Increased antigen-induced local and systemic mediator release in rhinitis subjects with pulmonary symptoms in the pollen season

In order to delineate parameters that might discriminate between allergic subjects who develop R or R-P symptoms during natural antigen exposure, 26 subjects allergic to grass or ragweed pollen were classified into R or R-P groups, and then the antigen sensitivity and degree of in vivo mediator release were compared. Antigen-skin sensitivity was quantitated by dilutional skin-test titration, and bronchial sensitivity was quantitated by the amount of inhaled antigen required to receive the FEV1 by 20%. Mediator release was determined by measuring the amount of histamine that was released into skin chambers during antigen incubation and the rise in plasma histamine and serum NCA during antigen-induced bronchospasm. Compared to the 13 R subjects, the 13 R-P subjects were: (1) more sensitive to antigen by both skin-test and inhalation challenge, (2) responded to inhalation of antigen with a greater fall in FEV1 and a greater rise in serum NCA and plasma histamine, and (3) released more histamine into skin chambers after antigen incubation. Even when R and R-P subjects were matched by comparing only subjects with equal skin sensitivity to antigen, greater increases in serum NCA and plasma histamine occurred after inhalation of antigen in the R-P subjects. These data are consistent with the hypothesis that allergic rhinitis subjects who develop pulmonary symptoms during natural pollen exposure are more sensitive to antigen and release more mediators in response to antigen administration. It is therefore possible that the degree of mediator release may be an important factor in determining the pattern of clinical responses to antigen exposure.     

Effect of inhaled diphemanil methylsulfate, a parasympatholytic agent, on histamine induced bronchoconstriction in asymptomatic asthmatics

Parenterally administered diphemanil methylsulfate, a quarternary ammonium compound with both parasympatholytic and direct bronchial smooth muscle relaxing properties, has been found effective in the treatment of bronchial asthma. The present study was undertaken to test the effectiveness of inhaled diphemanil in preventing histamine induced bronchoconstriction in asymptomatic adult asthmatics. Twenty subjects, aged 19-40 years (average 25) were studied, each on three different days, observing an interval of at least 70 hours between testing. On day one, airway sensitivity to inhaled histamine was determined. On days two and three, histamine challenge was repeated 20 minutes after inhalation of either diphemanil (2 mg) or its vehicle in a double-blind crossover design. Airway sensitivity was assessed by determining cumulative log dose units of inhaled histamine required to provoke a 20% decline in FEV1 (log PD20 - FEV1). Diphemanil did not prevent histamine induced bronchoconstriction nor did it significantly affect log PD20 - FEV1 (p = 0.59). We conclude that a 2 mg dose of diphemanil, administered by oral inhalation 20 minutes before histamine challenge, is ineffective in protecting against induced bronchospasm in asymptomatic adult asthmatics.     

The effects of an anti-CD18 antibody (R15.7) in antigen-induced airway hyperresponsiveness (AH) and cell influx in guinea pigs

Aerosol ovalbumin challenge (OA) of sensitized guinea pigs induced airway hyperreactivity (AH) to i.v. acetylcholine (Ach) and serotonin (5-HT) 24 hr post OA. Bronchoalveolar lavage fluid 24 hrs after OA showed increased leukocytes compared to unsensitized unchallenged animals. Treatment with monoclonal antibody R15.7 (3 mg/kg i.v.,) 1 hr prior and 4 hours after OA prevented the induction of AH to Ach but not to 5-HT and reduced influx of leukocytes. We conclude: 1) antigen inhalation induces an increase in AH with an increase in proinflammatory cell influx and 2) treatment with anti-CD18 antibody inhibits cell influx and airway hyperreactivity.     

