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

doi:10.1378/chest.119.5.1322

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Volume 119, Issue 5, May 2001, Pages 1322-1328

https://doi.org/10.1378/chest.119.5.1322 Get rights and content

Study objectives:

The fractional concentration of exhaled nitric oxide (Feno) is a marker of asthmatic airway inflammation. We determined the dose response and the reproducibility of the Feno fall following inhaled beclomethasone dipropionate (iBDP) therapy in nonsteroid-treated asthmatic patients.

Study design:

Study A: For four 1-week periods (period 1 to period 4), the following regimens were administered in sequential order to 15 nonsteroid-treated asthmatic patients: period 1, placebo; period 2, 100 μg/d of iBDP; period 3, 400 μg/D of iBDP; and period 4, 800 μg/d of iBDP. Spirometry, Feno, and provocative concentration of methacholine resulting in a 20% fall in FEV₁ (PC₂₀) were measured at each of five visits (visit 1 to visit 5). Study B: During four periods, 12 nonsteroid-treated asthmatic patients received placebo treatment for 7 days (period 1), 200 μg/d of iBDP for 14 days (period 2), washout on placebo treatment until the Feno was within 15% of baseline (period 3), and 200 μg/d of iBDP for 14 days (period 4).

Results:

Study A: Mean FEV₁ rose progressively from 3.10 L (visit 1) to 3.41 L (visit 5; p = 0.001). All iBDP doses caused a significant FEV₁ rise compared to placebo treatment, but with no significant separation of doses using FEV₁. Feno geometric mean (95% confidence limits) fell progressively from 103.5 parts per billion (ppb) (78.5 to 136.7) to 37.4 ppb (29.1 to 48.0) from visit 1 to visit 5 (p = 0.001). All doses of iBDP resulted in a significant change in Feno from placebo treatment, but with significant separation of only the 100-μg and 800-μg doses by Feno. Geometric mean (95% confidence limits) PC₂₀ rose progressively from 0.01 mg/mL (0.00 to 0.19) to 0.48 mg/mL (0.01 to 8.1) from visit 1 to visit 5 (p = 0.002). All doses of iBDP resulted in a significant change in PC₂₀ from baseline or placebo treatment, but with no significant separation of active iBDP doses using PC₂₀. Study B: Feno fell from 111.56 ppb (80.3 to 155.1) to 66.3 ppb (49.2 to 89.5; p < 0.001) from period 1 to period 2, and from 110.2 ppb (79.3 to 153.1) to 61.7 ppb (42.9 to 88.8; p < 0.001) from period 3 to period 4. There were no significant differences between Feno in period 1 and period 3 (p = 0.83) or between period 2 and period 4 (p = 0.220).

Conclusions:

Feno was superior to FEV₁ and PC₂₀ in separating doses of iBDP. The fall in Feno after two identical administrations of iBDP separated by placebo washout was highly reproducible.

Section snippets

Subjects:

We recruited 15 asthmatic patients (8 male patients; age range, 17 to 40 years) with baseline Feno> 60 parts per billion (ppb; a value > 2 SD above mean values for healthy control subjects in our laboratory), in order to select subjects with increased baseline Feno. Asthma was diagnosed according to American Thoracic Society recommendations (1986). Exclusion criteria included the use of oral or inhaled corticosteroids, other anti-inflammatory agents, of long-acting β₂agonists in the 4 weeks

Baseline Characteristics:

Fifteen subjects were recruited to the study. Geometric mean (95% confidence limit [CL]) baseline measurements were as follows: Feno, 103.5 ppb (78.5 to 136.7); PC₂₀, 0.01 mg/mL (0.00 to 0.19); mean ± SD FEV₁ and FVC at baseline were 3.01 ± 0.73 L (83.5 ± 16.6% predicted) and 4.49 ± 0.97 L (103.4 ± 12.2% predicted), respectively.

