The effect of inhaled frusemide on airway sensitivity to inhaled 4.5% sodium chloride aerosol in asthmatic subjects.

BACKGROUND: Frusemide inhaled by asthmatic subjects before a variety of indirect bronchial challenges inhibits the airway response to these challenges. Since inhalation of hyperosmolar saline is an indirect bronchial challenge, the effect of inhaled frusemide and its vehicle on airway sensitivity to a 4.5% sodium chloride (NaCl) aerosol challenge was investigated. METHODS: Eleven asthmatic subjects (five females, six males) who had a 20% fall in forced expiratory volume in one second after 4.5% NaCl challenge were enrolled in this double blind controlled crossover trial. Sensitivity was measured as the dose of aerosol required to provoke a 20% fall in FEV1. Frusemide (33.2 mg) or its vehicle was delivered through a Fisoneb ultrasonic nebuliser and inhaled 10 minutes before challenge with 4.5% NaCl. A Mistogen ultrasonic nebuliser was used to generate the 4.5% NaCl aerosol and FEV1 was measured before and one minute after each challenge period of 0.5, one, two, four, eight, eight and eight minutes. The doubling dose difference for PD20 was calculated. RESULTS: Frusemide or vehicle had no effect on baseline lung function. The geometric mean PD20 after vehicle was 1.3 ml with a 95% confidence interval of 0.7-2.3 and after frusemide was 8.2 ml with a 95% confidence interval of 4.7-14.1. This represented a 2.6 doubling dose increase in PD20 after frusemide inhalation. In five of the 11 subjects an increase from baseline FEV1 occurred after exposure to 4.5% NaCl challenge in the presence of frusemide. This transient bronchodilatation may be caused by the release of prostaglandin E2. CONCLUSION: Inhalation of frusemide is very effective in delaying airway narrowing induced by an aerosol of 4.5% NaCl in asthmatic subjects.     

Characterisation of bronchoconstrictor responses to sodium metabisulphite aerosol in atopic subjects with and without asthma.

Inhalation of sodium metabisulphite is thought to induce bronchoconstriction by release of sulphur dioxide. We sought to establish the reproducibility of the airway response to inhaled sodium metabisulphite given in increasing doubling concentrations (0.3 to 160 mg/ml) to 13 asthmatic and five atopic non-asthmatic subjects and the contribution of cholinergic mechanisms to this response. In 15 of the 18 subjects bronchoconstriction was sufficient to allow calculation of the dose of metabisulphite causing a 20% reduction in the forced expiratory volume in one second (FEV1) from baseline values (PD20 metabisulphite). The 95% confidence limit for the difference between this and a second PD20 metabisulphite determined 2-14 days later was 2.5 doubling doses. The difference between repeat PD20 metabisulphite measurements was unrelated to the number of days between challenges or change in baseline FEV1. Ten subjects returned for a third study 3-120 days after the second challenge; variability in PD20 metabisulphite did not differ from that seen between the first and second challenges. PD20 methacholine was determined between the two metabisulphite challenges and found to correlate with PD20 metabisulphite (r = 0.71). Inhaled ipratropium bromide 200 micrograms given in a randomised, placebo controlled, crossover study to 10 subjects increased PD20 methacholine 42 fold but had no significant effect on the response to metabisulphite. A single inhalation of the PD20 metabisulphite in five subjects induced maximal bronchoconstriction 2-3 minutes after inhalation, with a plateau in FEV1 lasting a further four minutes before recovery. A further single inhalation of the same PD20 dose 43 minutes later produced a 27% (SEM 4%) smaller fall in FEV1 than the first inhalation. These results show that metabisulphite PD20 values measured over days and weeks show similar reproducibility to those reported for histamine inhalation and that PD20 metabisulphite correlates with methacholine responsiveness. Most of the bronchoconstriction is not inhibited by antimuscarinic agents; the underlying mechanisms require further investigation.     

Effect of inhaled frusemide on the early response to antigen and subsequent change in airway reactivity in atopic patients.

