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Dose-Response Relationship and Reproducibility of the Fall in Exhaled Nitric Oxide After Inhaled Beclomethasone Dipropionate Therapy in Asthma Patients: Discussion

Dose-Response Relationship and Reproducibility of the Fall in Exhaled Nitric Oxide After Inhaled Beclomethasone Dipropionate Therapy in Asthma PatientsExhaled NO is widely regarded as a noninvasive marker of airway inflammation. In these two studies, we examined the dose response of sequential administration of increasing doses of iBDP on Feno, spirometry, and PC20, and also the reproducibility of the effect of a single dose of iBDP administered twice on Feno and spirometry. Exhaled NO, but not FEV1 or PC20, distinguished the 100 mg dose from the 800 mg/d dose of iBDP. The effect of repeated administration of 200 mg/d of iBDP on both Feno and FEV1 was highly reproducible.
In this study, Feno fell and PC20 rose significantly even with 100 mg/d of iBDP, a dose that is considered to be subtherapeutic. Furthermore, Feno, in contrast to FEV1 and PC20, distinguished between the 100 mg/d and 800 mg/d doses of iBDP. Inspection of the high-baseline Feno group (Fig 1) suggests that a larger sample size of subjects with Feno > 100 ppb might have demonstrated a significant dose response for all iBDP doses studied. If a high-baseline Feno means more inflammation, then selection of a group on the basis of Feno may allow a dose response to be demonstrated, as the change in a parameter after an intervention will always be directly proportional to the initial absolute level of that parameter. For Feno, it appears that the dose-response levels out at > 800 mg/d of iBDP. canada viagra

To our knowledge, there is only one published study using Feno to examine the dose response to inhaled corticosteroids. In three parallel groups, each containing from six to eight subjects, Jatakanon et al examined the dose response of inhaled bude-sonide (placebo, 100 mg/d, and 400 mg/d) using Feno, methacholine, and induced sputum as outcome measures. In a further crossover study, 10 subjects were randomized to treatment with 1,600 mg of budesonide or placebo. There were significant improvements in FEV1 following 400 |xg and 1,600 mg/d of budesonide (11.3% and 6.5%, respectively; p < 0.05) accompanied by significant reductions in eosinophil numbers in induced sputum (p < 0.05). However, levels of Feno were reduced following each budesonide dose, while PC20 rose only with 1,600 mg/d of budesonide. A plateau response of Feno was found at a dose of 400 mg/d of bude-sonide. Our study also found a detectable effect of even 100 mg/d of iBDP on Feno, but unlike Jata-kanon et al, this dose also affected PC20, and the Feno response bottomed out at 800 mg/d of beclomethasone, compared to 400 mg/d of budesonide. This difference may be related to differing potencies of these two compounds. Additionally, our study subjects were preselected for a raised baseline Feno.
PC20 significantly increased on as little as 100 mg/d of iBDP, but this parameter was unable to distinguish a significant dose response in the group as a whole. The high- and Iow-Feno groups show differing patterns of PC20 change, with the former showing a “flat” PC20 response while the latter showed a progressive PC20 rise (Fig 2). This can perhaps be explained on the basis of differing severity of airway inflammation between the two groups. The more inflamed group (high-baseline Feno) was more resistant to modulation of PC20 during the short period of this study. Longer treatment, however, at the higher dose level might have eventually resulted in PC20 modulation. This suggests that inflammation as assessed by Feno is unimportant in determining bronchial reactivity in the high-baseline Feno group. FEV1 also rose significantly with the 400 mg/d and 800 mg/d dose levels, but did not show a significant dose response.
Several designs for a dose-response study using inhaled steroids in asthma could have been employed, each with its own merits. The parallel group design, as used by Jatakanon et al, avoids the need to wash out the effect of the medication, but requires larger numbers of subjects, and for the groups to be matched in baseline characteristics. The single-cohort design, with each dose followed by a washout period, is probably the best theoretical design, but takes longer, thus increasing dropout rates and the chance of asthma exacerbation. Additionally, Feno in some subjects will not return to baseline, as seen in the reproducibility study. The design we used in this study is short, without need for washout. However, there is the possibility of carryover effects from the previous dose level.
Table 2—Reproducibility Study: the Changes in Feno and Spirometric Lung Volumes With iBDP

Variables Period 1 (Placebo Period) Placebo MDI Period 2 (Active Medication) iBDP, 200 |xg/d Period 3 (Washout) Placebo MDI Period 4 (Active Medication) iBDP, 200 |xg/d
Pre-BD 3.39 ± 0.27 3.66 ± 0.30 3.61 ± 0.27 3.72 ± 0.27
Post-BD 3.77 ± 0.29 3.91 ± 0.32 3.86 ± 0.30 3.94 ± 0.29
Pre-BD 4.53 ± 0.30 4.59 ± 0.30 4.59 ± 0.29 4.59 ± 0.28
Post-BD 4.67 ± 0.30 4.73 ± 0.29 4.67 ± 0.30 4.68 ± 0.29
Pre-BD 111.6 (80.3-155.1) 66.3 (49.2-89.5)t 110.2 (79.3-153.1) 61.7 (42.9-88.9)t
Post-BD 114.2 (81.7-159.7) 68.9 (50.6-93.8)t 113.7(80.9-159.9) 64.0 (43.9-93.3)t