Omeprazole reduces the response to capsaicin but not to methacholine in asthmatic patients with proximal reflux

Objective. To study the relationships between airway responsiveness to methacholine and capsaicin, proximal or distal reflux and the effects of short-term acid inhibition. Material and methods. Twenty-nine asthmatics, not taking steroids regularly, underwent respiratory symptom measurements, 24-h dual-probe pH monitoring, and challenges with methacholine and capsaicin. Challenges and symptom measurements were repeated after 12 days’ omeprazole treatment (20 mg b.i.d.). The results (median and range) were expressed as PD20 methacholine (mg) and PD5 capsaicin (dose causing five coughs, nmol). Results. Seventeen patients presented pathological reflux in the distal esophagus, and 17 in the proximal esophagus. At baseline no correlation was found between PD20 or PD5 and reflux. Treatment with omeprazole did not change bronchial responsiveness to methacholine (basal: 0.16 mg, 0.02–1.27; omeprazole: 0.15 mg, 0.02–1.60); omeprazole decreased the tussive response to capsaicin (basal: 0.08 nmol, 0.08–2.46; omeprazole: 0.61 nmol, 0.08–9.84, p<0.001) only in patients with pathological reflux. The decrease was positively correlated with proximal acid exposure (r²=0.70, p<0.001). Omeprazole reduced asthma symptoms in patients with proximal reflux, cough in those with proximal or distal reflux. Conclusions. In asthmatics, inhibition of gastric acid secretion does not influence bronchial hyperresponsiveness but decreases tussive sensitivity and this effect is related to proximal reflux.     

Effects of esophageal acid perfusion on cough responsiveness in patients with bronchial asthma

STUDY OBJECTIVES: The effect of gastroesophageal reflux (GER) on cough responsiveness in patients with bronchial asthma has yet to be studied in significant detail. The purpose of this study was to assess the effect of distal esophageal acid perfusion on cough responsiveness in patients with bronchial asthma. PATIENTS AND INTERVENTIONS: In seven patients with mild persistent bronchial asthma (mean +/- SD age, 57.7 +/- 3.7 years; four women and three men), esophageal pH was monitored by a pH meter and cough responsiveness was evaluated by single-breath aerosol inhalation of capsaicin with increasing dosage from 0.30 to 9.84 nmol. Simultaneously, esophageal perfusion was performed through an esophageal tube filled with either saline solution or 0.1 N hydrochloric acid (HCl), the order of which was selected at random, in 1-week intervals. Results were expressed as the lowest concentration of capsaicin eliciting three coughs (PD3). Spirometry was also performed during esophageal pH monitoring. RESULTS: A significant decrease in the geometric mean of log PD3 was observed during distal esophageal HCl perfusion (0.45 +/- 0.04 nmol) compared with that of the saline solution perfusion (0.04 +/- 0.06 nmol) [p < 0.01]. However, no significant changes were observed either in FVC, FEV1, or peak expiratory flow during the periods of the saline solution or HCl perfusion. CONCLUSION: The present data demonstrate that an increase in cough responsiveness may be induced when HCl stimulates the distal portion of esophagus in patients with bronchial asthma, suggesting that the GER would be one of the important factors that influence asthmatic status.     

Cough threshold in reflux oesophagitis: influence of acid and of laryngeal and oesophageal damage

