bluuebunny/crossref_metadata_2025 huggingface dataset:
A double‐blind placebo‐controlled trial of BRL 24924 on lower oesophageal sphincter pressure and gastro‐oesophageal reflux in healthy volunteers
Authors: ROBERTSON C. S. , EVANS D. F. , HICKS F. , ATKINSON M.
Published: July 2010

BRL 24924 is a new gastrointestinal prokinetic agent with properties similar to metoclopramide but with increased potency and devoid of side‐effects associated with blockade of dopamine receptors in the central nervous system. A double‐blind placebo‐controlled trial of the effect of a single oral dose of 2.2 mg BRL 24924 on lower oesophageal sphincter pressure and gastro‐oesophageal reflux has been performed in 20 healthy volunteers. BRL 24924 significantly increased mean lower oesophageal sphincter pressure (21.9 cmH2O BRL; 15.9 cmH2O placebo: P < 0.017) but failed to alter either the frequency or the duration of gastrooesophageal reflux after provocation following a test meal. BRL 24924 has significant effects on lower oesophageal sphincter pressure but no effect on provoked post‐prandial reflux in healthy volunteers. Further studies in patients with gastro‐oesophageal reflux and oesophagitis are needed to evaluate the clinical efficacy of this compound.
A comparative study of the effects on colon function caused by feeding ispaghula husk and polydextrose
Authors: TOMLIN J. , READ N. W.
Published: July 2010

Polydextrose is a new soluble food ingredient which cannot be digested by intestinal enzymes and so may affect colonic function. Studies in healthy volunteers compared the effects of diet supplementation with 30 g/day polydextrose, a standard dose of 7 g/day ispaghula and two mixtures containing 2 g/day ispaghula with either 30 g/day polydextrose or 10 g/day polydextrose with a control period. During the 10‐day periods, the mass, frequency and consistency of faeces were assessed as well as the whole‐gut transit time, ease of defaecation, flatulence and palatability of the preparations.

All preparations significantly increased the weekly faecal mass above control values (P < 0.05) but there were no significant differences between the preparations. Transit time and stool frequency were not affected significantly by any of the preparations (P > 0.05). Both preparations supplying 30 g/day polydextrose softened stool consistency equally but the other preparations had no effect. All preparations caused flatulence and other gas‐related problems but polydextrose caused more than ispaghula, even at the lowest dose of 10 g/day. More volunteers preferred taking the polydextrose drinks than the sachets of ispaghula which formed a viscous drink with water.

Despite superior palatability and equally effective stool bulking, polydextrose is unlikely to be an alternative laxative to ispaghula because of the unacceptable levels of flatulence.
The effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of metoprolol
Authors: CHELLINGSWORTH M. C. , LAUGHER S. , AKHLAGHI S. , JACK D. B. , KENDALL M. J.
Published: July 2010

The impact of cimetidine, ranitidine and placebo on the pharmacokinetics of metoprolol, given either as a single dose (100 mg) or for 7 days (100 mg b.d.), has been evaluated in two separate studies. The doses used were 800 mg cimetidine daily and 300 mg ranitidine daily. The subjects were all young, healthy volunteers. In the single dose study, cimetidine produced a marked increase in the peak plasma concentration of metoprolol and in the area under the plasma concentration‐time curve; ranitidine had less effect, though the area under the curve was significantly greater than placebo. In the chronic dosing study, the area under the curve for metoprolol was also significantly higher on cimetidine (1796 ng h/ml;P< 0.001) whereas the area under the curve on ranitidine (1258 ng h/ml) was comparable to that on placebo (1183 ng h/ml). Despite these drug‐induced changes in plasma metoprolol concentration, neither cimetidine nor ranitidine altered the change in exercise‐induced heart rate during dosing with metoprolol.
Epidemiology of NSAID‐induced gastrointestinal problems and the role of cimetidine in their prevention
Authors: GIERCKSKY K‐E. , HUSBY G. , RUGSTAD H. E. , REVHAUG A.
Published: July 2010