The effects of inhaled leukotriene E4 on the airway responsiveness to histamine in subjects with asthma and normal subjects

Eight subjects with asthma inhaled on separate occasions leukotriene E4 (LTE4) (6.1 nmol, geometric mean), methacholine, and diluent, which produced an average 41.0%, 37.0%, and 3.3% decrease in specific airway conductance (SGaw), respectively. When the SGaw had recovered to baseline levels at 60 minutes after challenge, the provocative dose of inhaled histamine that produced a 35% decrease in SGaw (PD35) was determined. The histamine PD35 observed after inhalation of LTE4 was 0.46 mumol, and this was significantly less than the histamine PD35 observed after inhalation of methacholine (0.88 mumol; p less than 10(-4) and diluent (0.97 mumol; p less than 10(-5). Histamine responsiveness was also enhanced by a fiftyfold lower dose of LTE4 (p = 0.005), and the enhancement was less than that elicited by the higher dose of LTE4 in the same individuals (p = 0.02). The changes in histamine PD35 during a 1-week period after LTE4 and methacholine challenges were compared in four subjects with asthma. There was a time-dependent enhancement in histamine responsiveness that reached a maximal of 3.5-fold at 7 hours after LTE4. The enhancement had disappeared by 1 week. Similar changes were not observed after methacholine challenge, which elicited the same degree of bronchoconstriction as LTE4. Inhalation of LTE4 in five normal subjects that produced a mean 37.6% decrease in SGaw did not change histamine responsiveness for up to 7 hours. These findings suggest that LTE4 may play a role in the perpetuation of nonspecific airway hyperresponsiveness in bronchial asthma.     

The effect of anti-IL-4 monoclonal antibody, rapamycin and interferon-γ on airway hyperreactivity to acetylcholine in mice

Background The role of IgE in airway hyperreaetivity is obscure. Objective In order to clarify the role of IgE in airway hyperreactivity, we investigated the effect of anti-IL-4 monoclonal antibody, rapamycin and interferon-γ on the antigen-induced IgE response, airway eosinophilia and hyperreactivity in mice. Methods Mice were immunized with an antigen (ovalbumin; OA) at intervals of 12 days. OA was inhaled 10 days after the secondary immunization. Twenty-four hours after the last inhalation, airway reactivity to acetylcholine was measured and bronchoalveolar lavage fluid (BALF) was obtained. Results Three inhalations of antigen caused an increase in the number of eosinophils in bronchoalveolar lavage fluid (BALF) and in airway hyperreactivity to acetylcholine with a significant elevation of serum IgE level. Anti-IL-4 at a dose of 1000 μg/animal and rapamycin at doses between 0.1 and 1 mg/kg inhibited the IgE production, but did not affect the airway eosinophilia or hyperreactivity to acetylcholine. In contrast, IFN-γ clearly inhibited the antigen-induced airway eosinophilia and hyperreactivity, but did not affect the IgE antibody production. Conclusion These results suggest that the inhibition of IgE production does not suppress the onset of airway hyperreactivity and eosinophilia in mice, and that IFN-γ inhibits the antigen-induced airway hyperreactivity, probably due to the inhibition of airway eosinophilia.     

Airway responses to histamine, acetylcholine, and propranolol in anaphylactic hypersensitivity in guinea pigs

Using changes in tidal volume and dynamic lung compliance, airway responses to histamine, acetylcholine, and propranolol were investigated in different groups of guinea pigs before and after active or passive sensitization. The threshold doses to inhaled histamine, acetylcholine, and propranolol were identical before and after sensitization. Similarly, the slope of dose response curves to these drugs and the time course of recovery from airway constriction were comparable in control and sensitized animals. The slopes of dose response curves to histamine and acetylcholine were parallel. Threshold doses to acetylcholine (T_ACH) and histamine (T_H) were proportional. The average ratio T_ACH/T_H was 7.7. There was no correlation between threshold doses and slopes of dose response curves for propranolol and those for histamine or acetylcholine. Antigen challenge resulted in decreases of dynamic lung compliance and in increases of airway resistance and frequency, which were maximal 60 to 130 seconds after challenge. When functional parameters after antigen challenge had returned to normal, bronchial responses to histamine, acetylcholine, and propranolol were exaggerated. These exaggerated responses were reproducible, transient, variable from animal to animal, and related to the antigen dose. Guinea pig anaphylaxis does not lead to the prolonged hypersensitivity to chemical mediators, which characterizes human reaginic asthma, but to a temporary enhancement of responses to acetylcholine, histamine, and propranolol.     

