Biomedical subjects
N C Barnes
Publications and source records attributed to N C Barnes.
Sputum cysteinyl leukotrienes increase 24 hours after allergen inhalation in atopic asthmatics.
We have used the relatively noninvasive technique of induced sputum to measure allergen-induced changes in the concentration of eicosanoid mediators in bronchial secretions from atopic asthmatics. Sputum induction was performed before and 24 h after inhalational allergen challenge in 14 atopic asthmatics who developed a late asthmatic reaction (LAR). Differential cell counts were made on sputum cytospins and eicosanoid (cysteinyl leukotrienes [cys LTs], prostaglandin D(2) [PGD(2)], and PGE(2)) concentrations were measured in the sputum supernatants. The percentage of eosinophils at baseline correlated with the concentration of cys LTs (r = 0.84, p < 0.001) but not prostanoid mediators. Allergen challenge produced a significant increase in the concentration of sputum cys LTs from 3. 45 ng/ml sputum to 11.95 ng/ml (p = 0.002), which correlated with the increase in sputum eosinophils (r = 0.55, p < 0.05). There were no significant changes in PGD(2) or PGE(2) concentrations in sputum supernatants in response to challenge. Thus, the noninvasive technique of induced sputum has been used to demonstrate increased cys LTs, but not prostanoids associated with LAR after allergen challenge. The correlation between eosinophil numbers and cys LT concentrations at baseline values and 24 h after allergen challenge is consistent with these cells being a principal source of cys LTs within the airways at these time points.
Effects of antileukotrienes in the treatment of asthma.
Explore the source record for details and available documents.
Attenuation of the allergen-induced late asthmatic reaction by cyclosporin A is associated with inhibition of bronchial eosinophils, interleukin-5, granulocyte macrophage colony-stimulating factor, and eotaxin.
The allergen-induced late asthmatic reaction (LAR) is associated with increases in bronchial eosinophils and basophils as well as upregulation of several eosinophil active cytokines and C-C chemokines. Cyclosporin A (CsA) was previously shown to inhibit the LAR, but not the early asthmatic reaction (EAR), and this was associated with a decrease in blood eosinophils. For these reasons, we determined whether CsA inhibited the allergen-induced increases in bronchial eosinophils, basophils, eotaxin, interleukin-5 (IL-5), and granulocyte macrophage colony-stimulating factor (GM-CSF). Subjects with a demonstrable LAR underwent bronchoscopy with biopsy and bronchoalveolar lavage (BAL) at baseline and then were randomly allocated to receive either CsA (n = 13) or placebo (n = 11) before challenge. A second bronchoscopy was performed 24 h later. The LAR, but not the EAR, was significantly attenuated in the CsA group compared with placebo (p < 0.05). CsA significantly inhibited the allergen-induced increases in IL-5 (p = 0.02) and GM-CSF (p = 0. 0028) in mRNA+ cells in BAL, and in a mAB against human activated eosinophils (EG2+) (p = 0.0227). We conclude that inhibition of the LAR by CsA may be related to its inhibitory effects on eosinophil-associated cytokines and chemokines. The beneficial effect of CsA in asthma may also be the result of inhibition of eosinophil accumulation.
Efficacy and safety of a novel beclomethasone dipropionate dry powder inhaler (Clickhaler) for the treatment of adult asthma. Amsterdam Clinical Study Group.
A randomized, double-blind, double-dummy protocol was used to compare the safety and efficacy of beclomethasone dipropionate (BDP) delivered by a novel dry powder inhaler (DPI, Clickhaler) or by a pressurized metered-dose inhaler (MDI) plus spacer. There was a four-week run-in period, completed by 240 adult patients, who received BDP via an MDI. Patients with stable asthma were then randomized into a 12-week treatment period and received BDP (< or =2 mg/day via DPI or MDI). There were no significant differences in morning peak expiratory flow (PEF) (primary endpoint), evening PEF, overall daytime or nighttime symptom scores, or lung function parameters (forced expiratory volume in 1 sec, forced vital capacity) between DPI and MDI. The safety profiles were similar and patient acceptability for Clickhaler was high. In conclusion, BDP administered via Clickhaler was found to be clinically equivalent to an optimally used MDI. Patients with stable asthma currently receiving BDP via MDI may be effectively switched to treatment via Clickhaler DPI.
