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Biomedical subjects

J P Finnerty

Publications and source records attributed to J P Finnerty.

At least 19 recordsLinked to original sources
PubMed1992

Role of leukotrienes in exercise-induced asthma. Inhibitory effect of ICI 204219, a potent leukotriene D4 receptor antagonist.

The sulfidopeptide leukotrienes C4, D4, and E4 are released from mast cells in response to allergen challenge and may be involved in the bronchoconstrictor response to inhaled allergen in asthma. Since mast cell activation may also be implicated in exercise-induced bronchoconstriction, we assessed the inhibitory effects of a potent orally active leukotriene D4 receptor antagonist, ICI 204219 (20 mg), on the bronchoconstrictor response to exercise in eight male asthmatic patients in a placebo-controlled, randomized crossover study. Exercise challenge respiring dry air was performed on a treadmill at constant speed and gradient 2 h after drug administration, and bronchoconstriction was assessed as change in FEV1 over 30 min postexercise. No significant effect on airway caliber, measured as FEV1, was noted 2 h after ICI 204219. The mean maximum percentage fall in FEV1 following exercise was 36.0% following placebo, and reduced to 21.6% after ICI 204219 (p less than 0.01). Analysis of the time course of bronchoconstriction showed that inhibition was most marked over the latter part of the period assessed. These data indicate that the release of sulfidopeptide leukotrienes makes a major contribution to exercise-induced bronchoconstriction.

Adult↗
PubMed1992

The relative contributions of histamine and prostanoids to bronchoconstriction provoked by isocapnic hyperventilation in asthma.

It has been proposed that exercise provokes bronchoconstriction in asthma by inducing mast cell degranulation, and that this occurs secondary to the hyperpnoea of exercise causing hypertonicity of the airway lining fluid. We investigated the contribution of the mast cell products, histamine and prostaglandins, to the bronchoconstriction induced by isocapnic hyperventilation (ISH) using single doses of terfenadine, a specific histamine H1-receptor antagonist, and flurbiprofen, a potent cyclooxygenase inhibitor. We also investigated the effect of flurbioprofen in single dose on bronchial histamine reactivity. Eleven asthmatics took part in a two phase, double-blind, randomized study. In phase 1, subjects attended on three occasions and received either terfenadine 180 mg, flurbiprofen 150 mg, or placebo, prior to 6 min of ISH. The mean maximum percentage fall in forced expiratory volume in one second (FEV1) induced by ISH was 31.5(+/- 3.2)% following placebo, 29.7(+/- 4.4)% following flurbiprofen (NS), and reduced to 16.6(+/- 3.7)% following terfenadine (p less than 0.01). In phase 2, subjects received bronchial challenge with histamine following either flurbiprofen 150 mg or placebo. No significant change in bronchial reactivity following flurbiprofen was seen. We conclude that as administered in this study, flurbiprofen has no effect on baseline bronchial reactivity to histamine. The inhibitory effect of terfenadine indicates that histamine, probably from airway mast cells, makes an important contribution to bronchoconstriction induced by isocapnic hyperventilation, whereas prostaglandin release has no significant role.

Adolescent↗
PubMed1991

Salmeterol.

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Adrenergic beta-Agonists↗
PubMed1991

Effect of GR32191, a potent thromboxane receptor antagonist, on exercise induced bronchoconstriction in asthma.

Previous work suggests a role for mast cell derived mediators in exercise induced asthma. The contribution of newly generated contractile prostaglandins to exercise induced asthma was assessed by using a potent and orally active thromboxane (TP1) receptor antagonist, GR32191. The effect of 120 mg GR32191 on exercise induced asthma was observed in 12 asthmatic subjects. For the exercise challenge the subjects performed six minutes of treadmill exercise, breathing dry air at a work load that had previously been shown to induce a fall in FEV1 of 25% or more from the pre-exercise baseline. No effect of GR32191 on pre-exercise baseline airway calibre was evident. There was no significant difference in the mean maximum percentage fall in FEV1 from baseline after exercise between drug and placebo (placebo 30.2%, GR32191 day 31.6%). It is concluded that the thromboxane antagonist GR32191 has no effect on exercise induced asthma. This suggests that prostaglandins, including PGD2, that act via the thromboxane receptor do not have an important role in exercise induced asthma.

