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Biomedical subjects

P H Howarth

Publications and source records attributed to P H Howarth.

At least 145 records · Page 8Linked to original sources
PubMed1985

Astemizole and other H1-antihistaminic drug treatment of asthma.

The disparity between the activation of mast cells in the airways of patients with allergic asthma and the lack of efficacy of H1-antihistamines in asthma therapy has been difficult to reconcile. Histamine causes bronchoconstriction when inhaled by subjects with asthma and is released in detectable amounts into the circulation after bronchial provocation with an antigen. However, it is only weakly antagonized at bronchial H1-receptors by conventional antihistamines such as chlorpheniramine and clemastine, achieving dose ratios of 2 to 4 at maximally tolerated doses. Astemizole and terfenadine are two new H1-histamine antagonists with greatly increased potency and no sedative and anticholinergic side effects. Astemizole has a delayed onset of maximal activity but induces prolonged H1-blockade that extends 15 to 30 days after the end of treatment, whereas terfenadine has a rapid onset of action with a much shorter duration of effect. With therapeutic doses (10 mg/day), astemizole is at least four times more potent in antagonizing histamine-induced bronchoconstriction than the previously available H1-antihistamines and also effectively antagonizes antigen-induced bronchoconstriction in asthma. Astemizole has been shown to be highly effective in the symptomatic treatment of seasonal allergic rhinoconjunctivitis, with the exception of nasal obstruction. With continued treatment, astemizole also offers useful protection from the symptoms of seasonal asthma. Thus the role of histamine in the pathogenesis of asthma should be reappraised. Potent H1-histamine antagonists such as astemizole and terfenadine may offer some benefit in asthma therapy, but the precise clinical indications for their use will require critical evaluation.

Astemizole↗
PubMed1985

Relationship between mediator release from human lung mast cells in vitro and in vivo.

There is now compelling evidence to incriminate bronchial mast cells in the pathogenesis of bronchoconstriction of allergic asthma. Human mast cells isolated from lung tissue or bronchoalveolar lavage release histamine and generate eicosanoids upon IgE-dependent activation. In this paper we present data that raise doubts about the significance of phospholipid methylation in IgE-dependent activation-secretion coupling and provide evidence that drugs such as 3-deazaadenosine inhibit mediator secretion by inhibiting phosphodiesterase, in addition to inhibiting putative methylation pathways. Activation of human mast cells and basophils also stimulates adenylate cyclase to increase levels of cyclic AMP, which, on the basis of pharmacological manipulation with purine nucleosides, we believe is involved in the progression of the secretory response. Human lung cells also generate both cyclo- and lipoxygenase products of arachidonate upon Ca++-dependent stimulation with complex interactions occurring between these pathways in the presence of the leukotriene inhibitor, Piriprost. The role of mast cells in the immediate airway response to inhaled allergens in asthma was demonstrated by showing an interaction between nonspecific bronchial reactivity and mast cell reactivity in predicting the airway response upon antigen inhalation. Further confirmation of this concept was obtained by showing an inverse relationship between the release of histamine and neutrophil chemotactic factor (NCF) into the circulation induced by antigen challenge, and nonspecific airway reactivity. The identification of significant increases in circulating mediators following antigen provocation of patients with seasonal asthma enabled the effects of drugs used in the treatment of asthma to be compared on airway calibre and mast cell mediator release. Sodium cromoglycate partially inhibited the airway and plasma histamine responses with antigen, but totally inhibited the increases in NCF. Salbutamol completely inhibited all responses, while ipratropium bromide, which produced the same bronchoconstriction as achieved with salbutamol, had no effect. The potent H1-antagonist astemizole partially inhibited bronchoconstriction without affecting histamine release. Antigen provocation produced a significant increase in circulating levels of the 13,14-dihydro-15-keto metabolite of PGF2 alpha which could originate from mast cell-derived PGD2. In both retrospective and prospective studies, a close relationship was shown between nonspecific bronchial reactivity and resting airway calibre in asthma.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Influence of albuterol, cromolyn sodium and ipratropium bromide on the airway and circulating mediator responses to allergen bronchial provocation in asthma.