Soluble, high-affinity dimers of T-cell receptors and class II major histocompatibility complexes: biochemical probes for analysis and modulation of immune responses.
T cell receptors (TCR) and major histocompatibility complex (MHC) molecules are integral membrane proteins that have central roles in cell-mediated immune recognition. Therefore, soluble analogs of these molecules would be useful for analyzing and possibly modulating antigen-specific immune responses. However, due to the intrinsic low-affinity and inherent solubility problems, it has been difficult to produce soluble high-affinity analogs of TCR and class II MHC molecules. This report describes a general approach which solves this intrinsic low-affinity by constructing soluble divalent analogs using IgG as a molecular scaffold. The divalent nature of the complexes increases the avidity of the chimeric molecules for cognate ligands. The generality of this approach was studied by making soluble divalent analogs of two different classes of proteins, a TCR (2C TCR2Ig) and a class II MHC (MCCI-Ek2Ig) molecule. Direct flow cytometry assays demonstrate that the divalent 2C TCR2Ig chimera retained the specificity of the native 2C TCR, while displaying increased avidity for cognate peptide/MHC ligands, resulting in a high-affinity probe capable of detecting interactions that heretofore have only been detected using surface plasmon resonance. TCR2IgG was also used in immunofluorescence studies to show ER localization of intracellular peptide-MHC complexes after peptide feeding. MCCI-Ek2Ig chimeras were able to both stain and activate an MCC-specific T cell hybridoma. Construction and expression of these two diverse heterodimers demonstrate the generality of this approach. Furthermore, the increased avidity of these soluble divalent proteins makes these chimeric molecules potentially useful in clinical settings for probing and modulating in vivo cellular responses.
Difficult asthma or Churg-Strauss syndrome?
Explore the source record for details and available documents.
Increases in eotaxin-positive cells in induced sputum from atopic asthmatic subjects after inhalational allergen challenge.
BACKGROUND: Eosinophils are believed to be critical proinflammatory cells in airway mucosal damage in asthma. Eotaxin is a C-C chemokine with selective activity for eosinophils and basophils. Previous studies have shown increased expression of eotaxin in the airways of asthmatics at baseline. We aimed to investigate eotaxin expression during the late-phase reaction to allergen inhalation in atopic asthmatics. METHODS: Sputum induction was performed before and 24 h after inhalational allergen challenge in atopic asthmatics, and eotaxin protein was detected immunocytochemically. RESULTS: Thirteen patients with a mean decrease in forced expiratory volume in 1 s of 28% (+/-1.5) during the early asthmatic reaction, and 39% (+/-4.7) during the late asthmatic reaction produced sufficient sputum for study. The percentage of eosinophils in sputum was increased 24 h after allergen challenge (P<0.004), and eosinophil percentages in sputum after challenge correlated with the magnitude of the late-phase reaction (r=0.56, P=0.05). The percentage of eotaxin-positive cells increased from 12.6% (range 2-43.8) to 24.3% (8.1-47.1, P<0.005). Allergen-induced increases in eotaxin-positive cells correlated with increases in eosinophils (r=0.63, P<0.01). CONCLUSIONS: These findings suggest that eotaxin may contribute to allergen-induced recruitment of eosinophils to the airway in asthmatic subjects.
The cost-effectiveness of inhaled fluticasone propionate and budesonide in the treatment of asthma in adults and children.
