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Twenty asthmatic children were studied in a double-blind within-patient comparative trial designed to assess the efficacy of nedocromil sodium (4 mg) and placebo in exercise-induced bronchoconstriction. The response to exercise challenge given 30 minutes after treatment showed statistically significant differences in favor of nedocromil sodium. No unusual symptoms were reported.
Nedocromil sodium, a pyranoquinoline decarboxylic acid derivative, is a new antiasthma compound undergoing clinical investigation. It has been shown to be effective in the management of asthma and to attenuate exercise-induced bronchoconstriction. We performed a randomized, double-blind, placebo-controlled, crossover study in 12 ragweed-sensitive subjects known to respond to inhaled ragweed antigen. On two study days, four to ten days apart, ragweed challenges were performed using a standard protocol 30 minutes after a single dose (two puffs of 2 mg/puff) of either active drug or placebo. The PD20 (20% fall in FEV1) for each treatment day was compared by parametric and nonparametric 2-period crossover analyses. Baseline FEV1 pre-drug and post-drug administration did not differ significantly between study days. On the nedocromil day, the mean +/- SD for log PD20 was 2.25 +/- 0.561 and on the placebo day, 1.73 +/- 1.048 (P = 0.04). There were no side effects associated with either treatment. These results demonstrate that nedocromil is effective in shifting the stimulus response curve to inhaled antigen in some ragweed-sensitive subjects. Its wide spectrum of efficacy against bronchoprovocation suggests it is useful in the treatment of hyperreactive airway disorders.
Allergen-induced bronchoconstrictive responses were examined in a guinea pig model actively sensitized by the inhalation of aerosolized ovalbumin (OA), which showed reproducible late bronchial responses (LBR). OA-challenge was performed under cover of mepyramine through the inhaled route in spontaneous breathing without anesthesia. The respiratory resistance (Rrs) was measured by the oscillation method for 96 h after OA challenge. All of the 22 guinea pigs displayed immediate bronchial responses (IBR), followed by 2 or 3 phase LBR that peaked at 6-8 h and 24 h after OA challenge. Examination of bronchoalveolar lavage fluid (BALF) revealed a significant increase in neutrophils at 1 h (p less than 0.01) and eosinophils at 7 h and 96 h (each p less than 0.01) after OA challenge. OA-challenge induced airway hyperresponsiveness to histamine (p less than 0.01) at 96 h that was associated with a significant increase in eosinophils (p less than 0.01) in BALF compared with lavages at 7 h. Intravenous administration of 1% OA induced a significant increase of leukotriene (LT)B4, C4, D4 in tracheal lavage fluids at IBR phase in each control (p less than 0.01). The increases of Rrs in LBR were inhibited almost completely by the pretreatment of KC-404, which is reported to have antagonistic action against LTC4/D4. These results suggest that allergen-induced late broncho-constrictions accompanied by airway hyperresponsiveness in guinea pigs are associated with the extensive infiltration into the airway lumen of inflammatory cells, and are concerned with the release of LTs. We also suggest that this LBR guinea pig model is useful in studying the mechanisms of the occurrence of LAR in humans, and in evaluating the action of anti-allergic drugs in LAR.
The principal feature which distinguishes asthmatics from normal subjects is that their airways constrict excessively to stimuli, to the extent that airway narrowing exceeds the maximum degree of bronchoconstriction which occurs in normal subjects. The load against which bronchial smooth muscle contracts is a very important determinant of the degree of airway narrowing. The elastic properties of the airway wall itself and the interdependence between the airways and the surrounding parenchyma are the elastic load which bronchial smooth muscle has to overcome to narrow the airway. The most likely explanation of a decreased load in asthma is oedema of the airway wall, because it may unlink the interdependence between the airway and the surrounding parenchyma.
The clinical effects of a calcium antagonist--nifedipine on Xinjiang local pollen sensitive asthmatics were reported. 15 asthmatics were studied in a randomized double blind fashion by observing the changes in ten parameters of pulmonary function test which includes FEV1, FEV1/FVC. FEF25-75, PEFR V50, V25, RawinSp, RawExp, SRaw and SGaw. Our study showed that premedication of nifedipine significantly attenuated the subsequent bronchoconstriction induced by pollen antigen and offered remarkable increase of PC20. The protecting effect was most distinct from 50 to 60 minutes after medication. It provides a new way of clinical applicability in asthma prophylaxis and treatment.
