Intranasal and inhaled fluticasone propionate for pollen-induced rhinitis and asthma.

BACKGROUND: Studies suggest that nasal treatment might influence lower airway symptoms and function in patients with comorbid rhinitis and asthma. We investigated the effect of intranasal, inhaled corticosteroid or the combination of both in patients with both pollen-induced rhinitis and asthma. METHODS: A total of 262 patients were randomized to 6 weeks' treatment with intranasal fluticasone propionate (INFP) 200 microg o.d., inhaled fluticasone propionate (IHFP) 250 microg b.i.d., their combination, or intranasal or inhaled placebo, in a multicentre, double-blind, parallel-group study. Treatment was started 2 weeks prior to the pollen season and patients recorded their nasal and bronchial symptoms twice daily. Before and after 4 and 6 weeks' treatment, the patients were assessed for lung function, methacholine responsiveness, and induced sputum cell counts. RESULTS: Intranasal fluticasone propionate significantly increased the percentages of patients reporting no nasal blockage, sneezing, or rhinorrhoea during the pollen season, compared with IHFP or intranasal or inhaled placebo. In contrast, only IHFP significantly improved morning peak-flow, forced expiratory volume in 1 second (FEV1) and methacholine PD20, and the seasonal increase in the sputum eosinophils and methacholine responsiveness. CONCLUSIONS: In patients with pollen-induced rhinitis and asthma, the combination of intranasal and IHFP is needed to control the seasonal increase in nasal and asthmatic symptoms.

Evaluation of different inhaled combination therapies (EDICT): a randomised, double-blind comparison of Seretide (50/250 microg bd Diskus vs. formoterol (12 microg bd) and budesonide (800 microg bd) given concurrently (both via Turbuhaler) in patients with moderate-to-severe asthma.

The aim of this study was to compare the efficacy safety and cost of Seretide (salmeterol/fluticasone propionate (Salm/FP), 50/250 microg bd) via Diskus with formoterol (Form; 12 microg bd) and budesonide (Bud; 800 microg bd) given concurrently (Form+Bud) via Turbuhaler in patients with moderate-to-severe asthma who were uncontrolled on existing corticosteroid therapy. The study used a randomised, double-blind, double-dummy, parallel-group design, consisting of a 2-week run-in period on current corticosteroid therapy (1000-1600 microg/day of BDP or equivalent) and a 12-week treatment period. Symptomatic patients (n = 428) with FEV1 of 50-85% predicted and increased symptom scores or reliever use during run-in were randomly allocated to receive either Salm/FP (50/250 microg bd) via a single Diskus inhaleror Form+Bud (12+800 microg bd) via separate Turbuhalers. Clinic, diary card and asthma-related health-care resource utilisation data were collected. Improvement in mean morning peak expiratory flow (PEFam was similar in the Salm/FP and Form+Bud groups. Both PEFam and mean evening PEF (PEFpm) increased by a clinically significant amount (>20 L/min) from baseline in both treatment groups. The mean rate of exacerbations (mild, moderate or severe) was significantly lower in the Salm/FP group (0.472) compared with the Form+Bud group (0.735) (ratio = 0.64; P < 0.001), despite the three-fold lower microgram inhaled corticosteroid dose in the Salm/FP group. Patients in the Salm/FP group also experienced significantly fewer nocturnal symptoms, with a higher median percentage of symptom-free nights (P = 0.04), nights with a symptom score <2 (P = 0.03), and nights with no awakenings (P = 0.02). Total asthma-related health-care costs were significantly lower in the Salm/FP group than the Form+Bud group (P<0.05). Both treatments were well tolerated, with a similar low incidence of adverse events. This study showed that in symptomatic patients with moderate-to-severe asthma, Salm/FP (50/250 microg bd), administered in a single convenient device (Diskus), was at least as effective as an approximately three-fold higher microgram corticosteroid dose of Bud (800 microg bd) given concurrently with Form (12 microg bd) in terms of improvement in PEFam, and superior at reducing exacerbations and nights with symptoms or night-time awakenings. Salm/FP was also the less costly treatment due primarily to lower hospitalisation and drug costs.

Some etiologic factors of speech comprehension disturbances.

