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.     

Effect of caffeine on histamine bronchoprovocation in asthma.

It was recently reported that caffeine may reduce the clinical symptoms of asthma and may prevent the clinical manifestations of this disease. The effect of caffeine on histamine responsiveness is unknown. The effect of caffeine (5 mg/kg) and placebo on histamine responsiveness (the provocation concentration causing a 20% fall in FEV1, PC20) was studied in 10 subjects with mild asthma (prechallenge FEV1 84% of predicted value). The PC20 for histamine bronchoprovocation after caffeine ingestion was 2.65 (95% confidence limits 0.99, 7.10) mg/ml. After placebo the PC20 was 1.89 (0.96, 3.71) mg/ml. It is concluded that caffeine in a dose equivalent to about three cups of coffee has a very small effect, if any, on histamine bronchoprovocation in those with mild asthma. Specific instructions about not having drinks containing caffeine before histamine challenge are therefore not necessary.     

Positive "alveolar" responses to antigen inhalation provocation tests: their validity and recognition.

The validity of inhalation tests in the investigation of extrinsic allergic alveolitis was assessed from the results of 144 antigen and control tests in 31 subjects. A definitive pattern of positive late responses was observed. Reactions to nebulised bird serum and droppings in subjects with bird fancier''s lung were identical to reactions after "natural" exposures in aviaries or lofts, and to reactions after "occupational" challenges in subjects with farmer''s lung and mushroom worker''s lung. In general, positive tests were easily recognised subjectively from symptoms and signs appropriate to an influenza-like illness and undue respiratory effort on exercise. They were associated with significant changes in six readily available objective monitoring measurements--exercise minute ventilation (greater than or equal to +15%), body temperature (> 37.2 degrees C), circulating neutrophils (greater than or equal to +2500/mm3), exercise respiratory frequency (greater than or equal to +25%), circulating lymphocytes (greater than ore equal to -500/mm3 with lymphopenia), and forced vital capacity (greater than or equal to -15%). These confirmatory monitoring tests had specificities of approximately 95% and sensitivities of 85-48%. Measurement of diffusing capacity, lung volume subdivisions, or resting minute ventilation/respiratory frequency proved to be too insensitive to be useful, as did auscultation and chest radiography. We conclude that responses that do provoke significant changes in these less sensitive tests are unnecessarily distressing and, presumable, unnecessarily hazardous.     

Effect of a leukotriene B4 receptor antagonist, LY293111, on allergen induced responses in asthma.

BACKGROUND: Leukotriene (LT) B4 is a potent neutrophil chemoattractant and also stimulates eosinophils in vitro, but its role in asthmatic inflammation is unknown. METHODS: The effect of the novel LTB4 receptor antagonist, LY293111, was examined using allergen challenge as a model for asthmatic inflammation in 12 atopic asthmatic subjects in a double blind placebo controlled crossover trial. Subjects with an established early (EAR) and late asthmatic response (LAR) to allergen at screening received oral LY293111 in a dose of 112 mg three times daily for seven days or placebo before further allergen challenge. Each treatment was separated by a washout period of 28 days. Individuals underwent histamine challenge one hour before and three hours after allergen challenge. Bronchoalveolar lavage (BAL) fluid was obtained at bronchoscopy 24 hours after allergen challenge. RESULTS: There was no difference in baseline lung function, EAR, LAR, or in airway responsiveness to histamine before and after allergen between placebo and LY293111. By contrast, treatment with LY293111 significantly reduced the number of neutrophils in BAL fluid expressed as both absolute cell numbers and percentage cell differential counts: absolute cell counts, median (range) 0.04 (0.02-0.15) x 10(6) after LY293111, 0.09 (0.02-0.43) x 10(6) after placebo; percentage differential cell counts 0.35 (0.1-2.0) after LY293111, 0.80 (0.1-3.6) after placebo (p < 0.05). Eosinophils, macrophages, and lymphocytes in BAL fluid did not differ between treatments. There was a significant reduction in the concentration of myeloperoxidase (MPO) with both placebo (16 (6.6) ng/ml) and LY293111 (3.5 (1.8) ng/ml) and of LTB4 (placebo 4.6 (1.2) pg/ml, LY293111 2.2 (0.2) pg/ml). Concentrations of LTC4 and interleukin 8 were reduced, although not significantly, whereas concentrations of interleukin 6, GM-CSF, and TNF-alpha were unchanged by LY293111. CONCLUSIONS: These results demonstrate an influence of LTB4 on neutrophil influx and activation in the airway following allergen challenge. Despite this anti-inflammatory effect, there was no measured physiological benefit and this questions the functional role of the neutrophil in the pathophysiology of allergen induced asthma.     