The Dose Response of the Fall in Feno:

The general model showed that the test for treatment differences in Feno was highly significant, indicating that at least two of the treatment means differed (p <

Discussion

Exhaled 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-μg dose from the 800-μg/d dose of iBDP. The effect of repeated administration of 200 μg/d of iBDP on both Fenoand

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Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations.
To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation.
This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18–65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV₁)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed.
Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41–222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: −6 (−43, 32) at 10 mg QD, −26 (−53, 2) at 30 mg QD, −55 (−78, −32) at 40 mg BID and −52 (−72, −32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful.
In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns.
Australian New Zealand Clinical Trials Registry: ACTRN12619000227190.
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The Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma.
We sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (Feno), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma.
We conducted a double-blind, randomized, placebo-controlled, phase 1 proof-of-activity study in adults with mild asthma and Feno higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in Feno from baseline to day 14. Baseline was defined as the average Feno during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed.
Thirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean Feno at baseline across all subjects was 93 ± 43 ppb. At day 14, placebo-corrected difference in Feno was −23% (95% CI, −37.3 to −9) for 15 mg QD and −42% (95% CI, −57 to −27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater Feno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition.
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Evidence regarding the role of non-invasive marker of airway inflammation, fractional exhaled nitric oxide (FeNO) to guide asthma treatment is equivocal. We aimed to evaluate if the use of FeNO to adjust inhaled corticosteroid treatment resulted in reduced daily corticosteroid use and lesser exacerbations.
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After the follow up period of 12 months, mean daily dose of ICS (SD) required in FeNO group was 267.5 μg (126.29), as opposed to control group in which mean daily dose of steroid was 320.00 μg (138.69). However this observed difference in steroid dose was statistically insignificant (p value = 0.061). The estimated mean (SD) rate of asthma exacerbation experienced in follow up period of 12 months in FeNO group was 0.3 episodes (0.54) per patient per year (95% confidence interval, 0.145–455) and 0.4 episodes (0.61) per patient per year in control group (95% confidence interval, 0.228–572). However this difference in rate of exacerbations between the two study groups was not statistically significant (p = 0.387).
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Citation Excerpt :
Higher FeNO and eCO levels have been observed in patients with lung diseases, especially asthma and COPD (Alving et al., 1993; Kharitonov et al., 1994; Malerba et al., 2014). Meanwhile, some studies reported the levels of FeNO and eCO decreased after anti-inflammatory therapy in asthmatic patients (Zayasu et al., 1997; Silkoff et al., 2001). The American Thoracic Society recommended to apply FeNO measurements for monitoring and detection of chronic inflammatory airway disease including asthma (Dweik et al., 2011).
