Pattern of acid reflux in patients with reflux esophagitis 'resistant' to H2-receptor antagonists

Ambulatory 24-h esophageal pH monitoring was carried out in 54 patients with erosive/ulcerative reflux esophagitis before a 12- to 24-week treatment with either ranitidine, 150 to 300 mg twice daily, or famotidine, 20 to 40 mg twice daily. After this period, 21 patients continued to present endoscopic evidence of esophagitis. Patients who did not respond to the therapy showed a more severe pretreatment pattern of acid reflux than those who healed, with regard to both median percentage time of reflux (16.2% versus 11.0%, respectively, p less than 0.05) and median number of reflux episodes (88.0 versus 55.0; p less than 0.05). Ambulatory 24-h esophageal pH-metry is therefore to be recommended in all patients with acid reflux symptoms, even in those who already show endoscopic lesions of the esophageal mucosa, since this test is a valid prognostic indicator of response to treatment.     

H2 antagonists in the treatment of reflux oesophagitis: can physiological studies predict the response?

Ambulatory oesophageal pH, oesophageal manometry and fasting serum gastrin concentrations were carried out on 28 patients with reflux oesophagitis, before and during treatment with ranitidine 300 mg bd. Fourteen patients healed endoscopically at six weeks (group A) and 14 had residual oesophagitis (group B). Group A were characterised by a lower serum gastrin concentration before treatment (4.52 pmol/l; 2.4-10: mean and range) than group B (11.1 pmol/l; 3.5-21: p less than 0.05) and showed a marked reduction in acid reflux on treatment to near normal values. Mean per cent time below pH4 fell from 14.9 to 4.2 in group A (p less than 0.05) but was not affected in group B (14.2-15.6, not significant). Abnormal oesophageal motility was found in 13 patients from each group. This did not inhibit the response to ranitidine, and was not improved by healing of oesophagitis.     

Vagotomy for duodenal ulcer resistant to H2-receptor antagonists

One hundred and twenty-seven male patients were subjected to antiulcer surgery for duodenal ulcer resistant to H2-receptor antagonist treatment. Fifty-four (group A) had been on conservative treatment for up to 6 months, while the remaining 73 (group B) had been on conservative treatment for more than 6 and up to 20 months. Of the group A, 43 underwent truncal vagotomy with pyloroplasty (group A1) and 11 highly selective vagotomy (group A2). Of group B, 52 underwent truncal vagotomy with pyloroplasty (group B1) and 21 highly selective vagotomy (group B2). Follow-up ranged between 18 and 72 months (mean 37 months). There were one ulcer recurrence in group A1, none in group A2, nine in group B1 and five in group B2, the difference between group A and group B being statistically significant (p less than 0.05). There was significantly higher nonulcer-associated morbidity after truncal than after highly selective vagotomy (p less than 0.05). No significant difference in the degree of peak acid output reduction was observed between the patients with and those without ulcer recurrence. These findings show that the administration of H2-receptor antagonists for more than 6 months in duodenal ulcer patients who, however, fail to have their ulcer healed is associated with high recurrence rate after vagotomy. It is suggested that such patients should undergo vagotomy as soon as they fulfill the criteria of resistance to H2-receptor antagonists. If conservative treatment has lasted for more than 6 months, vagotomy plus antrectomy has to be considered as the surgical treatment for these patients, with the possible cost of higher nonulcer-associated morbidity.     

Smoking and pH response to H2-receptor antagonists

Smoking has been shown to impair the therapeutic effect of H2-receptor antagonists. To evaluate the acid-reducing capacity of H2-receptor antagonists in relation to smoking habits, we tested the effect of ranitidine (Ran) and famotidine (Fam) under physiologic conditions, using ambulatory pH-metry. Intragastric pH was measured over 20 h. Each of 18 healthy volunteers, 9 smokers and 9 nonsmokers, received 40 mg Fam, 300 mg Ran, or placebo in a double-blind, randomized study as a single evening dose. With both drugs 20-h acidity was markedly suppressed. After Fam treatment mean inhibition was 61% in smokers and 76% in nonsmokers and after Ran 51% and 67%, respectively. When areas under the pH curves for each individual were calculated and treatment compared with placebo (= 100%), the response was smaller in smokers than in nonsmokers with either drug (Fam, 153 +/- 21% versus 214 +/- 19%, p less than 0.01; Ran, 176 +/- 21% versus 232 +/- 29%, p less than 0.05) during the first 4 h after drug intake. A similar effect was observed in the morning period from 0600 to 1000 h (Fam, 118 +/- 19% versus 206 +/- 19%, p less than 0.001; Ran, 133 +/- 21% versus 207 +/- 31%, p less than 0.02). During the nighttime there were no significant differences. These findings indicate that smoking impairs the response to both drugs tested.     