Effect of oral L-arginine on airway hyperresponsiveness to histamine in asthma

BACKGROUND: Nitric oxide (NO) may exert protective properties within the airways of asthmatic patients. It was postulated that airways obstruction in asthma may be associated with endogenous NO deficiency caused by limited availability of NO synthase substrate. METHODS: In a double blind, crossover study 14 asthmatic patients received pretreatment with oral L-arginine (50 mg/kg body weight) or placebo prior to histamine challenge. Histamine challenge was performed until a 50% fall in forced expiratory volume in one second (FEV(1)) occurred and the response was expressed as the provocative concentration causing a 20% fall in FEV(1) (PC(20)) and as the dose-response slope (maximal % fall in FEV(1)/cumulative dose (micromol)). RESULTS: Pretreatment with L-arginine did not affect PC(20) histamine (mean change in doubling dose 0.18 (95% confidence interval (CI) -0.36 to 0.71), p = 0.5) but the dose-response slope to histamine was slightly reduced (mean change: 0.7 (95% CI 0.6 to 0. 9), p = 0.016). CONCLUSIONS: Oral L-arginine does not influence airway hyperresponsiveness to histamine as reflected by PC(20), although the dose-response slope is slightly reduced in patients with asthma. This indicates only marginal, clinically unimportant limitation of NO synthase substrate in asthma.     

Exhaled nitric oxide in the diagnosis of asthma: comparison with bronchial provocation tests

BACKGROUND: Bronchial provocation tests such as exercise, methacholine (MCH), and adenosine-5'-monophosphate (AMP) challenges are used extensively in the diagnosis of asthma. A study was undertaken to determine whether exhaled nitric oxide (eNO) can be used to diagnose asthma in patients with non-specific respiratory symptoms and to compare this test with conventional provocation tests. METHODS: Patients with non-specific respiratory symptoms and normal spirometric parameters were included in the study. eNO was measured and exercise, MCH and AMP challenges performed in all subjects. Patients were defined as asthmatic based on clinical follow up 24 months after testing. RESULTS: Forty patients were considered asthmatic and 45 were not. The area under receiver operating characteristic curves gave values of 0.896 for eNO, 0.781 for exercise, 0.924 for MCH, and 0.939 for AMP (p = 0.033, 0.575 and 0.085 for eNO v exercise, MCH and AMP respectively). From our data, a cut off value of NO > 7 ppb at a flow rate of 250 ml/s best differentiates between asthmatics and non-asthmatics (sensitivity 82.5%, specificity 88.9%). Optimal cut off values for other tests were exercise: deltaFEV1 > or = 10% (sensitivity 57.9%, specificity 100%); PC20-MCH: < or = 3 mg/ml (sensitivity 87.5%, specificity 86.7%); and PC20-AMP: < or = 150 mg/ml (sensitivity 89.5%, specificity 95.6%). CONCLUSIONS: Measurement of eNO can be used as a safe, simple and rapid test for the diagnosis of asthma and is as good as bronchial provocation tests.     