BACKGROUND: Gastro-oesophageal reflux is often associated with cough. Patients with reflux show an enhanced tussive response to bronchial irritants, even in the absence of respiratory symptoms. AIM: To investigate the effect of mucosal damage (either oesophageal or laryngeal) and of oesophageal acid flooding on cough threshold in reflux patients. PATIENTS: We studied 21 patients with reflux oesophagitis and digestive symptoms. Respiratory diseases, smoking, and use of drugs influencing cough were considered exclusion criteria. METHODS: Patients underwent pH monitoring, manometry, digestive endoscopy, laryngoscopy, and methacholine challenge. We evaluated the cough response to inhaled capsaicin (expressed as PD5, the dose producing five coughs) before therapy, after five days of omeprazole therapy, and when oesophageal and laryngeal damage had healed. RESULTS: In all patients spirometry and methacholine challenge were normal. Thirteen patients had posterior laryngitis and eight complained of coughing. Twenty patients showed an enhanced cough response (basal PD5 0.92 (0.47) nM; mean (SEM)) which improved after five and 60 days (2.87 (0.82) and 5.88 (0.85) nM; p<0.0001). The severity of oesophagitis did not influence PD5 variation. On the contrary, the response to treatment was significantly different in patients with and without laryngitis (p = 0.038). In patients with no laryngitis, the cough threshold improved after five days with no further change thereafter. In patients with laryngitis, the cough threshold improved after five days and improved further after 60 days. Proximal and distal oesophageal acid exposure did not influence PD5. Heartburn disappeared during the first five days but the decrease in cough and throat clearing were slower. CONCLUSIONS: Patients with reflux oesophagitis have a decreased cough threshold. This is related to both laryngeal inflammation and acid flooding of the oesophagus but not to the severity of oesophagitis. Omeprazole improves not only respiratory and gastro-oesophageal symptoms but also the cough threshold.     

Successful Elimination of Reflux Symptoms Does Not Insure Adequate Control of Acid Reflux in Patients with Barrett's Esophagus

Objective: Patients with Barrett's metaplasia of the esophagus often lack the appropriate amount of heartburn for their severity of gastroesophageal reflux. Therefore, we studied patients with Barrett's metaplasia by prolonged ambulatory pH monitoring after completely suppressing their heartburn symptoms to determine whether acid reflux was underestimated in symptom assessment. Methods: Five patients with Barrett's esophagus, all of whom presented with heartburn, were treated with omeprazole (20–60 mg/day) until they were asymptomatic. Twenty-four-bour pH ambulatory monitoring was performed while they were on omeprazole. Results: Four of five patients showed persistent abnormal gastroesophageal reflux after treatment with omeprazole. Two patients showed abnormally increased supine reflux and two patients had an abnormal increase in both supine and uprigbt reflux. Only one patient had complete inbibition of tbe acid reflux by the omeprazole (20 mg b.i.d.). Conclusions: Treating the patient with Barrett's esophagus to the endpoint of eradication of heartburn does not insure adequate control of acid reflux. Prolonged ambulatory pH monitoring of the esophagus should be conducted to demonstrate that an adequate dose of omeprazole has been given, despite symptomatic improvement.     

Effects of inhaled corticosteroids on cough threshold in patients with bronchial asthma

In asthmatic subjects cough can be related to the degree of airway inflammation. The aim of this study was to evaluate the effect of treatment with high dose inhaled beclomethasone dipropionate (BDP) on cough threshold in asthmatic subjects. Cough threshold to inhaled capsaicin (one breath of 10(-8)-10(-4)M solution) and to citric acid (one breath of 10(-4)-1 M), expressed as provocative concentration of two (PC2) and four coughs (PC4), was measured in 16 normal and 36 asthmatic subjects. After baseline evaluation, asthmatic subjects were randomized in two groups: (a) Group A, n=20: treated with salbutamol (200 microg t.i.d.) plus BDP (500 microg t.i.d.); (b) Group B, n=16: treated with salbutamol plus placebo in the same doses. After 1 month, cough threshold and clinical and functional evaluation were repeated. After treatment, asthmatics of group A showed a significant improvement in PC4 citric acid, in total symptom and cough scores, and in PD20FEV1 methacholine. In asthmatics of group B, treatment caused no improvement in symptoms, PD20FEV1 methacoline and cough threshold. In addition, cough threshold was not different between normal and asthmatic subjects and, in asthmatics, cough threshold did not correlate with PD20FEV1 methacholine. These data confirm that cough in asthma can be partially related to airway inflammation.     