Comparison of plasma histamine and cyclic nucleotides after antigen and methacholine inhalation in man

Serial determinations of plasma histamine and cyclic nucleotides (adenosine monophosphate [AMP] and guanosine monophosphate [GMP]) were performed after inhalation of antigen and methacholine in four groups of subjects. In the first group, consisting of six antigen-sensitive subjects exhibiting bronchospasm after inhalation of ragweed or grass antigen, plasma histamine was elevated within 2 min and persisted for 30 min after inhalation of antigen. Peak histamine levels were between 18 to 80 ng/ml. In the second group, consisting of four nonatopic subjects, neither bronchospasm nor histamine was observed, despite inhalation of the same or 10-fold increased concentrations of antigen. In the third group, consisting of six subjects (three atopic and three nonatopic) exhibiting bronchospasm after inhalation of 2.5 to 10 mg of methacholine, sustained increases of histamine began at 1 min and persisted for 60 min after inhalation of methacholine. In the fourth group, seven subjects (two atopic, five nonatopic) without demonstrable bronchospasm despite inhalation of 2.5- to 10-fold increased doses of methacholine, no histamine was detected in the plasma at any time after inhalation of methacholine. Serial measurements of cyclic nucleotides showed no consistent changes in serum levels of cyclic AMP or cyclic GMP following inhalation challenge. We conclude that serum levels of histamine but not cyclic nucleotides change during bronchospasm induced by either antigen or methacholine.     

Comparison of the airway hyperreactivity produced by single and multiple antigen exposures in sensitized guinea pigs

Chronic airway hyperreactivity is a hallmark feature of asthma, but animal models of airway hyperreactivity often utilize a single antigen challenge. Therefore, we compared the airway hyperreactivity produced by single and multiple antigen challenges in ovalbumin-sensitized guinea pigs. Significant (2-fold) leftward shifts in dose-response curves for i. v. methacholine- or LTD₄-induced bronchoconstriction in anesthetized and ventilated animals occurred 24 h following a single ovalbumin challenge. This nonspecific airway hyperreactivity was prevented by pretreatment with ketotifen or dexamethasone. However, airway hyperreactivity was no greater 24h following the last of 3 daily antigen challenges than after 1 challenge and was absent 72h following one antigen challenge. These results raise concern over the similarity of antigen-induced airway hyperreactivity in guinea pigs to the chronic airway hyperreactivity in asthmatics.     

Effect of surfactant inhalation on allergic bronchoconstriction in guinea pigs

Background In the small airway, surfactant reduces surface tension, prevents liquid filling of bronchioles, thereby maintaining patency in the small airways. Recent reports demonstrated that surfactant dysfunction develops in experimental asthma in immunized guinea pigs. However, there are few reports concerning surfactant and lung function in an experimental asthma model. Objective To examine whether inhaled surfactant improves lung mechanics in antigen-induced bronchoconstriction in guinea pigs. Method We developed a passively immunized guinea pig model for allergic bronchoconstriction induced by antigen inhalation. Using this model, we investigated the effect of inhaled exogenous surfactant, surfactant TA. on the airway opening pressure (Pao) after antigen challenge. Results Aerosol antigen challenge produced a gradual and long-lasting increase in Pao. Twenty minutes after antigen challenge, aerosolized surfactant TA, 20 mg/ml. was inhaled for 90 s, and it significantly reduced the Pao by 32.8% in 12 min, while a 10.2% reduction was observed in a control group in the same period. When surfactant TA was administered by 90-s inhalation before antigen challenge, it inhibited the Pao increase in a dose-dependent manner: mean inhibitory rates of Pao were 33.6% in surfactant TA 10 mg/ml and 61.9% in surfactant TA 20 mg/mI, respectively. Conclusion Inhaled surfactant showed preventive and recovery effects on antigeninduced bronchoconstriction in an immunized guinea pig model.     