Relation between oesophageal acid exposure and healing of oesophagitis with omeprazole in patients with severe reflux oesophagitis.

BACKGROUND/AIMS--Reducing oesophageal acid exposure by suppressing acid secretion with omeprazole is highly effective in healing reflux oesophagitis. Some patients with severe oesophagitis, fail to heal and whether this results from inadequate acid suppression or other factors is unclear. The aim of this study, was to investigate the relation between oesophageal acid exposure and healing in patients with severe reflux oesophagitis treated with omeprazole. METHODS--Sixty one patients with grade 3 or 4 ulcerative oesophagitis were treated for eight weeks with omeprazole 20 mg every morning. Those patients unhealed at eight weeks were treated with 40 mg every morning for a further eight weeks. Endoscopy and 24 hour oesophageal pH monitoring were performed before treatment and at the end of each treatment phase while receiving treatment. RESULTS--Thirty per cent of patients failed to heal with the 20 mg dose. Unhealed patients had greater total 24 hour oesophageal acid exposure before treatment, and while receiving treatment also had greater acid exposure and a smaller reduction in acid exposure than did patients who healed. Forty seven per cent of the unhealed patients also failed to heal with the 40 mg dose. These patients had similar levels of acid exposure before treatment to those who healed, but had greater acid exposure while receiving treatment, particularly at night when supine. CONCLUSIONS--Patients with severe ulcerative oesophagitis who are refractory to omeprazole have greater oesophageal acid exposure while receiving treatment than responding patients. This is due to a reduced responsiveness to acid suppression, and is likely to be an important factor underlying the failure of the oesophagitis to heal.     

Eradication of Helicobacter pylori does not increase acid reflux in patients with mild to moderate reflux oesophagitis

BACKGROUND: A substantial minority of patients with gastro-oesophageal reflux disease (GERD) are infected with Helicobacter pylori, but there is controversy as to whether these patients should be treated for their infection. We hypothesized that H. pylori eradication increases gastro-oesophageal acid reflux in such patients with time. METHODS: Thirty-five consecutive H. pylori-infected patients (16 M and 19 F) with mild or moderate reflux oesophagitis were enrolled. Twenty-four-hour intra-oesophageal (n = 35) and intragastric (n = 12) pH-metry was recorded before and 15 months after H. pylori eradication. Gastric biopsy specimens from the antrum and corpus were obtained from 10 consecutive patients before and 15 months after H. pylori eradication. RESULTS: Fifteen months after eradication of H. pylori there was a significant decrease in percentage time oesophageal pH < 4 in the recumbent position only (P = 0.04). Despite a marked reduction in the severity of gastritis, there was no significant change in gastric acidity, total intra-oesophageal acid exposure or symptom score. Heartburn improved in 12, worsened in 7. and remained unchanged in 16 patients (P = 0.36) without any significant relationship to individual changes in acid exposure (P = 0.60). CONCLUSIONS: H. pylori eradication does not increase gastric acidity or gastro-oesophageal acid reflux in patients with mild to moderate reflux oesophagitis over the first 15 months.     

Tolerance and rebound to H2-receptor antagonists: Intragastric acidity in patients with duodenal ulcer

Tolerance to the antisecretory effects of H2-receptor antagonists develops consistently in healthy volunteers. The aim of this study was to determine whether tolerance occurs with repeated dosing of H2-receptor antagonists in patients with duodenal ulcer. Continuous intragastric 24-hr pH measurements were performed in 12 patients with duodenal ulcer in symptomatic remission before, on days 1 and 29, and two days after receiving ranitidine 300 mg four times a day for 34 days. The 24-hr median intragastric pH (interquartile range) was 5.4 (4.4-6.1) on day 1 and 4.6 (4.0-5.2) on day 29 of dosing with ranitidine (not significant). Median nighttime pH was 6.8 (6.3-7.0) on day 1 and 6.8 (6.6-7.1) on day 29 (not significant). During the daytime, the median pH decreased marginally from 4.7 (3.8-5.2) on day 1 to 3.8 (3.0-4.6) on day 29 (P less than 0.03). There was no difference in median intragastric pH during 24-hr, day and night periods before and two days after ranitidine dosing. No significant tolerance or rebound to H2-receptor antagonists was observed in patients with duodenal ulcer disease. This contrasts with data gathered in healthy volunteers and may be due to defects in the regulation of acid secretion in duodenal ulcer disease.     

