The effects of histamine and leukotriene receptor antagonism on nasal mannitol challenge in allergic rhinitis

Authors

  • Daniel K. C. Lee,

    1. Asthma & Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK and
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  • Kay Haggart,

    1. Asthma & Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK and
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  • Graeme P. Currie,

    1. Asthma & Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK and
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  • Sandra D. Anderson,

    1. Department of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
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  • Brian J. Lipworth

    Corresponding author
    1. Asthma & Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK and
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  • Note: An erratum for this article is available here.

Dr Brian J Lipworth, Professor of Allergy & Pulmonology, Asthma & Allergy Research Group, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital & Medical School, University of Dundee, Dundee DD1 9SY, UK. Tel.: + 44 13 8263 2983 (direct), + 44 13 8263 2180 (secretary); Fax: + 44 13 8264 4972; E-mail: b.j.lipworth@dundee.ac.uk

Abstract

Aims  It is unclear as to which mediators are involved in mediating the response to nasal mannitol challenge, a novel osmotic stimulus.

Methods  A double-blind, randomized, placebo-controlled, crossover design was employed. Nine patients with allergic rhinitis were randomized to receive a single-dose of desloratadine 5 mg, montelukast 10 mg or placebo, and underwent nasal mannitol challenges with nasal peak inspiratory flow recordings over 60 min. The change in peak nasal inspiratory flow was calculated as percentage change from baseline as the peak response and area under the time–response curve (AUC).

Results  Desloratadine and montelukast conferred a significant degree of protection compared to placebo for peak and AUC response, but there were no significant differences between the two drugs. For the peak response as percentage fall, the mean difference (95% CI) vs placebo was 27.7 (8.0, 47.4)% for desloratadine and 17.6 (1.9, 33.3)% for montelukast.

Conclusions  Our results suggest that histamine and cysteinyl-leukotrienes are involved in mediating the response to nasal mannitol in allergic rhinitis.

Introduction

Nasal hyper-reactivity is a hallmark of allergic rhinitis [1] in the same way that bronchial hyper-reactivity is a hallmark of asthma [2]. Conventional nasal provocation stimuli such as histamine are rather limited as they act through one mediator. Therefore, other stimuli have been investigated that act indirectly via inflammatory cell pathways, such as adenosine monophosphate or mannitol.

Inhaled dry powder mannitol for use as an indirect bronchial provocation is now well-described for asthma [3]. Nasal challenge using dry powder mannitol on the other hand has been less well-evaluated [4]. Mannitol acts as a hyperosmolar stimulus causing nasal hyper-reactivity as demonstrated by a reduction in nasal peak inspiratory flow. However it is unclear as to which inflammatory agents are involved in mediating this response to nasal mannitol challenge. Nasal provocation testing is widely used in allergic rhinitis research and provides useful information about the pathogenesis of airway diseases with a potential to develop into a diagnostic tool [5]. Nasal challenge with mannitol has the potential for clinical use in monitoring the state of allergic inflammation in the nose [4], so it is important to know if the commonly recognized mediators of mast cell activation, histamine and leukotrienes are involved in the response.

Desloratadine is a novel nonsedating histamine H1-receptor antagonist and represents the active metabolite of loratadine. In vitro studies have shown desloratadine to exhibit inhibition of the expression of cell adhesion molecules, along with suppression of the generation and  release of inflammatory mediators and cytokines, and attenuation of eosinophil chemotaxis, adhesion and superoxide generation [6]. The clinical pharmacological profile of desloratadine has been reviewed elsewhere [7, 8]. In patients with allergic rhinitis, desloratadine has been shown to exhibit clinical evidence of decongestant activity [9].

The role of histamine receptor antagonist in allergic rhinitis is well established, while the role of leukotriene receptor antagonist remains to be clearly defined. Clinical studies have shown leukotriene receptor antagonists to be effective in allergic rhinitis, although they seem to be less effective in the upper than the lower airway [10].

We therefore undertook a study to evaluate the relative effects of histamine and leukotriene antagonism on nasal mannitol challenge. Recommended doses of desloratadine (5 mg) and montelukast (10 mg) were used in order to reflect usual clinical practice.

