Search PubMed⌕ Search

Biomedical subjects

R Polosa

Publications and source records attributed to R Polosa.

At least 91 records · Page 5Linked to original sources
PubMed1992

Protective effects of inhaled ipratropium bromide on bronchoconstriction induced by adenosine and methacholine in asthma.

Although adenosine-induced bronchoconstriction is mainly due to mast cell mediator release, vagal reflexes have also been implicated in this response. We have investigated the effect of a specific muscarinic-receptor antagonist, ipratropium bromide, on methacholine- and adenosine-induced bronchoconstriction in a randomized, placebo-controlled, double-blind study of 12 asthmatic subjects. Airway response was evaluated as forced expiratory volume in one second (FEV1). Inhaled ipratropium bromide (40 micrograms), administered 20 min prior to bronchoprovocation, increased the provocation dose of inhaled methacholine and adenosine required to reduce FEV1 by 20% from baseline (PD20) from 0.11 to 0.79 mg (p less than 0.01) and from 0.57 to 1.27 mg (p less than 0.01), respectively. The mean baseline FEV1 values after administration of ipratropium bromide were significantly higher than after placebo administration (p less than 0.05). However, there was no correlation between the degree of bronchodilatation and dose-ratios for methacholine and adenosine. The findings of the present study implicate vagal reflexes in the bronchospastic response induced by inhaled adenosine in asthma.

Adenosine↗
PubMed1992

Repeated inhalation of bradykinin attenuates adenosine 5'-monophosphate (AMP) induced bronchoconstriction in asthmatic airways.

Repeated bronchial challenges with inhaled bradykinin lead to a rapid loss of the bronchoconstrictor response and this has been suggested to be due to depletion of contractile neuropeptides from sensory nerve endings. If adenosine 5'-monophosphate (AMP), another potent bronchoprovocant in asthma, and bradykinin share a common pathway in inducing bronchoconstriction in asthmatic subjects, then repeated bradykinin bronchoprovocation tests should reduce the response to subsequent inhalation of AMP. We examined this hypothesis in eight asthmatic subjects in a double-blind, randomized study. On the histamine study day, two consecutive concentration-response studies with inhaled histamine were followed by a third consecutive challenge with AMP and the provocation concentration producing a 20% fall in forced expiratory volume in one second from the post-diluent baseline value (PC20 FEV1) for this agonist was calculated. On the bradykinin study day, two consecutive bronchoprovocation tests with bradykinin were followed by a third inhalation challenge to obtain the PC20AMP value. On a further occasion, the asthmatic subjects underwent two consecutive concentration-response studies with inhaled bradykinin followed by a third consecutive challenge with histamine. On the histamine study day, the geometric mean PC20AMP value was 28.1 mg.ml-1, whilst on the bradykinin study day, the fifteenfold reduction in bradykinin responsiveness after the second bradykinin challenge was accompanied by a significant reduction of the airway responsiveness to AMP, the PC20AMP being 59.8 mg.ml-1. A similar reduction in bradykinin responsiveness failed to alter the airway response to a subsequent inhalation with histamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Monophosphate↗
PubMed1991

The effect of inhaled ipratropium bromide alone and in combination with oral terfenadine on bronchoconstriction provoked by adenosine 5'-monophosphate and histamine in asthma.

The aim of this study was to investigate the effect of terfenadine, an antihistamine, 180 mg orally, the anticholinergic drug, ipratropium bromide (IB), 0.5 mg nebulized aerosol, the combination of these two drugs, and placebo tablets and aerosol on histamine- and adenosine 5'-monophosphate (AMP)-induced bronchoconstriction in a randomized, double-blind fashion. Airway response was evaluated as FEV1. After placebo, the geometric mean (GM) provocative concentration causing a 20% in FEV1 from the postsaline baseline value (PC20) for histamine and AMP was 0.63 and 5 mg/ml, respectively. Terfenadine displaced the FEV1 concentration-response curves obtained with both histamine (GM PC20 values increasing to 26.92 mg/ml) and AMP (GM PC20 values increasing to 26.7 mg/ml) to the right. IB had a small, but significant, protective effect against the fall in FEV1 produced by histamine and AMP, the GM PC20 values increasing to 1.69 and to 12.6 mg/ml, respectively. Terfenadine and IB in combination produced protection against histamine and AMP that was more than the production produced by either drug alone, the GM PC20 values increasing to 54.76 and 47.7 mg/ml, respectively. There was no correlation between degree of bronchodilatation induced by active treatments and concentration ratios for AMP or histamine. These data suggest that histamine release and vagal reflexes both contribute to AMP-induced bronchoconstriction in clinical asthma in man.