Hyperventilation of cold dry air causes bronchoconstriction in asthmatic subjects and has been proposed as a test for assessing bronchial hyperresponsiveness. The influence of the duration of inhalation of unconditioned cold air has not been studied. We have investigated the question in 12 asthmatic subjects in a clinically stable state. Each subject underwent three inhalation tests at a maximum interval of two weeks. On each day, the duration of inhalation was different, being randomly 2, 3 or 4 min depending on the subject. Doubling doses of cold air produced by a freon conditioner were administered, increasing ventilation from 7.5 to 15, 30, 60 l.min-1 and maximum voluntary ventilation (MVV). Forced expiratory volume in one second (FEV1) was assessed after each period of cold air inhalation. The test was stopped when the FEV1 had decreased by 20% or more, or when MVV had been achieved. The dose of cold air expressed as the level of ventilation causing a 20% change in FEV1 (PD20) was interpolated from individual dose-response curves. Dose-response curves shifted to the left when the duration of ventilation was increased. PD20 was significantly lower after 3 min of ventilation than after 2 min (mean +/- SD PD20 of 41.7 +/- 1.4 l.min-1 compared with 53.3 +/- 1.2 l.min-1; p = 0.002). There was a further fall in PD20 after 4 min of ventilation (PD20 = 36.1 +/- 1.5 l.min-1) but the difference compared with the values obtained after 3 min was not significant (p = 0.09), thus suggesting a plateau.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of placebo and 1 mg, 4 mg, or 8 mg nedocromil sodium, administered 60 minutes prior to treadmill challenge, was determined in a double-blind study of 12 adult asthmatics with reproducible exercise-induced bronchoconstriction. All nedocromil sodium treatments gave significantly smaller falls in PEFR than placebo. Four and 8 mg gave significantly greater protection than 1 mg.
The purpose of this study was to compare the protective effect of nedocromil sodium with that of sodium cromoglycate against adenosine-induced bronchoconstriction in 15 asymptomatic asthmatic patients. Airways response was evaluated as FEV1 and adenosine was administered as an aerosol diluted in 0.9% saline to produce a concentration range of 0.03-4.00 mg/ml. When FEV1 was decreased by 20% of the post-saline value, inhalation was discontinued and the PD20 adenosine calculated. Patients were studied on four separate days. On the first day the adenosine challenge was performed and on subsequent days patients were pretreated with either placebo or test drug in a randomized double-blind manner. In this study both sodium cromoglycate and nedocromil sodium showed a significant protective effect against adenosine in comparison with placebo. Their activity was not related to a bronchodilator action. Nedocromil sodium showed a greater protective effect against adenosine challenge which may be indicative of a broader spectrum of activity against nonantigenic stimuli.
Sulfinpyrazone (100 microM) and its thioether metabolite G25671 (50 microM) suppressed arachidonic acid-induced platelet aggregation, thromboxane (Tx) B2 formation and ATP release. Platelet activation by the endoperoxide analog U46619 also was prevented by sulfinpyrazone or G25671 (0.3-1 mM). Previous studies have shown that human platelets pre-exposed to arachidonic acid or to U46619 and then washed and resuspended failed to respond to a second challenge by both arachidonic acid and U46619; desensitization by arachidonic acid and U46619 occurred at a site sensitive to endoperoxides/Tx receptor antagonists; and the desensitizing effects of U46619 were direct, whereas those of arachidonic acid were mediated by a cyclooxygenase-dependent metabolite. We now demonstrate that the presence of sulfinpyrazone or G25671 during platelet exposure to arachidonic acid or U46619 prevented desensitization. We also studied the threshold aggregating concentration of arachidonic acid and U46619 in healthy subjects before and after treatment with sulfinpyrazone and we found a good correlation between ex vivo and in vitro findings. We finally examined the actions of sulfinpyrazone and G25671 on the bronchoconstriction in vivo and parenchymal lung strip contraction in vitro induced by U46619. Neither drug had any preventive effect. Our results demonstrate that sulfinpyrazone and its metabolite G25671 are not only cyclooxygenase inhibitors but can also act as endoperoxide/Tx antagonists and indicate clearly that antagonism of U46619 by both drugs is selective for platelets.
We have investigated whether the inspiratory flow at which sodium cromoglycate (SCG) is inhaled influences the efficacy of SCG. Seven atopic asthmatic subjects (age 25 +/- 2 yrs) inhaled dry powder SCG from a Spinhaler on separate occasions at three flow rates, maximum (V1), 100 l.min-1 (V2), and 50 l.min-1 (V3), or placebo, according to a double-blind structured study. Thirty minutes after administration a bronchial provocation test was performed with adenosine 5'-monophosphate (AMP). Blood samples for measurement of plasma SCG concentration were taken and the area under the plasma concentration-time curve (AUC) calculated for each flow rate. Both inspiratory flow rate and AUC correlated significantly with the degree of protection afforded against AMP-induced bronchoconstriction (r = 0.73, p less than 0.001; r = 0.66, p less than 0.001). These findings indicate that the flow rate used to inhale powdered SCG is a major factor in determining the protective efficacy of this drug against bronchial challenge and therefore has important clinical implications.
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)
Nineteen asthmatic patients, 11 with and eight without aspirin (ASA) intolerance were studied in order to test possible platelet and coagulation system involvement in the pathogenesis of aspirin-induced bronchoconstriction (AIB). Aspirin-intolerant asthmatics were challenged with a previously established ASA threshold dose and, in nine of them, a positive asthmatic reaction occurred (mean fall in FEV1 39.4%). Seven out of nine patients with a positive reaction had a significant decrease in euglobulin lysis time (P less than .01) during AIB. A positive reaction after ASA was accompanied by an increase in the plasma recalcification time in five of these patients. There were no concomitant statistically significant changes in the platelet count, circulating platelet aggregates, and platelet factor 4 activity. In a control group of ASA-tolerant asthmatics, aspirin at a 200-mg dose did not evoke any respiratory reaction and, during two hours after ASA, no significant variation was found in any of the laboratory parameters studied. We conclude that activation of fibrinolysis accompanying AIB results from intrinsic pharmacologic properties of aspirin, and may contribute to the pathogenesis of aspirin intolerance through a more generalized activation of plasma proteolytic activity.