Adult↗
PubMed1991

The inhibitory effect of nebulized albuterol on the early and late asthmatic reactions and increase in airway responsiveness provoked by inhaled allergen in asthma.

It is widely held that inhaled beta 2-adrenoceptor agonists inhibit the early asthmatic response (EAR) but not the late response (LAR) or attendant increase in bronchial responsiveness. In this study of 10 atopic asthmatic subjects, we have investigated the effects of a high dose of nebulized albuterol (2.5 mg) on the allergen-provoked EAR, LAR, and increase in histamine responsiveness. In a randomized blinded fashion, study subjects inhaled the following combinations: albuterol followed 10 min later by allergen, placebo followed by allergen, albuterol followed by saline (albuterol, placebo, and control study periods, respectively). Airway caliber was measured as FEV1 and followed at regular intervals for 7.5 h postallergen. Bronchial responsiveness to histamine was measured and recorded as the PC20 value before and at 1.5, 3.5, 5.5, and 7.5 h after allergen or control challenge. During the placebo study period, allergen challenge caused mean 29.6 +/- 6.4 and 24.4 +/- 6.4% falls in FEV1 at 20 min and 7.5 h, respectively (both p less than 0.05), and a progressive decrease in PC20 amounting to a geometric mean of 1.9 doubling dilutions at 7.5 h (p less than 0.05). Albuterol followed by allergen resulted in a 13.1 +/- 2.2% increase in FEV1 prior to allergen followed by abolition of the EAR and inhibition of the LAR with only a 9.2 +/- 3.5% fall in FEV1 at 7.5 h, significantly different from that of placebo at 7.5 h (p = 0.048). Similarly, PC20 histamine fell by only 0.64 doubling dilutions at 7.5 h, not significantly different from baseline values but different from placebo values (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1991

Inhalation of the propeller from a spinhaler.

A 39 yr old man with a 5 yr history of asthma opened his spinhaler to inspect it. He sucked at the capsule to see if its contents were damp. The capsule and propeller came off the spindle, and he aspirated them. He attended a casualty department. The chest radiogram was normal. Over the next three months he developed dypnoea and pain in his chest. He also noticed a whistling noise from his chest, more marked when he lay on his right side. On renewed examination, expiration was prolonged over the right side of the chest, and an occasional whistling wheeze could be heard on that side. A renewed chest radiogram was normal. By means of rigid bronchoscopy, the spindle was removed from its lodged position in the right intermediary bronchus just beyond the orifice to the right upper lobe.

Adult↗
PubMed1990

Protection against allergen-induced asthma by salmeterol.

The effects of the long-acting beta 2-agonist salmeterol on early and late phase airways events provoked by inhaled allergen were assessed in a group of atopic asthmatic patients. In a placebo-controlled study, salmeterol 50 micrograms inhaled before allergen challenge ablated both the early and late phase of allergen-induced bronchoconstriction over a 34 h time period. Salmeterol also completely inhibited the allergen-induced rise in non-specific bronchial responsiveness over the same time period. These effects were shown to be unrelated to prolonged bronchodilatation or functional antagonism. These data suggest novel actions for topically active long-acting beta 2-agonists in asthma that extend beyond their protective action on airways smooth muscle.

Administration, Inhalation↗
PubMed1990

Lack of tachyphylaxis to histamine in both moderate and mild asthmatic subjects.

While some studies have clearly shown that tachyphylaxis occurs in asthmatic subjects when challenged consecutively with inhaled histamine, others were unable to demonstrate this phenomenon. There is reason to believe that these conflicting findings may be related to the different degrees of bronchial reactivity in the subjects studied. We selected 2 groups of 10 asthmatics on the basis of their degree of bronchial reactivity: a group with PC20 less than 1 mg/ml (moderate asthmatics); and a group with PC20 greater than 2.5 mg/ml (mild asthmatics). Each subject underwent 3 successive histamine challenges, allowing recovery of FEV1 after each to within 5% of the baseline value prior to the first challenge. Test results were recorded as the provoking concentration of histamine needed to produce a 20% fall in FEV1 (PC20). No significant change in histamine reactivity occurred in either group. However, one moderate and two mild asthmatics appeared to develop some tachyphylaxis. We conclude that tachyphylaxis to histamine is not a general phenomenon in asthma.

