Daniel K.C. Lee

Long-Acting Bronchodilator or Leukotriene Modifier as Add-on Therapy to Inhaled Corticosteroids in Persistent Asthma?

Despite the widespread use of inhaled corticosteroids, many asthmatic patients experience persistent symptoms. In such individuals, the addition of a long-acting beta2-agonist (LABA) is frequently more effective than doubling the dose of inhaled corticosteroid. However, the role of additional therapy with a leukotriene receptor antagonist (LTRA) as an alternative to an LABA has been the focus of attention in recent studies. In order to determine the overall efficacy of the pharmacologic armamentarium used in asthma, it is imperative that a combination of end points, including lung function, airway hyperresponsiveness, effects on underlying inflammation, symptoms, and more long-term sequelae such as exacerbations, are assessed. This evidence-based systematic review outlines the pharmacologic properties of LABAs and LTRAs and the importance of evaluating end points in addition to lung function when assessing these drugs. We also highlight the results of all published studies that have performed direct comparisons of both LABAs and LTRAs as add-on therapy to inhaled corticosteroids.

Effects of butterbur treatment in intermittent allergic rhinitis: a placebo-controlled evaluation

BACKGROUND Butterbur (Petasites hybridus) contains the active ingredient petasin, which exhibits antileukotriene and antihistamine activity. Previous studies of intermittent allergic rhinitis (IAR) have demonstrated a comparable response to butterbur compared with a histamine H1-receptor antagonist on the 36-Item Short-Form Health Survey quality-of-life score. However, there has been no placebo-controlled study of the effects of butterbur use on objective and subjective outcomes in IAR. OBJECTIVE To evaluate the effects of treatment with butterbur vs placebo on objective and subjective outcomes in IAR. METHODS A double-blind, placebo-controlled, crossover study was carried out during the grass pollen season in Tayside, Scotland. Thirty-five patients (14 men and 21 women) with IAR received butterbur, 50 mg twice daily, or placebo for 2 weeks. Domiciliary measurements were taken in the morning and evening for peak nasal inspiratory flow (PNIF) (the primary outcome variable), nasal and eye symptoms, and rhinoconjunctivitis-specific quality-of-life score. RESULTS Butterbur treatment had no significant effect on PNIF, total nasal symptom score, eye symptom score, or quality of life compared with placebo use. Mean (SEM) morning and evening PNIF values were 107 (6) and 114 (6) L/min, respectively, for butterbur vs 105 (6) and 117 (6) L/min for placebo. Mean (SEM) morning and evening total nasal symptom scores (maximum total score, 12) were 3.4 (0.4) and 3.5 (0.4), respectively, for butterbur vs 3.7 (0.3) and 3.8 (0.4) for placebo. CONCLUSIONS There was no significant clinical efficacy of butterbur use vs placebo use on objective and subjective outcomes in IAR. Further studies are now indicated to investigate the use of butterbur in persistent allergic rhinitis.

Recent developments in asthma management

Asthma is a common chronic heterogeneous condition with several characteristic features (%fig 1). It can present in early childhood as well as in adulthood, and it varies markedly in severity, clinical course, subsequent disability, and response to treatment. In common with other atopic disorders such as allergic rhinitis, atopic dermatitis, and food allergy, the prevalence of asthma has risen over the past few decades in both developed and developing countries.1 The increasing burden of asthma in primary and secondary care has led to extensive research into its genetics, pathophysiology, and treatment. In this review, we highlight some of the recent developments in the clinical management of asthma and identify key areas in which further research is needed. Fig 1 The key components of asthma We did a comprehensive literature search using Medline, Clinical Evidence, the Cochrane Library, and Embase. We used the following keywords in the search: acute asthma, chronic asthma, leucotriene receptor antagonist, long acting β2 agonist, inhaled corticosteroid, action plans, allergen, diet, magnesium, vitamin, Buteyko, anti-immunoglobulin E, and interleukin. We selected and extracted recent articles from 2000 onwards that we felt to be of relevance or interest to practising clinicians, as well as choosing topics that we were aware of being potentially important. All the authors are respiratory physicians with an interest in airways disease. ### Non-pharmacological management #### Allergen avoidance Atopy and asthma are separate conditions with differing genetic and epidemiological associations. Although atopic sensitisation increases the likelihood of asthma, this is not an absolute association. Allergen avoidance is commonly recommended in patients with asthma, especially those who show type 1 hypersensitivity to common aeroallergens.1 2 However, a surprising lack of evidence based data exists to substantiate the effectiveness of this approach. Several major studies have specifically evaluated allergen avoidance and its impact on asthma control. In a double blind randomised placebo …

Effects of high-dose inhaled fluticasone propionate on the hypothalamic-pituitary- adrenal axis in asthmatic patients with severely impaired lung function