The purpose of this study was to investigate whether inhaled frusemide was able to inhibit the increase in nonspecific bronchial reactivity that occurs after the early response to allergen exposure in subjects with allergic rhinitis or asthma (or both). Ten symptom free patients initially underwent a challenge with methacholine, to determine the dose of methacholine that caused a 15% fall in FEV1 (PD15 FEV1 meth) and a challenge with a specific allergen, to determine the concentration of allergen that caused a fall in FEV1 of at least 15%. On two further occasions they inhaled allergen concentration that had caused the greater than or equal to 15% fall in FEV1 preceded by inhaled frusemide (40 mg frusemide in 4 ml buffered saline) or placebo (4 ml of diluent solution), according to a randomised, double blind, crossover design. All allergen studies were separated by at least seven days. A methacholine challenge was performed two hours after the allergen challenge, a time when the early response to allergen had completely resolved. Frusemide inhibited the early response to antigen, causing mean (95% confidence interval) protection of 87.6% (96-80%) for the maximum fall in FEV1. The increase in non-specific airway reactivity that occurred after antigen when this was preceded by placebo was reduced by frusemide. The mean (95% CI) difference in PD15 values between the placebo and the frusemide days was 1.73 (2.30-1.16) doubling doses of methacholine. These results confirm that frusemide is highly effective in preventing the early response to allergen, and show that it inhibits the increase in reactivity to methacholine that follows the early response.     

Relation between the bronchial obstructive response to inhaled lipopolysaccharide and bronchial responsiveness to histamine.

BACKGROUND: Bronchoconstriction has developed after inhalation of lipopolysaccharide in a dose of 20 micrograms in asthmatic patients and of 200 micrograms in normal subjects. This study set out to determine whether the bronchial response to lipopolysaccharide was related to non-specific bronchial responsiveness and atopy. METHODS: Sixteen subjects with a fall in specific airway conductance of 40% (PD40sGaw) after inhaling up to 900 micrograms histamine inhaled 20 micrograms lipopolysaccharide (from Escherichia coli type 026:B6) a week after bronchial challenge with a control solution of saline. The bronchial response over five hours was measured as change in FEV1 and area under the FEV1-time curve. RESULTS: FEV1 fell significantly more after lipopolysaccharide than after diluent inhalation, the difference in mean (SE) FEV1 being 4.6% (5.4%); response was maximal 60 minutes after lipopolysaccharide inhalation and lasted more than five hours. Histamine PD20FEV1 and PD40sGaw correlated with the fall in FEV1 after lipopolysaccharide inhalation. There was no difference in the proportions of responders and non-responders to lipopolysaccharide who were atopic. CONCLUSION: Lipopolysaccharide induced bronchial obstruction is associated with non-specific responsiveness but not with atopy.     

Evaluation of ultrasonically nebulised solutions for provocation testing in patients with asthma.

The airway response to the inhalation of ultrasonically nebulised distilled water was determined in 55 asthmatic patients and 16 normal subjects. We calculated the dose of water required to induce a 20% reduction (PD20) in forced expiratory volume in one second (FEV1) by measuring the output of the nebuliser and the volume ventilated by each subject. Forty-eight of the asthmatic patients had a PD20 of 9 ml or less but three patients required as much as 24 ml. A PD20 was not recorded in the normal subjects and the challenge was stopped after 33 ml. In 12 patients the challenge was repeated within six months and the airway response was shown to be reproducible at equivalent doses of water. In a separate group of 11 patients there was, however, a highly significant reduction in the percentage fall in FEV1 when equivalent doses of water were given on two occasions 40 minutes apart. When the temperature of the inhaled water was increased from 22 degrees C to 36 degrees C eight of 10 patients had a similar change in FEV1 with equivalent doses of water. The airways obstruction induced by the inhalation of water was readily reversed with salbutamol administered by aerosol. In some patients a challenge with water or 3.6% saline was repeated after pretreatment with sodium cromoglycate, atropine methonitrate, and verapamil hydrochloride, all given as aerosols. The airway response to the equivalent dose of water or saline was significantly reduced after treatment with sodium cromoglycate but not atropine or verapamil.     

Comparison of sulphur dioxide and metabisulphite airway reactivity in subjects with asthma.