N-Nitrosamines in gastric juice of patients with gastric ulcer before and during treatment with histamine H2-receptor antagonists

The clinical implications of N-nitrosamines (NAs) were studied by analyzing their concentration in the gastric juice of 72 healthy subjects and 279 patients with gastric ulcer before and during treatment with histamine H₂-receptor antagonists. NAs were measured by combined gas chromatography and thermal energy analyzer. The detection ratios of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in the patients were 35.3% and 34.6%, respectively, which were significantly higher than the corresponding values in healthy subjects (19.4% and 16.7%, P<0.01). Analysis among the patients showed that this trend was mainly due to higher values in patients who were given histamine H₂-receptor antagonists, as their detection ratios increased to 40.2% (NDMA) and 39.9% (NDEA). Patients without histamine H₂receptor antagonists showed moderate increases of detection ratios (NDMA; 24.2% NDEA; 22.6%) compared with healthy controls. The differences in these values between those receiving and not receiving histamine H₂-receptor antagonists were statistically significant (P<0.01). The maximum concentrations of NDMA and NDEA were 7.9 and 9.8 ng/ml in patients, and 1.2 and 1.3 ng/ml in healthy subjects (the difference between the 2 groups P<0.02). These results indicated that patients with gastric ulcer had higher detection ratios and concentrations of NDMA and NDEA in gastric juice and that, while significant increases occurred during treatment with histamine H₂-receptor antagonists, the extent of increase was below toxic or experimental carcinogenic levels.     

N-nitrosamines in gastric juice of patients with gastric ulcer before and during treatment with histamine H2-receptor antagonists

The clinical implications of N-nitrosamines (NAs) were studied by analyzing their concentration in the gastric juice of 72 healthy subjects and 279 patients with gastric ulcer before and during treatment with histamine H2-receptor antagonists. NAs were measured by combined gas chromatography and thermal energy analyzer. The detection ratios of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in the patients were 35.3% and 34.6%, respectively, which were significantly higher than the corresponding values in healthy subjects (19.4% and 16.7%, P less than 0.01). Analysis among the patients showed that this trend was mainly due to higher values in patients who were given histamine H2-receptor antagonists, as their detection ratios increased to 40.2% (NDMA) and 39.9% (NDEA). Patients without histamine H2-receptor antagonists showed moderate increases of detection ratios (NDMA; 24.2% NDEA; 22.6%) compared with healthy controls. The differences in these values between those receiving and not receiving histamine H2-receptor antagonists were statistically significant (P less than 0.01). The maximum concentrations of NDMA and NDEA were 7.9 and 9.8 ng/ml in patients, and 1.2 and 1.3 ng/ml in healthy subjects (the difference between the 2 groups P less than 0.02). These results indicated that patients with gastric ulcer had higher detection ratios and concentrations of NDMA and NDEA in gastric juice and that, while significant increases occurred during treatment with histamine H2-receptor antagonists, the extent of increase was below toxic or experimental carcinogenic levels.     

Relevant inhibition of acetylcholinesterase with H2-receptor antagonists

An inhibition of acetylcholinesterase activity by ranitidine and cimetidine as described by Hansen and Bertl (Z. Gastroenterol. 21: 164, 1983; Arzneimittelforsch. 33: 161, 1983) could only be confirmed by use of 1000-fold higher concentrations of the H2-antagonists (ID50 for ranitidine: 3,2 X 10(-4) M, for cimetidine: 3,1 X 10(-2) M) than those reported by the authors. The discrepancy may be explained by the fact that the authors did not consider the dilution factor in their method. In a typical therapeutic situation in 8 patients with ranitidine 150 mg twice daily and cimetidine 400 mg twice daily an inhibiton of the acetylcholinesterase could not be demonstrated. The inhibition of the acetylcholinesterase activity by H2-antagonists is of no practical relevance.     