Late asthmatic reactions and changes in histamine responsiveness provoked by occupational agents

The temporal and quantitative relationship between increases in airway responsiveness and late asthmatic reactions provoked by inhalation challenge with occupational agents was studied in nine individuals who underwent a total of thirteen active inhalation challenge tests with one of the following agents: toluene diisocyanate (TDI), maleic anhydride (MA), trimellitic anhydride (TMA), carmine, or colophony (pine wood resin). Airway responsiveness to inhaled histamine (histamine PC20) was measured before and at approximately 3 and 24 h after control and active challenge exposure, when, on all but four occasions, FEV1 was within 10% of pre-challenge values. Significant increases (p less than 0.02) in histamine responsiveness were present at 3 h following challenge exposures which subsequently provoked a definite late asthmatic reaction (FEV1 decrease greater than 15% 3-11 h post challenge). These increases in histamine responsiveness were significantly greater than those at 3 h following the challenges which provoked an isolated early (FEV1 decrease less than 6% 3-11 h post-challenge) or equivocal late asthmatic reaction (FEV1 decrease 6-15% 3-11 h post-challenge) (p less than 0.03). Although histamine responsiveness remained high at 24 h after challenges provoking late asthmatic reactions (p less than 0.05), this was less than the increase at 3 h and not significantly different from the PC20 at 24 h after challenges provoking either single early or equivocal late asthmatic reactions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective protective effects of nitric oxide inhalation on allergen-induced acute airway reactions in the pig

BACKGROUND: Nitric oxide (NO) is thought to be an important mediator of inflammatory processes during allergic reactions in the respiratory tract. OBJECTIVE: This study was undertaken to investigate the effects of inhalation of NO on the allergen-induced acute airway reactions in the pig. METHODS: Specific pathogen-free pigs were sensitized with Ascaris suum antigen and challenged with an allergen aerosol during mechanical ventilation and anaesthesia. One group (n = 8) was treated with inhaled NO (20 ppm) which was given from 30 min before allergen challenge until the experiments were completed at 120 min after challenge. A control group (n = 8) did not receive NO (< 0.001 ppm). RESULTS: Inhalation of 20 ppm NO prevented the fall in arterial pO2/FiO2 levels that was observed in the control group (areas under the curve between 0 and 120 min were 3.7 +/- 1.4 kPa/min in NO-treated pigs vs. 15.9 +/- 3.4 in controls, P < 0.01, Mann-Whitney U-test) and it decreased baseline pulmonary arterial pressure (change from time-point - 30-0 was 3.1 +/- 5.3% in the control and - 19.9 +/- 3.5% in the NO group, P < 0.01), which in turn resulted in a lower pulmonary arterial pressure during allergen challenge. NO also caused vasodilatation in the bronchial circulation, resulting in increased bronchial vascular conductance throughout the experiment. NO inhalation caused a small, but non-significant, reduction in the allergen-induced bronchoconstrictor response, whereas histamine release, as detected in urine, was not changed. Total protein levels in bronchoalveolar lavage (BAL) fluid were significantly decreased in the NO group at 120 min after challenge compared with 45 min (373 +/- 101 microg/mL vs. 631 +/- 184, respectively, P < 0.05, Wilcoxon matched pairs test), whereas levels in the control group did not change between these two time-points (513 +/- 282 vs. 599 +/- 354, not significant). CONCLUSION: These findings indicate that NO inhalation improves ventilation/perfusion matching and causes some bronchodilatation during the allergen-induced acute airway reaction, whereas histamine release is not affected. Moreover, NO inhalation enhanced the clearance of extravasated protein in the airways, possibly through increased bronchial blood flow. Even though some protective effects were seen, this study does not support a therapeutic role for exogenous NO in acute allergic reactions.     