The effect of bronchoalveolar lavage on bronchial responsiveness in patients with airflow obstruction

This study assessed the effect of bronchoalveolar lavage (BAL) on nonspecific bronchial responsiveness in 31 patients. Of these, 20 had airflow obstruction; 11 control subjects had normal pulmonary function. Bronchial responsiveness to methacholine, expressed as the dose of inhaled methacholine required to provoke a 20 percent fall in forced expiratory volume in one second (PD20 FEV1), was measured before and after BAL. We found no evidence for the induction of responsiveness by BAL in 11 control subjects with negative methacholine tests prior to the procedure. There were small but significant falls in FEV1 following BAL in both the control group and in patients with airflow obstruction. Thus, BAL does not appear to induce nonspecific bronchial hyperresponsiveness in subjects without airflow obstruction, nor does it affect airway responsiveness in emphysema patients. Among asthmatics, bronchial responsiveness can be increased as a result of BAL; this increase was greatest in patients who were most responsive initially.     

The relative responsiveness to inhaled leukotriene E4, methacholine and histamine in normal and asthmatic subjects

The relative bronchoconstricting potencies of leukotriene E4 (LTE4) methacholine and histamine have been compared in asthmatic and normal subjects. LTE4 responsiveness in asthmatic subjects, as measured by the dose which produced a 35% fall in specific airways conductance (PD35), ranged from 0.06-24.4 nmol (geom mean 4.1 nmol, n = 20). This was significantly less than the PD35 in normal subjects (range 39.0-370 nmol, geom mean 105 nmol, n= 6; p less than 0.001). There was a correlation between LTE4 and methacholine responsiveness (r = 0.84, p less than 0.001) and between LTE4 and histamine responsiveness (r = 0.79, p less than 0.001). LTE4 was 73 times more potent than methacholine and 112 times more potent than histamine in asthmatic subjects. LTE4 was 20 times more potent than methacholine and 58 times more potent than histamine in normal subjects. LTE4 is a potent bronchoconstrictor agent, and LTE4 responsiveness correlates with both histamine and methacholine responsiveness.     

Does acid reflux cause pulmonary disease?

BACKGROUND/AIMS: Gastroesophageal reflux is considered as a factor in pulmonary diseases. The aim of this study was to assess whether gastroesophageal reflux is associated with abnormalities in lung function in patients without respiratory disease. METHODS: Forty- four patients with reflux symptoms were studied prospectively. Standardized methods of esophageal manometry and ambulatory 24-h esophageal pH testing were used throughout the study period, along with a standardized reflux and respiratory symptom questionnaire. Spirometric measurements were performed in all patients. RESULTS: Reflux to distal esophagus was observed in 9 patients, to proximal esophagus in 4 and to both distal and proximal in 20 of the 44 patients. Eleven patients revealed reflux neither to distal nor proximal esophagus. Respiratory function tests of these groups showed no significant differences (p>0.05). CONCLUSION: There is no correlation between esophageal acid events and respiratory function tests. There are no data to answer the question of whether or not reflux precedes onset of cough/asthma. Better-designed prospective cohort studies may provide further insight.     

Bronchial responsiveness to eucapnic hyperventilation and methacholine following exposure to organic dust