In 16 asymptomatic asthmatics a functional study was carried out under controlled conditions during histamine bronchial provocation test (HBPT) and after bronchodilation test with either SCH 1000 or fenoterol by evaluating both SRAW and the slope of the alveolar plateau of nitrogen washout curve (N2 ph III). During HBPT, 9 of 16 subjects showed a central response (increase in RAW and SRAW only), whereas in the remaining 7 subjects histamine induced a mixed response due to an increase in both SRAW and N2 ph III. No differences between the two groups were observed in age and functional data during controlled conditions. Doses of delivered histamine were not significantly different. In 5 of 9 central responders to HBPT, SCH 1000 induced a decrease in SRAW only, whereas in 3 of the remaining 4 fenoterol caused both central and peripheral bronchodilation (decrease in both SRAW and N2 ph III). All mixed responders to HBPT showed a mixed bronchodilation during SCH 1000 (three subjects) or fenoterol (the remaining four). These data seem to indicate that the mechanism of bronchodilation induced by SCH 1000 is related to that of histamine-induced bronchoconstriction. Moreover, bronchodilation due to fenoterol could be related to a vagal modulation or be a systemic direct effect.
The effect of premedication with cromolyn 40 mg on the bronchial response to inhaled carbachol was investigated in four atopic and four non-atopic subjects with mild asthma. Paired carbachol inhalation tests were carried out on consecutive days in a double-blind fashion following randomized premedication with cromolyn or placebo. Bronchial sensitivity was expressed as the log dose of carbachol provoking a 15% decrease in FEV1 (log PD15 FEV1) or a 30% decrease in FEF25-75 (log PD30 FEF25-75). The mean log PD15 FEV1 was significantly greater following cromolyn compared to placebo (2.34 +/- .22 vs 1.87 +/- .10; mean +/- SE; p less than 0.05) as was log PD30 FEF25-75 (2.30 +/- .16 vs 1.72 +/- .08; p less than 0.005). These results indicate that cromolyn interferes with cholinergic induced bronchoconstriction and support the suggestion that it has an effect at a more fundamental level than the inhibition of antigen induced mediator release from mast cells.
We studied the effect of ipratropium on exercise-induced bronchoconstriction (EIB) at cold or warm temperatures. Although pulmonary function was better with ipratropium, its benefit was related to pre-exercise bronchodilation and not prevention of EIB. Ipratropium did not affect the augmented EIB in cold weather. Therefore, these phenomena are not primarily mediated via cholinergic mechanisms.
To study the time-course of exercise-induced bronchoconstriction (EIB) in asthmatics, we have developed a method for continuous measurement of respiratory resistance using the forced oscillation technique during tidal breathing throughout the exercise challenge. Twenty-three out of 38 asthmatics were exercise responders and five of these responders showed an increase in resistance during exercise. The present technique may be clinically applicable in examination of different types of EIB and as a screening test.
In 27 asthmatic patients a single cold stimulus into the nose resulted in a sudden increase of airway resistance, measured continuously by a forced-oscillation technique. The effect could be blocked by previous intrabronchial application of an anticholinergic drug. In laryngectomised patients, who no longer have a connection between the upper and the lower airways, a cold stimulus into the nose also caused bronchoconstriction. So the cold effect must be based on a reflex mechanism.
SK&F 88046, an imidodisulfamide initially reported as an end organ leukotriene (LT)D4 antagonist on guinea-pig lung parenchyma (Gleason et al., 1982), was studied further in order to elucidate its mechanism of action. The LTD4-induced contraction of the guinea-pig lung parenchyma, which occurs via both a direct action and an indirect, thromboxane (Tx)-dependent pathway (Weichman et al., 1982), was antagonized by SK&F 88046 and FPL 55712. SK&F 88046 was not acting on the lung parenchyma as a result of antagonism of cyclooxygenase or Tx synthetase, as SK&F 88046 did not block the LTD4-induced generation of TxB2 from the parenchyma. In contrast, the LTD4-induced contraction of the guinea-pig trachea, which is only directly mediated, was antagonized by FPL 55712 but not by SK&F 88046. However, SK&F 88046 did antagonize the contractions elicited by carbocyclic TxA2, a stable Tx analog, as well as those elicited by prostaglandins F2 alpha and D2, but not those elicited by histamine, carbachol or KCI. FPL 55712 weakly antagonized the actions of carbocyclic TxA2, but not the contractions induced by the other agonists. These results demonstrate that SK&F 88046 is an antagonist of the indirect, Tx-dependent component of LTD4 action in the guinea pig, presumably via antagonism of Tx on the end organ. These results provide additional evidence that LTD4 can exert its bronchoconstrictive actions via two mechanisms, a direct pathway and an indirect, Tx-dependent pathway.