It is difficult to ascertain the incidence of gastrointestinal side‐effects associated with intake of non‐steroidal anti‐inflammatory drugs (NSAIDs). In retrospective studies, some NSAIDs have been reported to be associated with a higher incidence of gastrointestinal side‐effects than others. However, this has not been verified either in a prospective casereview study or in a large double‐blind study. Serious side‐effects, such as bleeding, perforation and heart failure, occur in approximately 1 % of patients using NSAIDs. One‐third of all patients receiving NSAIDs will have gastrointestinal complaints. Since at least 10% of patients terminate treatment with NSAIDs as a result of side‐effects, even reduction of those that are not life‐threatening would be of great benefit. H2‐receptor antagonists have proved effective in ulcer treatment, and their use as prophylaxis against the side‐effects of NSAIDs is being widely studied. In a recent study, 63 patients who had experienced serious upper gastrointestinal side‐effects were given cimetidine while continuing their NSAID therapy. All but 4 of the 47 who had gastric or duodenal ulcer on first admission were healed at 8 weeks, and none of the remaining 16 with diffuse bleeding gastritis experienced further clinical episodes of bleeding or ulcer‐related dyspepsia.
Mechanisms of NSAID‐induced gastrointestinal mucosal injury: a basis for preventing ulceration and symptoms from these agents
Authors: RAINSFORD K. D.
Published: July 2010

Concepts are reviewed of the effects of anti‐ulcer agents in counteracting the biochemical and cellular pathology of gastrointestinal injury by non‐steroidal anti‐inflammatory drugs (NSAIDs). While some measure of control of NSAID‐induced mucosal damage is achieved in the upper gastrointestinal tract by the currently available anti‐ulcer drugs, none can effectively counteract the major biochemical changes induced by NSAIDs. Some experimental approaches, which have been developed from recent studies in laboratory animals, are considered as a possible basis towards developing improvements in preventive procedures against NSAID‐induced gastrointestinal injury in man.
Non‐steroidal anti‐inflammatory drugs and the gastric mucosa: mechanisms of damage and protection
Authors: HAWKEY C.J.
Published: July 2010

Prostaglandins have numerous mucosal protective properties, impairment of which contribute to NSAID injury. It is not clear which is the most important injurious factor affecting patients taking NSAIDs. Is it the NSAID itself, either by topical toxidty and/or production of toxic mediators or does the patient become more sensitive to NSAIDs as a result of some other luminal component, such as acid or bile acids, food (by physical or chemical mechanisms) or accompanying alcohol? Intrinsic irritancy/toxicity probably accounts for the greater mucosal toxicity of aspirin, although it is not clear whether this is due to a direct (non‐prostaglandin‐dependent) effect on mucus or bicarbonate secretion, membrane integrity, interference with intermediary metabolism or the production of toxic products. Similarly, the relationship of irritancy to the symptom of dyspepsia, to which patients on aspirin are prone, is as yet not well understood. While strategies for short‐term protection of experimental animals and humans are well established, protection against important, but relatively rare clinical events, is more difficult to study and much less well understood. In particular, the importance of the ability of NSAIDs to exacerbate bleeding, independent of injury, has been largely neglected in the context of presentation with haematemesis and melaena.
NSAIDs: a clinical approach to the problems of gastrointestinal side‐effects
Authors: BUTT J. H. , BARTHEL J. S. , HOSOKAWA M. C. , MOORE R. A.
Published: July 2010

Despite the fact that non‐steroidal anti‐inflammatory drugs (NSAIDs) are among the most widely used drugs in medicine today, 2–10% of patients must discontinue their use primarily due to gastrointestinal (GI) side‐effects. While the development of non‐aspirin NSAIDs (NA‐NSAIDs) has significantly reduced GI side‐effects, major problems persist. A practical clinical approach to these problems includes informing the patient about the risks and benefits of NSAIDs, risk management during treatment with NSAIDs and investigation of symptomatic side‐effects during treatment. Prophylaxis of GI side‐effects is feasible in selected populations, but it has not been studied widely and may not be cost‐effective. At present, costs of prophylaxis in all but selected populations with multiple risks probably outweigh the benefits.
Review article: the management of hepatitis A, B, D and non‐A non‐B
Authors: DUSHEIKO G. M.
Published: July 2010

This paper reviews the modern management of viral hepatitis: hepatitis A, hepatitis B, hepatitis D and non‐A non‐B hepatitis. It describes the treatment of uncomplicated acute viral hepatitis, complicated acute viral hepatitis, and chronic viral hepatitis. The roles for corticosteroids, synthetic nucleotides, and interferons are reviewed. Finally, passive and active immunization against viral hepatitis are discussed.
Determining the optimal dosage regimen for H2‐receptor antagonist therapy—a dose validation approach
Authors: YOUNG M. D. , FRANK W. O. , DICKSON B. D. , PEACE K. P. , BRAVERMAN A. , MOUNCE W.
Published: July 2010