STUDY OBJECTIVE: Inhalation of dust in a swine confinement building causes an intense airway inflammatory reaction in the airways and increased bronchial responsiveness to methacholine. The aims of the present study were to investigate whether exposure to organic dust also influences bronchial responsiveness to an indirect stimulus, and to assess the duration of increased postexposure bronchial responsiveness. DESIGN: Twenty-two healthy nonatopic, nonsmoking subjects were exposed to dust for 3 h in a swine confinement building. Lung function was assessed, and either a methacholine bronchial provocation (n = 11) or a challenge with eucapnic hyperventilation of dry air (n = 11) was performed before exposure and at 7 h, 1 week, 2 weeks, and 4 weeks after exposure. RESULTS: Vital capacity and FEV(1) decreased 3% and 6%, respectively (p < 0.001), and airway resistance increased 15% (p < 0.05) after exposure. The median provocative dose of methacholine causing a 20% decline in FEV(1) fell from 1.38 mg (25th to 75th percentiles, 0.75 to 7.20 mg) before exposure to 0.18 mg (0.11 to 0.30 mg) after exposure (p = 0.004). Corresponding values for the dose-response slope were 15.3%/mg (2.88 to 25.3%/mg) and 100.2%/mg (2.1 to 27.3%/mg), respectively (p = 0.01). Bronchial responsiveness to eucapnic hyperventilation was not affected by the exposure: FEV(1) fell 4.3% (- 7.2 to - 1.8%) before and 4.8% (- 6.7 to - 1.6%) after exposure (p = 0.72). One week after exposure, the bronchial responsiveness to methacholine was normalized. CONCLUSIONS: The bronchial responsiveness to methacholine but not to dry air increases after exposure to swine house dust. Thus, exposure to organic dust induces increased bronchial responsiveness with different characteristics from that frequently found in asthma.     

Effect of elimination of acid reflux on epithelial cell proliferative activity of Barrett esophagus

BACKGROUND: Barrett esophagus (BE) is a premalignant condition resulting from chronic acid gastroesophageal reflux and is associated with increased epithelial cell proliferation. Elimination of acid reflux might decrease cancer risk by affecting cell proliferation in BE. The effect of elimination of acid reflux on epithelial cell proliferation in BE was studied. METHODS: Forty-five patients with long segment Barrett esophagus were treated in a randomized 2-year follow-up study with either omeprazole 40 mg b.i.d. (OME) or ranitidine 150 mg b.i.d. (RAN) and were compared for the effect on epithelial cell proliferation. Biopsies were taken 3 cm above the GE junction and just below the Z-line, at 0, 3, 9, and 24 months. Epithelial cell proliferation was determined by in vitro labeling with 5-bromo-2-deoxyuridine and immunohistochemistry. Labeling indices (LI) were established for luminal and crypt epithelium separately. Ambulatory 24-h esophageal pH-metry was performed at 0 and 3 months. Comparisons were made for the timeframes 0-3 months, 3-24 months, and 0-24 months. RESULTS: OME reduced mean acid reflux to 0.1 %/24 h, RAN to 9.4%. In the distal and the proximal biopsies, change in LI after 3 months was n.s. at either level for both treatments. In the distal biopsies (OME 22, RAN 23 patients) luminal LI increased significantly for RAN from 3 to 24 months (+12.64% month, mean area under the curve (AUC)), while that for OME remained stable, RAN versus OME P < 0.05. Crypt LI increased in both groups, only in RAN significantly so (+30.75% month), RAN versus OME n.s. In the proximal biopsies luminal LI at 24 months (OME 20, RAN 21 patients) had increased slightly but not significantly in RAN (+8.86% month), RAN versus OME n.s., whereas in the crypts LI in OME it had increased significantly (+28.80% month), OME versus RAN n.s. CONCLUSION: Elimination of acid reflux resulted in a stabilization of luminal cell proliferative activity of Barrett epithelium in the distal esophagus, whereas this activity increased during continued acid reflux. Whether this finding has any implication for the cancer risk in Barrett esophagus remains to be seen.     

Effects of esophageal acid perfusion on airway hyperresponsiveness in patients with bronchial asthma