Adenosine Monophosphate↗
PubMed1991

Comparative nasal effects of bradykinin, kallidin and [Des-Arg9]-bradykinin in atopic rhinitic and normal volunteers.

1. The structure-activity relationship of kinins within the nose has been investigated in atopic rhinitic (n = 7) and non-rhinitic (n = 7) subjects. On 4 separate days, each separated by a week, subjects randomly underwent nasal challenge with incremental doses of either the B1 agonist [Des-Arg9]-bradykinin, the B2 agonists kallidin or bradykinin, or vehicle placebo in a double-blind comparative study. The nasal response was monitored objectively by measurement of nasal airways resistance (NAR) by active posterior rhinomanometry and subjectively by symptom reporting of nasal blockage, rhinorrhoea, nasal itch and nasal pain. 2. The B2 agonists kallidin and bradykinin both induced a dose-dependent increase in NAR (P less than 0.001) and were associated with symptomatic reporting of nasal blockage (P less than 0.05), rhinorrhoea (P less than 0.01) and nasal discomfort (P less than 0.05) compared to placebo. In contrast the effects of the B1 agonist [Des-Arg9]-bradykinin on NAR and symptom reporting were indistinguishable from placebo. No difference could be identified in the nasal response to kallidin and bradykinin between rhinitic and non-rhinitic subjects and there was no evidence of B1 receptor upregulation in the disease state. For the whole group the provocative dose of agonist inducing a 50% increase in NAR (PD50) was 1.77 x 10(-4) mol for bradykinin and 2.86 x 10(-4) mol for kallidin (P greater than 0.05). 3. These findings identify that the nasal effects of kinins are mediated through B2 receptors and the advent of B2 receptor antagonists will permit a further evaluation of the role of kinins in rhinitis.

Adult↗
PubMed1991

Effect of inhaled 15-(s)-hydroxyeicosatetraenoic acid on tracheobronchial clearance in normal human airways.

15-(s)-Hydroxyeicosatetraenoic acid (15-HETE) is the predominant metabolite of arachidonic acid in normal and asthmatic human airways and a potent mucus secretagogue in canine and human airways. A study was carried out on the effect of inhaled 15-HETE on tracheobronchial clearance, measured for six hours by a radioaerosol technique, in 10 normal subjects. Subjects inhaled 80 nmol 15-HETE or the diluent (sodium phosphate buffer) on two occasions at least two weeks apart in a double blind and randomised fashion (20 minutes after radioaerosol inhalation. Tracheobronchial clearance after inhaled 15-HETE was almost identical to that after placebo for all measurements up to six hours. It is concluded that 15-HETE has no effect on tracheobronchial clearance in normal human airways and is unlikely to account for the impaired mucociliary clearance seen in asthma.

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

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

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

Adenosine bronchoconstriction in asthma: investigations into its possible mechanism of action.

1. Inhaled adenosine and its parent nucleotide, adenosine 5'-monophosphate (AMP) provoke bronchoconstriction in atopic and asthmatic individuals but not in normal subjects. 2. In clinical studies, histamine H1-receptor antagonists, cyclo-oxygenase inhibitors and the mast cell 'stabilising' drugs, sodium cromoglycate and nedocromil, protect against the effects of adenosine bronchoprovocation suggesting the involvement of secondary mast cell mediator release. 3. Adenosine and its analogues potentiate histamine and leukotriene release from mast cells activated by other stimuli in vitro, and may also increase net mediator release from mast cells by counteracting the inhibitory effect of circulating adrenaline. 4. Although adenosine fulfils many of the criteria required for a mediator in asthma, its importance is not fully understood, and the mechanisms by which it provokes bronchoconstriction in asthmatic subjects is far from concluded. 5. Two possibilities are that either adenosine acts directly on luminal mast cells to upregulate histamine secretion, or it acts to initiate neuronal reflexes which stimulate histamine release indirectly and possibly activate peptidergic and/or cholinergic pathways.