The effect of pharmacologic agents on mast cell mediator release was investigated in vivo. Eight atopic asthmatic subjects with airways relatively unreactive to nonspecific stimuli (geometric mean PC20 methacholine, 4.0 mg/ml) underwent single-concentration allergen challenge before (control) or after inhaling albuterol 200 micrograms, cromolyn sodium 20 mg, or 0.9% sodium chloride placebo. Six of the same subjects also underwent allergen challenge after pretreatment with ipratropium bromide, 1 mg. Airway responses to pharmacologic agents and bronchial challenge were measured by change in both specific airway conductance (SGaw) and FEV1. Mast cell mediator release was monitored by serial change in plasma histamine and, in addition, serum neutrophil chemotactic factor (NCF) on the placebo, albuterol, and cromolyn sodium challenge days. Control and placebo allergen challenges were associated with repeatable mean maximal falls in SGaw (48.5 versus 49.6%) and FEV1 (25.7 versus 25.5%). The mean increments in plasma histamine were not significantly different on the control (0.17 to 0.44 ng/ml) or placebo challenge days (0.18 to 0.64 ng/ml), with maximal levels occurring 5 min after challenge. A sustained increase in NCF was identified on the placebo challenge day (155.0% above baseline). Pretreatment with albuterol abolished any significant bronchoconstriction, with mean maximal falls in SGaw and FEV1 after challenge of 7.5 and 1.4%, respectively. These changes in airway caliber were not associated with any significant increment in mean plasma histamine (0.17 to 0.22 ng/ml) or serum NCF (4.1% increase). Cromolyn sodium pretreatment, while attenuating the airway response, was still associated with significant falls in SGaw (22.7%) and FEV1 (7.3%) and increases in plasma histamine (0.18 to 0.27 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Exercise and isocapnic hyperventilation-induced bronchoconstriction in asthma: relevance of circulating basophils to measurements of plasma histamine.

The relationship of airway cooling during exercise to changes in airway caliber, plasma histamine levels, and circulating basophils was investigated in eight allergic asthmatic and eight normal subjects. In asthma matched RHE during exercise and ICH produced almost identical bronchoconstriction with maximum falls in SGaw of 61.0 +/- 4.5% and 57.9 +/- 5.2%, respectively. A similar RHE in normal subjects was associated with a 7.9 +/- 3.3% fall in SGaw. The resting plasma-histamine levels were higher in the asthmatic (0.52 +/- 0.06 ng/ml) than in the normal (0.31 +/- 0.07 ng/ml, p less than 0.05) subjects. No significant change in plasma histamine occurred after exercise in either group nor in the asthmatic subjects with ICH. In contrast, exercise but not ICH stimulated an increase in leukocytes, basophils, and total blood histamine in parallel with the airway response that reached a maximum at 2 to 5 min in both normal and asthmatic subjects. There was a positive correlation between basal plasma and total blood-histamine levels (r = 0.67, p less than 0.01) in normal and asthmatic subjects suggesting that basophils contribute significantly to plasma histamine. The spontaneous basophil release of histamine was greater in asthmatic (13.4 +/- 2%) than in normal subjects (6.46 +/- 7%, p less than 0.005), which is consistent with the higher resting plasma-histamine levels in the asthmatic subjects. These findings suggest that plasma-histamine changes with exercise in asthma but not ICH may be related to the associated basophilia and sample handling rather than intrapulmonary mast cell degranulation.

Adult↗
PubMed1984

Astemizole, a potent histamine H1-receptor antagonist: effect in allergic rhinoconjunctivitis, on antigen and histamine induced skin weal responses and relationship to serum levels.

The efficacy of astemizole, a new, long acting, oral histamine H1-receptor antagonist was compared to placebo for the treatment of allergic rhinitis and conjunctivitis during the grass pollen season of 1982. Sixty-three patients with a positive skin prick test to grass pollen and current symptoms participated in an 8 week, double-blind, randomized study. Astemizole, 10 mg, was significantly better than placebo in alleviating both nose (P less than 0.05) and eye (P less than 0.01) symptoms despite significantly greater use of the reserve medication, clemastine, by the placebo group (P less than 0.003). There was a lag period of 5 days after initiation of therapy before treatment benefit became manifest. Subdivision of nasal symptoms indicated significant improvement compared to placebo over the 8 weeks for sneezing (P less than 0.05) and runny nose (P less than 0.05) but not blocked nose. The absence of effect on nasal blockage was confirmed by parallel measurement of nasal calibre by body plethysmography. The antihistaminic potency of astemizole was indicated by an 80% inhibition of the histamine induced skin weal response after 8 weeks therapy. A positive correlation was found between serum drug levels and % inhibition of histamine skin weal (r = 0.64, P less than 0.001). Astemizole was free from adverse sedative or anticholinergic effects but did cause a mean increase in weight of 1.3 kg (P less than 0.01) after 8 weeks therapy, not found with placebo.

