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Biomedical subjects

S Holgate

Publications and source records attributed to S Holgate.

At least 19 recordsLinked to original sources
PubMed2001

Inhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma.

BACKGROUND: APC 366, a selective inhibitor of mast cell tryptase, has been shown to inhibit antigen-induced early asthmatic response (EAR), late asthmatic response (LAR), and bronchial hyperresponsiveness (BHR) in a sheep model of allergic asthma. OBJECTIVE: The purpose of this study was to investigate the effects of APC 366 on antigen-induced EAR, LAR, and BHR in mild atopic asthmatics not on any anti-inflammatory therapy. METHODS: Sixteen mild atopic asthmatics, each with a demonstrable antigen-induced EAR, LAR, and BHR to histamine, were recruited into this randomized, double-blinded, crossover study. APC 366 (5 mg)/placebo was administered by aerosol inhalation 3 times per day on treatment days 1 through 4. Allergen challenge was carried out on day 4. Histamine challenge was performed the following morning, 1 hour after final dosing. RESULTS: Subjects were shown to have a significantly smaller overall mean area under the curve for the LAR (P =.012) and mean maximum fall in FEV(1) for the LAR (P =.007) after pretreatment with APC 366 in comparison with placebo. No significant effects on BHR were demonstrable. Although the EAR was reduced by 18% after treatment with APC 366 in comparison with placebo, this was not statistically significant. CONCLUSION: Short-term repeated administration of APC 366 significantly reduced the magnitude of antigen-induced LAR in atopic asthmatics, which supports the role of mast cell tryptase in the pathophysiology of the LAR.

Administration, Inhalation↗
PubMed2001

Efficacy of omalizumab, an anti-immunoglobulin E antibody, in patients with allergic asthma at high risk of serious asthma-related morbidity and mortality.

AIM: Add-on therapy with omalizumab, an anti-immunoglobulin E antibody, is effective in improving disease control in patients with allergic asthma of varying severity. The aim of the present study was to determine the efficacy of omalizumab in a subgroup of patients at high risk of serious asthma-related morbidity and mortality. METHODS: A meta-analysis was performed of three randomised, double-blind, placebo-controlled studies (studies 1, 2 and 3) that enrolled 1412 patients with moderate or severe allergic asthma, all requiring daily treatment with inhaled corticosteroids (ICS). Omalizumab was administered subcutaneously every 2 or 4 weeks at a total 4-weekly dose of at least 0.016 mg/kg/IgE [IU/ml]. Each study consisted of a 16-week steroid-stable phase and a 12-16-week steroid-reduction phase, followed by a 24-week extension phase (studies 1 and 2 only). The primary outcome measure was the annualised rate of significant asthma exacerbation episodes (sAEEs) during the steroid-stable phase for the pooled subgroup of 254 high-risk patients (omalizumab, n = 135; placebo, n = 119). sAEEs were those requiring a doubling of baseline ICS dose (studies 1 and 2 only) or use of systemic steroids (all three studies). RESULTS: Overall, the number of patients with at least one sAEE during the steroid-stable phase was reduced from 35% (42/119) with placebo to 18% (24/135) with omalizumab. Mean sAEE rates were 1.56 and 0.69 per patient-year, respectively, a reduction of 56% with omalizumab (p = 0.007). Similar reductions in exacerbations in favour of omalizumab were observed for the whole study period and for all AEEs. In those with a history of hospitalisation in the last year, 6/49 (12%) on placebo vs. 2/44 (4.5%) on omalizumab were re-hospitalised during the study period. Patients treated with omalizumab also showed significantly greater improvements from baseline in PEFR (p = 0.026), overall AQoL (p = 0.042) and mean nocturnal (p = 0.007) and mean total (p = 0.011) asthma symptom scores compared with placebo. CONCLUSIONS: In patients at high risk of serious asthma-related morbidity and mortality, treatment with omalizumab offers the potential to halve the rate of asthma exacerbations and improve disease control.

Adolescent↗
PubMed2000

CAM research and development.

The growth in complementary medicine and its integration into conventional medicine will certainly require the development of a well defined research strategy within the UK. This paper summarizes discussions that occurred under the umbrella of the Foundation for Integrated Medicine, involving both conventional and complementary medical practitioners. It is the first UK-based consensus document that defines a research strategy for complementary and alternative medicine and looks specifically at problems such as priority setting, research methodology, research capacity and support, potential funding streams and possible routes for the dissemination of CAM research. It concludes that for CAM to have an established future within UK healthcare, it must be subject to rigorous scrutiny. The methods employed should be appropriate to the task and should embrace a wide spectrum, both quantitative, qualitative and incorporating projects that involve good practice and audit.

Complementary Therapies↗
PubMed1999

The relationship between anthropometric measurements at birth: asthma and atopy in childhood.