Adenosine↗
PubMed1990

Contribution of histamine and prostanoids to bronchoconstriction provoked by inhaled bradykinin in atopic asthma.

Bradykinin, a nonapeptide cleavage product of high molecular weight kininogen, is a potent bronchoconstrictor agonist in asthma; however, its mechanism of action is not known. Since bradykinin has been shown to stimulate mediator release from mast cells and augment the release of prostanoids, we have examined the effect of a selective histamine H1 receptor antagonist, terfenadine and a potent cyclooxygenase inhibitor, flurbiprofen on bronchoconstriction provoked by inhaled bradykinin in asthma. As a bronchial provocation procedure bradykinin challenge was repeatable to within 1 doubling dilution. In nine atopic asthmatic subjects, terfenadine 180 mg, when compared to placebo, increased the geometric mean provocation concentration of inhaled agonist required to reduce FEV1 by 20% of baseline (PC20) from 0.7 to greater than 22.9 mg/ml for histamine (P less than 0.01) and 0.3 to 0.5 mg/ml for bradykinin (P less than 0.01). In a further nine atopic asthmatics, flurbiprofen 150 mg when compared to placebo produced a small but significant protection of the airways against bradykinin, geometric mean PC20 increasing from 0.40 to 0.79 mg/ml (P less than 0.05). We conclude that bradykinin is a potent bronchoconstrictor agonist in asthma, being approximately 9.5 times more potent than histamine in molar terms. Pharmacological intervention with terfenadine and flurbiprofen led to a significant protection of the airways against the constrictor effect of bradykinin but the effect in each case was small. Thus, while histamine and prostanoids may contribute as mediators of bradykinin-induced bronchoconstriction, they are unlikely to account for the majority of the response.

Adult↗
PubMed1990

Inhaled PAF fails to induce airway hyperresponsiveness to methacholine in normal human subjects.

The effects of three increasing doses of platelet-activating factor (PAF) on airway caliber and methacholine bronchial responsiveness were studied. On separate occasions nine normal subjects inhaled a single cumulative provocation concentration of methacholine (control) causing a 40% fall (PC40 Vp30) in maximum expiratory flow rate at 70% of base-line vital capacity below total lung capacity during a partial forced expiratory maneuver or 100 or 200 micrograms PAF, and seven subjects inhaled a further dose of 400 micrograms PAF. Methacholine responsiveness was measured before, at 3 and 7 h, then on days 1, 2, 3, 4, 7, 10, and 14 after each challenge. The maximum falls in Vp30 appeared dose dependent, but a significant difference between the magnitude of the responses was only observed between the 400- and 100-micrograms PAF dose (P less than 0.05). During the control period repeated methacholine challenges resulted in a progressive increase in cumulative provocation concentration of an agonist causing a 20% fall in forced expiratory volume in 1 s from base line, reaching significance on days 1 and 2 (2.44- and 2.4-fold of base line, respectively, P less than 0.01) before returning to base line on day 7. No difference was seen in methacholine responsiveness after any of the three doses of PAF compared with that after the control. We conclude that PAF causes dose-dependent bronchoconstriction but does not change airways responsiveness to methacholine and that repeated high-dose methacholine challenge leads to loss of responsiveness to this agonist.

Administration, Inhalation↗
PubMed1990

Effect of 15-(s)-hydroxyeicosatetraenoic acid on allergen-induced asthmatic responses.