Adolescent↗
PubMed1984

Comparative trial of two non-sedative H1 antihistamines, terfenadine and astemizole, for hay fever.

Ninety patients participated in a randomised, double blind, placebo controlled comparison of terfenadine with astemizole in the treatment of hay fever. They entered the trial as a cohort before the grass pollen season and recorded daily their symptoms of itching eyes, sneezing, running nose, and blocked nose on visual analogue scales in diary cards. Over the eight weeks of the trial astemizole was significantly better than either terfenadine or placebo in alleviating itching eyes, sneezing, and running nose (p less than 0.0001) but no better than placebo for the treatment of blocked nose. The placebo was significantly better than terfenadine for the treatment of running nose and blocked nose (p less than 0.002). Neither of these H1 antihistamine drugs was associated with sedative adverse effects despite significantly inhibiting histamine induced skin weal responses. These results suggest that astemizole is a satisfactory non-sedative H1 antihistamine for maintenance treatment of hay fever. Terfenadine is ineffective by comparison.

Adolescent↗
PubMedDate not supplied

Invited lecture: activation of the epithelial mesenchymal trophic unit in the pathogenesis of asthma.

BACKGROUND: A recent NIH Workshop and an ERS Task Force concluded that more work was needed to understand mechanisms of severe and chronic asthma. This report describes a series of studies that identify aberrant epithelial mesenchymal signalling in the airways as an important event in maintaining inflammation and driving remodelling in response to environmental injury. METHODS: Immunohistochemistry, genotyping and functional studies conducted on cultured asthmatic cells and mucosal biopsies were used to identify biochemical pathways involved in epithelial injury and repair in asthma and their relationship to disease severity. RESULTS: Our findings suggest that the asthmatic state results from an interaction between a susceptible epithelium and Th-2-mediated inflammation to alter the communication between the epithelium and the underlying mesenchyme - the epithelial mesenchymal trophic unit - leading to disease persistence, airway remodelling and refractoriness to corticosteroid treatment. CONCLUSIONS: Asthma is more than an inflammatory disorder, but requires engagement of important signalling pathways involved in epithelial repair and tissue remodelling. These pathways involving EGFRs and TGF-betaRs provide targets against which to develop novel therapies for chronic asthma.

Asthma↗
PubMedDate not supplied

Genetic and environmental influences on airway inflammation in asthma.

The clear recognition that asthma has an inflammatory basis has led to a search for genetic and environmental causes. Genetic linkage studies provide evidence for allelic association between polymorphic markers of interleukin-9 on chromosome 5 and a principal component of the allergic phenotype, log IgE. Further studies that intrauterine environmental factors are an important determinant of the allergic phenotype in addition to allergen exposure during the first year of life. Once sensitised, the respiratory mucosa provides the allergic interface between the environment and internal milieux involving autacoid and cytokine release from mast cells. Up-regulation of endothelial cell adhesion molecules, specifically E-selectin and ICAM-1, is responsible for the leucocyte recruitment of the late-phase asthmatic response, while recruitment of T cells and their subsequent activation contribute to the ongoing inflammatory response of asthma. The epithelium is the origin and target tissue for the inflammatory response, resulting in detachment of suprabasal cells, up-regulation of adhesion molecules and enhanced mediator and cytokine secretion. These latter findings, being more evident in severe chronic disease, suggest that the 'formed' airway elements are also important in mediating the ongoing inflammation characteristic of asthma.

Allergens↗
PubMedDate not supplied

Epithelially derived endothelin and nitric oxide in asthma.

Immunohistochemical staining of endobronchial biopsies has identified increased expression of the 21-amino-acid peptide endothelin (ET) and the inducible form of the enzyme nitric oxide synthase (iNOS) within the airway epithelium in asthma. Elevated concentrations of ET are also recovered in bronchoalveolar lavage fluid from asthma patients. iNOS generates the gas nitric oxide from L-arginine, and elevated levels of NO in exhaled air have been described in asthma. ET is a potent bronchoconstrictor and levels of ET in lavage and resting airflow obstruction are correlated. The effects of ET on bronchomotor tone may be modified by NO as this is a bronchodilator. The relative balance between ET and NOS may thus contribute to resting bronchomotor tone. ET also stimulates fibroblast proliferation, collagen gene expression and through its inhibitory actions on collagenase will promote airway wall collagen deposition and contributes to airway wall thickening which underlies bronchial hyperresponsiveness. The regulation of these epithelial events may thus be important to the control of asthma.

Amino Acid Oxidoreductases↗