Asthma↗
PubMed1990

Comparative protective effect of the inhaled beta 2-agonist salbutamol (albuterol) on bronchoconstriction provoked by histamine, methacholine, and adenosine 5'-monophosphate in asthma.

We have investigated the ability of salbutamol to protect against bronchoconstriction induced by methacholine, histamine, and adenosine 5'-monophosphate (AMP) in nine subjects with asthma. In a double-blind, placebo-controlled study, salbutamol, 2.5 mg administered by nebulization, increased the geometric mean provocation concentrations of methacholine, histamine, and AMP required to produce a 20% decrease in FEV1 from 0.3 to 2.2, 0.4 to 3.8, and 4.0 to 106.7 mg/ml after placebo and active treatment, respectively (p less than 0.01). Thus, this dose of beta 2-adrenoceptor agonist displaced the concentration-response curves for methacholine, histamine, and AMP to the right in a parallel fashion by 8.8 (0.6 to 29.3)-, 10.3 (1.4 to 33)-, and 26.6 (1.5 to 76.6)-fold, respectively, the difference between the results for AMP and those for histamine and methacholine being statistically significant (p less than 0.01). For six of the nine subjects studied, salbutamol displaced the concentration-response curve for AMP to the right by greater than 50-fold. There was no correlation between bronchodilatation and protection against bronchoconstriction induced by any of the agonists. We conclude that salbutamol protects against bronchoconstriction provoked by methacholine and histamine by functional antagonism, whereas with AMP, an additional activity is demonstrable, possibly involving inhibition of mast cell-mediator release.

Adenosine Monophosphate↗
PubMed1990

Tachyphylaxis to inhaled histamine in asthma: its significance and relationship to basal airway responsiveness.

Although some studies have clearly demonstrated tachyphylaxis to inhaled histamine in subjects with asthma, other studies have not. We speculated that histamine tachyphylaxis might be related to the degree of bronchial hyperreactivity (BHR) to histamine. We undertook three successive bronchial histamine challenges in two groups of 10 subjects with asthma chosen on the basis of their baseline BHR. In the group with mild asthma, the baseline provocative concentration of histamine causing a 20% fall in FEV1 (PC20) was greater than 2.5 mg/ml, and in the group with severe asthma, the baseline PC20 histamine was less than 1 mg/ml. The second and third histamine challenges in each subject were performed when FEV1 values had recovered to within 5% of the baseline FEV1 before the first challenge. There was no significant shift in reactivity to histamine from the first to the third challenge in either group. The geometric mean PC20 (+/- geometric SE) for the group with mild asthma was 4.27 (3.86 to 4.72) mg/ml for the first challenge and 5.42 (4.47 to 6.57) mg/ml for the third challenge. There was a mean increase of 0.34 doubling dilutions in PC20 for the group with mild asthma from the first to the third challenge, although this did not reach statistical significance. For the group with severe asthma, the geometric mean PC20 was 0.48 (0.39 to 0.59) mg/ml for the first challenge and 0.47 (0.38 to 0.59) mg/ml for the third challenge. There was no trend in this group toward any increase in PC20.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Repeated exposure of asthmatic airways to inhaled adenosine 5'-monophosphate attenuates bronchoconstriction provoked by exercise.