Disturbances of speech comprehension were analyzed in a prospective study of 97 children, aged from 23 to 77 months. Pregnancy, birth and early psychomotor development were normal for all the children and no focus of neurological deficit was found. A tonal audiometer did not detect any auditory disturbances, and psychological testing with non-verbal tests showed normal mental functioning for the age. In this group of selected subjects, family and personal case histories were taken. In addition, a detailed neurological physical examination, standard EEG and auditory evoked potentials, and a psychiatric examination were performed during several appointments. The results showed that disturbances in speech comprehension were more frequent in boys, and that in 13.4% of cases it was caused by pervasive developmental disturbances and in 41.24% of cases by external stimulating factors of speech development (pedagogy, social and emotional stimulation and growing up in a multilingual community). The study emphasizes the importance of non-verbal methods for the study of speech and the use of auditory evoked potentials.

Allergen inhalation challenge induces decrease of serum neutral endopeptidase (NEP) in asthmatics.

There is accumulating evidence that tachykinins are implicated in inflammation, including asthma. Therefore, we hypothesized that the neutral endopeptidase (NEP), under challenge conditions, could be affected. Serum from 21 asthmatics and six healthy volunteers was sampled before, 30, and 120 min after allergen challenge. NEP-IR was determined using an ELISA and was found in all subjects. Compared to prechallenge, no difference was seen between asthmatics and controls; however, under challenge conditions, NEP-IR in asthmatics was significantly lower (30 min, P = 0.058; 120 min, P = 0.0017, respectively). This finding supports indirectly the hypothesis that tachykinins are released during allergen exposure, and suggests a regulatory role of NEP.

Non-specific nasal and bronchial reactivity are not correlated in non-asthmatic subjects occupationally exposed to irritants and in healthy subjects.

BACKGROUND: Non-specific nasal and bronchial reactivity are frequently correlated in disease (rhinitis and asthma). It is not known whether such a correlation exists in subjects exposed to irritants and in healthy subjects. In order to test the hypothesis that a correlation between non-specific nasal and bronchial reactivity exists in non-asthmatic subjects, two groups of subjects were studied: 110 workers occupationally exposed to respiratory irritants, and 86 non-exposed healthy controls. METHODS: Allergy, non-specific nasal, and non-specific bronchial reactivity were tested, and smoking habits were categorized in each subject. RESULTS: Respiratory irritants cause a substantial increase in nasal and bronchial reactivity when compared with the group of healthy, non-exposed subjects (33.6% nasal hyperreactors and 20.0% bronchial hyperreactors vs. 4.7% nasal hyperreactors and 2.3% bronchial hyperreactors, respectively). But, occupational exposure to respiratory irritants does not induce a correlation between non-specific nasal and bronchial reactivity frequently found in asthmatic and rhinitic subjects. CONCLUSIONS: We found no correlation between non-specific nasal and bronchial reactivity either in subjects occupationally exposed to respiratory irritants or in the group of healthy subjects. This lack of correlation in both studied groups seems to be a feature of non-diseased airways. Smoking as an additional factor does not increase nasal and bronchial reactivity either in workers exposed to irritants or in healthy subjects. Smoking also does not strengthen the correlation between upper and lower airways' reactivity in both groups.

Decrease in CD23+ B lymphocytes and clinical outcome in asthmatic patients receiving specific rush immunotherapy.

Rush immunotherapy (RIT) has been documented as useful in the treatment of patients with allergic bronchial asthma. To investigate the mechanisms of its action, we studied changes in the serum levels of total IgE, allergen-specific IgE and IgG4, and expression of CD23 on peripheral blood B cells in patients receiving RIT. Twenty patients with perennial bronchial asthma were evaluated before the beginning of RIT, as well as 6 weeks and 6 months later. Compared to pretreatment values, the level of Der-p-specific IgG4 and IgE significantly increased after 6 weeks and 6 months of RIT, while the total serum IgE remained unchanged. Furthermore, after 6 months of RIT, the percentage of CD23+B cells and its CD23 receptor density significantly decreased. Since the symptom score improved and the need for medication decreased, we evaluated RIT as a useful procedure. After 6 months, 30% of patients did not have an asthma attack, with no medication in the last month, while 10% of them were asthma free for the last 3 months. No significant correlation between the clinical improvement, and in vitro changes was found. Furthermore, the observed in vitro changes were not significantly different in patients who responded with clinical improvement, compared to those with unchanged intensity of asthma. In conclusion, during specific RIT we found a significant increase in Der-p-specific IgE and IgG4 antibodies, as well as a moderate decrease in CD23+ B cells and its CD23 receptor density. These findings suggest a change in the lymphokine profile of patients receiving specific immunotherapy, and that the inhibition of IL-4-induced B cell stimulation may be hypothesized as the most important mechanism.

