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Notes: This study was undertaken in nine fasting healthy volunteers to compare the effect of intravenous continuous infusion versus bolus injection of ranitidine on 12-h intragastric pH, and to compare the efficacy of these two modes of administration of pH-stat-adjusted infusion of ranitidine using the Gastrojet. Each volunteer had three study sessions with 12-h pH measurements. In the ranitidine infusion treatment arm (RAN-INF), ranitidine was continually infused intravenously using an IVAC-pump at a dose of 0.125 mg mg.kg over a 12-h period. In the ranitidine bolus treatment arm (RAN-BOL), ranitidine bolus 50 mg was given over 10 min, every 6 h. When ranitidine infusion was given by the pH stat method using the Gastrojet (RAN-JET), sufficient ranitidine was given to maintain a preset value of pH ≥ 5. The study was analysed with a 3 × 3 Latin square cross-over design with multiple measurements of each phase of the cross-over. No difference was found between RAN-INF and RAN-BOL in 12-h or in daytime (10.00–18.00 h) mean pH, median pH, or percentage of pH ≥ 5. Using RAN-JET, 89.5% of the pH values were ≥ 5, compared with 39.7% and 40.0% with RAN-INF or RAN-BOL. RAN-JET also gave higher (P 〈 0.05) mean and median 12-h or daytime pH values, as compared with RAN-INF or RAN-BOL. The mean doses of ranitidine given in the 12-h infusion periods were 100 mg, 109 mg and 112 mg (RAN-BOL, RAN-INF and RAN-JET, respectively). Thus, this superior inhibition of acid inhibition achieved with Gastrojet does not require higher mean doses of ranitidine. These findings cannot necessarily be applied to persons with duodenal ulcer disease or to patients in an intensive-care unit setting. However, the data do raise the possibility that much greater inhibition of acid inhibition can be achieved by individualizing the dose of ranitidine using the Gastrojet.

Notes: Investigators: This multicentre study was conducted by 29 principal investigators in 11 countries. Aims: To compare the safety and efficacy of oral mesalazine (Mesasal/Claversal, 5-ASA) 1.5 g b.d. in comparison with placebo in the maintenance of remission in 286 patients with Crohn's disease. Materials and Methods: Patients had to score less than 150 in their Crohn's Disease Activity Index (CDAI), and had to have had one period of clinical activity (CDAI 〉 150) within 18 months of the study start. Patients were randomized to receive 5-ASA 1.5 g b.d. daily or matching placebo for 12 months. Study visits were scheduled for months 1, 3, 6, 9 and 12, or when symptoms suggested a relapse of the disease. Relapse was defined as a CDAI score greater than 150, with at least a 60-point increase from the baseline index score. None of the patients used glucocorticoids or immunosuppressants during the trial. Results: In the first group, 207 patients with Crohn's colitis or ileocolitis were randomized: there were 101 females and 106 males, in age range 18–71 years. A total of 106 patients (51 in the 5-ASA group and 55 in the placebo group) were withdrawn from the study due to adverse events, insufficient therapeutic effect, or for other reasons. This left 101 patients (51 in the 5-ASA group and 50 in the placebo group) who completed the 12-month trial. In the second group, 79 patients with Crohn's ileitis were randomized to treatment. There were 53 females and 26 males, age range 18–66 years. A. total of 41 patients (19 in the 5-ASA group and 22 in the placebo group) were withdrawn from the study. This left 38 patients (17 in the 5-ASA group and 21 in the placebo group) who completed the 12-month trial. the primary efficacy variable was the CDAI. A protocol-eligible analysis and an intent-to-treat analysis were performed. No statistical differences were noted Between the two analyses. In patients with Crohn's colitis or ileocolitis, or in those with ileitis, no statistically significant differences were noted with: espect to the relapse rates between the 5-ASA and the, placebo treatment groups. Adverse events in the gastrointestinal system were the most frequently, eported in both treatment groups. Many of the events such as diarrhoea or abdominal pain are symptoms of crohn's disease. The majority of the events reported were mild or moderate in severity. In neither study was he prevalence of adverse events or the proportion of drop-outs different between patients in the treatment or in the placebo groups. The site of the Crohn's disease had no effect on the frequency of adverse events. conclusion: The relapse rates of Crohn's disease were similar for up to 12 months in both the 5-ASA 1.5 g b.d. and the placebo treatment groups.