A large number of clinical studies have been performed to establish the safety and efficacy of H2‐receptor antagonist therapy. Few if any of these studies have attempted to address the rationale for the dosage and/or dosage regimens being studied. This study is the first large‐scale clinical trial, the purpose of which is to validate the chosen regimen and to address the issue of an optimal therapy for a specific patient population. A regimen of a single nightly dosage is generally acknowledged to offer the potential for improved patient compliance. Furthermore, recent research had suggested that suppression of nocturnal acid secretion is all that is required to heal duodenal ulcers. Hence such a regimen offered the potential for an effective lowered dosage of cimetidine with minimal interference with gastric physiology, increased safety and substantial efficacy. This multicentre, double‐blind, placebo‐controlled trial therefore evaluated a 4‐week course of single night‐time dosage of cimetidine. After 4 weeks of treatment the cumulative, endoscopically proven, ulcer healing rate with an 800 mg regimen was 73%, which was statistically higher and significantly superior to the 41% healing seen with placebo (P < 0.001). The 400 mg nocte dosage regimen of cimetidine normally used as maintenance therapy was significantly inferior to the 800 mg nocte regimen (P = 0.01), and increasing the dosage to 1600 mg nocte for 4 weeks failed to provide a significant improvement in healing over the 800 mg nocte regimen. This 800 mg nocte regimen provided rapid pain relief, with 75 YO of the patients being free of night‐time pain and 65% free of day‐time pain, by the end of the first week. The 400 mg ‘maintenance dosage’ was unable to provide this degree of rapid, complete and early relief to patients with a duodenal ulcer. Furthermore, increasing the dosage to 1600 mg nocte failed to increase the level of early pain relief significantly, perhaps because the extensive response of duodenal ulcer patients to the 800 mg nocte regimen leaves little room for improvement. Based both on the early symptom relief and the ulcer healing rate during 4 weeks of treatment, it is concluded that an 800 mg night‐time dosage of cimetidine may be an optimal regimen for many duodenal ulcer patients, particularly those who in the physician's opinion will benefit from a once‐daily regimen.
Cyclosporin for the treatment of severe inflammatory bowel disease
Authors: BAKER K. , JEWELL D. P.
Published: July 2010

A pilot study was performed to assess the role of cyclosporin in the management of severe inflammatory bowel disease. Twelve patients with Crohn's disease and 12 with ulcerative colitis were admitted to hospital with a severe attack. They were treated with an intravenous regimen of corticosteroids for 5 days followed by oral therapy. In addition, they received a 6‐week course of oral cyclosporin, initially 15 mg kg−1 day−1 reduced to 7.5 mg kg−1 day−1. In comparison with historical controls, the addition of cyclosporin to standard corticosteroid therapy appeared to have no benefit. Adverse effects were common but minor. The expression of Class II molecules on the inflamed epithelium was rapidly reversed by cyclosporin therapy which may indicate a potential therapeutic benefit over longer periods of time.
Comparative efficacy of coated, oral 5‐aminosalicylic acid (Claversal*) and sulphasalazine for maintaining remission of ulcerative colitis
Authors: RUTGEERTS P.
Published: July 2010

The safety and efficacy of Claversal (coated, oral 5‐aminosalicylic acid (5‐ASA) 0.75 g/day) and sulphasalazine 1.5–2.0 g/day were compared for the maintenance treatment of ulcerative colitis in a 1‐year double‐blind trial. Three hundred and thirty‐four patients, whose disease was controlled on a stable dose of sulphasalazine (1.5–2.0 g/day) for a 1‐month pre‐trial, entered the study. On entry, patients were assigned in a random manner to continue sulphasalazine or to switch to coated 5‐ASA. One hundred and thirty‐one patients in the coated 5‐ASA group and 142 on sulphasalazine were analysed for efficacy.

No significant difference was observed between treatments with respect to the cumulative rate of relapse. Over the 12 months, 30 (28%) of the coated 5‐ASA patients versus 29 (23%) of those treated with sulphasalazine had an exacerbation of their disease (log rank testP= 0.7011).