BACKGROUND--In asthmatic subjects bronchoconstriction is induced by inhalation of the common food preservatives sulphur dioxide (SO2) and metabisulphite (MBS). SO2 and MBS challenges share many similarities, but it is not known whether they are equivalent. In this study of subjects with mild clinical asthma equivalence was assessed by comparing SO2 and MBS reactivity by estimating the total dose of SO2 inhaled during SO2 and MBS challenges, and by calculating SO2 uptake during both challenges. In addition, as the MBS solutions inhaled were acidic and hyperosmolar, the effect of these factors on MBS responsiveness was investigated. METHODS--Fifteen subjects were challenged on separate days with doubling (0.5 to 8.0 ppm) concentrations of SO2 gas inhaled during three minute periods of isocapnic hyperventilation and MBS administered in doses ranging from 0.1 to 12.8 mumol using the Wright protocol. On two other days SO2 and MBS challenges were preceded by a challenge with phosphate buffered saline (PBS) solutions of pH and osmolarity similar to MBS solutions. Response was measured as the dose or concentration causing a 20% fall in FEV1 (PD20 or PC20). RESULTS--All subjects reacted to MBS and 14 responded to SO2. Geometric mean histamine PD20 was 1.61 mumol (95% confidence interval 0.72 to 3.60). MBS and SO2 airway responsiveness were not significantly related. Estimates of the mean concentration of SO2 inhaled during SO2 and MBS challenges differed, as did estimates of the mean SO2 uptake during both challenges. MBS and SO2 reactivity were not affected by prior challenge with PBS solutions. CONCLUSIONS--SO2 and MBS challenges are not comparable. MBS reactivity was not affected by the hyperosmolar, acidic nature of its solutions.     

Lidocaine exerts its effect on induced bronchospasm by mitigating reflexes, rather than by attenuation of smooth muscle contraction

BACKGROUND: Lidocaine inhalation attenuates histamine-induced bronchoconstriction, as well as bronchoconstriction elicited by mechanical irritation. This effect could be mediated by direct effects on smooth muscle or by reflex attenuation. Therefore, we evaluated whether lidocaine attenuated the bronchial response of direct smooth muscle stimulation with methacholine. METHODS: In 15 volunteers with bronchial hyperreactivity, a methacholine challenge was performed following the inhalation of lidocaine, dyclonine (which does not attenuate bronchial reactivity) or saline on three different days in a randomized, double-blind fashion. Lung function, response to methacholine, and lidocaine and dyclonine plasma concentrations were measured. RESULTS: The inhaled methacholine concentration (PC20) necessary for a 20% decrease in the forced expiratory volume in 1 s (FEV1) was 8.8 +/- 6.1 mg/ml at the screening evaluation. The sensitivity to methacholine challenge (PC20) remained unchanged regardless of which solution was inhaled (9.1 +/- 7.5 mg/ml for lidocaine, 10.2 +/- 9.0 mg/ml for dyclonine and 9.8 +/- 8.3 mg/ml for saline; P = 0.58, means +/- standard deviation). Furthermore, the inhalation of all three solutions caused a significant decrease in FEV1 from baseline (P = 0.0007), with a significantly larger effect for dyclonine than lidocaine (P = 0.0153). CONCLUSIONS: Although both inhaled and intravenous lidocaine attenuates histamine-evoked bronchoconstriction, it does not alter the response to methacholine. Therefore, the attenuation of bronchial reactivity by lidocaine appears to be related solely to neurally mediated reflex attenuation, rather than to the attenuation of direct constriction of airway smooth muscle.     

Dose equivalence and bronchoprotective effects of salmeterol and salbutamol in asthma

BACKGROUND: Salbutamol is the most widely prescribed short acting beta 2 agonist and salmeterol is the first long acting inhaled beta 2 agonist. The dose equivalence of salmeterol and salbutamol is disputed. Estimates of weight-for-weight dose ratio have ranged from 1:2 to 1:16. A study was undertaken to clarify the true dose ratio. METHODS: The bronchoprotection afforded against repeated methacholine challenge by inhaled salmeterol 25 micrograms and 100 micrograms and salbutamol 100 micrograms and 400 micrograms was compared in a randomised, double blind, placebo controlled, crossover trial. Subjects were 16 stable asthmatics with a baseline forced expiratory volume in one second (FEV1) of > or = 65% predicted, screening concentration provoking a fall in FEV1 of 20% (PC20FEV1) of < or = 8mg/ml, and a shift in PC20FEV1 of more than two doubling concentration steps following inhalation of salbutamol 400 micrograms. On five separate occasions subjects underwent methacholine challenge before and 30 and 120 minutes after drug administration. PD20FEV1 was calculated for each challenge. FEV1 at 90 minutes after drug administration was also recorded. RESULTS: Bronchoprotection afforded by salmeterol was increased at 120 minutes compared with 30 minutes and protection by salbutamol was decreased. Protection by both doses of salmeterol was similar to salbutamol 100 micrograms at 30 minutes but significantly greater at 120 minutes. FEV1 at 90 minutes was significantly greater after salmeterol 100 micrograms than after placebo, but there were no other significant differences between treatments. Maximal observed protection was equivalent for salmeterol 100 micrograms and salbutamol 400 micrograms. CONCLUSIONS: The data are compatible with a weight-for- weight dose ratio for salmeterol:salbutamol of < or = 1:4.