Notes: Methods: This randomized, double-blind, single-centre, crossover study was designed to assess the effects of three regimens of ranitidine (150 mg b.d., 300 mg b.d. and 300 mg q.d.s.) and placebo on intra-oesophageal and intragastric pH in subjects with gastro-oesophageal reflux disease (GERD). Twenty-six subjects were screened, and 9 were evaluable by the admission criteria. These 9 subjects received each of the regimens for 72 h, and a wash-out period of at least 48 h followed each dosing period. Standard meals and beverages were provided.Results: With increasing doses of ranitidine, 24-h intragastric mean H+ and integrated H+ fell, and the percentage of the time the pH was equal to or greater than 4 (% time pH ≥ 4) rose; the minimum effective dose for these effects was ranitidine 300 mg daily. With increasing doses of ranitidine there was also a progressive decline in mean 24-h intra-oesophageal H+ and integrated H+, and increasing % time pH ≥ 4. The minimal effective dose was 300 mg daily for intra-oesophageal mean H+ and integrated H+, and 600 mg for % time pH ≥ 4. The minimal effective dose to decrease the number of reflex episodes was 1200 mg ranitidine. For the daytime upright position, a dose effect of increasing ranitidine was also seen, with minimal effective ranitidine doses of 300 mg for a decrease in mean H+, and 1200 mg for % time pH ≥ 4. Conclusion: If these higher doses of ranitidine are confirmed to be more effective than the standard 150 mg b.d. regimen for the treatment of patients with gastro-oesophageal reflux disease, then the mechanism of this action probably relates to the lower exposure of the oesophageal mucosa to acid.

Notes: To compare the effect of lansoprazole, 30 mg once daily, with that of pantoprazole, 40 mg once daily, for the inhibition of gastric acid secretion.〈section xml:id="abs1-2"〉〈title type="main"〉Methods:Two randomized, single-blind, two-way, crossover studies were conducted in 74 healthy male volunteers. Lansoprazole, 30 mg, or pantoprazole, 40 mg, was administered once daily for five consecutive days with at least a 2-week washout period between regimens. Ambulatory 24-h intragastric pH was recorded at baseline and on days 1 and 5 of each crossover treatment period.〈section xml:id="abs1-3"〉〈title type="main"〉Results:On day 1 in both studies, lansoprazole, 30 mg, produced significantly higher mean 24-h intragastric pH values when compared to pantoprazole, 40 mg (3.78 vs. 3.08, P 〈 0.001, and 3.97 vs. 3.20, P 〈 0.001, in the first and second studies, respectively). In both studies, lansoprazole, 30 mg, produced significantly greater proportions of time that the intragastric pH was above 3, 4 and 5 when compared with pantoprazole, 40 mg (P 〈 0.005 in all comparisons). By treatment day 5 in the first study, lansoprazole, 30 mg, continued to produce a higher mean 24-h intragastric pH (4.15 vs. 3.91, P=0.014) and a significantly greater percentage of time that the intragastric pH was above 4 (63% vs. 56%, P=0.017) and 5 (41% vs. 30%, P 〈 0.001) when compared with pantoprazole, 40 mg. In the second study, the effects on intragastric pH were comparable between the two treatment groups. Headache was the most commonly reported adverse experience (nine lansoprazole-treated subjects, seven in the first study and two in the second study; six pantoprazole-treated subjects, five in the first study and one in the second study).〈section xml:id="abs1-4"〉〈title type="main"〉Conclusions:Lansoprazole, 30 mg once daily, produces a faster onset and greater degree of acid inhibition than pantoprazole, 40 mg once daily. The implications for these differences on symptom relief and healing of erosive oesophagitis should be explored.

Notes: Sulphasalazine is composed of sulphapyridine and mesalazine (5-aminosalicylic acid, 5-ASA or mesalazine) joined by an azo bond. Sulphasalazine has been used clinically for 40 years but less than 10 years ago it was recognized that the active moiety is 5-ASA. Sulphapyridine appears to act only as a carrier molecule to deliver mesalazine to the bowel, yet it is the sulphapyridine which appears to be responsible for many of the adverse effects observed with sulphasalazine. Normally, mesalazine is rapidly absorbed from the upper gastrointestinal tract. Since the action of mesalazine is thought to be locally at the site of disease in the intestine, the 5-ASA must be ‘protected’ to ensure its release in the terminal ileum and colon, the site of bowel inflammation in patients with Crohn's disease or ulcerative colitis. Recent clinical studies have confirmed the efficacy of topical (suppositories and enemas) therapy for ulcerative proctitis and left-sided colitis; oral mesalazine has been proven to be useful for the treatment of acute ulcerative colitis and for the maintenance of remission. There is preliminary evidence for the clinical usefulness of mesalazine in acute Crohn's disease as well as for the maintenance of remission.