15-(s)-hydroxyeicosatetraenoic acid (15-HETE), a major oxidative metabolite of arachidonic acid in human lungs, has complex actions on the 5-lipoxygenase pathway in different cell systems. We have examined the effect of inhaled 15-HETE on the early and late asthmatic responses (EAR and LAR) and the associated change in nonspecific bronchial responsiveness to inhaled allergen in 10 subjects with atopic asthma. On 2 separate days 3 wk apart, subjects inhaled either 70 nmol 15-HETE or the diluent (sodium phosphate buffer) in a randomized and double-blind fashion, followed by a dose of allergen that had previously been shown to produce a 25% fall in baseline FEV1. Analysis of the area under the FEV1 response time course curves (AUC) in the first hour revealed that preinhalation with 15-HETE increased the EAR by 39% from that achieved after the diluent (p less than 0.05). In the seven subjects who were classified as dual responders by developing a LAR previously (greater than 15% fall in baseline FEV1 3 to 8 h after allergen challenge), 15-HETE did not cause any significant change in the magnitude of the LAR when compared with that observed after placebo. The values of the provocation concentration of histamine causing a 20% fall in FEV1 (Pc20) at 8 h postchallenge were significantly reduced on both study days when compared with the corresponding preallergen challenge values, whether analyzed for the whole group or for the seven dual responders (p less than 0.05). 15-HETE had no effect on this allergen-acquired airway hyperresponsiveness to histamine when compared with the diluent.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Comparative airway response to inhaled bradykinin, kallidin, and [des-Arg9]bradykinin in normal and asthmatic subjects.

Bradykinin, kallidin (lys-bradykinin), and [des-Arg9]bradykinin are oligopeptides that may contribute as mediators in the pathogenesis of asthma by interacting with specific receptors designated B1 and B2. In this study, we have investigated the airway response to inhaled bradykinin, kallidin, and [des-Arg9]bradykinin in normal and asthmatic subjects. Changes in airway caliber were followed as maximum expiratory flow at 30% of the vital capacity (Vp30) and as forced expiratory volume in 1 s (FEV1). Only one of the six normal subjects responded to bradykinin at the maximum cumulative concentration (5.33 mg/ml). Neither kallidin nor [des-Arg9]bradykinin had any measurable bronchoconstrictor effect in the normal subjects whether airway caliber was measured as Vp30 or FEV1. In the 10 subjects with asthma, bradykinin and kallidin, but not [des-Arg9]bradykinin, produced a concentration-related fall in FEV1. The geometric mean provocation concentrations of inhaled agonist reducing FEV1 by 20% of baseline were 0.03, 0.08, and 0.44 mg/ml for bradykinin, kallidin, and histamine, respectively. Bronchoconstriction produced by bradykinin and kallidin was maximal within 3 to 5 min with recovery occurring over 30 to 45 min. Because bradykinin and kallidin are agonists of B2 receptors and [des-Arg9]bradykinin is an agonist for B1 receptors, these in vivo structure activity studies suggest that asthmatic, but not normal, airways are hyperresponsive to kinins when compared to histamine and that this potent bronchoconstrictor action is a specific pharmacologic effect compatible with the stimulation of B2 receptors or a variant of these.

Adult↗
PubMed1990

Influence of antihistamine (astemizole) and anticholinergic drugs (ipratropium bromide) on bronchoconstriction induced by substance P.

Several studies have demonstrated that neuropeptides are present in bronchial tissue. The aim of this study was to evaluate in vivo the influence of antihistamine in comparison to an anticholinergic drug on bronchospasm induced by inhalation of substance P (SP). Seven moderate asthmatic patients (mean age = 34.4 +/- 8.9), five being female, were studied. The acetate salt of SP was prepared in 0.9% saline to produce a dose range of 23 to 184 x 10(-6) mol. Patients were studied on three separate days with an interval of 3 weeks between challenges. On the first day the dose of SP producing a 20% change in FEV1 was calculated from the individual semilogarithmic dose-response curve. On subsequent days, in a randomized double-blind manner, the patients were treated either with astemizole (20 mg BID for three days) and placebo ipratropium bromide or with placebo of astemizole (twice a day for three days) and with pressurized aerosol of ipratropium bromide (IB) (40 micrograms 20 minutes before the challenge). Two way analysis of variance was used for statistical analysis. Our results demonstrated that inhaled SP is able to produce a dose-response curve of bronchoconstriction with a geometric mean of PD20 of 50.51 x 10(-6) moles (37.38 to 68.19 x 10(-6) mol). Treatment with astemizole induced a geometric mean PD20 of 65.51 x 10(-6) mol (33.02 to 130.21 x 10(-6) mol) and the premedication with the IB induced a significant (P less than .05) shift of dose-response curve to SP (geometric mean PD20 = 109.1 x 10(-6) mol; 58.67 to 204.05 x 10(-6) mol). Our results demonstrated that bronchoconstriction induced by SP could be attributed to a weak cholinergic activation and not to histamine release.