Bronchoprotective effects of atrial natriuretic peptide against propranolol-induced bronchoconstriction after allergic reaction in guinea pigs

OBJECTIVE: To study the effects of intravenous atrial natriuretic peptide (ANP) on antigen-induced bronchoconstriction, propranolol-induced bronchoconstriction (PIB) after antigen challenge, and histamine-induced bronchoconstriction in guinea pigs. METHODS: Allergic bronchoconstriction was evoked by inhalation of ovalbumin (OA) and PIB was caused when 10 mg/mL of propranolol was inhaled 20 min after OA challenge in passively sensitized and artificially ventilated guinea pigs. 25, 50, 100 and 200 microg/mL of histamine were inhaled for 20 s at 5-min intervals in non-sensitized guinea pigs. RESULTS: Pretreatment with ANP in doses of 0.1 and 1.0 nmol/kg injected intravenously 15 min after antigen challenge reduced PIB in a dose-dependent manner, and 5 min before antigen challenge significantly attenuated PIB but not antigen-induced bronchoconstriction. Intravenous ANP significantly reduced bronchial responses to increasing concentrations of inhaled histamine in a dose-dependent manner. CONCLUSION: These results suggest that ANP possesses protective effects against propranolol-induced and histamine-induced bronchoconstriction, albeit by a non-specific mechanism in guinea pig in vivo.     

Airway mucosal permeability in the Ascaris suum-sensitive rhesus monkey.

The permeability of the airways to technetium 99m-labeled albumin was measured in Ascaris suum-sensitive rhesus monkeys. All 8 animals were skin-sensitive to Ascaris suum (AA) antigen, 4 being respiratory responders (R) and 4 nonresponders (NR) to aerosolized antigen. In the absence of antigen challenge there were no differences in the accumulation in the blood of radioactive material from the tracheobranchial tree between the R and NR animals. After a five-minute challenge with aerosolized AA, there was a threefold increase in the rate of accumulation of radioactive material in the blood over control for the R group with no effect noted in the NR group. Gel filtration data indicated that the radioactivity in the blood most likely represented low molecular weight albumin fragments, resulting from spontaneous degradation of Tc-albumin, that crossed the mucosa and partially bound to circulating albumin. It is concluded that hyperpermeability of the airway mucosa probably is not a factor that contributes to the selective responsiveness of the R group to aerosolized antigen, and that airway permeability is increased consequent to the allergic reaction mediating acute bronchoconstriction.     

The effect of inhaled hexamethonium bromide and atropine sulphate on airway responsiveness to histamine

The degree of protection against inhaled histamine achieved by inhalation of the ganglion blocker hexamethonium bromide plus placebo, hexamethonium plus atropine sulphate, and placebo plus placebo was examined in six atopic subjects, four of whom had current asthma. Hexamethonium was administered until there was systemic evidence of ganglionic blockade with a postural drop in blood pressure of 31 +/- 7.5 mm Hg (mean +/- SD) (p = 0.01) and an increase in heart rate of 30 +/- 3.1 bpm (mean +/- SD) (p = 0.01). Atropine was inhaled in a dose (18 mg nebulized during tidal breathing) known to produce systemic inhibition of cardiac and salivary cholinergic (muscarinic) receptors. The airway effects were measured by FEV1. Hexamethonium caused bronchoconstriction in all four subjects with asthma, which was reversed by atropine. The mean provocation concentration of histamine to provoke a 20% fall in FEV1 was 2.97 mg/ml after premedication with placebo, it was not different at 2.84 mg/ml after hexamethonium alone, and it increased slightly to 5.31 mg/ml after both hexamethonium and atropine (p = 0.06). The results suggest that the main effect of inhaled histamine is not by reflex bronchoconstriction but rather through stimulation of H1-receptors on airway smooth muscle. Therefore, histamine hyperresponsiveness in asthma is not primarily caused by a defect in the parasympathetic nervous supply to the airway.     