STUDY OBJECTIVES: The effects of gastroesophageal reflux on airway hyperresponsiveness in patients with bronchial asthma have yet to be studied in significant detail. The purpose of the present study was to determine how esophageal acid perfusion could change airway responsiveness in patients with bronchial asthma. PATIENTS AND INTERVENTIONS: In seven patients with bronchial asthma (mean +/- SD age, 55.1 +/- 6.4 years; four women and three men), esophageal pH was monitored by a pH meter and airway responsiveness was evaluated by aerosol inhalation of methacholine, during esophageal perfusion through an esophageal tube filled with either saline solution or 0. 1N hydrochloric acid (HCl), the order of which was selected at random, in 1-week intervals. Spirometry was also performed during esophageal pH monitoring. RESULTS: A significant decrease in the geometric mean of airway sensitivity or the concentration of methacholine causing a 35% fall in respiratory conductance was observed during esophageal HCl perfusion compared with that of saline solution perfusion (p < 0.01 or p < 0.003), although no significant changes were observed in vital capacity, FEV(1), peak expiratory flow, respiratory resistance, or slope of respiratory conductance during the periods of saline solution and HCl perfusion. CONCLUSION: We concluded that an increase in airway hyperresponsiveness was induced when HCl stimulated the esophagus in patients with bronchial asthma. These results suggest that esophageal reflux is one of the important factors that aggravate asthmatic status.     

Determinants of Long-Term Outcome of Patients with Reflux-Related Ear, Nose, and Throat Symptoms

Gastroesophageal reflux disease (GERD) is present in up to 75% of patients with chronic refractory ear, nose, and throat (ENT) symptoms, and proton pump inhibitor (PPI) therapy induces symptom relief in the majority of these patients. It has been suggested that endoscopic findings and quantification of esophageal acid exposure may help to predict the long-term outcome of medical therapy, but prospective studies that confirm this hypothesis are lacking. The aim of the present study was to investigate the relationship of endoscopic findings and quantification of reflux with long-term outcome in patients with reflux-related ENT symptoms. One hundred six consecutive patients with chronic refractory unexplained ENT symptoms underwent upper GI endoscopy, 24-hr dual-channel esophageal pH and Bilitec (n = 35) monitoring, and esophageal manometry. Subsequently, all were treated with omeprazole, 20 mg b.i.d., and patients were followed at 2-week intervals until symptom relief. Four weeks later, omeprazole therapy was gradually decreased and the lowest effective omeprazole maintenance dose, if any, was determined. Eighty-one patients (49 men; mean age, 50) experienced a clear or excellent therapeutic response after, on average, 4 weeks of omeprazole, 20 mg b.i.d. In 36 patients (44%; group A), PPI treatment could be stopped completely, 27 patients (33%; group B) required a maintenance dose of omeprazole, 20 mg/day, and 18 patients (22%; group C) required maintenance with omeprazole, 40 mg/day. The prevalence of reflux esophagitis was significantly lower in group A patients, who also had significantly lower distal esophageal acid exposure, proximal esophageal acid exposure, and esophageal duodenogastroesophageal reflux exposure compared to groups B and C. Multivariate analysis identified the presence of esophagitis and pathological distal esophageal acid exposure as risk factors for the need of maintenance therapy. In patients with reflux-related ENT symptoms, initial findings on upper GI endoscopy and 24-hr pH-metry help to predict the need for maintenance therapy.     

Acid exposure and altered acid clearance in GERD patients treated for Helicobacter pylori infection

BACKGROUND: After the eradication of Helicobacter pylori, an increased incidence of gastroesophageal reflux disease and acid gastric secretion have been reported. AIM: To evaluate the effect of Helicobacter pylori-eradication on proximal and distal gastroesophageal reflux and acid clearance in patients with gastroesophageal reflux disease. PATIENTS AND METHODS: Sixty-eight gastroesophageal reflux disease patients (age range 18-61 years) were studied by upper endoscopy. All underwent esophageal manometry and dual probe 24-h pH-metry. RESULTS: Percent of time at pH<4 was significantly increased in the proximal esophagus of Helicobacter pylori-eradicated patients compared to Helicobacter pylori-negative (2.4+/-0.5 vs. 1.0+/-0.2; p<0.01); no differences were found in the distal esophagus (14.0+/-3.7 vs. 9.0+/-1.4%, NS). The total number of reflux episodes was significantly higher in the proximal oesophagus of Helicobacter pylori-eradicated patients (37+/-3 vs. 22+/-3, p<0.05). In the distal esophagus, acid clearance was significantly longer, both during total time (1.4+/-0.2 vs. 0.8+/-0.7 min, p<0.01), and in the supine period (8.5+/-2.7 vs. 2.7+/-0.4 min, p<0.05). No differences were reported in the manometric parameters of the two groups of patients. CONCLUSION: In patients with gastroesophageal reflux disease, Helicobacter pylori eradication is associated with increased acid exposure of the proximal esophagus and delayed distal acid clearance.     