     

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.     

Effect of regular inhaled salbutamol on airway responsiveness and airway inflammation in rhinitic non-asthmatic subjects

BACKGROUND: Regular, inhaled beta 2 agonists may increase airway responsiveness in asthmatic subjects. The mechanism is not known but may be via an increase in airway inflammation. A study was undertaken to examine the effect of regular inhaled salbutamol on airway responsiveness to methacholine and hypertonic saline, on the maximal response plateau to methacholine, and on inflammatory cells in induced sputum in rhinitic non-asthmatic subjects. METHODS: Thirty subjects with a baseline maximal response plateau of > 15% fall in forced expiratory volume in one second (FEV1) entered a randomised, placebo controlled, parallel trial consisting of two weeks run in, four weeks of treatment, and two weeks washout. Methacholine challenges were performed at the beginning of the run in period, before treatment, after treatment, and after washout. Hypertonic saline challenges were performed before and after treatment and induced sputum samples were collected for differential cell counting. RESULTS: There was no change in airway responsiveness, maximal response plateau to methacholine, or in induced sputum eosinophils or mast cells. The maximum fall in FEV1 after hypertonic saline increased in the salbutamol group (median change 6.0%, interquartile range (IQR) 11.0) but did not change in the placebo group (median change 1.3%, IQR 5.5). CONCLUSIONS: Regular inhaled salbutamol for four weeks increases airway responsiveness to hypertonic saline but does not alter airway responsiveness to methacholine or cells in induced sputum in non-asthmatic individuals with rhinitis. The relevance of these findings to asthmatic subjects has not been established.


     

Repeatability of methacholine challenge in asthmatic children measured by change in transcutaneous oxygen tension.

BACKGROUND: The airway response to bronchial provocation may be evaluated by monitoring the fall in transcutaneous oxygen tension (PtcO2) but the repeatability of this method has not been rigorously assessed. METHODS: To determine the repeatability of this indirect method of assessment, bronchial challenge was performed with methacholine in nine children with stable asthma (age range 6-12 years) and was repeated 24 hours later. The response was determined by the fall both in forced expiratory volume in one second (FEV1) and in PtcO2. A modified tidal inhalation protocol was used in which quadrupling concentrations of methacholine were given, thereby reducing the time taken for the full challenge by almost half. The concentrations of methacholine that provoked a 20% decrease in FEV1 (PC20FEV1) and 15% and 10% falls in PtcO2 (PC15PtcO2, PC10PtcO2) were calculated. RESULTS: Repeatability measures, assessed as the 95% range for a single determination, were +/- 0.96 and +/- 1.12 doubling concentration differences respectively for PC15PtcO2 and PC10PtcO2 and +/- 0.80 for PC20FEV1. CONCLUSION: This challenge method using quadrupling concentrations and an indirect assessment of the response by PtcO2 was sufficiently repeatable for clinical use and compared favourably with repeated challenge assessed by FEV1. The PtcO2 method is simple and effort independent, and should prove particularly useful for measuring bronchial reactivity in young children.     

Effect of inhaled prostaglandin E2 on bronchial reactivity to sodium metabisulphite and methacholine in patients with asthma.