The incidence of drug‐related adverse events and subsequent withdrawals was similar. The high incidence of side‐effects usually associated with sulphasalazine was not observed, probably due to the fact that this population was tolerant of sulphasalazine pre‐trial. Of the 37 patients who reported adverse events with previous sulphasalazine therapy, however, only two (8%)of the 24 experienced those events when randomized to coated 5‐ASA while five (38%) of the 13 who continued on sulphasalazine reported those same events. Coated 5‐ASA is a safe, effective therapy for maintaining ulcerative colitis in remission.
The trophic effects of gastrin on fundic neuroendocrine cells of the rat stomach
Authors: EASON C. T. , SPENCER A. J. , PATTISON A. , BONNER F. W.
Published: July 2010

The histomorphological effect of multidose administration of 6 mg/kg pentagastrin b.d. for 5 weeks, and 1000 mg/kg sodium bicarbonate b.d. for 13 weeks, on the rat fundic mucosa has been examined. Sodium bicarbonate induced a significant hypergastrinaemia (plasma gastrin concentrations were 370.5 pg/ml in the control versus 642.6 pg/ml in sodium bicarbonate‐treated rats after 13 weeks, P < 0.01). Both treatment regimens induced fundic neuroendocrine cell hyperplasia. The cellular proliferation that occurred following hypergastrinaemia of endogenous or exogenous origin suggests that systemic gastrin concentrations play a major role in the control of fundic neuroendocrine cell populations.
Twenty‐four‐hour intragastric acidity in duodenal ulcer patients during dosing with placebo, and 150 mg ranitidine twice or four times daily
Authors: HOWDEN C. W. , TSAI H. H. , REID J. L.
Published: July 2010

Twenty‐four‐hour intragastric acidity was measured in 10 patients with past history of duodenal ulcer on the fourth day of dosing with placebo, and either 150 mg ranitidine given twice or four times daily. The order the treatments was randomized and a double‐blind design was employed. Ranitidine (150 mg) b.d. decreased median integrated 24‐h intragastric acidity by 65.1%, nocturnal acidity by 89.1%, and daytime acidity by 54.6% (all P < 0.01 compared to placebo). The corresponding decreases with 150 mg ranitidine q.d.s. were 62.3, 89.9 and 48.8%, respectively (all P < 0.01 compared to placebo). There were no significant differences between the two dosage regimens of ranitidine (P > 0.05).

This study shows that giving extra doses of 150 mg ranitidine during the day does not increase the degree of suppression of intragastric acidity.
Acute treatment of reflux oesophagitis: a multicentre trial to compare 150 mg ranitidine b.d. with 300 mg ranitidine q.d.s.
Authors: JOHNSON N. J. , BOYD E. J. S. , MILLS J. G. , WOOD J. R.
Published: July 2010

H2‐receptor antagonists administered in conventional dosage regimens fail to heal a significant proportion of patients with moderate or severe reflux oesophagitis. We have compared the effects of a higher dose of ranitidine (300 mg q.d.s.) with the currently recommended dosage regimen (150 mg b.d.) in 138 patients suffering from reflux oesophagitis. After 4 weeks of treatment 29% of patients who received 150 mg ranitidine b.d., and 63% of patients who received 300 mg ranitidine q.d.s. had complete endoscopic healing of their lesions (P < 0.0001). After 8 weeks these proportions had increased to 54% and 75%, respectively (P < 0.01). After 4 weeks of treatment, compete symptomatic relief had been achieved in 46% of patients who received 150 mg ranitidine b.d and in 67% of patients who received 300 mg ranitidine q.d.s. (P < 0.05). After 8 weeks these proportions were 64% and 84%, respectively (P < 0.05). Both dosage schedules were well‐tolerated. We conclude that more rapid symptom relief and healing in reflux oesophagitis can be achieved with 300 mg ranitidine q.d.s. than with 150 mg ranitidine b.d.
Pharmacokinetics of a 5‐aminosalicylic acid enteric‐coated tablet and suppository dosage form
Authors: NORLANDER B. , GOTTHARD R. , STRÖM M.
Published: July 2010

An Eudragit‐L coated oral 5‐aminosalicylic acid (5‐ASA; mesalazine) product (Mesasal), has been formulated to deliver 5‐ASA to the distal small intestine and colon for the treatment of inflammatory bowel disease. The purpose of this study was to compare the pharmacokinetic profile of this product to sulphasalazine (SASP; Salazopyrin) and to assess the pharmacokinetics of a suppository 5‐ASA dosage form.

Twelve healthy volunteers randomly received four single doses of 5‐ASA delivering formulations not less than 1 week apart. (a) Mesasal tablets, 2 × 250 mg, fasting; (b) Mesasal tablets, 2 × 250 mg, fed; (c) Salazopyrin tablets, 3 × 500 mg (corresponding to 576 mg 5‐ASA), fasting; and (d) Mesasal suppository, 1 × 500 mg, fasting. Plasma 5‐ASA and acetyl‐5‐ASA (Ac‐5‐ASA) concentrations were followed for 48 h and urine and faecal concentrations for 72 h.