Inhaled corticosteroids form the mainstay of the treatment and management of asthma and the results of a meta-analysis comparing two of the most frequently prescribed inhaled corticosteroids, fluticasone propionate and budesonide, administered in a clinically equivalent 1:2 dose ratio to 1980 patients with asthma, demonstrated that fluticasone propionate had an improved efficacy:safety ratio. However, limited data are available on the relative economic benefits of fluticasone propionate and budesonide. The database for clinically relevant parameters, for which the efficacy:safety meta-analysis had demonstrated statistical significance between the two corticosteroids, was used for this pharmacoeconomic analysis. Treatment with fluticasone propionate was more cost-effective than budesonide with respect to improvement in morning peak expiratory flow rate, successfully treated weeks, symptom-free days, symptom-free 24 h and episode-free days. The costs of treatment for fluticasone propionate and budesonide were 7.78 Pounds per week and 12.33 Pounds per week, respectively. The main contributing factor to the higher costs of budesonide was the higher cost of health care contacts, which were 4.53 Pounds per week for budesonide and 0.57 Pounds per week for fluticasone propionate. The pharmacoeconomic difference increased in favour of fluticasone propionate as the criteria for success were made more stringent. These results demonstrate that, for asthma patients requiring modification of therapy treatment with fluticasone propionate is more effective and also cheaper, in terms of overall health-care costs, than treatment with budesonide.
Randomised, dose-ranging, placebo-controlled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma.
BACKGROUND: There is substantial circumstantial evidence that CD4 lymphocytes have a role in the pathogenesis of chronic asthma. We investigated the efficacy and safety in severe corticosteroid-dependent asthma of a single intravenous infusion of keliximab (IDEC CE9.1), a chimeric monoclonal antibody to CD4. METHODS: 22 patients were recruited from two asthma clinics. In an ascending-dose design, the first eight patients were assigned 0.5 mg/kg keliximab (six) or placebo (two); the next seven were assigned 1.5 mg/kg (five) or placebo (two); and the last seven were assigned 3.0 mg/kg (five) or placebo (two). Masked data on safety for each dose group were assessed before progression to the next dose. Patients kept a daily symptom diary and measured morning and evening peak expiratory flow (PEF) at home. PEF and forced expiratory volume in 1 s (FEV1) were measured at follow-up clinic visits. FINDINGS: Patients given 0.5 mg/kg or 1.5 mg/kg keliximab and placebo recipients did not differ in change from baseline of PEF, FEV1, or symptom score. Those given 3.0 mg/kg keliximab differed significantly from placebo recipients in change in morning PEF (median area under curve [AUC] 445 vs -82.5, p=0.005) and evening PEF (median AUC 548 vs -85, p=0.014). Symptom score showed the same pattern (though differences did not achieve significance), but there was no difference in clinic FEV1. There were no serious adverse effects related to treatment. Two patients had mild exacerbations of eczema and one developed a transient maculopapular rash. All doses of keliximab were associated with a reduction from baseline in CD4 count. INTERPRETATION: Our findings raise the possibility that T-cell-directed treatment may be an alternative approach to the treatment of severe asthma.
Inhaled steroids in COPD.
Explore the source record for details and available documents.
Non-steroidal anti-inflammatory therapy for asthma.
Explore the source record for details and available documents.
Clinical experience with fluticasone propionate in asthma: a meta-analysis of efficacy and systemic activity compared with budesonide and beclomethasone dipropionate at half the microgram dose or less.
The relative clinical efficacy and systemic effects of different inhaled corticosteroids is controversial. To obtain further information on this matter, the authors have performed meta-analysis of seven trials comparing fluticasone propionate (FP) with budesonide (Bud), and seven trials comparing FP with beclomethasone dipropionate (BDP) for the treatment of asthma of all severities in adult and paediatric patients. In all cases, the drugs were compared at clinically equivalent doses, i.e. FP was given at half (or less) the microgram dose. The total number of patients was 1980 (1000 treated with FP 200-800 micrograms day-1 and 980 with Bud 400-1600 micrograms day-1), and 1584 patients in the second analysis (780 treated with FP 200-1000 micrograms day-1 and 804 with BDP 400-2000 micrograms day-1). FP significantly improved mean morning peak expiratory flow rate (PEFR) compared with Bud, with an overall difference of +11 l min-1. Analysis of serum cortisols showed no differences between FP and Bud treatment at low doses, but at higher dosages, and overall, significant differences in favour of FP were observed. In the second meta-analysis, no significant differences in PEFR were observed between FP and BDP in any of the seven individual studies or in the pooled analysis. Analysis of serum cortisols showed a similar trend to the previous analysis, however, no overall difference in serum cortisol results were seen between FP and BDP. In conclusion, the pooled analysis shows that FP at half the dose (or less) is more effective than Bud and as effective as BDP in improving PEFR; in addition, these improvements were achieved with a reduction in cortisol suppression compared with BUD and with no greater degree of cortisol suppression compared with BDP. This demonstrates, in patients with asthma, that FP has an improved efficacy to safety ratio compared with older inhaled corticosteroids.