Administration, Inhalation↗
PubMed1990

The influence of cyclooxygenase inhibition on the loss of bronchoconstrictor response to repeated bradykinin challenge in asthma.

Bradykinin is a naturally occurring nonapeptide which may contribute to the pathogenesis of bronchial asthma. When inhaled by asthmatic subjects it is a potent bronchoconstrictor, but with repeated challenge airways responsiveness to the peptide decreases markedly. In vitro studies suggest that loss of bradykinin responsiveness may be due to the secondary generation of relaxant prostanoids. We have used the potent cyclooxygenase inhibitor flurbiprofen to investigate the potential role of prostanoid generation in bradykinin tachyphylaxis in eight asthmatic patients. The effects of oral flurbiprofen (150 mg) and matched placebo were observed on two consecutive dose response studies with inhaled bradykinin and histamine in a double-blind, randomized study. Venous blood was taken to measure the serum concentration of thromboxane B2 (TxB2) as a check on the extent of cyclooxygenase blockade achieved by flurbiprofen. Following recovery from the first challenge with bradykinin, the asthmatic airways showed a reduced response to a second challenge with this nonapeptide, the provocative concentration producing a 20% fall from baseline (PC20) increasing from 0.07 to 0.42 mg.ml-1 (p less than 0.01). The airway response to inhaled histamine after the second bradykinin challenge was not significantly changed. In the presence of demonstrable cyclooxygenase inhibition, flurbiprofen failed to prevent the development of reduced responsiveness to bradykinin observed on the second challenge, the PC20 increasing from 0.10 to 0.48 mg.ml-1 (p less than 0.01). This study demonstrates that repeated exposure to inhaled bradykinin results in loss of the bronchoconstrictor response which appears specific for this agonist and not secondary to the increased generation of protective prostanoids.

Adolescent↗
PubMed1990

Inhibition of adenosine 5'-monophosphate- and methacholine-induced bronchoconstriction in asthma by inhaled frusemide.

Recent studies have shown that inhaled frusemide exerts a protective effect against various bronchoconstrictor stimuli in asthma including exercise, fog and allergen. Since mast cell activation seems to be a component of bronchoconstriction by these stimuli it is possible that inhibition of mediator release accounts for some or all of the inhibitory effects of frusemide in asthma. Since inhaled adenosine 5'-monophosphate (AMP) is another stimulus that produces bronchoconstriction by augmenting mast cell mediator release, we have investigated the ability of this drug to antagonise the airway effects of inhaled AMP and methacholine in a randomized, placebo-controlled, double-blind study of 12 asthmatic subjects. Inhaled frusemide (approximately 28 mg) administered 5 min prior to challenge increased the provocation concentration of inhaled AMP and methacholine required to reduce forced expiratory volume in one second (FEV) by 20% from baseline from 30 to 96 mg.ml-1 (p less than 0.01) and from 1.1 to 1.8 mg.ml-1 (p less than 0.01), respectively. The protection that frusemide afforded against AMP was significantly greater than that against methacholine (p less than 0.05). These data suggest that inhaled frusemide may serve as a functional antagonist against a smooth muscle spasmogen, such as methacholine, possibly by augmenting prostanoid generation. Its more potent activity against AMP and other bronchoconstrictor stimuli, that are considered to involve mast cell mediators, suggests an additional action on mast cell functions possibly at the level of the Ca++/Mg(++)-ATPase.

Adenosine Monophosphate↗