Inhaled frusemide protects against the bronchoconstrictor response to a wide range of stimuli that cause bronchoconstriction by indirect mechanisms. One possible explanation for this protection relates to the known ability of frusemide to enhance synthesis of prostaglandin E2 (PGE2). Studies in vitro suggest that PGE2 might protect against indirectly acting bronchoconstrictor challenges rather than those that act directly on airway smooth muscle, though little is known about the effects of PGE2 in vivo. The effect of inhaled PGE2 on the bronchoconstrictor response to inhaled sodium metabisulphite (a stimulus with an indirect action) and methacholine (which acts directly on airway smooth muscle) was studied in nine patients with asthma. Subjects were studied on four days, inhaling PGE2 (100 micrograms) or placebo in a double blind fashion followed immediately by a cumulative dose challenge with sodium metabisulphite or methacholine. The response to the constrictor stimuli was measured as the provocative dose causing a 20% fall in FEV1 (PD20). There was no significant change in FEV1 after inhaled PGE2 compared with placebo, nor any significant change in the response to methacholine; the geometric mean methacholine PD20 was 0.9 mumol after PGE2 and 0.56 mumol after placebo (mean difference 0.7 (95% confidence limits--0.1, 1.5) doubling doses). PGE2, however, protected against sodium metabisulphite, the geometric mean sodium metabisulphite PD20 being 11.8 mumol after PGE2 and 1.8 mumol after placebo (mean difference 2.5 (95% CL 1.9, 3.1) doubling doses). PGE2 conferred significantly greater protection against sodium metabisulphite than methacholine (mean difference 1.8 (95% CL 0.8, 2.8) doubling doses). This suggests that PGE2, like frusemide, has an inhibitory effect on pathways relevant to the bronchoconstriction induced by sodium metabisulphite, with little or no effect on those relevant to methacholine.     

Effects of platelet activating factor on airway calibre, airway responsiveness, and circulating cells in asthmatic subjects.

The effects of inhaled platelet activating factor were compared with those of inhaled methacholine (control) on airway calibre, airway responsiveness to methacholine and isoprenaline, and circulating cells in eight subjects with mild, stable asthma. Platelet activating factor was given in six doses at 15 minute intervals and airway response measured as change in partial expiratory flow at 30% of vital capacity (Vp30). Platelet activating factor caused a fall in Vp30, the mean (SEM) maximum percentage fall being 28.9 (4.2) five minutes after the first dose (12 micrograms) and 50.9 (8.0) after the second dose (24 micrograms). Tachyphylaxis occurred, however, with the four subsequent doses of inhaled platelet activating factor. There was transient neutropenia after the first dose, from a mean of 3.6 (0.2) x 10(9) to 2.2 (0.5) x 10(9) neutrophils/l; this response also showed tachyphylaxis with subsequent doses. The mean PC40 (the concentration of methacholine needed to cause a 40% fall in Vp30) was unchanged one, three, and seven days after administration of platelet activating factor. There was no significant correlation between baseline PC40 methacholine and the maximal fall in Vp30 after either the first (12 micrograms) or the second dose (24 micrograms) of platelet activating factor. The control challenge with methacholine produced a degree of bronchoconstriction similar to that of platelet activating factor but was not associated with any significant change in bronchial responsiveness or in circulating cells. The bronchodilator response to inhaled isoprenaline measured three days after inhalation of platelet activating factor and of methacholine was similar after the two challenges. Thus asthmatic subjects who are hyperresponsive to methacholine show a similar bronchoconstrictor response to platelet activating factor, as has been observed in normal subjects; overall this did not cause airway hyperresponsiveness to methacholine.     

Effect of allergen challenge on airway responsiveness to histamine and sodium metabisulphite in mild asthma.

BACKGROUND: Airway responsiveness to histamine and methacholine, direct smooth muscle spasmogens, is increased following inhalation of allergen. Although the aetiology of this phenomenon is unclear, increased cellular or neural activity may be involved since allergen also induces increases in airway responsiveness to the mast cell stimulus adenosine-5'-monophosphate (AMP) and the neural stimulus bradykinin. METHODS: To explore this further, the airway responsiveness to sodium metabisulphite (MBS), an indirect neural stimulus with similar characteristics to bradykinin, was compared in 18 mild steroid-naive asthmatic subjects with the airway responsiveness to histamine before and after allergen challenge with extracts of house dust mite, grass pollen, or cat. All subjects inhaled doubling increments of histamine and MBS until the concentration provoking a 20% fall in forced expiratory volume in one second (PC20) was reached before and three hours after allergen challenge. Twelve of the subjects had additional challenges at 24 hours after the allergen. RESULTS: Following allergen challenge all subjects showed an early response and 14 also had a late asthmatic response. For histamine there was a significant increase in airway responsiveness at both three and 24 hours compared with values before the allergen (0.89 (0.25) and 1.53 (0.52) doubling dose changes, respectively). In contrast, airway responsiveness to MBS was unaltered by allergen challenge (0.29 (0.27) and -0.33 (0.28) doubling dose changes compared with pre-allergen values at three and 24 hours, respectively). CONCLUSION: These data suggest that activation of airway sensory nerves is unlikely to contribute to the increase in airway responsiveness following inhalation of allergen. The previously observed allergen induced increase in airway responsiveness to bradykinin and AMP may involve non-neural pathways.     