Methods

Nine patients with an established diagnosis of allergic rhinitis were recruited in the study out of the local pollen season (Table 1). All patients had a positive skin-prick test to at least one common aeroallergen and had normal full blood count and biochemical profile.

Table 1.  Patient details.
SubjectAge (years)Skin-prick test positiveRegular therapy for allergic rhinitis
120House dust mite and catNone
240Grass and house dust miteNone
324Grass, house dust mite and catMometasone furoate 200 µg
420Grass, weed, house dust mite, dog and catNone
524Grass, house dust mite and dogNone
641Grass, tree, weed, aspergillus and catNone
757Grass and catNone
849House dust mite and catNone
936Grass, house dust mite and dogNone

Skin-prick testing was performed following a standard protocol (Bencard Testing Solutions, Welwyn Garden City, Herts, UK) using extracts including grass, tree, and weed pollen in addition to a negative control. Results were read after 15 min, a positive reaction being defined as a weal diameter of at least 2 mm greater than the negative control.

Nasal septal deviation of more than 50% and nasal polyposis were excluded by nasal endoscopy using a rigid 30°° Hopkins® Telescope (Karl Storz Endoscopy Ltd, Slough, UK). Patients who were on current therapy with intranasal corticosteroids (n = 1) had treatment discontinued during a  1-week washout period. None of the patients was on antihistamines, leukotriene receptor antagonists or any other treatment for their allergic rhinitis. All patients received appropriate instructions and were required to demonstrate good technique in recording their peak nasal inspiratory flow using the In-Check® domiciliary nasal peak inspiratory flow meter (Clement Clarke International Ltd, Harlow, Essex, UK). All patients gave informed consent, and approval for the study was obtained from the Tayside Medical Ethics Committee.

Study design

A double-blind, randomized, placebo-controlled, crossover design was used. Patients were randomized to receive a single-dose of desloratadine (Neoclarityn®, 5 mg; Schering-Plough Ltd, Welwyn Garden City, Herts, UK), montelukast (Singulair®, 10 mg; Merck Sharp & Dohme Ltd, Hoddesdon, Herts, UK) or placebo. Patients had a 1- week washout period if they were on allergic rhinitis therapy prior to the randomized treatment blocks. All tablets were encapsulated to blind the study. Patients took their study tablets between 07.00 h and 09.00 h on the day of their study visit and arrived in the department between 13.00 h and 15.00 h, allowing at least 6 h postmedication to coincide with peak plasma concentrations of each drug [11, 12], and underwent a nasal mannitol challenge with nasal peak inspiratory flow recordings.

Nasal mannitol challenge

Mannitol powder was provided by the Department of Respiratory Medicine, Royal Prince Alfred Hospital, Australia and was prepared in a manner as previously described [4]. The mannitol powder was weighed into gelatin capsules (50 ± 5 mg) and was delivered via Teijin nasal insufflators (Teijin Ltd, Tokyo, Japan). Patients were requested to initially clear their noses simply by blowing and had their head slightly tilted forwards. They then took a deep breath and while holding their breath, had the insufflator inserted into one nostril, forming a tight a seal as possible. The insufflator was actuated 30 times with both hands while the other nostril was pinched by the investigator. Each actuation was forceful with time being allowed for the insufflator to reinflate prior to the next actuation. This process was repeated for the other nostril with a separate insufflator. Mannitol capsules were weighed prior to and after each challenge. Peak nasal inspiratory flow was measured before and following the challenge at 2, 5, 10, 20, 40 and 60 min. Patients’ techniques were assessed and the correct method further re-emphasized at each study visit.

Expression of results and statistical analysis

The change in peak nasal inspiratory flow was calculated as percentage change from baseline on each challenge visit as the peak response and area under the time–response curve (AUC). Comparisons were made of the randomized treatments (desloratadine and montelukast) and placebo by an overall analysis of variance with subject, treatment and period, as factors. To obviate multiple pair-wise comparisons and assess significant differences between active treatments and placebo, multiple-range testing with Bonferroni's correction was applied, set with 95% confidence limits. In order not to confound the overall alpha error, differences from the Bonferroni multiple range testing are all given as significant (P < 0.05, two-tailed) or not.

