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Notes: The inflammatory response of airway mucosa to allergen exposure is a complex phenomenon featuring symptoms, the influx of inflammatory cells, the release of mediators, and changes in local reactivity. These features and their pharmacological modifications can be successfully studied in nasal challenge models. We performed a nasal allergen challenge followed by a rechallenge with allergen 24 h later in order to monitor changes in specific reactivity due to the initial allergen challenge. Symptoms were monitored, as was the generation of TAME-esterase activity in nasal lavage fluids. Prior to each challenge a nasal brush specimen was taken. In a double blind, cross-over, double-dummy manner the patients were pretreated with placebo, a single dose of 200 μg of budesonide (topical corticosteroid) given 2 h prior to rechallenge with allergen or 600 mg ibuprofen (cyclooxygenase inhibitor) given per os t.i.d. to steady state starting 24 h prior to the initial allergen challenge. Treatment with ibuprofen induced a slightly lower composite symptom score (P 〈 0.05) at the initial allergen challenge when compared with placebo. No differences were noted in the relevant TAMF-esterase activities. The allergen challenge resulted in significantly increased proportions of eosinophils in the brush specimens 24 h after the initial allergen challenge (P 〈 0.001) with no differences between the different treatment alternatives. At rechallenge there was a reduction in the symptoms of secretion and nasal blockage in both groups receiving active treatment compared with placebo (P 〈 0.05), whereas the number of sneezes was not affected and no differences were noted m TAME-esterase activity. We conclude that allergen-induced changes in reactivity appear to involve cyclooxygenase metabolites to some extent and that a reduction in eosinophil numbers is not a prerequisite when it comes to demonstrating an inhibition of the change in reactivity.

Notes: The present study evaluates the possibility of allergen-induced unspecific and specific dermal hyperreactivity with special reference to the presence of late cutaneous reactions and allergen-induced nasal hyperreactivity. Twenty-six patients with strictly seasonal allergic rhinitis participated. All had a positive skin prick test for birch (Betula verrucosa) and/or timothy (Phleum pretense). Ten patients had previously displayed an allergen-induced nasal hyperreactivity and six patients a late cutaneous reaction. An initial skin prick test with a relevant pollen allergen was done in triplicate. The immediate skin reactions were recorded after 15 min and any late-phase reaction after 6 h. Twenty-four hours later the patients were retested. The same pollen allergen was sited in the first flare reaction from the previous day. A histamine prick test was sited in the weal as well as in the third reaction from day 1. A histamine control was also performed in a previously unaffected area. The allergen-induced weal reactions decreased significantly at re-challenge compared with the results from the previous day (P 〈 0.05). The histamine tests resulted in similar skin reactions regardless of whether or not they were done on a previous allergen test site. This was true for both specific and unspecific reactions when the subgroups of patients with previously demonstrated allergen-induced nasal hyperreactivity or late-phase skin reactions were evaluated separately. These results indicate that allergen-induced hyperreactivity is not a general feature of allergic inflammation but is a phenomenon restricted to specific sites, such as the airway mucosa.

Notes: A long-term safety study of intranasally administered budesonide, a topical glucocorticoid, has been performed. 104 patients with perennial rhinitis, allergic or non-allergic, participated in a multicentre study in seven ENT-clinics utilising an identical protocol. A budesonide dosage of 400 μg/day was used as starting dose, but the patients were at liberty to reduce the daily dose to 200 μg. The patients were observed at intervals up to 12 months. At the entry and follow-up visits the following parameters were recorded: rhinoscopic findings, nasal symptom scores, blood chemistry, hematology, urinalysis and determination of plasma cortisol levels before and after stimulation with ACTH (Synacthen®). Nasal biopsies taken from 50 of the patients at the beginning and completion of the study were examined in a blinded way by an indepndent pathologist. The analysis revealed no histopathological changes of the nasal mucosa. At rhinoscopy no signs of atrophy or Candida were reported. Lividity of the nasal mucosa was significantly reduced during the trial, which was also the case for nasal congestion and secretion. All nasal symptom parameters assessed by the patients were significantly reduced from baseline during the follow-up period. No clinically significant changes in the hematological and blood chemistry parameters were observed. Plasma cortisol analysis before and after challenge with ACTH revealed no influence on the hypothalamic pituitary adrenal axis. No tachyphylaxis was observed; on the contrary, there was a clear tendency for reduction of the daily dose of budesonide necessary to keep the patients symptom-free. The present study suggests that intransal budesonide in the dose of 400 μg/day is a safe and valuable addition to our therapeutic armory for perennial rhinitis.