Effects of halothane and isoflurane on antigen- and leukotriene-D4-induced constriction of guinea pig trachea.

We investigated the mechanism of the action of volatile anesthetics on the airway smooth muscle constricted by an antigen and leukotriene-D4 (LTD4). Excised tracheal rings from ovalbumin-sensitized guinea pigs were suspended in eight tissue baths. Halothane or isoflurane was aerated into four tissue baths, while the remaining four served as time controls. To assess the antispasmogenic activity of halothane and isoflurane, concentration-response curves for antigen and LTD, were constructed exposed to anesthetics and compared to controls. The spasmolytic activity of halothane and isoflurane was measured in the tracheal rings constricted by a single antigen challenge or by EC50 of LTD. Both halothane and isoflurane produced significant rightward shifts of ovalbumin and LTD, concentration-response curve with corresponding increases in the EC50 values. Halothane increased the EC50 value for LTD, from 5.38 +/- 0.43 x 10-9 M to 1.2 +/- 0.18 x 10-8 M, and for ovalbumin from 1.2 +/- 0.06 x 10-4 mg/ml to 3.03 +/- 0.28 x 10-4 mg/ml. Isoflurane increased the EC50 value for LTD, from 5.17 +/- 0.64 x 10-9 M to 8.98 +/- 1.01 x 10-9 M, and for ovalbumin from 1.21 +/- 0.09 x 10-4 mg/ml to 2.61 +/- 0.19 x 10-4 mg/ml. Furthermore, halothane and isoflurane significantly reduced the magnitude of the antigen-and LTD4-induced constriction. In 30 min intervals, 1% and 2% halothane reduced the magnitude of the ovalbumin-induced constriction by 32% and 50%, respectively, while isoflurane (2% and 4%) caused relaxation of 16% and 35%, respectively. The magnitude of LTD4-induced constriction was reduced by 17% and 24%, with 1% and 2% halothane, respectively. Isoflurane (2% and 4%) reduced this constriction by 25% and 25% respectively. In conclusion, halothane and isoflurane attenuate and prevent the constrictive response of airway smooth muscle to allergen and LTD. A direct, nonspecific dilating effect is suggested as the mechanism responsible for the observed effects.

Inhibition of neutral endopeptidase potentiates compound 48/80-induced constriction of guinea-pig tracheal smooth muscle.

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic construction of guinea-pig tracheal smooth muscle. To investigate this observation further, we examined the effects of phosphoramidon, an inhibitor of a neutral endopeptidase, on constriction induced by the non-immunological mast cell degranulator-compound 48/80. Phosphoramidon produced significant leftward shift of the compound 48/80 concentration-response curve with corresponding decrease in the EC50 value from 51 (28-80) micrograms/ml to 42 (20-72) micrograms/ml. When added during the compound 48/80-induced constriction, phosphoramidon significantly increased the magnitude of this constriction by 69.7% after 30 min, and 78.9% after 45 min. Phosphoramidon was ineffective in tracheal rings from tachykinin-depleted guinea pigs. The incubation of tracheal rings with H1-histamine receptor antagonist (diphenhydramine HCl, 10 microM) and leukotriene receptor antagonist (ICI 198.615, 5 microM) significantly diminished the contractile response to compound 48/80 and prevented a phosphoramidon-dependent increase of this constriction. These results suggest that compound 48/80 induces the release of tachykinins by the stimulatory activity of histamine and leukotrienes. Anaphylactic release of tachykinins would therefore not depend directly on the antigen-antibody reaction.

Phosphoramidon augments contraction of guinea pig tracheal smooth muscle induced by histamine and leukotriene-D4.