Effect of infused angiotensin II on the bronchoconstrictor activity of inhaled endothelin-1 in asthma

STUDY OBJECTIVES: Endothelin (ET)-1 is a potent bronchoconstrictor, and asthmatics demonstrate bronchial hyperresponsiveness to ET-1 given by inhalation. Angiotensin II (Ang II) is increased in plasma in acute severe asthma, causes bronchoconstriction in asthmatics, and potentiates contractions induced by ET-1 in bovine bronchial smooth muscle in vitro, and contractions induced by methacholine both in vitro and in vivo. We wished to examine any potentiation of the bronchoconstrictor activity of inhaled ET-1 by infused Ang II at subbronchoconstrictor doses. DESIGN: Double-blind randomized placebo-controlled study. SETTING: Asthma research unit in university hospital. PATIENTS: Eight asthmatic subjects with baseline FEV1 88% predicted, bronchial hyperreactivity (geometric mean, concentration of methacholine producing 20% fall, methacholine PC20 2.5 mg/mL), and mean age 37.1 years. INTERVENTIONS: We examined the effect of subbronchoconstrictor doses of infused Ang II (1 ng/kg/min and 2 ng/kg/min) or placebo on bronchoconstrictor responses to inhaled ET-1 (dose range, 0.96 to 15.36 nmol). MEASUREMENTS: Oxygen saturation, noninvasive BP, and spirometric measurements were made throughout the study visits. Blood was sampled for plasma Ang II levels at baseline and before and after ET-1 inhalation. RESULTS: Ang II infusion did not produce bronchoconstriction per se at either dose prior to ET-1 challenge. Bronchial challenge with inhaled ET-1 produced dose-dependent bronchoconstriction, but there was no difference in bronchial responsiveness to ET-1 comparing infusion of placebo with Ang II at 1 ng/kg/min or 2 ng/kg/min (geometric mean, concentration of ET-1 producing 15% fall, 5.34 nmol, 4.95 nmol, and 4.96 nmol, respectively) (analysis of variance, p > 0.05). There was an increase in systolic and diastolic BP at the higher dose of Ang II compared to placebo (mean 136/86 vs 117/75 mm Hg, respectively). Plasma Ang II was elevated following infusion of both doses of Ang II compared to placebo. CONCLUSIONS: In contrast to the potentiating effect on methacholine-induced bronchoconstriction, Ang II at subbronchoconstrictor doses does not potentiate ET-1-induced bronchoconstriction in asthma.     

Comparison of maximal airway narrowing to methacholine between children and adults.

Bronchial hyperresponsiveness in adults is characterized by an increased sensitivity as well as an elevated maximal response to inhaled bronchoconstrictors. In children, however, it is unknown whether the maximal response increases with increasing sensitivity. We investigated the maximal degree of airway narrowing to methacholine in nonasthmatic and asthmatic children (7-12 yrs), and compared it to that in adults. Nineteen children (9 normals, 10 asthmatics) and 19 adults (8 normals, 11 asthmatics) were selected in order to cover a wide distribution of bronchial responsiveness. All subjects underwent 2 methacholine challenge tests on separate days, by inhaling doubling doses using a standardized dosimeter technique (up to a noncumulative dose of 59 mumol). The response was measured by forced expiratory volume in one second (FEV1) and expressed as a percentage fall from baseline value. The complete dose-response curves were characterized by their position (PD20, the provocative dose causing a 20% fall in FEV1) and maximal response (MFEV1, the mean response on the plateau, defined as greater than or equal to 2 points within a 5% response range). Plateaus were observed in 13 children and 9 adults, the coefficient of repeatability of MFEV1 being 10.8 and 10.4% fall, respectively. There was an inverse relationship between log PD20 and MFEV1, which did not differ between children and adults (p greater than 0.15). In most of the asthmatic children and adults the plateau could not be measured (exceeding 50% fall in FEV1) if PD20 was less than 1 mumol. We conclude that, for a given bronchial sensitivity, the maximal response to inhaled methacholine is similar between children and adults.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of inhaled 15-(s)-hydroxyeicosatetraenoic acid (15-HETE) on airway calibre and non-specific responsiveness in normal and asthmatic human subjects

