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Biomedical subjects

P Rafferty

Publications and source records attributed to P Rafferty.

At least 37 records · Page 2Linked to original sources
PubMed1988

The contribution of histamine release to bronchoconstriction provoked by inhaled benzalkonium chloride in asthma.

1. To investigate the possibility that benzalkonium chloride-induced bronchoconstriction results from the endogenous release of histamine, we examined the effect of the selective histamine antagonists terfenadine and astemizole, on the airways response to inhaled benzalkonium chloride and histamine in 12 asthmatic subjects. 2. Double-blind concentration- and time-course studies were undertaken, 3 h after treatment with terfenadine or matched placebo. 3. Benzalkonium chloride and histamine caused concentration-related falls in FEV1 in all subjects with benzalkonium chloride being 7.4 times less potent as a bronchoconstrictor agonist than histamine. Terfenadine displaced to the right the benzalkonium chloride and histamine concentration-response curves by 3.7 and 111 fold respectively. Terfenadine attenuated the initial (5 min) bronchoconstrictor response to benzalkonium chloride by 40%. However, over the whole 45 min period, the response was reduced by only 13% compared with 86% inhibition of the response to histamine. 4. In an open study, eight of the 12 subjects undertook a time course study with inhaled benzalkonium chloride after pretreatment with the chemically unrelated histamine antagonist astemizole. Astemizole inhibited benzalkonium chloride-induced bronchoconstriction to an almost identical degree as that achieved with terfenadine. 5. We conclude that the initial bronchoconstrictor effect of benzalkonium chloride is due, in part, to histamine release. However, the majority of the adverse effect relates to other, as yet unrecognised effects of this bacteriocidal substance.

Adult↗
PubMed1988

Comparison of the efficacy of preservative free ipratropium bromide and Atrovent nebuliser solution.

The paradoxical bronchoconstriction observed with commercially available isotonic ipratropium bromide nebuliser solution (Atrovent) in patients with asthma results from an adverse reaction to the preservatives, benzalkonium chloride and ethylenediaminetetra-acetic acid (EDTA). The airway response to inhaled Atrovent and preservative free ipratropium bromide nebuliser solutions has been examined in a double blind study. On separate occasions 30 asthmatic subjects inhaled 2 ml of the solutions and airway calibre was measured in terms of FEV1 for 45 minutes. Atrovent nebuliser solution provoked a greater than 20% fall in FEV1 in five of the 30 subjects, whereas this did not occur after preservative free ipratropium bromide. Inhalation of the preservative free solution resulted in more rapid and greater overall bronchodilatation than Atrovent, with mean maximum increases in FEV1 of 29.2% and 18.5% respectively. It is concluded that the risk of paradoxical bronchoconstriction with ipratropium bromide is considerably reduced by removal of benzalkonium chloride and EDTA and that preservative free ipratropium bromide is a more potent bronchodilator than the currently available Atrovent solution.

Airway Resistance↗
PubMed1988

Dose-related antagonism of leukotriene D4-induced bronchoconstriction by p.o. administration of LY-171883 in nonasthmatic subjects.

Leukotriene D4 (LTD4) has been suggested as a proinflammatory mediator in asthma. We have investigated the inhibitory activity of the p.o. LTD4 antagonist LY-171883 (1-[2-hydroxy-3-propyl]-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl]et hanone) on LTD4-induced bronchoconstriction in nonasthmatic subjects, in a double-blind, placebo controlled, randomized, cross-over study. Twelve subjects, mean age 26.3 +/- 1.7 years, participated. On 4 separate days, base-line measurements of forced expiratory volume in 1 second (FEV1) and maximum flow at 70% of vital capacity below total lung capacity (Vp30) were performed, after which subjects ingested either 50 or 200 or 400 mg of LY-171883, and then undertook a dose-response study with inhaled LTD4. Measurements of FEV1 and Vp30 were made at intervals for 8 min after inhalation of each dose of LTD4, and increasing doses administered until FEV1 had fallen by greater than 20% or the maximum cumulative dose of LTD4 (88.2 nmol) had been given. Cumulative dose-response curves were constructed on a logarithmic scale, and the provocation doses of LTD4 producing a 12% fall in FEV1 (PD12 FEV1) and a 30% fall in Vp30 (PD30Vp30) after placebo determined by linear interpolation to be 5.5 (0.9-176.4) and 1.2 (0.1-6.2) nmol, respectively. Following the 50-, 200- and 400-mg doses of LY-171883, the geometric mean PD12 FEV1 values were 7.0 (NS), 10.5 (NS) and 25.3 (P less than .01) nmol, respectively, whereas corresponding values for PD30Vp30 were 1.7 (NS), 2.6 (NS) and 6.1 (P less than .01) nmol.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetophenones↗
PubMed1987

Inhibition of exercise-induced asthma by nifedipine: a dose-response study.