Notes: Six asymptomatic, non-smoking men with endoscopically proven duodenal ulcer disease received single nocturnal doses of placebo, 40 mg famotidine and 300 mg ranitidine each for 1 week prior to serial measurement of pH, peptic activity and serum gastrin concentrations over 24 h and of acid output. The intragastric pH fluctuated between 1.53 and 5.07 when subjects were given placebo but within 2 h of taking famotidine or ranitidine it rose to 5.57 or higher; the effect lasted for 12 h from midnight. Peptic activity fell during famotidine and ranitidine treatment and the decline was somewhat greater 8–15 h after using famotidine. Serum gastrin levels did not change materially with any treatment. The study shows the equivalent effect of standard bed-time doses of famotidine and ranitidine on intragastric pH, acid output and serum gastrin concentrations in asymptomatic men with duodenal ulcer disease.

Notes: Gastric aspiration was performed continuously overnight and at hourly intervals during the daytime in 20 healthy male volunteers. Medications used included enisoprost 100, 200 or 400 μg, misoprostol 200 μg and placebo, given at bedtime. Each dose of enisoprost markedly inhibited nocturnal mean acid output, hydrogen ion activity, pH and peptic activity. The duration of these effects was up to 10 h. Misoprostol, given at bedtime, also decreased acid secretion, but the effect was significantly less than that observed with any of the doses of enisoprost. A dose—response effect for enisoprost was found for the mean nocturnal hydrogen ion activity and pH, as well as for maximum pH attained. Although enisoprost, given at bedtime, had a marked inhibitory effect on acid and pepsin secretion for the overnight interval, this did not result in rebound hyperacidity or a rise in serum total gastrin concentration. The results of this study suggest that enisoprost should be tested by clinical trial for the treatment of peptic ulcer disease.

Notes: Systemic steroids have been used in gastrointestinal disorders, such as ulcerative colitis and Crohn's disease. However, glucocorticosteroids are associated with potentially serious adverse effects. For that reason there is a search for a steroid which would have rapid first-pass metabolism in the intestine and liver, low systemic bioavailability, high topical activity and rapid excretion. This review will consider the absorption, transport, metabolism, mechanisms of action, general effects and effects of steroids on the intestine, and the new steroids in particular.

Notes: Background : There are few data on empiric, stepped therapy for heartburn relief or subsequent relapse in primary care.Aims : To compare heartburn relief produced by a proton pump inhibitor-start or an H2-receptor antagonist-start with step-up therapy, as needed, followed by a treatment-free period to assess relapse.Methods : Heartburn-dominant uninvestigated dyspepsia patients from 46 primary care centres were randomized to one of two active treatment strategies: omeprazole 20 mg daily (proton pump inhibitor-start) or ranitidine 150 mg bid (H2-receptor antagonist-start) for the first 4–8 weeks, stepping up to omeprazole 40 or 20 mg daily, respectively, for 4–8 weeks for persistent symptoms. Daily diaries documented heartburn relief (score ≤3/7 on ≤1 of 7 prior days) and relapse (score ≥4 on ≥2 of 7 prior days).Results : For ‘proton pump inhibitor-start’ (n = 196) vs. ‘H2-receptor antagonist-start’ (n = 194), respectively, heartburn relief occurred in 55.1% vs. 27.3% (P 〈 0.001) at 4 weeks and in 88.3% vs. 87.1% at 16 weeks. After therapy, 308 patients were heartburn-free (159 vs. 149); median times to relapse were 8 vs. 9 days and cumulative relapse rates were 78.6% vs. 75.8%, respectively.Conclusions : An empiric ‘proton pump inhibitor-start’ strategy relieves heartburn more effectively than an ‘H2-receptor antagonist-start’ strategy up to 12 weeks but has no effect on subsequent relapse, which is rapid in most patients.

Notes: Background : The clinical course of Crohn's disease after the induction of remission with medical therapy is characterized by unpredictable relapse.Aim : To evaluate three surrogate markers, intestinal permeability, mucosal TNFα and nuclear factor (NF)-κB/IκBα expression, in order to determine the relationship of these parameters to clinical relapse.Methods : Thirty patients with active Crohn's disease were treated with a 10 week course of prednisone using a tapering dosing regimen. Intestinal permeability (lactulose/mannitol [L/M ratio]) was determined at baseline and at the end of prednisone tapering. TNFα production and the levels of expression of NF-κB/IκBα were measured in colonic mucosal biopsies obtained after the induction of remission.Results : Twenty-two patients (73%) achieved remission and 50% of patients experienced a clinical relapse during the ensuing 12 months. Treatment with prednisone resulted in a significant decrease in the L/M ratio. Of the patients that relapsed, 75% had a raised L/M ratio at the time of remission compared with 20% of patients with a normal L/M ratio (P 〈 0.008; hazard ratio = 6.094; CI 1.55, 17.43). Mucosal TNFα production was greater in relapsers compared with those who remained in remission. The levels of NF-κB in relapsers were significantly greater and levels of cytosolic IκBα were significantly lower compared with those measured in patients who remained in remission.Conclusions : These findings underscore the importance of incorporating biological parameters of inflammation in determining the clinical course of Crohn's disease.