Notes: Forty patients suffering from allergic conjunctivitis, due to birch pollen, participated in a double-blind parallel group comparison between levocabastine (a potent new specific histamine (H1) antagonist) and placebo, both given as eye drops. Symptom scores were recorded during a 4-week period. A 1-week run-in period was followed by a 3-week treatment period. To enable a fair evaluation of the treatment effect on the ocular symptoms only, all patients were treated with topical nasal glucocorticoids for possible rhinitis symptoms during the whole study period. Plasma levels of levocabastine were determined in all subjects at the end of the 3 weeks' treatment period. Pollen counts for birch pollen were followed simultaneously. The evaluation of the symptom score cards revealed a significant reduction of ocular symptoms following use of the active compound. The resorption of the active substance through the conjunctiva was low. In accordance with the present trend of more topical treatment for allergic rhinitis, levocabastine may constitute a valuable compound for the topical treatment of allergic conjunctivitis.

Notes: Various mediator systems have been stressed as important in the generation of the signs and symptoms of allergic disease such as hay fever. Nevertheless, in the upper airways, histamine is still the only mediator which behaves consistently in terms of release at appropriate challenge, produces all the major symptoms of rhinitis at a local challenge, and the specific antagonist influences the signs and symptoms of rhinitis in the challenge situation as well as during natural allergen exposure. Although the majority of hay fever symptoms are influenced by H1-receptors, there are exceptions. An important one is the symptom of nasal blockage, which is due to tissue oedema and a decrease in the tone of the capacitance vessels. Another point to be stressed is that histamine alone does not induce any protracted mucosal inflammatory response with associated symptoms, influx of eosinophils and increase in responsiveness that is associated with the exposure to allergen. Nevertheless, from a clinical point of view, antihistamines are still valuable pharmacological agents for the clinical management of hay fever symptoms.

Notes: A‘nasal pool’(NP) device, a compressible plastic container with an adapted nozzle, was used to perform a continuous 10-min nasal provocation and lavage. This novel technique brings known concentrations of agents into contact with a large and defined area of the nasal mucosal surface for extended periods of time. Simultaneously, the surface exudations/secretions of the same nasal mucosa are effectively sampled by the NP fluid. A concentration-response study of histamine (80, 400 and 2000 μg/ml) was performed in 12 normal subjects on three different occasions. Exudation of plasma albumin into the lavage fluid was measured to quantitate the histamine-induced airway inflammation. The effect of the dwell time on exudation was examined using histamine (400 μg/ml) instilled in the nasal cavity for time periods from 10 sec to 10 min. The time course of histamine-induced plasma exudation response was studied by exposing the mucosa to histamine (400 μg/ml) for 12 min, with the NP renewed every minute. Allergen-provocations were performed in subjects with hay fever and TAME-esterase activity in the returned lavage fluid was determined to indicate the degree of response. Histamine produced a concentration-dependent increase in albumin levels in the NP fluid; 123·3 ± 25·6, 213·8 ± 19·7 and 430·2 ± 32·0 μg/ml (mean ± s.e.m.), respectively. The time-course study demonstrated that plasma exudation into the lumen occurred promptly and that the exudation response reached a maximum after exposure to histamine for 6–10 min. The dwell-time experiments supported this finding. After 10 min the exudation appeared to decline despite the continued presence of histamine. Allergen provocation resulted in a concentration-dependent increase in TAME-esterase activity of the NP-fluids. It is concluded that the NP technique provides new possibilities in studies of pathophysiology and pharmacology of human airway mucosa. With the NP technique controlled concentrations of mediators, drugs, tracers, etc. can be applied for desirable lengths of time on a well-defined mucosal surface area. This particular area is gently and effectively lavaged during the presence of the NP fluid and when the fluid is recovered by decompressing the NP device.