1. The effect of three single doses of nifedipine on exercise-induced asthma has been examined in 11 asthmatic subjects. 2. On four separate days patients undertook 6 min of exercise on a treadmill 30 min after taking placebo or nifedipine 10, 20 or 30 mg administered double-blind and in random order. 3. Nifedipine had no significant effect on resting FEV1 measurements. 4. Nifedipine, in doses of 10, 20 and 30 mg, inhibited exercise induced bronchoconstriction, reducing the maximum fall in FEV1 from 30.8 +/- 3.5% after placebo to 21.9 +/- 3.4% (NS), 13 +/- 3.4% (P less than 0.01) and 15 +/- 3.9% (P less than 0.01) respectively. 5. This study has shown that the protective effect of nifedipine against exercise-induced asthma is dose related with the maximum inhibitory effect being observed with a single dose of 20 mg.

Adult↗
PubMed1987

Transient shock and myocardial impairment caused by phaeochromocytoma crisis.

A patient admitted to hospital after injury to the abdomen was found to have transient hypertension which was followed by profound hypotension. ST elevation developed and extensive myocardial akinesia was seen at echocardiography, but coronary angiograms at this stage were normal. After treatment with intravenous fluids and dopamine he progressively recovered normal cardiac function. A partly necrotic catecholamine secreting tumour was later removed from the abdomen and it is likely that a kick to the abdomen had damaged the tumour and the consequent release of catecholamine had triggered a phaeochromocytoma crisis.

Adrenal Gland Neoplasms↗
PubMed1987

Effect of oral terfenadine on the bronchoconstrictor response to inhaled histamine and adenosine 5'-monophosphate in non-atopic asthma.

Inhaled adenosine 5'-monophosphate (AMP) causes bronchoconstriction in atopic asthma, probably after in vivo conversion to adenosine. It has been suggested that adenosine potentiates preformed mediator release from mast cells on the mucosal surface of the airways by interacting with specific purinoceptors, without affecting the release of newly generated mediators. The airway response of nine non-atopic subjects with "intrinsic" asthma to inhaled AMP and the influence of the oral, selective H1 histamine receptor antagonist terfenadine on this response was investigated. The geometric mean provocation concentrations of histamine and AMP required to produce a 20% fall in FEV1 (PC20) were 1.82 and 13 mmol/l. In subsequent placebo controlled time course studies the FEV1 response to a single inhalation of the PC20 histamine was ablated after pretreatment with oral terfenadine 180 mg. This dose of terfenadine caused an 80% inhibition of the bronchoconstrictor response to the PC20 AMP when measured as the area under the time course-response curve and compared with the response to PC20 AMP preceded by placebo. Terfenadine 600 mg failed to increase protection against AMP further, but both doses of terfenadine delayed the time at which the mean maximum fall in FEV1 after AMP was achieved. Terfenadine 180 mg had no effect on methacholine induced bronchoconstriction in the same subjects. These data suggest that inhaled AMP may potentiate the release of preformed mediators from preactivated mast cells in the bronchial mucosa of patients with intrinsic asthma.

Adenosine Monophosphate↗
PubMed1987

Effects of a cyclo-oxygenase inhibitor, flurbiprofen, and an H1 histamine receptor antagonist, terfenadine, alone and in combination on allergen induced immediate bronchoconstriction in man.