A comparison of responses to bronchodilator drugs in chronic bronchitis and chronic asthma

Isoprenaline by inhalation, adrenaline by inhalation, subcutaneous adrenaline, intravenous aminophylline, and subcutaneous atropine were administered to two groups of 18 patients suffering from either chronic bronchitis or chronic asthma using a Latin square design. Prednisolone was then given to both groups of patients for six days. The responses to the drugs were assessed by recording the F.E.V._1·0 before and 20 minutes after the administration of the short-acting drugs and daily during the period of prednisolone therapy. No significant differences were found between the responses to the short-acting antispasmodic drugs in the group of patients suffering from chronic bronchitis and only an insignificant improvement in the mean F.E.V._1·0 occurred during the period of prednisolone administration. Significant differences between mean responses to the anti-spasmodic drugs of the group of patients suffering from chronic asthma were observed. The mean F.E.V._1·0 response following subcutaneous adrenaline was 44%, which was significantly better than the 23·7% improvement after adrenaline inhalation (p=0·005) and the mean improvement in F.E.V._1·0 of 17·1% after subcutaneous atropine sulphate (p=0·001). A dramatic improvement in the mean F.E.V._1·0 of 49·5% occurred after six days of prednisolone administration. It is tentatively suggested that a good response to subcutaneous adrenaline and a poor response to subcutaneous atropine, as judged by improvement in the F.E.V._1·0, may be an indication that a good response to prednisolone can be expected in wheezy patients.     

Changes in bronchial responsiveness to histamine at intervals after allergen challenge.

Bronchial responsiveness to inhaled histamine was measured two, seven, and 30 hours after allergen inhalation challenge in 19 atopic subjects. The provocative histamine concentrations causing a 20% fall in FEV1 (PC20) at these three times were compared with the baseline value, with values obtained two and seven hours after diluent inhalation, and with those obtained five to seven days after allergen challenge in the 12 late responders. Seven subjects had allergen induced isolated early asthmatic responses (delta FEV1 22.6% (SD 6.6%)) with less than a 5% late fall in FEV1. There was no change in the six histamine PC20 values measured in these seven subjects; the geometric mean PC20 was 1.0-1.3 mg/ml on all six occasions. Twelve subjects had an allergen induced early asthmatic response (delta FEV1 26.3% (9.8%)) followed by a definite (greater than 15% delta FEV1, n = 7) or equivocal (5-15% delta FEV1, n = 5) late asthmatic response. The geometric mean histamine PC20 was not significantly different two hours after allergen inhalation either from baseline (0.67 v 0.78 mg/ml) or from that seen two hours after diluent (0.67 v 0.95). It was significantly reduced at seven (0.24 mg/ml) and at 30 hours (0.44 mg/ml) but had returned to baseline when repeated five to seven days later (0.74 mg/ml). In 10 subjects with a dual response who had a repeat antigen challenge the mean early and late response and delta PC20 at seven and 30 hours were similar. These data show that bronchial responsiveness to a non-allergic stimulus has not increased two hours after allergen inhalation following spontaneous recovery of the early asthmatic response but before the start of the late asthmatic response.     

Effects of forearm venous drainage on responses to the volume provocation test.

The volume provocation test (VPT) has been shown to induce a transitory increase of forearm and hand volume. Although these changes have been quantified in previous studies, the postulated mechanism underlying the VPT required further investigation. This study used a test-retest design in which the VPT was applied to 20 subjects before and during blood donation. During the standard VPT, the experimental arm was cuffed for 4 minutes at 15 mm Hg less than diastolic blood pressure, but a cannula siphoned blood from a superficial forearm vein during blood donation. Subjects rated the level of discomfort for each protocol, and reported data regarding symptom quality and location. Discomfort data during the VPT (1.95/10) was higher (p(1-tailed) < 0.005) than during blood donation (1.1/10), and subjects reported fewer volume-related symptoms during blood donation. These findings support the hypothesis that the VPT operates through a vascular mechanism, which is milder during blood donation.     

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

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

Forced oscillation technique and spirometry in cold air provocation tests.