Inhaled adenosine 5'-monophosphate (AMP) induces bronchoconstriction in subjects with asthma, probably caused by histamine release from airway mast cells, and repeated AMP bronchial challenge leads to attenuation of the bronchoconstrictor response. Since exercise-induced bronchoconstriction may be mediated by hypertonic mast cell degranulation, we postulated that repeated AMP bronchial challenge should reduce the response to subsequent exercise challenge. Eight atopic subjects with asthma took part in an unblinded, randomized trial. On the control study day, a treadmill exercise test previously demonstrated to induce a greater than 20% fall in FEV1 was performed. On the AMP study day, three AMP dose-response bronchial challenges were performed at 1-hour intervals. Each AMP challenge was continued until either a provocative concentration causing a 20% fall in FEV1 had been achieved (PC20) and the PC20 was calculated, or the maximum concentration of AMP (400 mg/ml) had been administered. After recovery of the FEV1 from AMP challenge, a treadmill exercise test identical to the test on the control study day was performed. On the AMP study day, the geometric mean PC20 was 15.3 (7.9 to 29.5) mg/ml for the first test, and 28.2 (10.7 to 77.4) mg/ml for the third test (not significant). On the control study day, the mean maximum percentage fall in FEV1 after exercise was 28.0% +/- 2.7%, whereas on the AMP study day, it was reduced to 13.0% +/- 4.3% (p less than 0.01). A significant correlation was found between the change in responsiveness to AMP induced by repeated challenge and the attenuation of the subsequent exercise response (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1990

The effect of 2 weeks treatment with cetirizine on bronchial reactivity to methacholine in asthma.

1. We investigated the effect of 2 weeks therapy with oral cetirizine (10 mg twice daily) on methacholine bronchial reactivity in 14 asthmatics. All had bronchial hyperreactivity to methacholine on entry to the study, with a geometric mean cumulative PC20 of 0.83 mg ml-1 (range 0.1-3.61 mg ml-1) and eight were atopic on skin prick testing. 2. The study was placebo-controlled and in randomised order, with a minimum 1 month washout period between cetirizine and placebo study periods. Four methacholine challenges were performed in all, at the beginning and at the end of each study period. 3. No significant change in methacholine reactivity was found following 2 weeks therapy with cetrizine. The repeatability coefficient for the PC20 methacholine over 2 weeks was found to be 2.90 doubling dilutions for the placebo period and 1.73 doubling dilutions for the cetirizine period. The study had a 80% power at the 5% significance level (two-tailed) to detect a 1.16-doubling concentration change in methacholine reactivity. 4. We conclude that 2 weeks therapy with cetirizine has no significant effect on non-specific bronchial hyperreactivity.

Adult↗
PubMed1990

Evidence for the roles of histamine and prostaglandins as mediators in exercise-induced asthma: the inhibitory effect of terfenadine and flurbiprofen alone and in combination.

We investigated the effects of terfenadine, a histamine H1-receptor antagonist, and flurbiprofen, a cyclooxygenase inhibitor, on exercise-induced bronchoconstriction to assess the contribution of the mast cell products histamine and prostaglandins. Eight asthmatics were studied on 4 occasions with treadmill exercise tests. Terfenadine or placebo was administered 3 h prior to exercise, and flurbiprofen or placebo was administered 2 h prior to exercise, in a double-blind randomized trial. Airway calibre was determined by measurement of the forced expiratory volume in one second (FEV1) immediately prior to exercise challenge, and over 30 min post-exercise. Following placebo, the mean maximum percentage fall in FEV1 was 39%. This fell to 25% after terfenadine (p less than 0.05), 27% after flurbiprofen (p less than 0.05), and 30% after the active combination (NS). Analysis of the areas under curves of percentage falls in FEV1 over 30 min showed significant inhibition on all 3 active drug days (p less than 0.05). We conclude that histamine release and prostaglandin generation contribute to exercise-induced bronchoconstriction, although the interaction between these mediators appears complex.

Adult↗
PubMed1989

Antihistamines in asthma.

Substantial evidence indicates that airway hyperresponsiveness in asthma is associated with the inflammatory response directed toward the airway epithelium and submucosa. Endogenously released spasmogenic mediators interacting with smooth muscle have a greater effect on hyperresponsive than on normal airways. Histamine, a bronchoactive and vasoactive mediator, is released in patients with naturally occurring or allergen-induced asthma. It is clear that mast cells are activated as part of the asthmatic response, and they have now been implicated as effector cells of mediator secretion based on the results of provocative tests. The advent of more potent histamine antagonists selective for H1 receptors has led to a reappraisal of antihistamine therapy in asthma. Drugs such as terfenadine and azelastine inhibit early bronchoconstriction and to some extent the late-phase asthmatic response as well. The efficacy of other new antihistamines (e.g., ketotifen and cetirizine) may extend beyond H1-receptor blockade to inhibit some of the chronic (and perhaps more important) cellular events in asthma.