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic contraction of guinea pig tracheal smooth muscle. Anaphylactic release of tachykinin-like substances was indicated. To investigate this observation further, we examined the effects of phosphoramidon, an inhibitor of a neutral endopeptidase, on contraction induced by mediators of anaphylaxis. Phosphoramidon significantly increased histamine- and leukotriene D4-induced contractions of tracheal rings from unsensitized animals (by 14 and 48%, respectively), but failed to alter the contractile responses to prostaglandins D2 and F2 alpha. In tracheal rings preincubated with tachykinin antagonist-[D-Pro4, D-Trp7,9]-substance P(4-11), or in capsaicin-desensitized tracheal rings, phosphoramidon did not change histamine- and leukotriene D4-induced contractions. In the second part of the study, performed on tracheal rings obtained from ovalbumin-sensitized guinea pigs, we examined the effects of phosphoramidon on contractile responses to histamine and leukotrienes which are released after antigen challenge. The incubation of tracheal rings with H1-histamine receptor antagonist (diphenhydramine HCl) or leukotriene receptor antagonist (ICI 198.615) prevented a phosphoramidon-dependent increase of antigen-induced contraction. These results indicate that histamine and leukotrienes may be involved in the anaphylactic release of tachykinin-like substances or other neutral endopeptidase substratum.

Phosphoramidon modulates effects of the 5-lipoxygenase inhibition on anaphylactic contraction of the guinea pig trachea.

Our previous studies have shown that the inhibition of neutral endopeptidase, an enzyme which degrades tachykinins, increases anaphylactic contraction of guinea pig tracheal smooth muscle. It was suggested that anaphylactic release of tachykinin-like substances is likely to be responsible for the observed increases in tracheal contractions. To obtain additional information on the mechanisms responsible for anaphylactic release of tachykinins in guinea pig trachea, we examined the effects of phosphoramidon, an inhibitor of neutral endopeptidase, on contractile response to antigen after preincubation with the selective 5-lipoxygenase inhibitor AA-861. AA-861 (5 microM) significantly reduced ovalbumin-induced contraction, although the effect was not constant. A marked spontaneous increase in contraction was observed. Phosphoramidon (10 microM) produced significant increase of this contraction (27% after 30 min, and 33% after 45 min). The addition of H1-histamine receptor antagonist (diphenhydramine HCl, 10 microM) produced additional inhibition of the initial phase of antigen-induced contraction, while its later phase, apart from a spontaneous increment in magnitude, remained similar. Phosphoramidon (10 microM) increased the contraction by 26% after 30 min, and by 34% after 45 min. Since the effects of histamine and 5-lipoxygenase pathway products were prevented, we hypothesize that cyclooxygenase pathway products are responsible for the phosphoramidon-dependent increase in antigen-induced contraction. In accordance with previously reported ineffectiveness of contractile prostaglandins, we suggest that the relaxant prostaglandins are most important in mediating the release of tachykinins during the immediate hypersensitivity reaction in guinea pig trachea.

Inhibition of neutral endopeptidase augments anaphylactic constriction of guinea pig tracheal smooth muscle.

To determine whether tachykinins participate in antigen-induced constriction of tracheal smooth muscle, we examined the effects of a neutral endopeptidase inhibitor, phosphoramidon, the tachykinin antagonist (D-Pro4, D-Trp7,9,10)-substance P(4-11), and capsaicin-induced tachykinin depletion on the responses to antigen in tracheal rings from ovalbumin-sensitized guinea pigs. In these preparations, the antigen (ovalbumin, 0.1 microgram/ml) produced reproducible and durable constriction of tracheal smooth muscle. Incubation with phosphoramidon (10 min, 10 microM) prior to antigen challenge significantly augmented the magnitude of ovalbumin-induced constriction by 22% after 30 min and by 31% after 45 min. The addition of phosphoramidon at the plateau level of antigen-induced constriction produced a similar, significant increase in the magnitude of the constriction. Following incubation with tachykinin antagonist (D-Pro4,D-Trp7,9,10)-substance P(4-11) (5 microM), the contractile response of the tracheal rings to the antigen was not altered. Furthermore, the addition of phosphoramidon (10 microM) did not significantly affect this contraction. Similarly, neither tachykinin antagonist nor phosphoramidon altered the ovalbumin-induced constriction of the tracheal rings from capsaicin-treated guinea pigs. Based on these findings, we hypothesize that tachykinins or similar broncho-constricting neutral endopeptidase substrates were released from tachykinin-containing nerve endings during immediate hypersensitivity reaction in airways, manifesting a modest and delayed constrictive effect. Following alteration of endopeptidase activity, these substances could modulate the anaphylactic constriction of the airway smooth muscle.