BACKGROUND: Impedance measurements by the forced pseudo random noise oscillation technique can be used to study the mechanical characteristics of the respiratory system. The objective of this study was to analyse the changes in impedance to a cold air provocation test in patients with asthma, and to correlate these changes with those in the forced expiratory volume in one second (FEV1). METHODS: The response to isocapnic hyperventilation with cold air was assessed by respiratory impedance measurements and spirometry in 60 patients with bronchial asthma in whom the provocative dose of histamine resulting in a 20% fall in FEV1 (PD20) was < or = 8 mumol. RESULTS: Cold air provocation resulted in a mean(SD) fall in FEV1 from 3.75(0.85) litres to 3.10(0.90) litres. The mean(SD) decrease in FEV1 as a percentage of predicted was 15.4(3.8)%. The oscillatory resistance at 8 Hz increased from a mean(SD) of 0.367(0.108) kPa/l/s to 0.613(0.213) kPa/l/s and at 28 Hz the resistance increased from 0.348(0.089) to 0.403(0.099) kPa/l/s. Frequency dependence of resistance became significantly more negative. The reactance at 8 Hz decreased from a mean(SD) of -0.035 (0.041) kPa/l/s to -0.234(0.199) kPa/l/s, and the resonant frequency increased from 12.5(4.9) Hz to 25.7(9.1) Hz. Significant correlations were calculated between the decrease in FEV1 and changes in the various impedance parameters, especially between the decrease in FEV1 and the increase in resistance at 8 Hz (r = -0.66), and the decrease in FEV1 and the increase in the resonant frequency (r = -0.63). CONCLUSION: Cold air provocation in asthmatic subjects results in changes in the impedance of the respiratory system that correlate well with the changes in FEV1. These changes in impedance reflect ventilatory inhomogeneities in the peripheral compartment of the bronchial tree. These observations show the value of this technique in the evaluation of induced bronchoconstriction, as both a quantitative and a qualitative analysis of the response is possible.     

Effect of inhaled frusemide on responses of airways to bradykinin and adenosine 5'-monophosphate in asthma.

BACKGROUND--Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma. This effect could be caused by interference with neural pathways. The effect of inhaled frusemide on bronchoconstriction induced by inhaled bradykinin, which is thought to cause bronchoconstriction via neural mechanisms, was studied and compared with the effects of adenosine 5'-monophosphate (AMP) which probably produces its airway effects by augmenting mast cell mediator release and interfering with neural pathways. METHODS--Patients first underwent AMP and bradykinin challenges. They were then studied in a randomised, placebo controlled, double blind fashion. Ten atopic asthmatic subjects, studied on four days, were pretreated with inhaled frusemide (40 mg) or placebo for 10 minutes, five minutes before challenge with increasing concentrations of nebulised AMP or bradykinin. RESULTS--On the open visit days the provocative concentrations required to reduce forced expiratory volume in one second (FEV1) by 20% from baseline (PC20) for AMP and bradykinin were 16.23 (1.42-67.16) and 2.75 (0.81-6.6) mg/ml. There was a significant correlation between baseline AMP and bradykinin PC20 values. For AMP the geometric mean PC20 values following pretreatment with inhaled frusemide and matched placebo were 80.97 (9.97- > 400.0) and 14.86 (2.6-104.6) mg/ml respectively (95% CI 0.49 to 0.98). For bradykinin the geometric mean PC20 values following pretreatment with inhaled frusemide and matched placebo were 13.22 (2.53- > 16.0) and 2.52 (0.45-5.61) mg/ml respectively (95% CI 0.43 to 1.01). Frusemide afforded 5.45 and 5.24 fold protection against AMP and bradykinin-induced bronchoconstriction respectively. Furthermore, there was a significant correlation between protection afforded to the airways against AMP and bradykinin. CONCLUSIONS--These data suggest that inhaled frusemide affords protection against bradykinin-induced bronchoconstriction which is comparable to that against AMP, supporting a common mechanism of action for frusemide.     

H2 receptor blockade and bronchial hyperreactivity to histamine in asthma.