Asthma↗
PubMed1989

Wheal-and-flare responses to intradermally injected adenosine 5'-monophosphate, hypertonic saline, and histamine: comparison of atopic and nonatopic subjects.

Adenosine 5'-monophosphate (AMP) in increasing concentrations, and saline solutions of corresponding tonicity, were injected intradermally in seven atopic and seven normal subjects. Skin wheal-and-flare responses were elicited in a dose-dependent fashion in all subjects, and no difference was found between responses produced by AMP and responses produced by saline of corresponding tonicity. Also, no difference in response to AMP and saline was found between atopic and nonatopic subjects. We further investigated, in seven atopic subjects, whether the skin wheal-and-flare response to the single, highest dose of AMP, saline, and histamine could be inhibited by preadministration of 180 mg of terfenadine, a potent H1 antagonist. A significant inhibition of the wheal-and-flare response to histamine and no significant inhibition to AMP were found. There was a significant inhibition of the flare response caused by hypertonic saline but no inhibition of the wheal response. We interpret these findings as indicating that AMP does not specifically lead to mast cell degranulation in the skin and that there are functional differences between cutaneous and lung mast cells. The observation that terfenadine significantly inhibited the flare response to hypertonic saline suggests that this stimulus produced histamine release.

Adenosine Monophosphate↗
PubMed1989

Relationship between skin-prick tests, the multiple allergosorbent test and symptoms of allergic disease.

In 47 atopic subjects, skin-prick testing to 10 common allergens was performed, and specific IgE to the same allergens was assessed by the multi-allergosorbent chemiluminescent assay (MAST-CLA). Overall agreement between the tests was 66.4% for conventionally positive skin tests (weal diameter greater than or equal to 3 mm), rising to 78.5% when a positive skin test was defined as having a weal diameter greater than or equal to 5 mm. Agreement between the tests was statistically significant for all allergens except Alternaria. A history was obtained from each subject of the presence or absence of allergic symptoms on exposure to cats, and whether there was a history of grass pollen allergy. MAST-CLA testing for specific IgE to cat dander predicted a history of cat allergy with an efficiency of 74.5%, while a positive MAST-CLA test for Cocksfoot grass predicted a history of grass pollen allergy with an efficiency of 85.1%. Similar results were obtained on skin testing for these allergens. We conclude that MAST-CLA gave results comparable to those obtained by skin-prick testing, and correlated equally well with the history of allergic symptoms.

Adult↗
PubMed1989

Inhibition of hypertonic saline-induced bronchoconstriction by terfenadine and flurbiprofen. Evidence for the predominant role of histamine.

We investigated the possible inhibitory effects of terfenadine, a histamine H1-receptor antagonist, and flurbiprofen, a cyclooxygenase inhibitor, on the bronchoconstrictor effect of inhaled 3.6% hypertonic saline in a randomized, double-blind study. Nine mildly asthmatic subjects with a history of exercise-induced asthma took part. This was conducted, first as a dose-response study and, second, as a time-course study. In the dose-response study, the provocative dose of saline-laden air causing a 25% fall in FEV1 was calculated (PD25). Terfenadine (180 mg) and the combination of terfenadine (180 mg) plus flurbiprofen (100 mg) both protected significantly against hypertonic saline challenge, achieving increases in PD25 values by factors of 7.24 and 6.30, respectively. Flurbiprofen (100 mg) also displaced the dose-response to the right, increasing the PD25 by a factor of 1.92, but this protection was significantly less than that afforded by terfenadine. In the time-course studies, a single inhalation of hypertonic saline previously shown to cause at least a 25% fall in FEV1 was administered, and FEV1, was followed for 30 min. Preadministration of terfenadine reduced the mean area under the curve of percentage fall in FEV1-time response by 68.5%, with similar results obtained with the combination of terfenadine and flurbiprofen. We conclude that the bronchoconstriction in asthma provoked by inhaled hypertonic saline is mediated predominantly through the hyperosmolar release of histamine from airway mast cells, with a minor contribution being made by prostanoids.

Adult↗