Dose-related effects of growth hormone on IGF-I and IGF-binding protein-3 levels in non-islet cell tumour hypoglycaemia.
Mesenchymal tumours are a well recognised cause of spontaneous hypoglycaemia. The mechanism is thought to relate to hypersecretion by tumour cells of high molecular mass insulin-like growth factor-II (pro-IGF-II), with consequent suppression of growth hormone (GH) secretion. The use of recombinant human (rh)GH has been reported to alleviate hypoglycaemia in non-islet cell tumour hypoglycaemia, and the mechanism is thought to relate to GH-mediated increments in serum levels of IGF-binding protein-3 (IGFBP-3), thereby reducing the bioavailability of IGF-II. We report the effect of increasing doses of rhGH on the clinical condition and serum IGF-I and IGFBP-3 levels in two patients with solitary pleural fibrous tumours causing severe hypoglycaemia. Hypoglycaemia was successfully alleviated in each patient although, despite using large doses of rhGH, the observed increments in IGFBP-3 were only modest. We postulate that the beneficial effects of rhGH in this situation are likely to be multifactorial and not simply related to increments in serum IGFBP-3 levels.
Drug trials.
Explore the source record for details and available documents.
Effect of cyclosporin A on the allergen-induced late asthmatic reaction.
BACKGROUND: The allergen-induced late asthmatic reaction (LAR) is associated with mucosal inflammation involving several cell types including activated T lymphocytes and eosinophils. In contrast, the early asthmatic reaction (EAR) is considered to results from rapid allergen-induced release of bronchoconstrictor mediators from IgE sensitised mast cells. Cyclosporin A has efficacy in chronic severe corticosteroid-dependent asthma and is believed to act principally by inhibiting cytokine mRNA transcription in T lymphocytes. However, it has effects on other cell types in vitro, including the inhibition of exocytosis/degranulation events in mast cells. It was therefore hypothesised that cyclosporin A would attenuate both the EAR and LAR in subjects with mild asthma. METHODS: Twelve sensitised atopic asthmatic subjects with documented dual asthmatic responses were studied in a double blind, placebo controlled, crossover trial. On two separate study visits subjects received two oral doses of either cyclosporin A or matched placebo before inhaled allergen challenges. The forced expiratory volume in one second (FEV1) was measured half hourly for eight hours and blood eosinophil counts were analysed three, six, and 24 hours after the challenge. Treatment effects on blood eosinophil counts as well as the EAR and LAR, respectively defined as the areas under the curve (AUC) of FEV1 changes from baseline between 0-1 and 4-8 hours after challenge, were compared by non-parametric crossover analysis. RESULTS: Cyclosporin A reduced both the LAR (median AUC -41.9 1.h (interquartile range -82.7 to -12.4) for cyclosporin A and -84.5 1.h (-248.9 to -39.1) for placebo; p = 0.007) and the late increase in blood eosinophils (median 0.2 x 10(9)/1 (0.15 to 0.4) for cyclosporin A and 0.4 x 10(9)/1 (0.25 to 0.55) for placebo; p = 0.024) but had no effect on the EAR. The reduction of the LAR by cyclosporin A correlated significantly with prechallenge blood concentrations of cyclosporin A (r = 0.6, p = 0.028). CONCLUSIONS: These data are consistent with the concept that cyclosporin A has anti-inflammatory actions in asthma resulting from inhibition of mRNA transcription of eosinophil-active cytokines, predominantly in T lymphocytes. Cyclosporin A, possibly in its inhaled form, or other agents which prevent cytokine gene transcription may therefore have potential in ameliorating the inflammatory component of asthma.
Effect of pranlukast, an oral leukotriene receptor antagonist, on leukotriene D4 (LTD4) challenge in normal volunteers.