15-hydroxyeicosatetraenoic acid (15-HETE) is the predominant oxidative metabolite of arachidonic acid in human lung. We have studied its effects on airway calibre and non-specific bronchial responsiveness (NSBR) in eight normal and eight asthmatic subjects. 15-HETE, at doses up to 70 nmol, had no effect on airway calibre in either group of subjects. However, 3 h after its administration, 15-HETE reduced NSBR in the normal subjects (geometric mean methacholine PD40 Vp30 increased by 2.29-fold from baseline compared with a corresponding 1.14-fold increase after diluent, p less than 0.05). Similarly, 4 h after inhaled 15-HETE, the spontaneous increase in NSBR in the asthmatics was completely inhibited (geometric mean histamine PD40 Vp30 decreased significantly to 0.41-fold of baseline after diluent (p less than 0.01) compared with a 1.1-fold increase after 15-HETE, p less than 0.01). These data suggest 15-HETE may play an autacoid role in airway function.     

Effect of the GABA-agonist baclofen on bronchial responsiveness in asthmatics.

Gamma-aminobutyric acid (GABA) is a central inhibitory neurotransmitter. Recently, the presence of GABA and its receptors has been confirmed in peripheral tissues, including the lungs. GABA and the GABA agonist baclofen have been shown in animal studies to inhibit airway responsiveness to various bronchoconstricting agents. The results of these investigations suggest the possibility of a role for baclofen in the therapy of human airway hyperreactivity. To investigate this question, a randomized, double-blind, placebo-controlled, cross-over study was performed to evaluate the effect of a 14-day course of oral baclofen (10 mg three times daily) on pulmonary function and bronchial responsiveness to methacholine in a group of six stable asthmatics. In five of six subjects, hyperresponsiveness was enhanced after therapy with baclofen. Mean (+/- SEM) log PC(20)pre-and post-baclofen were 0.160 +/- 0.247 and -0.223 +/- 0.282, respectively (P=0.023). Baseline pulmonary function (FEV(1)) was unaffected by baclofen. The mechanism(s) underlying this apparent paradoxical enhancement by baclofen of bronchial responsiveness remains speculative, but may be relevant to the recently-proposed concept of dysfunction in asthmatics of prejunctional GABA receptors, whose normal role may be to inhibit cholinergic contraction of bronchial smooth muscle.     

Gastroesophageal reflux and bronchial responsiveness: correlation and the effect of fundoplication

BACKGROUND: A causal relationship between gastroesophageal reflux (GER) and asthma has been suggested. Should this be the case, one could expect treatment of GER to diminish bronchial sensitivity. There has been a lack of trials evaluating the efficacy of antireflux surgery on airway reactivity. OBJECTIVES: To investigate the correlation between GER and bronchial responsiveness, and to determine the efficacy of Nissen fundoplication on bronchial responsiveness and pulmonary function. METHODS: A methacholine inhalation challenge was performed on 15 consecutive GER patients preoperatively and approximately 5 months after Nissen fundoplication. Airway responsiveness was quantified with a dose-response slope (DRS), calculated by dividing the decrease in FEV(1) (%) with the dose of methacholine administered (micromoles). RESULTS: A positive correlation between the severity of distal esophageal reflux and bronchial responsiveness was found (r = 0.83, p < 0.001). There was an improvement in FEV(1) after fundoplication (p = 0.03). All 3 asthmatic patients participating in the study presented with bronchial hyperresponsiveness (BHR) which improved clearly in all of these patients after fundoplication. This resulted in an apparent trend for DRS to improve when the entire study population was considered (p = 0.12). CONCLUSIONS: According to the current study there seems to be a positive correlation between the severity of distal esophageal reflux and bronchial responsiveness. These data suggest that operative treatment of GER may ameliorate BHR in asthmatic patients. Moreover, the results of the present study suggest that fundoplication may improve pulmonary function in patients with GER.     