The role of histamine H1 and H2 receptors in the lung is not clear. H1 receptor blockade results in bronchodilatation and inhibition of histamine induced bronchoconstriction. H2 receptor blockade in vitro prevents the normal negative feedback of histamine on further mediator release in antigen challenge. Bronchospasm in guinea pigs given antigen challenge is enhanced by previous administration of metiamide or burimamide but not of cimetidine. These findings suggest the possible deleterious effect of H2 receptor antagonists in asthmatic subjects. The effects of H2 receptor blockade with cimetidine on bronchial hyperreactivity to histamine were studied in 10 asthmatic volunteers by whole body plethysmography. Cimetidine 800 mg and placebo were administered orally on two separate days, eight hours and two hours before study. No significant difference in baseline levels of airways obstruction was seen with the two agents. Inhalational challenge with increasing concentrations of histamine revealed no significant difference in bronchial hyperreactivity to histamine between cimetidine and placebo treatment days. H2 receptor blockade with cimetidine does not appear to affect ventilatory function or bronchial hyperreactivity to histamine in asthmatic subjects. It has been suggested that cimetidine may have H1 as well as H2 receptor blocking properties which prevent this effect.     

Effect of bradykinin on allergen induced increase in exhaled nitric oxide in asthma

Background: Exposure of patients with atopic asthma to allergens produces a long term increase in exhaled nitric oxide (FE_NO), probably reflecting inducible NO synthase (NOS) expression. In contrast, bradykinin (BK) rapidly reduces FE_NO. It is unknown whether BK suppresses increased FE_NO production after allergen exposure in asthma, and whether it modulates FE_NO via NOS inhibition. Methods: Levels of FE_NO in response to aerosolised BK were studied before (day 3) and 48 hours after (day 10) randomised diluent (diluent/placebo/BK (Dil/P/BK)), allergen (allergen/placebo/BK (All/P/BK), and allergen/L-NMMA/BK (All/L/BK)) challenges (day 8) in 10 atopic, steroid naïve, mild asthmatic patients with dual responses to inhaled house dust mite extract. To determine whether BK modulates FE_NO via NOS inhibition, subjects performed pre- and post-allergen BK challenges after pretreatment with the NOS inhibitor L-NMMA in the All/L/BK period. Results: Allergen induced a fall in FE_NO during the early asthmatic reaction (EAR) expressed as AUC_0–1 (ANOVA, p=0.04), which was followed by a rise in FE_NO during the late asthmatic reaction (LAR) expressed as AUC_1–48 (ANOVA, p=0.008). In the Dil/P/BK period, FE_NO levels after BK on pre- and post-diluent days were lower than FE_NO levels after placebo (difference 23.5 ppb (95% CI 6.2 to 40.9) and 22.5 ppb (95% CI 7.3 to 37.7), respectively; p<0.05). Despite the long lasting increase in FE_NO following allergen challenge in the LAR, BK suppressed FE_NO levels at 48 hours after allergen challenge in the All/P/BK period, lowering the increased FE_NO (difference from placebo 54.3 ppb (95% CI 23.8 to 84.8); p=0.003) to the baseline level on the pre-allergen day (p=0.51). FE_NO levels were lower after L-NMMA than after placebo on pre-allergen (difference 10.85 ppb (95% CI 1.3 to 20.4); p=0.03) and post-allergen (difference 36.2 ppb (95% CI 5.5 to 66.9); p=0.03) days in the All/L/BK and All/P/BK periods, respectively. L-NMMA did not significantly potentiate the pre- and post-allergen reduction in BK induced FE_NO. Conclusions: Bradykinin suppresses the allergen induced increase in exhaled NO in asthma; this is not potentiated by L-NMMA. Bradykinin and L-NMMA may follow a common pathway in reducing increased NO production before and after experimental allergen exposure. Reinforcement of this endogenous protective mechanism should be considered as a therapeutic target in asthma.     

Reproducibility and comparison of responses to inhaled histamine and methacholine.