Notes: Changes in local skin blood flow after prick-tests with histamine and allergen challenge were evaluated using laser doppler flowmetry. Two series of measurements were performed; each included 11 subjects with seasonal allergic rhinitis. In the first series vascular reactions were registered intermittently for a period of 6 hr. This was then repeated with additional registrations after 14 and 24 hr. Registrations were made in the skin close to where the test substances were applied which was in the area of the initial weal reaction. Pre-loaded skin-prick test needles were used for the histamine and allergen tests. Controls using ‘blank’ needles were also set on the same occasion. The control induced a transient increase in blood flow which had disappeared after 1 hr. After histamine challenge, the initial rapid increase in blood flow was followed by a slow return to baseline within 1 hr, and no further changes were noticed during the registration period. A different blood flow response was seen after the application of allergen. After an initial increase, the blood flow remained at this higher level for more than 6 hr. Thereafter a slow decrease towards baseline was seen within 24 hr. The pronounced difference between the histamine- and allergen-induced responses in the later part of the registrations after similar initial peak responses indicates that actions other than an initial burst of released histamine are responsible for the changes in dermal blood flow observed after allergen. Furthermore, our results suggest that an allergen challenge induces a continuous change in blood flow for up to 24 hr, rather than a biphasic response, in only some subjects which might be suspected from the visual reappearance of redness and induration of the skin which characterizes a dermal late-phase reaction.

Notes: The effect of topical anaesthesia on the nasal mucosa before and after allergen challenge was evaluated in 12 subjects with strictly seasonal allergic rhinitis. A single-blind randomized placebo-controlled design was used. The nasal challenge was carried out after pre-treatment of the nasal cavity with 52 mg of lidocaine/nasal cavity, or placebo applied topically in spray form. The number of sneezes was counted. The amount of nasal secretion was estimated by weighing used paper handkerchiefs. The capacitance and resistance vessel reactions were monitored by determining nasal peak flow and 133Xe wash-out respectively. After placebo pre-treatment the two doses of allergen induced moderate symptoms and vascular changes. Pre-treatment with local anaesthesia did not affect any of the symptoms nor did it affect the decrease in the tone of the capacitance vessels. It was found that topically applied lidocaine per se did not have any effect on nasal mucosal blood flow as measured using the 133Xe wash-out technique. However, the local anaesthesia did block the allergen-induced increase in the tone of the resistance vessels. In conclusion, a redundancy of systems appears to be involved in nasal allergic reactions. Although a reflex-induced mechanism may well play a significant role in the induction of the signs and symptoms of nasal allergic reactions, the redundancy of systems involved may well override any reduction in one single system, as appears to be the case in the present study. Lidocaine peer se did not influence the nasal mucosal blood flow.

Notes: The study focuses on the relationship between the tissue density of mast cells, the tissue hislamine levels and the levels of markers of mast cell activation after an allergen challenge of the nasal mucosa of allergic patients. The effect of 4 weeks' treatment with a topical glucocorticoid, fluticasone propionate, was studied in a double-blind, placebo-controlled study of 25 hay fever patients. Nasal biopsies were obtained before and after the treatment period for the evaluation of mast cell density and tissue histamine levels. Nasal challenges were performed at 2-week intervals for 8 weeks using a standardized nasal lavage model. TAME-esterase was analysed in the returned lavage fluid from all the challenges (weeks 0–8), while the levels of histamine and tryptase were analysed in lavage fluids from challenges performed before and after the treatment period (weeks 0 and 4). The symptoms of nasal allergy were assessed after each challenge. Treatment with fluticasone proprionate did not influence mast cell density, the tissue histamine concentration, the lavage histamine levels or the TAME-esterase activity, while a reduction in nasal symptoms and tryptase in nasal lavagc fluid was revealed. Our present study again emphasizes the fact that the mast cell is an important trigger cell in the immediate nasal allergic response. The study also demonstrates the usefulness of the measurements of tryptase as an indicator of both mast cell activation and the efficacy of topical steroid treatment.