Results

All patients of 35 ± 4 years (mean age ± SE) with allergic rhinitis completed the study (Table 1). The mean total amount of mannitol delivered to both nostrils was 84.8 ± 2.4 mg.

Both desloratadine and montelukast conferred a significant (P < 0.05) degree of protection against nasal mannitol challenge compared with placebo for peak and AUC responses, but there were no significant differences between the two drugs (Figure 1 and Table 2).

Figure 1.

Time–response profile over 60 min after nasal mannitol following pretreatment with single dose of desloratadine 5 mg, montelukast 10 mg or placebo. % AV, average peak nasal inspiratory flow over 60 min as percentage change with SE. *Denotes P < 0.05 for desloratadine or montelukast vs placebo. s, Desloratadine; ,, montelukast; u, placebo.

Table 2.  Peak fall and AUC response.
 PlaceboDesloratadineMontelukast
  • *

    Denotes P < 0.05 for desloratadine or montelukast vs placebo. Values for each randomized treatment are given as mean ± SE. Values in brackets are 95% CI for difference between desloratadine or montelukast vs placebo.

Peak fall (%)33.7 ± 3.66.0 ± 7.2*16.1 ± 5.3*
(8.0, 47.4)(1.9, 33.3)
AUC (% min)1306.8 ± 196.8213.6 ± 246.6*627.6 ± 177.6*
(321.1, 1865.7)(30.0, 1328.3)

The time profile of response for individual patients showed the peak response occurred between 20 and 40 min in most patients, in terms of the percentage of patients with a fall in peak nasal inspiratory flow of ≥ 15% (Figure 2). Dispersion of individual data (Figure 3) for AUC responses showed seven out of nine patients improved with desloratadine vs placebo, while five out of the seven desloratadine responders showed a lesser response with montelukast. Seven out of nine patients improved with montelukast vs placebo.

Figure 2.

Percentage of patients with peak nasal inspiratory flow ≥ 15% fall from baseline. bsl00023, Placebo; u, montelukast; j, desloratadine.

Figure 3.

Individual data for peak nasal inspiratory flow change as area under curve (% min).

Discussion

The present results showed significant attenuation of the response to nasal mannitol challenge by histamine and leukotriene receptor antagonists. This was the case for both the peak and AUC response compared with placebo. There was a numerical trend towards greater protection with histamine than leukotriene antagonism, although the study was probably not adequately powered to detect a 10% difference in peak response between desloratadine and montelukast. We used peak nasal inspiratory flow rate to measure mannitol response, which has been shown to be more sensitive than acoustic rhinometry or rhinomanometry in detecting nasal response to histamine challenge [13].

Our results with nasal mannitol challenge suggest that histamine and cysteinyl-leukotrienes play a part in the response to this novel osmotic stimulus. This is in keeping with a previous bronchial mannitol challenge study using a dose–response protocol showing involvement of the same two mediators [14]. It has also been previously shown that airway epithelial cells were involved in the response to airway hyperosmolar challenge in patients with allergic rhinitis with the release of 15-hydroxyeicosatetraenoic acid, an epithelial cell derived inflammatory mediator [4]. In this same study, tryptase, a specific marker of mast cell release, was only detected in five of the subjects with rhinitis and the authors could not clarify whether mannitol could induce mast cell release of mediators. In the present study the amount of mannitol delivered to the nose was higher being around 86 mg compared with 65 mg in the Koskela et al. study [4]. The possibility that mast cell release of histamine occurs more readily with a greater osmotic stimulus has been raised in respect to exercise induced asthma [15].

We acknowledge that the sample size was small in our study and further research will be required to assess the reproducibility of nasal mannitol challenge along with dose–response measurements to evaluate the PC20 threshold value [16]. However, one would usually consider the AUC to a given mannitol dose to be more sensitive in detecting response than measuring the shift of the PC20 threshold value. Nevertheless, we anticipate that the results of this preliminary study may be used as a guide to future trials involving this novel stimulus.

The application for the use of mannitol described in this paper is covered by US Patent 5817 028 and internationally by PCT AU95/00086 and is owned by the Central Sydney Area Health Service.

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