Outcomes with New Solutions in Asthma

When discussing goals related to the use of inhaled corticosteroids, preventing remodeling and loss-of-function decline is important. Another target is reduction and prevention of exacerbations.

The FHA formulations of most steroids have particles sizes near 1 micron. This means there is less medication delivered to the palate and less potential for side effects.

“When you tease out the numbers, you see differences in distribution throughout the airways,” said George Bensch, MD, Chief, Allergy, Immunology and Asthma at San Joaquin General Hospital, Stockton, CA. “The most important figure is probably that 23% of the medication gets to the lower airways. You get more where you want it and with lower effective doses”

Studies have shown that HFA solutions tend to have extra fine particle aerosols. This leads to reduced oropharyngeal deposition and enhanced lung deposition. The HFA flunisolide showed a 10-fold decreased deposition in the oropharynx and 68.3% increased deposition in the lung when compared to CFC. Beclomethasone showed a three-fold decrease and a 55% increase respectively. This improved deposition allowed for a one-third decrease in the effective dose for flunisolide and a 50% decrease for beclomethasone. At the same time, there was a decrease in both systemic and local adverse effects (Richards J, et al. J Aerosol Med. 2001;14:197; Leach CL, et al. Eur Respir J. 1998;12:1346).

The question then becomes, are there clinical benefits to changing to HFA medications? Drs. Bensch and Newman compared HFA flunisolide versus CFC and the impact on exacerbation rates. Over the nearly 90 days of the study, 96% of those being administered HFA had no exacerbations compared to less than 94% on the CFC delivery system and less than 76% of the placebo arm (Bensch G, Newman K. Poster presented at the Third Triennial World Asthma Meeting. 2001).

The HFA formulation also showed increases in symptom-free days when compared to CFC. There was 43.6% increase in symptom-free days in wheezing, 44.5% in chest tightness, and 42.6% in shortness of breath. This compared to 10.2%, 27.9%, and 28.4% increases respectively in the CFC group. Cough was the only symptom with a positive difference for CFCs (16% to 13.1%).

“When you look at growth, the great concern of all pediatricians, there were no differences found between flunisolide at 340 micrograms a day versus cromolyn,” noted Dr. Bensch. “Budes-onide may have had a trend toward lower growth.”

Another adverse effect concern is the impact of medications on the Hypothalamus-Pituitary-Adrenal Axis (HPA). Lipworth and others looked at the effects of beclomethasone HFA on HPA function at 12 weeks. The percent of patients with a.m. cortisol less than the reference range was essentially the same across BDP-HFA, BPD-CFC, and HFA-placebo. The BDP-HFA dose was half the CFC dosing (Lipworth BJ. Respir Med. 2000;94 (suppl D): S21).

There also appears to be no concerns about candidiasis. Using cromolyn as a reference, Dr. Newman and others found that 3% to 4% of children had candidiasis, consistent with general populations. With flunisolide there is an increase with HFA. Budesonide had by far the biggest increase both on the KOH preparation and in cultures (Newman K, et al. Poster presented at Third Triennial World Asthma Meeting. 2001).

“Overall, there is a greater deposition of medications in the deeper parts of the lungs with FHA inhaled steroids,” said Dr. Bensch. “They are associated with good responses at lower doses and exhibit fewer systemic side effects.”

Faculty Disclosures:

George Bensch, MD
Research: PDL, AstraZeneca, Schering Plough; Wovartz
Speaker: Forest, AstraZeneca, Schering Plough, PDL; Wovartz

Myrna Dolovich, MD
Reported nothing to disclose

Richard Martin, MD
Consultant: GlaxoSmithKline, Schering, 3M, Aventis, Forest, Merck, AstraZeneca, ALTANA
Speaker’s Bureau: GlaxoSmithKline, Schering, 3M, Aventis, Forest, Merck, AstraZeneca, ALTANA
Research Grant: GlaxoSmithKline, Schering, 3M, Aventis, Forest, Merck, AstraZeneca, ALTANA