BACKGROUND: Recent studies have reported that a large head circumference at birth is associated with an increased risk of raised serum IgE in adult life, and asthma during childhood. OBJECTIVE: To examine the relationship between head circumference and other anthropometric measurements at birth and asthma and indices of atopy in childhood. METHODS: The presence of asthma and measures of atopic status (total serum IgE level and skin prick tests to common allergens) were assessed prospectively in offspring of families participating in a community-based genetic study in Southampton, UK. Measures of perinatal variables including birth weight, head circumference at birth, and gestational age were obtained from hospital records of 239 offspring aged 6-23 years. RESULTS: Children with a head circumference of 37 cm or more at birth had a relative risk of an elevated serum total IgE (> 150 IU) of 3.2 (95% CI 1.0-10.4). There were no consistent relationships between head circumference at birth and either skin prick positivity or the development of clinical asthma. There was no significant association between other perinatal markers and measures of atopic status or clinical asthma. CONCLUSION: The study has identified that a large head circumference at birth is associated with an increased risk of an elevated total serum IgE in childhood. The reasons for this association, and the lack of an association with asthma are unclear and will require further research.

Adolescent↗
PubMed1999

The effects of regular inhaled formoterol, budesonide, and placebo on mucosal inflammation and clinical indices in mild asthma.

The present study was designed to observe the effects of 8 wk of treatment with formoterol (Foradil) 24 microgram, budesonide 400 microgram, and matched placebo inhaled twice a day on inflammatory indices in the bronchial mucosa of 64 patients with mild atopic asthma. Biopsies were obtained at the start and 1 wk before stopping a 9-wk period of treatment, and inflammatory cell numbers were assessed in the submucosa and epithelium by immunohistochemistry. Regular formoterol significantly reduced the number of submucosal mast cells, with a similar trend for eosinophils but not activated T cells. A subgroup analysis conducted in biopsies with >= 10 eosinophils per mm2 revealed a significant reduction in eosinophil numbers when compared with both pretreatment baseline (p < 0.01) and changes after placebo (p < 0.01). Parallel, but less pronounced, effects were observed on mast cell but not on CD25(+) T cell numbers. There was no effect of any of the three treatments on BAL levels of mast cell or eosinophil mediators. We conclude that regular treatment with inhaled formoterol reduces rather than increases inflammatory cells in the mucosa of asthmatic patients. It is possible that these cellular effects of formoterol may contribute to the therapeutic efficacy of this drug when used regularly in the treatment

Administration, Inhalation↗
PubMed1999

B7 costimulation is required for IL-5 and IL-13 secretion by bronchial biopsy tissue of atopic asthmatic subjects in response to allergen stimulation.

Asthma is a complex disorder characterized by airway hyperreactivity and inflammation. To analyze cellular interactions required for the secretion of cytokines by the bronchial mucosa, we have evaluated the ex vivo response of tissue explants to allergen. Endobronchial mucosal biopsy tissue from mild atopic asthmatic subjects and normal control subjects were maintained in culture for 24 h. To detect reactivity to allergen, the explants were stimulated with dust mite extract Dermatophagoides pteronyssinus (Der p). Our analysis revealed that without any overt stimulation, mRNA transcripts for interleukin (IL)-5 and IL-13 were expressed by asthmatic but not normal bronchial tissue. In contrast, the expression of interferon-gamma was observed in a higher proportion of cultured bronchial biopsies from the normal control subjects than in those from asthmatic subjects. Addition of Der p allergen did not change the cytokine profile of the explants from control volunteers but augmented the expression of IL-5 mRNA and induced secretion of the protein by the asthmatic bronchial tissue. In most cases, allergen also increased the production of IL-13 by bronchial tissue from asthmatic subjects. The allergen-induced secretion of IL-5 and IL-13 was inhibited by the fusion protein CTLA-4Ig, reflecting a requirement for CD80 (B7-1) and/or CD86 (B7-2) costimulation for the expression of the Th2 cytokines. This requirement for B7/CD28 costimulation is consistent with the hypothesis that IL-5 and IL-13 are produced by allergen-specific T cells resident in the asthmatic bronchial mucosa.

Adult↗
PubMed1999

Interleukin-5 production by human airway epithelial cells.

Interleukin (IL)-5 is a pleiotropic cytokine that exhibits biologic activity on cells of diverse hemopoieitic lineages. IL-5 enhances mediator release from human basophils and plays a pivotal role in the chemoattraction, proliferation, differentiation, survival, and activation of eosinophils. Th2- and Tc2-like T cells, mast cells, basophils, and eosinophils are the known cellular sources of this cytokine. Using a sensitive and novel reverse transcription-polymerase chain reaction enzyme-linked immunosorbent assay system, we found that IL-5 messenger RNA (mRNA) was constitutively expressed in bronchial biopsies obtained from healthy individuals, and that the levels of IL-5 mRNA expression decreased 1. 5 h after exposure to 0.12 ppm ozone for 2 h. Because the oxidative effects of ozone are confined to the epithelial cell surface and it is known that ozone induces epithelial damage and shedding, we hypothesized that epithelial cells might be a source of IL-5 mRNA. We demonstrate here that both transformed human bronchial epithelial cell lines (A549 and 16HBE14o-) and primary human bronchial and nasal epithelial cells grown in culture constitutively express IL-5 mRNA, which is upregulated on stimulation with tumor necrosis factor (TNF)-alpha. Culture supernatants derived from A549 cells exposed to TNF-alpha and interferon-gamma demonstrated detectable levels of IL-5 protein, and immunostaining of bronchial biopsies obtained from healthy human airways revealed the presence of IL-5 protein localized to the bronchial epithelium. To our knowledge, this is the first report demonstrating IL-5 production by human airway epithelial cells. This observation provides further evidence for the role of airway epithelium in regulating airway immune responses, in particular enhancing chemotaxis, activation, and survival of eosinophils, which could play an important role in the pathogenesis of bronchial asthma.