BACKGROUND: There is increasing evidence to show that leukotrienes are important mediators in asthma. Leukotriene receptor antagonists protect against antigen and exercise challenges in patients with chronic asthma. A study was undertaken to investigate the activity of the leukotriene receptor antagonist pranlukast (SB 205312, ONO-1078) in blocking bronchoconstriction induced by leukotriene D4 (LTD4) inhalation. The selectivity of pranlukast was evaluated using histamine challenge. METHODS: Pranlukast, 450 mg twice daily, was given to eight healthy non-smoking men for five days in a randomised, double blind, placebo controlled, crossover study. The specific airways conductance (sGaw) was measured before and after bronchial provocation with inhaled LTD4 at 3.5 hours after the first dose and at 3.5 and 9.5 hours after the last dose of pranlukast on the morning of day 5. The concentration of LTD4 required to produce a fall in sGaw of 35% (PC35) was calculated. Subjects also underwent a histamine challenge 3.5 hours after a single dose of pranlukast, 450 mg, or placebo. RESULTS: A single dose of pranlukast produced a 10.6 fold increase in PC35sGaw (95% confidence interval (CI) 4.4 to 25.5; p < 0.001) for LTD4 at 3.5 hours after dosing compared with placebo. Three and a half hours after the morning dose of pranlukast on day 5 the PC35sGaw for LTD4 was increased 25.9 fold (95% CI 10.8 to 62.2; p < 0.001) and was still increased sevenfold (95% CI 2.9 to 16.7; p < 0.001) relative to placebo 9.5 hours after administration of the morning dose. No significant differences were noted for the PC35sGaw to histamine for pranlukast compared with placebo. CONCLUSIONS: This study shows that pranlukast is a potent and selective LTD4 receptor antagonist in humans which blocks LTD4 challenge after initial and repeated administration when given twice daily for five days.
Pranlukast, a novel leukotriene receptor antagonist: results of the first European, placebo controlled, multicentre clinical study in asthma.
BACKGROUND: Leukotriene receptor antagonists have been shown to protect against bronchoconstriction induced by antigens, exercise, and cold air. There are relatively few clinical studies reported in patients with asthma. The present study is the first clinical evaluation of pranlukast (SB 205312, ONO-1078) outside Japan in patients with asthma. METHODS: A randomised, double blind, placebo controlled, parallel group, multicentre four week study of the safety and tolerability of oral pranlukast, 225 or 337.5 mg twice daily, was performed in patients with mild to moderate asthma. Preliminary efficacy data were obtained; the main efficacy variables evaluated were forced expiratory volume in one second (FEV1) and morning domiciliary (home) peak expiratory flow rates (PEFR). Clinic PEFR and daytime and night-time asthma symptom scores were also recorded. RESULTS: Compared with the placebo group the improvement in morning home PEFR was statistically significant at all time points for patients receiving pranlukast 337.5 mg twice daily and at weeks 1 and 2 for those treated with pranlukast in a dose of 225 mg twice daily. Mean morning home PEFR increased by 10.8 to 18.61/min (95% CI 0.2 to 29.3 l/min) in patients treated with pranlukast compared with a slight deterioration in those given placebo. FEV1 significantly increased within one hour after the first dose of pranlukast compared with baseline and this increase was maintained for eight hours. Improvements in trough FEV1-that is, at the end of the dosing interval-were statistically significant for the group treated with pranlukast 225 mg twice daily compared with placebo at week 4. Mean increases in FEV1 ranged from 210 ml to 340 ml (95% CI 60 to 500 ml) at trough in the pranlukast group. Patients treated with pranlukast also showed improvements in summary symptom and night-time asthma scores. Pranlukast was well tolerated, and no drug related changes in haematological and biochemical variables were observed. CONCLUSIONS: Pranlukast, an oral leukotriene receptor antagonist, is well tolerated and is effective for the treatment of asthma. It increased FEV1 within one hour of dosing, improved patient summary symptom and night-time asthma scores, and reduced the use of rescue bronchodilators, thus providing further evidence of a role for leukotrienes in the pathogenesis of asthma.