The efficiency of a standardised inhalation test procedure was studied by examining the reproducibility of responses to histamine and methacholine. In addition, the responses to the two agents were compared. Each set of duplicate tests was carried out on a separate day within one week, and all factors known or presumed to influence responses were carefully controlled. The results were expressed as the provocative concentration of the agent causing a 20% fall in forced expired volume in one second (PC20). Responses to histamine and methacholine were highly reproducible (coefficients of determination [r2] = 0.994 and 0.990 respectively). Responsiveness to histamine correlated closely with responsiveness to methacholine (r2 = 0.85). There was a small but significant cumulative dose effect with methacholine (P less than 0.01) but not with histamine. Side effects of throat irritation, flushing, and headache were more frequent with histamine than methacholine, and were dose-related. The high level of reproducibility indicates the efficiency of the test procedure. The similar severity of effects by agents with different mechanisms of action suggests that the primary cause of non-specific bronchial hyperreactivity lies at the level of bronchial smooth muscle.     

Effect of endogenous nitric oxide inhibition on airway responsiveness to histamine and adenosine-5'-monophosphate in asthma

BACKGROUND—Nitric oxide (NO) may bebronchoprotective in asthma, possibly due to a direct action on airwaysmooth muscle or through mast cell stabilisation. To investigate thisthe effects of two doses of nebulisedN^G-nitro-L-arginine methyl ester(L-NAME), a non-selective NO synthase (NOS) inhibitor, onexhaled NO levels and airway responsiveness to histamine, a directsmooth muscle spasmogen, and adenosine-5'-monophosphate (AMP), anindirect spasmogen which activates mast cells, were evaluated inpatients with mild asthma.
METHODS—The study consisted of two phaseseach with a double blind, randomised, crossover design. In phase 1, 15 subjects inhaled either L-NAME 54 mg or 0.9% saline 30 minutes before histamine challenge. Nine of these subjects were studiedin a similar fashion but were also challenged with AMP. In phase 2, 13 subjects (eight from phase 1) performed the same protocol but inhaledL-NAME in a dose of 170 mg or 0.9% saline before beingchallenged with histamine and AMP.
RESULTS—The mean (95% CI) reduction in exhaled NOlevels after L-NAME 54 mg was 78% (66 to 90) but this didnot alter airway responsiveness; the geometric mean (SE) concentrationprovoking a fall of 20% or more in forced expiratory volume in onesecond (PC₂₀) after L-NAME and saline was 0.59 (1.26) and 0.81 (1.26) mg/ml, respectively, for histamine and 20.2 (1.7) and 17.2 (1.6) mg/ml, respectively, for AMP. In contrast,L-NAME 170 mg reduced NO levels to a similar extent (81%(95% CI 76 to 87)) but increased airway responsiveness byapproximately one doubling dose to both spasmogens; the geometric mean(SE) PC₂₀ for histamine after L-NAME 170 mg andsaline was 0.82 (1.29) and 1.78 (1.19) mg/ml, respectively (p<0.001),and for AMP was 11.8 (1.5) and 24.3 (1.4) mg/ml, respectively(p<0.001).
CONCLUSIONS—These results suggest thatL-NAME increases airway responsiveness in asthma. This mayoccur through mechanisms separate from NO inhibition or throughpathways independent of those responsible for production of NO measuredin exhaled air.

     

Severe histamine mediated reactions to intravenous drugs used in anaesthesia.

Severe histamine mediated reactions to intravenous drugs used in anaesthesia may occur as a result of anaphylactic and anaphylactoid reactions. The incidence is rare, but appears to be increasing. The difficulties in diagnosing such reactions and in determining the drug responsible and how these difficulties have led to confusion in the literature are discussed. Six cases of severe histamine mediated reactions are presented and detailed analyses of the drugs in these and other reported reactions is made showing varied clinical patterns with different drugs. The prevention, treatment, and follow-up of severe histamine mediated reactions are considered.     

Reproducibility of histamine challenge tests in asthmatic children.

The measurement of bronchial reactivity by histamine challenge testing is of increasing clinical importance in paediatrics. By means of a simple tidal breathing technique for the measurement of histamine sensitivity (expressed as PC20--the concentration of histamine which produces a 20% fall in peak flow rate) in childhood asthma, the reproducibility of pairs of tests was estimated over one hour and 24-hour intervals in 22 children. Under carefully controlled conditions the 95% confidence limits of PC20 were 0.8-1.25 X baseline PC20 after one hour and 0.36-2.8 X baseline PC20 after 24 hours.