BACKGROUND The effects of high-dose fluticasone propionate therapy on dynamic cortisol stimulation in severe asthma are unknown. OBJECTIVE To evaluate the human corticotropin-releasing factor (hCRF)-stimulated plasma cortisol response to fluticasone propionate therapy in severe asthmatic patients with impaired airway caliber (forced expiratory volume in 1 second [FEV1] < 60% of predicted) and in control subjects. METHODS Ten severe asthmatic patients (mean FEV1, 47% of predicted) and 10 controls (mean FEV1, 104% of predicted) received fluticasone propionate, 2,000 microg/d, via a 750-mL primed spacer for 2 weeks. Plasma cortisol levels before and after hCRF stimulation and overnight 10-hour urinary cortisol excretion corrected for creatinine concentration (OUCC) were measured at baseline after washout and 12 hours after the last dose of fluticasone propionate. RESULTS Baseline values before fluticasone propionate use were not significantly different in asthmatic patients vs controls for plasma cortisol before and after hCRF stimulation and OUCC. Comparing values at baseline vs after fluticasone propionate use, there was no significant suppression of plasma cortisol levels before (378.2 vs 357.4 nmol/L) or after (510.5 vs 507.9 nmol/L) hCRF stimulation or OUCC (8.2 vs 7.5 nmoL/mmoL) in asthmatic patients. In controls, all outcomes were significantly suppressed comparing values before vs after fluticasone propionate therapy: plasma cortisol levels before (423.5 vs 200.2 nmol/L; P = .002) and after (503.5 vs 291.1 nmol/L; P = .001) hCRF stimulation and OUCC (6.5 vs 2.4 nmol/mmol; P = .002). CONCLUSION Patients with severe persistent asthma and impaired airway caliber seem to be protected from developing systemic adverse effects with high-dose fluticasone propionate therapy, as evaluated by basal and dynamic measures of hypothalamic-pituitary-adrenal axis activity.

Determinants of airway hyperresponsiveness in mild asthma

Background Patients with mild asthma may have coexisting severe airway hyperresponsiveness (AHR), although the reasons for this are uncertain. Objective To evaluate the factors that determine AHR in mild asthma. Methods We performed a retrospective database evaluation of two groups of patients with mild asthma with forced expiratory volume in 1 second (FEV 1 ) of 80% or more than predicted. Group A (n = 92; mean inhaled corticosteroid dose, 491 μg) had moderate-to-severe AHR to methacholine (provocative dose causing a 20% decrease in FEV 1 [methacholine PD 20 ], ≤100 μg), whereas group B (n = 92; mean inhaled corticosteroid dose, 509 μg) had borderline AHR (methacholine PD 20 , ≥800 μg). Both groups were matched for age, sex, inhaled corticosteroid use, and FEV 1 . Results From our database, we found 361 patients with an FEV 1 of 80% or more than predicted of whom 123 (34%) had a methacholine PD 20 of 100 μg or less and 138 (38%) had a methacholine PD 20 of 800 μg or more. The methacholine PD 20 geometric means (geometric SE) of groups A and B were 25 μg (3 μg) and 5,392 μg (295 μg), respectively. Despite matched mean values for FEV 1 , compared with group B, group A had a lower predicted forced expiratory flow between 25% and 75% (71% vs 81%, P = 0.007). A greater proportion of group A compared with group B patients were sensitized to house-dust mite (76% vs 54%, P = 0.002). No significant differences were found between groups in terms of presence of rhinitis and sensitization to other individual aeroallergens. Conclusions Increased sensitization to house-dust mite and reduced small airway caliber were associated with moderate-to-severe AHR in mild asthma. Skin prick testing to common aeroallergens, especially house-dust mite, should be a routine part in the evaluation of asthmatic patients, including those patients with mild disease.

The effects of butterbur on the histamine and allergen cutaneous response.