The effect of flurbiprofen, a potent cyclo-oxygenase inhibitor, on histamine and methacholine reactivity was assessed in seven atopic subjects with asthma. Flurbiprofen 150 mg daily for three days displaced the histamine-FEV1 concentration-response curve to the right by 1.5 doubling doses, whereas no effect was observed on the response to methacholine. Subsequently the effects of flurbiprofen and terfenadine, a specific H1 histamine receptor antagonist, on allergen induced bronchoconstriction were studied in seven atopic but non-asthmatic subjects. The subjects inhaled the concentration of grass pollen allergen that had previously been shown to produce a 20% fall in FEV1 on separate occasions after prior treatment with placebo, flurbiprofen 150 mg daily for three days, terfenadine 180 mg three hours before challenge, and the combination of flurbiprofen and terfenadine. After placebo, allergen challenge caused a mean (SEM) maximum fall in FEV1 of 37.6% (2.6%) after 20 (3.7) minutes, followed by a gradual recovery to within 15% of baseline at 60 minutes. Terfenadine reduced the maximum allergen provoked fall in FEV1 to 21.5% (2.2%) and reduced the area under the time-response curve (AUC) by 50% (6%). Flurbiprofen alone reduced the mean maximum fall in FEV1 to 29.6% (3.2%) and reduced the AUC by 26%. The effect of the combination of flurbiprofen and terfenadine did not differ significantly from that of terfenadine alone. We conclude that histamine and prostaglandins contribute to immediate allergen induced bronchoconstriction and that a complex interaction occurs between the two classes of mediators.

Adult↗
PubMed1987

Effect of prednisolone on theophylline pharmacokinetics in patients with chronic airflow obstruction.

The effect of prednisolone on the elimination kinetics of theophylline was studied in a group of nine patients with chronic airflow obstruction. Volume of distribution, plasma half life, and clearance after a single intravenous dose of aminophylline (5.6 mg/kg) were unchanged by prednisolone treatment (20 mg daily for three weeks). The metabolism of an intravenous bolus of theophylline is not influenced by oral prednisolone.

Aged↗
PubMed1987

The role of histamine in allergen and adenosine-induced bronchoconstriction.

We have investigated the role of histamine in allergen and adenosine-5'-monophosphate (AMP)-induced bronchoconstriction in asthmatic subjects by performing inhalation challenge tests with histamine, AMP and allergen after treatment with placebo or the potent H1 histamine receptor antagonist, terfenadine. Single concentrations of each agonist which had previously been shown to produce a 30% fall in FEV1 were used. After placebo, AMP and histamine both produced rapid bronchoconstriction reaching a maximum within 5 min and returning to within 10% of baseline after 25 min. Terfenadine inhibited this reaction to histamine completely and to AMP by 86%. The response to allergen was slower in onset and was sustained over 45 min and was inhibited 50% by terfenadine. We interpret these results as reflecting the contribution of histamine to the various airway challenges, both histamine and newly generated mediators comprise the response to allergen, whereas AMP selectively enhances mast cell degranulation without affecting the production of arachidonic acid derived mediators.

Adenosine Monophosphate↗
PubMed1987

Primary and secondary effector cells in the pathogenesis of bronchial asthma.

The immediate and late asthmatic reactions provoked by inhaled allergens have provided useful models enabling the dissection of individual inflammatory cells and their mediators that may contribute to the pathogenesis of asthma. The immediate reaction is considered to be mast cell-mediated on the basis that about 50% of the response is inhibitable by potent and selective H1-receptor antagonists such as terfenadine and astemizole. Additional inhibition (approximately 30%) by the potent cyclooxygenase inhibitor flurbiprofen implies an important role for prostanoids in the immediate response, the most likely mast cell-derived product being prostaglandin (PG) D2. In man, PGD2 is selectively metabolised to 9 alpha 11 beta-PGF2, a unique prostaglandin which shares with PGD2 contractile properties on guinea-pig and human airways smooth muscle. The inability of piriprost, a potent leukotriene synthesis inhibitor, to influence the allergen-provoked immediate reaction raises the possibility that sulphidopeptide leukotrienes play a minor role in this response. The late asthmatic reaction is considered to resemble clinical asthma since it is accompanied by increased responsiveness of the airways to a wide range of stimuli. The late reaction in man is inhibited by nedocromil sodium (4 mg) but only marginally attenuated by salbutamol (200 micrograms) if both drugs are administered prior to allergen challenge. Since salbutamol, in the dose administered, is a potent mast cell-stabilising agent, these findings must question the obligatory role of mast cell mediator release in the pathogenesis of the late response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

The contribution of histamine to immediate bronchoconstriction provoked by inhaled allergen and adenosine 5' monophosphate in atopic asthma.