Comparison of three inhaled non-steroidal anti-inflammatory drugs on the airway response to sodium metabisulphite and adenosine 5'-monophosphate challenge in asthma.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are used to assess the role of prostaglandins in asthma but their effects on bronchoconstrictor challenges have been inconsistent. The effects of three nebulised nonsteroidal anti-inflammatory drugs on the airway response to inhaled sodium metabisulphite (MBS) and adenosine 5'-monophosphate (AMP) were compared in the same asthmatic subjects to see whether contractile prostaglandins were involved in MBS or AMP induced bronchoconstriction. A possible protective effect of the osmolarity or pH of the inhaled solutions was also assessed. METHODS: Two double blind placebo controlled studies were carried out. In study 1, 15 non-aspirin sensitive patients with mild asthma attended on four occasions and inhaled 5 ml of lysine aspirin (L-aspirin) 900 mg, indomethacin 50 mg, sodium salicylate 800 mg, or saline 20 minutes before an inhaled MBS challenge. On four further occasions 14 of the patients inhaled the same solutions followed by an inhaled AMP challenge. In study 2, 10 of the patients attended on four additional occasions and inhaled 5 ml of 0.9%, 3%, 10%, or 9.5% saline with indomethacin 50 mg 20 minutes before an inhaled MBS challenge. RESULTS: In study 1 inhaled lysine aspirin had a similar effect on MBS and AMP induced bronchoconstriction, increasing the provocative dose causing a 20% fall in FEV1 (PD20) by 1.29 (95% CI 0.54 to 2.03) and 1.23 (95% CI 0.53 to 1.93) doubling doses, respectively. Indomethacin increased the MBS PD20 and AMP PD20 by 0.64 (95% CI -0.1 to 1.38) and 0.99 (95% CI 0.29 to 1.69) doubling doses, respectively. Sodium salicylate had no significant effect on either challenge. The two solutions causing most inhibition were the most acidic and the most alkaline. In study 2 inhaled 9.5% saline with indomethacin (osmolarity 3005 mOsm/kg) increased the MBS PD20 by 1.1 doubling doses (95% CI 0.2 to 2.0) compared with only 0.09 (95% CI -0.83 to 1.0) and 0.04 (95% CI -0.88 to 0.95) doubling doses with 3% saline (918 mOsm/kg) and 10% saline (2994 mOsm/ kg), respectively. CONCLUSIONS: Inhaled L-aspirin and indomethacin have broadly similar protective effects against MBS and AMP induced bronchoconstriction in the doses given, although the effect of indomethacin on MBS was not quite statistically significant. The osmolarity and pH of the solutions did not appear to be important determinants of the response. The effect of L-aspirin and indomethacin is likely to be the result of cyclooxygenase inhibition reducing the production of contractile prostaglandins during MBS and AMP challenge.     

Perception of breathlessness during bronchoconstriction induced by antigen, exercise, and histamine challenges.