BACKGROUND Butterbur or Petasites hybridus is an herbal remedy that exhibits antihistamine and antileukotriene activity and has been shown to attenuate the response to adenosine monophosphate challenge in patients with allergic rhinitis and asthma. However, no data are available regarding its effects on the histamine and allergen cutaneous response. OBJECTIVE To evaluate the effects of butterbur compared with fexofenadine and montelukast on the histamine and allergen wheal and flare cutaneous responses. METHODS Atopic patients were randomized into a double-blind, double-dummy, crossover study to receive for 1 week butterbur, 50 mg twice daily (8 AM and 10 PM); fexofenadine, 180 mg once daily (10 PM), and placebo once daily (8 AM); montelukast, 10 mg once daily (10 PM), and placebo once daily (8 AM); or placebo twice daily (8 AM and 10 PM). Patients attended the department at 10 AM and had measurements of the cutaneous wheal and flare responses to histamine, allergen, and saline control at 10-minute intervals for 60 minutes. RESULTS Twenty patients completed the study. The mean +/- SE histamine wheal and flare responses, respectively, were significantly attenuated (P < .05) by fexofenadine (9.4 +/- 1.8 mm2 and 13.5 +/- 3.2 mm2) compared with placebo (15.5 +/- 3.3 mm2 and 179.8 +/- 74.3 mm2) but not by butterbur (16.4 +/- 2.1 mm2 and 297.7 +/- 121.2 mm2) or montelukast (19 +/- 1.9 mm2 and 240.2 +/- 66.6 mm2). The allergen wheal and flare responses, respectively, were also significantly attenuated (P < .05) by fexofenadine (31.1 +/- 6.3 mm2 and 256.9 +/- 86.5 mm2) compared with placebo (65.4 +/- 15.2 mm2 and 1,014.5 +/- 250.0 mm2) but not by butterbur (50.4 +/- 9.2 mm2 and 1,110.3 +/- 256.1 mm2) or montelukast (58.8 +/- 9.1 mm2 and 1,463.6 +/- 295.6 mm2). CONCLUSIONS Butterbur did not produce any significant effects on the histamine and allergen cutaneous response compared with placebo, whereas mediator antagonism with fexofenadine but not montelukast produced significant attenuation. This finding would suggest that butterbur may not be effective in allergic skin disease.

Reproducibility of response to nasal lysine-aspirin challenge in patients with aspirin-induced asthma

BACKGROUND Peak nasal inspiratory flow (PNIF) and acoustic rhinometry objectively measure the effects of nasal provocation testing. Although the latter is conventionally used in nasal lysine-aspirin challenge, use of the former in aspirin-induced asthma (AIA) has never been evaluated. OBJECTIVE To evaluate the reproducibility of PNIF and acoustic rhinometry following nasal lysine-aspirin challenge in AIA. METHODS Fourteen patients with a clear-cut history of AIA underwent nasal lysine-aspirin challenge at 2 separate visits 1 week apart. Both PNIF and minimum cross-sectional area (MCA) were measured using acoustic rhinometry for 120 minutes following standard nasal lysine-aspirin challenge (25 mg). RESULTS Prechallenge values were not significantly different at visit 1 vs visit 2 for mean [SEM] PNIF (128 [13] vs 127 [9] L/min) and MCA (6.89 [0.51] vs 6.94 [0.57] cm2). The mean (SEM) maximum percent PNIF change from baseline for visit 1 and visit 2 was -42 (5) and -42 (6), respectively, and the mean (SEM) average percent PNIF change from baseline was -25 (4) and -25 (6), respectively. The mean (SEM) maximum percent MCA change from baseline for visit 1 and visit 2 was -49 (4) and -48 (3), respectively, and the mean (SEM) average percent MCA change from baseline was -25 (8) and -24 (4), respectively. Coefficients of variation for maximum and average responses were 2.3% and 6.5%, respectively, for PNIF and 7.4% and 16.1% for MCA. CONCLUSIONS Measurement of PNIF following nasal lysine-aspirin challenge is a simple and reproducible alternative to acoustic rhinometry, with maximum response being a more reproducible outcome measure than average response.

Addition of fexofenadine to inhaled corticosteroid therapy to reduce inflammatory biomarkers in atopic asthma

BACKGROUND We previously showed that H1-antihistamines may shift the PC20 (provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20%) threshold to adenosine monophosphate (AMP) challenge but may paradoxically prolong recovery. OBJECTIVES To measure AMP recovery using a constant predetermined AMP PC20 and to evaluate whether fexofenadine use confers add-on effects to treatment with either fluticasone propionate alone or combined fluticasone propionate-salmeterol. METHODS Fourteen atopic patients with mild-to-moderate asthma (forced expiratory volume in 1 second of 76%) completed a double-blind, randomized, crossover study consisting of 3-week treatment blocks of either fluticasone propionate-salmeterol, 250 microg twice daily, or fluticasone propionate alone, 250 microg twice daily, in conjunction with either fexofenadine, 180 mg once daily, or matched placebo. Recovery after a predetermined AMP PC20 challenge was measured (primary outcome), along with exhaled nitric oxide levels, plasma eosinophil cationic protein levels, peripheral eosinophil counts, pulmonary function, diary card outcomes, and quality of life (all secondary outcomes). RESULTS There were no differences in any of the primary or secondary outcomes when fexofenadine was added to treatment with either fluticasone propionate-salmeterol or fluticasone propionate alone. The mean AMP recovery time was 25.0 vs 23.4 minutes for fexofenadine and placebo, respectively, as add-on to fluticasone-salmeterol and 22.5 vs 23.9 minutes, respectively, as add-on to fluticasone alone. CONCLUSION Fexofenadine did not affect recovery to a fixed dose of AMP challenge or any other surrogate inflammatory markers when given as add-on therapy to corticosteroid-treatedatopic asthmatic patients.

Beneficial Antiinflammatory Effects of Leukotriene Receptor Antagonists in Asthma

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