In order to investigate the contribution of histamine to bronchoconstriction provoked by inhaled allergen and adenosine monophosphate (AMP), we have observed the effects of prior treatment with the potent H1-receptor antagonists, terfenadine and astemizole. Nine mild, atopic asthmatics underwent inhalation challenge tests on 6 separate days with histamine, allergen extract, and AMP using single concentrations previously shown to produce a 30% fall in FEV1. For each agonist, bronchoprovocation was performed 3 h after treatment with either terfenadine 180 mg or matched placebo, and airway caliber assessed by measurement of FEV1 over a period of 45 min. AMP challenge was also performed after prior treatment with astemizole. After placebo, histamine produced rapid bronchoconstriction, reaching a maximum within 5 min and returning to within 10% of baseline at 25 min. Pretreatment with terfenadine abolished the bronchoconstrictor response to histamine completely. In contrast, bronchoconstriction provoked by allergen after placebo was slower in onset and sustained during the 45 min of observation. Terfenadine only partially inhibited this response to allergen by 50 +/- 10% (mean +/- SEM) with the maximal effect being observed within the first 5 to 8 min of challenge. AMP inhalation provoked rapid bronchoconstriction similar in time course to that of histamine, and this reaction was inhibited by 86 +/- 8.1% by terfenadine. Astemizole produced inhibition of the response to AMP that was almost identical to that of terfenadine. On the basis of in vitro studies, we interpret these differential effects of terfenadine as reflecting the contribution of histamine to the various airway challenges.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Monophosphate↗
PubMed1987

Terfenadine (Seldane) is a potent and selective histamine H1 receptor antagonist in asthmatic airways.

Terfenadine (Seldane) is a new, highly potent H1 histamine receptor antagonist that in clinically effective doses is free of side effects. Because the low potency and specificity of many H1 receptor antagonists have made it difficult to define the precise role of histamine as a bronchoconstrictor mediator in asthma we have used terfenadine to define the degree and selectivity of H1 blockade that can be achieved in asthmatic airways. In a double-blind study, 9 asthmatic patients received placebo or terfenadine 60, 120, and 180 mg on separate days followed 3 h later by bronchial provocation with increasing concentrations of either histamine or methacholine. Terfenadine at 60, 120, and 180 mg produced significant bronchodilation with increases in FEV1 above baseline of 9.0, 9.5, and 10%, respectively (p less than 0.05, p less than 0.01, p less than 0.01). All 3 doses of terfenadine displaced the histamine-FEV1 concentration response curves in a parallel fashion to the right in all subjects. When the degree of protection against histamine is expressed as a concentration ratio, terfenadine 60, 120, and 180 mg displaced the response curves by factors of 14.8 +/- 4.6, 22.9 +/- 6.7, and 34.3 +/- 8.4. In contrast to its effect on histamine-induced bronchoconstriction, terfenadine failed to protect the airways against the constrictor effect of inhaled methacholine. Thus, terfenadine is a much more potent and selective H1 receptor antagonist in asthmatic airways than previously available antihistamines and should provide a powerful tool to define the contribution of histamine as a bronchoconstrictor mediator in asthma.

Adult↗
PubMed1986

The action of natural and synthetic isomers of quisqualic acid at a well-defined glutamatergic synapse.

L-, D- and DL-quisqualic acid have been synthesized and their activities at the glutamatergic locust nerve-muscle junction have been compared with those of natural quisqualic acid and with glutamic acid. Two well-characterised locust nerve-muscle preparations were used in these studies, the retractor unguis nerve-muscle system and the extensor tibiae nerve-muscle system. The amino acids were tested on the whole nerve-muscle system in the former, when reduction in neurally evoked twitch contraction amplitude was the measured parameter, and by ionophoretic application to single excitatory junctional sites in the latter, when amplitude of junctional depolarization was the measured parameter. Synthetic L-quisqualic acid exhibited identical potency to its natural counterpart. However, D-quisqualic acid and DL-quisqualic acid were more active than expected from the known stereospecificity of this glutamatergic system towards D- and L-glutamic acid. The hydantoin analogue of quisqualic acid was inactive. X-ray crystallographic analysis of L-quisqualic acid and the hydantoin analogue showed that the ring junction in the former is pyramidal whereas in the latter it is planar. This may account for the high potency of L-quisqualic acid on a receptor system which identifies a partially folded conformation of L-glutamic acid. A pyramidal configuration of D-quisqualic acid would allow either rapid interconversion between active and inactive configurations at its ring junction or adoption of a trigonal configuration in solution. Either interpretation could explain the unexpected potency of D-quisqualic acid.

Animals↗