Effectiveness of omeprazole in seven patients with Zollinger-Ellison syndrome resistant to histamine H2-receptor antagonists

The inhibitory effect of omeprazole, a benzimidazole derivative, on gastric acid secretion was investigated in seven patients with Zollinger-Ellison syndrome resistant to treatment with large doses of histamine H₂-receptor antagonists administered alone or in combination with pirenzepine. In two patients with an acute form of the syndrome, rapid control of acid overproduction was achieved with 180-mg intravenous and 120-mg oral daily doses, respectively. The other five patients, who were free of complication, initially received a standard regimen of omeprazole 60 mg orally once a day; dosage was subsequently adjusted until the basal acid output, measured 1 hr before the next dose of the drug, was less than 10 mmol/hr. The initial daily dose proved to be adequate in three patients and had to be increased to 80 mg and 60 mg bid, respectively in the remaining two patients. In all patients omeprazole therapy resulted in clinical recovery and rapid healing of mucosal lesions. The seven patients have now been followed up for 4–24 months (average 15 months). The adequacy of the daily dosage was periodically reassessed by measuring basal acid output in the hour preceding the morning dose. In one patient initially treated with 180 mg/day, dosage could be reduced to 60 mg/day. In three others, who were initially controlled with 60 mg/day, dosage had to be increased during follow-up. Despite adequate control of gastric acid secretion, one patient underwent total gastrectomy and tumor resection and another died of extensive liver metastases. The five patients still receiving omeprazole remain free of symptoms and mucosal lesions. No side effects or laboratory abnormalities ascribable to the drug were observed. It is concluded that omeprazole therapy is a good alternative in patients with Zollinger-Ellison resistant to currently available antisecretory drugs. Its safety and effectiveness in long-term therapy remain to be evaluated.     

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.     

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.     

Frequent non-response to histamine H2-receptor antagonists in cirrhotics.

The effect of ranitidine 300 mg po given at 1800 h (famotidine 40 mg/cimetidine 800 mg) on the night time gastric pH was tested using longterm intragastric pH monitoring in 27 patients with and 32 patients without liver cirrhosis. A rise in the gastric pH above 4.0 for more than six hours between 1800 h and 0600 h was considered as sufficient effect (response) of the H2-receptor antagonists on gastric acidity. Among the patients with cirrhosis, there were significantly (p less than 0.005) more non-responders to ranitidine (16 of 27 patients) than in the control group (six of 32). When 13 of the 22 non-responders to ranitidine were subsequently treated with famotidine, only two showed a sufficient rise in their gastric pH. Of the 11 patients not responding to both H2-receptor antagonists, 10 were finally treated with cimetidine and eight did not respond. Plasma levels of all three drugs measured two and four hours after oral administration were not significantly different between cirrhotic and noncirrhotic patients as well as between responders and non-responders. In addition, in all patients plasma levels were far above the corresponding IC50 values. Therefore, differences in the absorption and plasma levels of these drugs cannot account for the frequent non-response in cirrhotics.     

Low bedtime doses of H2-receptor antagonists for acute treatment of duodenal ulcer

Twenty-four-hour intragastric acidity was measured continuously over five separate occasions in 15 patients with healed duodenal ulcers. They were randomized to receive either placebo, cimetidine 800 mg, ranitidine 150 mg, famotidine 20 mg, or nizatidine 150 mg, given at 2200 hr in doubleblind fashion. All H₂-receptor blockers were more effective than placebo in suppressing both circadian (P<0.05–P<0.01) and nocturnal (P<0.002) gastric acidity, while there was no significant difference between the effects of the four active drugs in the same time periods. The percentage of nocturnal acid inhibition (2300–0800 hr) over placebo in terms of H⁺ values was virtually 100% with all active treatments. The effect on daytime (0800–1700 hr) and evening (1700–2300 hr) acidity of both placebo and the four H₂-receptor antagonists was similar. Therefore, in the above doses, H₂-receptor blockers guarantee overnight anacidity to a similar degree and cause the physiological buffering of daily meals on gastric acidity to be fully exploited. Furthermore, the reducing effect of daily meals on drug action can be prevented. Since strong acid suppression strictly confined to the nocturnal period has been shown to be closely correlated with the highest ulcer healing rates, it is suggested that single low bedtime doses of H₂-receptor antagonists should be evaluated in the acute treatment of duodenal ulcer.This study was supported in part by CNR grant 86.02120.03 and by CARIGE grant 104819/12.