Perception of breathlessness was studied in eight patients with mild, stable asthma after a histamine and exercise challenge performed before and 24 and 48 hours respectively after an antigen challenge. FEV1 and perception of breathlessness, evaluated by Borg's 10 point category scale, were measured after each administration of doubling antigen or histamine concentrations to achieve a greater than 20% fall in FEV1, and after six minutes of steady state exercise at 80% of maximal oxygen consumption (VO2max). The geometric mean provocative concentration of histamine causing a 20% fall in FEV1 (PC20) fell from 1.67 mg/ml before antigen challenge to 0.52 mg/ml 24 hours after the challenge. The median maximal % fall in FEV1 with exercise was 24.9% (range 10.5-40.5%) before and 30.6% (range 13.8-52.3%) 48 hours after antigen challenge. The median maximum % fall in FEV1 after antigen inhalation was 20.1% (range 13.3-35.2%) within the first hour; only two subjects had a late fall in FEV1 (23% and 58%). The median (range) of Borg scores obtained when FEV1 was reduced by 20% did not differ significantly for the three types of acute challenges: 1.25 (0.5-2.5) and 1.0 (0.5-3.0) after histamine tests, 1.0 (0.5-4.1) and 1.55 (0.5-2.0) after exercise, and 1.5 (0-3.0) after antigen challenge. In the two subjects who had a late response to antigen the Borg score was reduced for the same % fall in FEV1 as with the early response. It is concluded that the perception of breathlessness does not differ appreciably during the early response to histamine, antigen exposure, or exercise, but that it is reduced during the late asthmatic response. It was not influenced by previous antigen exposure, despite an increase in airway responsiveness.     

Effects of methacholine induced bronchoconstriction and procaterol induced bronchodilation on cough receptor sensitivity to inhaled capsaicin and tartaric acid.

BACKGROUND: The direct effect of bronchoconstriction on cough receptor sensitivity is unknown, and the antitussive effect of beta 2 adrenergic agonists in man has been controversial. This study was designed to throw light on these questions. METHODS: The threshold of the cough response to inhaled capsaicin, a stimulant acting on C fibre endings, and tartaric acid, a chemostimulant, was measured before and 10 minutes after inhalation of methacholine, which caused a nearly 20% fall in forced expiratory volume in one second (FEV1), in 14 normal subjects (study 1), and also before and 30 minutes after inhalation of procaterol (30 micrograms), placebo, and saline in eight normal subjects (study 2). Progressively increasing concentrations of capsaicin and tartaric acid solutions were inhaled for 15 seconds by mouth tidal breathing at one minute intervals and cough threshold was defined as the lowest concentration of capsaicin and tartaric acid that elicited five or more coughs. RESULTS: In study 1 the geometric mean values of the cough threshold of response to capsaicin and tartaric acid before methacholine callenge, 2.98 (GSE 1.30) micrograms/ml and 46.6 (1.22) mg/ml, were not significantly different from those of the response to methacholine inhalation, 3.45 (1.33) micrograms/ml and 32.9 (1.37) mg/ml. In study 2 the geometric mean value of the cough threshold of response to capsaicin before inhalation of procaterol (4.61 (GSE 1.84) micrograms/ml) was not different from that after inhalation of procaterol (4.61 (GSE 1.84) micrograms/ml), which had significant bronchodilator effects. The cough threshold was not altered by placebo or saline. CONCLUSIONS: These findings suggest that muscarinic receptor stimulation, bronchoconstriction, beta 2 receptor stimulation, or bronchodilation might have no direct effect on the sensitivity of the cough receptors in normal subjects.     

Attenuation of early and late phase allergen-induced bronchoconstriction in asthmatic subjects by a 5-lipoxygenase activating protein antagonist, BAYx 1005