Adult↗
PubMed1998

Case-control study of salmeterol and near-fatal attacks of asthma.

BACKGROUND: A case-control study was undertaken to investigate the hypothesis that the use of the long acting beta agonist salmeterol increases the risk of a near-fatal attack of asthma. METHODS: The cases comprised admissions to the intensive care unit (ICU) for asthma in 14 major hospitals within the Wessex region in 1992. For each of the cases four age-matched controls were selected from asthma admissions to the same hospital during the same period. Information on prescribed drug therapy for the 48 cases and 185 controls was collected from the hospital admission records. RESULTS: The patients admitted to the ICU had greater chronic asthma severity and had generally been prescribed more asthma drugs than the control admissions to hospital. The relative risk of a near-fatal attack of asthma in patients prescribed inhaled salmeterol was 2.32 (95% CI 1.05 to 5.16), p = 0.04. However, the salmeterol relative risk decreased to 1.42 (95% CI 0.49 to 4.10), p = 0.52 when the analysis was restricted to the more chronically severe patients (those in the subgroup of patients with a hospital admission for asthma in the previous 12 months). These findings suggest that the increased unadjusted relative risk with salmeterol is predominantly due to confounding by severity--that is, the increased relative risk is due to patients with more severe asthma (at greatest risk of a near-fatal asthma attack) being preferentially prescribed salmeterol. This interpretation is supported by the finding in this study that, within the control group (selected from the population of asthmatics requiring hospital admission), salmeterol was preferentially prescribed to the most severe patients (a threefold greater prescription of salmeterol to control patients if they had been admitted to hospital in the 12 months prior to the index admission). There was no increased risk of a near-fatal attack of asthma in patients prescribed a beta agonist by metered dose inhaler (OR 0.75 (95% CI 0.31 to 1.78), p = 0.51). In contrast, the relative risks for beta agonists delivered by nebulisation (OR 3.86 (95% CI 1.99 to 7.50), p < 0.001) and oral theophylline (OR 2.45 (95% CI 1.26 to 4.78), p < 0.01) were increased and did not markedly decrease when the analysis was restricted to the more severe asthmatic subjects. CONCLUSIONS: Although these findings are not conclusive, particularly because of the small numbers involved in some subgroup analyses, they suggest that the use of salmeterol by patients with chronic severe asthma is not associated with a significantly increased risk of a near-fatal attack of asthma. If a near-fatal asthma attack is considered to be an intermediate step in a process by which a severe attack of asthma may become fatal, these results would suggest that salmeterol is unlikely to be associated with an increased risk of death, at least by this mechanism.

Adolescent↗
PubMed1998

Atopy phenotype.

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Genetic Variation↗
PubMed1998

Cyclo-oxygenase.

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Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

The effect of intravenous administration of a chimeric anti-IgE antibody on serum IgE levels in atopic subjects: efficacy, safety, and pharmacokinetics.

CGP 51901 is a non-anaphylactogenic mouse/human chimeric anti-human IgE antibody that binds to free IgE and surface IgE of IgE-expressing B cells but not to IgE bound to high affinity IgE receptors (Fc epsilonR1) on mast cells and basophils or low affinity IgE receptors (Fc epsilonR2) on other cells. A phase 1 double-blind, placebo-controlled, single dose study with doses of 3, 10, 30, and 100 mg of CGP 51901 was conducted in 33 pollen-sensitive subjects who had raised levels of serum IgE and received either intravenous CGP 51901 or placebo. The administration of CGP 51901 was well tolerated and resulted in a decrease of serum free IgE levels in a dose-dependent manner, with suppression after 100 mg of CGP 51901 reaching > 96%. Time of recovery to 50% of baseline IgE correlated with the dose of administered antibody and ranged from a mean of 1.3 d for the 3 mg to 39 d for the 100 mg dose. Total IgE, comprised of free and complexed IgE, increased as stored and newly synthesized IgE bound to CGP 51901. Complexed IgE was eliminated at a rate comparable with the terminal half-life of free CGP 51901 (11-13 d at all doses). Only one subject showed a weak antibody response against CGP 51901. We conclude that the use of anti-human IgE antibody is safe and effective in reducing serum IgE levels in atopic individuals and provides a potential therapeutic approach to the treatment of atopic diseases.

Adolescent↗