Inhibitory effect of inhaled procaterol on anaphylactic bronchoconstriction and thromboxane A2 production in guinea-pigs

This study was designed to examine whether an inhaled beta 2-agonist, procaterol, inhibits thromboxane A2 (TXA2) production induced by antigen challenge in passively sensitized guinea-pigs in vivo. Antigen-induced bronchoconstriction was markedly inhibited by pre-treatment with procaterol. Inhaled procaterol significantly reduced in a dose-dependent manner the increment in TXB2 concentration in bronchoalveolar lavage fluid obtained 5 min after antigen challenge. Aerosol administration of procaterol significantly inhibited bronchoconstriction induced by inhaled histamine. These results suggest that inhalation of procaterol has an inhibitory effect on antigen-induced TXA2 production as well as a protective effect against bronchoconstriction induced by bronchoactive agents.     

Inhaled sodium fluoride decreases airway responsiveness to acetylcholine analogs in vivo

The study was conducted to characterize the action of NaF, which had relaxing property in carbachol precontracted isolated bovine bronchus, on airway responsiveness challenged by acetylcholine receptor agonists in rats and asthmatic humans.Tracheal flow rate and airway resistance were measured in anaesthetized rats. NaF was delivered either before carbachol challenge or together with carbachol. Patients with mild asthma were challenged with methacholine aerosol, and NaF was delivered when FEV1 fell by more than 20%. The results indicated that: (1) in rats NaF significantly inhibited carbachol-induced bronchial constriction when inhaled prior to carbachol challenge as airway resistances in the NaF and NaF+verapamil groups were significantly lower than those in the control group; (2) NaF significantly reversed carbachol or methacholine-induced bronchial constriction in asthmatic patients. In conclusion, NaF, delivered in form of aerosol, reduced bronchial responsiveness to carbachol in rats and had a bronchodilating effect on rat and human airways precontracted by inhalation of acetylcholine analogs.     

DNA-Based immunization for asthma

BACKGROUND: Immunostimulatory DNA sequences (ISS) containing a CpG motif are able to inhibit Th2-mediated airway eosinophilia and bronchial hyperresponsiveness in a mouse model of asthma. METHODS: To determine the optimal frequency and timing of intervention with ISS in inhibiting Th2 cytokine production and airway eosinophilia, we used ISS administration protocols which differed in the frequency (one vs. two doses), route (systemic vs. mucosal) and timing of ISS administration (before or together with antigen) in a mouse model of ovalbumin-induced eosinophilic airway inflammation. RESULTS: ISS induced Th1 cytokine production (IFN-gamma) and effectively inhibited Th2 cytokine production (IL-5) as well as eosinophilic inflammation when ISS was administered before or coadministered with inhaled allergen challenge. Although ISS was effective when coadministered with inhaled allergen, it was most effective when administered once 6 days prior to allergen challenge. Mucosal (intranasal and intratracheal) delivery of ISS was as effective as systemic (intraperitoneal) ISS delivery in inhibiting airway eosinophilia and switching cytokine responses from a Th2 to a Th1 response. CONCLUSIONS: ISS is most effective in inhibiting airway eosinophilia when administered as a single dose 6 days prior to antigen inhalation. However, ISS can also significantly inhibit eosinophilic inflammation, when coadministered with antigen inhalation. Thus, ISS administered prior or together with allergen should be considered as a novel method of allergen-based immunotherapy.     

Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline

We performed a double-blind crossover study to compare the effects of long-term treatment of inhaled budesonide and terbutaline on bronchial hyperreactivity in 17 patients with allergic asthma. Both drugs were administered for 4 weeks with a placebo-treatment period before and after each active-treatment period. To assess bronchial hyperreactivity, standardized inhalation provocation tests with histamine and propranolol were performed every 2 weeks. Before each inhalation provocation the drugs were withheld for at least 12 hours. Before the budesonide treatment the FEV1 value (percent predicted) was 85.3 +/- 4.1% (mean +/- SEM). After 2 and 4 weeks of treatment with this drug, the value increased significantly to 89.4 +/- 4.1% and 96.2 +/- 3.8%, respectively (p less than 0.05 and p less than 0.005). The histamine provocation concentrations causing a decrease in FEV1 of 20% (PC20) on the same days were 4.0, 7.2, and 9.5 mg/ml, respectively (both p less than 0.001). The PC20 values for propranolol, which were measured 1 hour after the histamine provocation, were 11.7, 13.3, and 14.0 mg/ml (ns). The FEV1 values before and after 2 and 4 weeks of treatment with terbutaline were 86.2 +/- 4.0%, 84.8 +/- 4.1%, and 87.0 +/- 4.6%, respectively. The histamine PC20 values on the same days were 4.7, 3.1 (p less than 0.05), and 3.8 mg/ml, respectively. The propranolol PC20 values were 14.2, 8.7, and 10.1 mg/ml (p less than 0.001 and p less than 0.05, respectively. We conclude that budesonide improves bronchial hyperreactivity, possibly by a dampening of late allergic reactions, whereas treatment with terbutaline may lead to a temporary increase of bronchial hyperreactivity, possibly as a result of beta-receptor desensitization.     

The effect of oral zindotrine (MDL-257), a bronchial smooth muscle relaxant, on histamine airways responsiveness in asymptomatic asthmatics

We evaluated the efficacy of an oral dosage form of the investigational smooth muscle relaxant, zindotrine, a novel pyridazine derivative, in counteracting histamine-induced bronchospasm in a group of 12 non-medicated asymptomatic asthmatics. Histamine inhalation challenges were performed before (control) and 45, 150, and 300 minutes after zindotrine (200 and 300 mg), or the corresponding dose of placebo was administered orally in a randomized, double-blind crossover fashion. When compared to the control state, the 300-mg zindotrine dose markedly lowered histamine airway responsiveness as indicated by a significant (P less than .01) increase in the inhaled histamine dose necessary to provoke a 20% decrease in the forced expired volume in one second (PD20FEV1) 45 minutes after drug administration. The PD20FEV1 then decreased linearly over time but remained higher than the control PD20FEV1 value (P less than .05) during the entire observation period. The 200-mg zindotrine dose failed to affect the PD20FEV1. Our data indicate that orally administered zindotrine lowers airways responsiveness to inhaled histamine in asymptomatic asthmatics in a dose-dependent and time-dependent fashion.     

Sensitivity to methacholine and capsaicin in patients with unclear respiratory symptoms

BACKGROUND: Capsaicin, the pungent ingredient in red pepper, is known to stimulate coughing via the sensory nervous system. Earlier studies showed that patients with airway symptoms induced by chemicals and strong scents cough more after inhalation of capsaicin than healthy control subjects and this has been interpreted as a hyperreactivity of airway sensory nerves. Our aim was to study airway sensitivity to inhaled capsaicin and the occurrence of airway symptoms induced by strong scents in patients who underwent a bronchial methacholine test, primarily because of suspected asthma. METHODS: Fifty-two consecutive patients referred for testing with methacholine were also provoked with inhaled capsaicin in increasing concentrations. Cough sensitivity to capsaicin was compared with that in 40 healthy control subjects. RESULTS: The patients coughed significantly more compared with the healthy control subjects with each dose of capsaicin (P < 0.0001). Twelve patients (23%) had a positive methacholine test, and of these, nine were diagnosed with asthma. There was no difference in capsaicin sensitivity between patients sensitive or insensitive to methacholine. CONCLUSIONS: The majority of the patients had no increased sensitivity to methacholine but did demonstrate sensory hyperreactivity (SHR). SHR appears to be a common diagnosis in investigations of patients with obscure airway symptoms.