BACKGROUND: The cysteinyl leukotrienes (LTC4, LTD4 and LTE4) have been implicated in the pathogenesis of allergen-induced airway responses. The effects of pretreatment with BAYx 1005, an inhibitor of leukotriene biosynthesis via antagonism of 5-lipoxygenase activating protein, on allergen-induced early and late asthmatic responses has been evaluated. METHODS: Eight atopic subjects with mild asthma participated in a two period, double blind, placebo controlled, cross-over trial. Subjects were selected on the basis of a forced expiratory volume in one second (FEV1) of > 70% predicted, a methacholine provocative concentration causing a 20% fall in FEV1 (PC20) of < 32 mg/ ml, a documented allergen- induced early response (EAR, > 15% fall in FEV1 0-1 hour after allergen inhalation) and late response (LAR, > 15% fall in FEV1 3-7 hours after allergen inhalation), and allergen-induced airway hyperresponsiveness (at least a doubling dose reduction in the methacholine PC20 30 hours after allergen inhalation). During the treatment periods subjects received BAYx 1005 (500 mg twice daily) or placebo for 3.5 days; treatment periods were separated by at least two weeks. On the third day of treatment, two hours after administration of medication, subjects performed an allergen inhalation challenge and FEV1 was measured for seven hours. RESULTS: Treatment with BAYx 1005 attenuated the magnitude of both the allergen-induced early and late asthmatic responses. The mean (SE) maximal fall in FEV1 during the EAR was 26.6 (3.3)% during placebo treatment and 11.4 (3.3)% during treatment with BAYx 1005 (mean difference 15.2 (95% confidence interval (CI) 9.4 to 21.00) with a mean protection afforded by BAYx 1005 of 57.1%. The mean (SE) maximal fall in FEV1 during the LAR was 19.8 (5.7)% during placebo treatment and 10.7 (4.4)% during BAYx 1005 treatment (mean difference 9.2 (95% CI 1.4 to 17.0) with a mean protection afforded by BAYx 1005 of 46.0%. The area under the time response curve (AUC0-3) was also reduced after treatment with BAYx 1005 compared with placebo by 86.5%.h (mean difference 26.3 (95% CI 17.1 to 38.5)) and the AUC3-7 by 59.6%.h (mean difference 26.9 (95% CI-3.8 to 57.6)). CONCLUSIONS: These results show that antagonism of 5-lipoxygenase activating protein can attenuate allergen-induced bronchoconstrictor responses and support an important role for the cysteinyl leukotrienes in mediating these asthmatic responses.


     

Effect of inhaled piriprost (U-60, 257) a novel leukotriene inhibitor, on allergen and exercise induced bronchoconstriction in asthma.

The leukotrienes, a group of oxidative metabolites of arachidonic acid, have potent pharmacological actions on human airways. We have investigated the effects of a leukotriene synthesis inhibitor, piriprost (U-60, 257) administered by inhalation on allergen and exercise induced bronchoconstriction in 12 subjects with allergic asthma. Subjects underwent diagnostic challenges with allergen and treadmill exercise to define the strengths of the stimuli required to reduce the FEV1 to about 25% of baseline (PS25). On separate study days subjects inhaled either piriprost 1 mg or vehicle placebo, followed 15 minutes later by the PS25 allergen or exercise. The FEV1 was measured at regular intervals before and after challenge up to 60 minutes. After allergen challenge in six subjects peak expiratory flow (PEF) was measured for the following 20 hours. When compared with placebo, inhalation of piriprost had no significant protective effect on the fall in FEV1 at any time point within 60 minutes of allergen or exercise challenge. In the four subjects with a documented late asthmatic reaction 2-12 hours after allergen challenge piriprost had no protective effect when compared with placebo. In the subjects who recorded PEF over 20 hours after allergen challenge there was no significant difference between piriprost and placebo. Piriprost was appreciably more irritant to the respiratory tract than was placebo. On the assumption that inhaled piriprost was bioavailable in the airways, this study casts doubt on any theory of a pivotal role for leukotrienes in the pathogenesis of acute exercise and allergen induced airway bronchoconstriction in asthma.     

Prevalence of bronchial reactivity to inhaled methacholine in New Zealand children.

The prevalence of bronchial hyperreactivity to inhaled methacholine and of a clinical history of symptoms of asthma was determined in a birth cohort of 9 year old New Zealand children. A history of current or previous recurrent wheezing was obtained in 220 of 815 children. Of 800 who had spirometric tests, 27 (3.4%) had resting airflow obstruction (FEV1/FVC less than 75%). Methacholine challenge was undertaken without problem in 766 children, the abbreviated protocol being based on five breaths and four concentrations. A fall in FEV1 of more than 20% was observed in 176 children (23% of challenges, 22% of the full cohort) after inhalation of methacholine in concentrations of up to 25 mg/ml. The prevalence of bronchial reactivity in children with symptoms was related to the frequency of wheezing episodes in the last year, and the degree of reactivity to the interval since the last episode. Sixty four children (8.0%) with no history of wheeze or recurrent dry cough were, however, also responsive to methacholine 25 mg/ml or less, while 35% of children with current or previous wheezing did not respond to any dose of methacholine. Bronchial challenge by methacholine inhalation was not sufficiently sensitive or specific to be useful as a major criterion for the diagnosis of asthma in epidemiological studies. The occurrence of airway reactivity in children without symptoms of asthma, however, raises the possibility that adult onset asthma and the development of airways obstruction in some subjects with chronic bronchitis could have origins in childhood.