Bronchial hyperresponsiveness in subjects with gastroesophageal reflux

BACKGROUND: The relationship between gastroesophageal reflux (GER) and asthma has been widely studied in the last years. GER may interfere with airway reactivity and aggravate or even induce asthma. OBJECTIVE: To assess the prevalence of bronchial hyperresponsiveness (BHR) in patients with GER disease with a view to judging the potential influence of GER on BHR. METHODS: 30 patients with GER disease and no clinical evidence of asthma and 30 normal subjects underwent a methacholine bronchial challenge. The methacholine concentration that caused a 20% fall in the FEV(1) (PC20) was used to assess bronchial responsiveness. RESULTS: In the GER group 11 subjects of the 30 studied showed a PC20 methacholine equal to or less than 8 mg/ml while in the control group only 2 subjects had a PC20 methacholine equal to or less than 8 mg/ml (p < 0.01; ANOVA test). CONCLUSIONS: Subjects with GER had a greater increase in airway reactivity when inhaling methacholine compared to disease-free normal subjects.     

Effect of Elimination of Acid Reflux on Epithelial Cell Proliferative Activity of Barrett Esophagus

Background: Barrett esophagus (BE) is a premalignant condition resulting from chronic acid gastroesophageal reflux and is associated with increased epithelial cell proliferation. Elimination of acid reflux might decrease cancer risk by affecting cell proliferation in BE. The effect of elimination of acid reflux on epithelial cell proliferation in BE was studied. Methods: Forty-five patients with long segment Barrett esophagus were treated in a randomized 2-year follow-up study with either omeprazole 40 mg b.i.d. (OME) or ranitidine 150 mg b.i.d. (RAN) and were compared for the effect on epithelial cell proliferation. Biopsies were taken 3 cm above the GE junction and just below the Z-line, at 0, 3, 9, and 24 months. Epithelial cell proliferation was determined by in vitro labeling with 5-bromo-2-deoxyuridine and immunohistochemistry. Labeling indices (LI) were established for luminal and crypt epithelium separately. Ambulatory 24-h esophageal pH-metry was performed at 0 and 3 months. Comparisons were made for the timeframes 0-3 months, 3-24 months, and 0-24 months. Results: OME reduced mean acid reflux to 0.1%/24 h, RAN to 9.4%. In the distal and the proximal biopsies, change in LI after 3 months was n.s. at either level for both treatments. In the distal biopsies (OME 22, RAN 23 patients) luminal LI increased significantly for RAN from 3 to 24 months (+ 12.64% month, mean area under the curve (AUC)), while that for OME remained stable, RAN versus OME P &lt; 0.05. Crypt LI increased in both groups, only in RAN significantly so (+ 30.75% month), RAN versus OME n.s. In the proximal biopsies luminal LI at 24 months (OME 20, RAN 21 patients) had increased slightly but not significantly in RAN (+ 8.86% month), RAN versus OME n.s., whereas in the crypts LI in OME it had increased significantly (+ 28.80% month), OME versus RAN n.s. Conclusion: Elimination ofacid reflux resulted in a stabilization of luminal cell proliferative activity of Barrett epithelium in the distal esophagus, whereas this activity increased during continued acid reflux. Whether this finding has any implication for the cancer risk in Barrett esophagus remains to be seen.