Exposure to Polycyclic aromatic hydrocarbons (PAHs) has been associated with inflammatory responses. Fractional exhaled nitric oxide (FeNO) and exhaled carbon monoxide (eCO) are both important inflammatory mediators especially in airways. However, few studies have investigated associations of PAH exposures with FeNO or eCO. Therefore, we aimed to quantify the associations of urinary PAH metabolites with FeNO and eCO levels, and investigate their potential effect modifiers by linear mixed models among 4133 participants from the Wuhan-Zhuhai cohort in China. We further performed stratified analyses to estimate effect modification. We found significant associations of increased urinary PAH metabolites with elevated eCO and FeNO. Among all participants, each 1% increase of 1-hydroxynaphthalene, 2-hydroxynaphthalene, 2-hydroxyfluorene, 4-hydroxyphenanthrene, 3-hydroxyphenanthrene, and total PAH metabolites was significantly associated with a 12.6% (95% confidence interval: 9.3%, 15.9%), 9.7% (6.5%, 12.9%), 7.5% (4.1%, 10.9%), 3.2% (0.2%, 6.2%), 2.7% (0.1%, 5.3%), and 6.5% (2.7%, 10.4%) increased eCO level, respectively; while each 1% increase of urinary 1-hydroxynaphthalene, 9-hydroxyphenanthrene, 3-hydroxyphenanthrene, and 2-hydroxyphenanthrene was associated with a − 3.0% (− 5.8%, − 0.2%), 2.9% (0.3%, 5.6%), 3.2% (1.0%, 5.4%), and 4.5% (2.2%, 6.9%) change of FeNO level, respectively. Positive associations between certain urinary PAH metabolites and eCO were observed among both ever-smokers and non-smokers, and the associations were stronger among ever-smokers than that among non-smokers. Increased urinary PAH metabolites were associated with decreased FeNO among ever-smokers and elevated FeNO levels among non-smokers. Our findings suggest that PAH exposures may impair airway through inducing inflammatory response, especially among ever-smokers.
Inhaled corticosteroid dose response in asthma: Should we measure inflammation?
2017, Annals of Allergy, Asthma and Immunology
Inhaled corticosteroid (ICS) titration in asthma is primarily based on symptoms and pulmonary function. ICSs may not be increased on this basis despite residual airway inflammation.
To compare the dose-response relationships of ICSs on measures of pulmonary function, symptoms, and inflammation in patients with persistent asthma.
We performed a pooled post hoc analysis of 121 patients with mild to moderate asthma from 4 randomized clinical trials that incorporated an ICS dose ramp. Dose ramps were 0 to 200, 0 to 800, and 200 to 800 μg/d (beclomethasone equivalents). Outcome measures included spirometry, fractional exhaled nitric oxide, airway hyperresponsiveness (AHR), symptoms, serum eosinophilic cationic protein, and blood eosinophils.
We found a plateau beyond a small improvement at 0 to 200 μg for forced expiratory volume in 1 second: 3.3% (95% confidence interval [CI], 2.0%–4.7%) at 0 to 200 μg vs 0.3% (95% CI, −0.8% to 1.4%) 200 to 800 μg (P = .001). A similar plateau was seen for symptom improvement beyond 0 to 200 μg. Inflammatory and AHR outcomes revealed further room for improvement beyond low-dose ICSs. There was dose-related suppression (P < .001) for fractional exhaled nitric oxide: 40.4 ppb (95% CI, 34.7–46.9 ppb) for ICS free, 26.8 ppb (95% CI, 23.4–30.2 ppb) for 200 μg, and 20.8 ppb (95% CI, 18.8–23.1 ppb) for 800 μg. Eosinophilic cationic protein concentration was significantly reduced with both higher dose ramps. Eosinophil counts also improved across all 3 dose ramps, with dose separation of 370/μL (95% CI, 280–450/μL) for ICS free vs 250/μL (95% CI, 200–300/μL) 800 μg (P = .03). AHR improved with all 3 dose ramps, with greater improvement at lower doses for indirect vs direct challenges.
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ClinicalTrials.gov Identifiers: NCT00667992, NCT00995657, NCT01216579, NCT01544634.

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: This study was sponsored by Novex Pharma Ltd, Richmond Hill, Ontario, Canada.

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Chest

Clinical InvestigationsASTHMADose-Response Relationship and Reproducibility of the Fall in Exhaled Nitric Oxide After Inhaled Beclomethasone Dipropionate Therapy in Asthma Patients

Study objectives:

Study design:

Results:

Conclusions:

Section snippets

Subjects:

Baseline Characteristics:

The Dose Response of the Fall in Feno:

Discussion

Lancet

J Allergy Clin Immunol

NIH conference: airway inflammation

Ann Intern Med

NHLBI Workshop summary: nitric oxide and the lung

Am J Respir Crit Care Med

Increased amount of nitric oxide in exhaled air of asthmatics

Eur Respir J

Inhaled glucocorticoids decrease nitric oxide in exhaled air of asthmatic patients

Am J Respir Crit Care Med

Exhaled nitric oxide and bronchial reactivity during and after inhaled beclomethasone in mild asthma

J Asthma

Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: effect of inhaled glucocorticoid

FASEB J

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