Mesasal tablets (fasting) produced a greater area under the concentration–time curve (AUC), peak and time to peak for both plasma 5‐ASA and Ac‐5‐ASA than Salazopyrin. Median urinary recovery values were 21.7% for Salazopyrin and 35.5% for Mesasal (fasting) (P < 0.01). This means that the systemic absorption was higher after Mesasal than after Salazopyrin. The total faecal recovery values were 38.3 and 26.5%, respectively (NS). Except for a delay of 1.5–3 h in the time to peak of 5‐ASA and Ac‐5‐ASA plasma levels, the pharmacokinetics of Mesasal tablets were essentially the same in fasting or fed subjects. Suppository administration of 5‐ASA resulted in a low median urinary recovery of 10.8%.
Geographical differences of gastric ulcer healing rate in patients treated with ranitidine or placebo
Authors: DIXON J. S. , WORTHINGTON P. R. , MILLS J. G. , WOOD J. R.
Published: July 2010

The literature was searched for clinical trials evaluating the use of 300 mg ranitidine daily in the acute treatment of gastric ulcer. All available trials were examined, and the results compared between countries to determine the extent of any geographical variation in ulcer healing rates. Published placebo studies in gastric ulcer were also reviewed for comparison. Sixty‐six publications were inspected to determine the trial design, country of origin, gastric ulcer healing rates, determined endoscopically, and details of patient demography.

Overall worldwide healing rates for ranitidine treatment were 63% at week 4 and 86% at week 8 (n= 2349 and 2256 respectively), compared with 34% at week 4 and 52% at week 8 for placebo (n= 790 and 231 respectively). Statistically significant differences were found between the healing rates for individual countries at week 4 (P < 0.001) and week 8 (P < 0.001). However, after exclusion of the results from Japan (35%, n= 278) and Yugoslavia (97%, n= 32) at week 4, and from Japan (80%, n= 467) and France (65%, n= 52) at week 8, the healing rates from the remaining countries were not statistically different from one another. The limited data available in relation to age, sex and smoking habits, or placebo healing rates contributed little to explaining these aberrant results.

It is concluded that there is variation in gastric ulcer healing rates between countries, but only results from Japan seem to be out of line with the rest of the world.
Does misoprostol given as a single large dose improve its antisecretory effect?
Authors: CHIVERTON S. G. , BURGET D. W. , SALENA B. J. , HUNT R. H.
Published: July 2010

H2‐receptor antagonists have been shown to be effective in the suppression of nocturnal acidity. This double‐blind, randomized, crossover Latin‐square study of 24‐h intragastric pH in 12 normal volunteers investigated the effect of large single‐dose administration of misoprostol on intragastric acidity. Efficacy of 800 μg misoprostol h.s., 600 μg h.s., 400 μg h.s. and 800 μg after supper was compared to placebo and 200 μg misoprostol q.d.s. Twenty‐four hour mean pH ± s.d. was placebo 2.1 ± 0.3, misoprostol 200 μg q.d.s. Twenty‐four hour mean pH ± s.d. was placebo 2.1 ± 0.3, misoprostol 200 μg q.d.s. 2.2 ± 0.3, 800 μg p.m. 2.6 ± 1.1, 400 μg h.s. 2.6 ± 0.7, 600 μg h.s. 2.6 ± 0.4, 800 μg h.s. 2.6 ± 0.5. The effect of misoprostol on gastric acidity was short and limited to the nocturnal period. Only misoprostol 800 μg and 600 μg reduced 24‐h acidity compared to placebo (P < 0.04).
Can higher doses of an H2‐receptor antagonist accelerate duodenal ulcer healing?
Authors: PAGE M. C. , LACEY L. A. , MILLS J. G. , WOOD J. R.
Published: July 2010

Drugs that inhibit gastric acid secretion heal duodenal ulcers at a rate that correlates with the ability of individual treatment regimens to decrease 24‐h intragastric acidity. As current therapeutic regimens of ranitidine decrease 24‐h intragastric acidity submaximally, higher dosages may expedite duodenal ulcer healing. To test this hypothesis a randomized, double‐blind clinical trial was conducted in 245 patients with duodenal ulcer to compare the effects of standard dose (300 mg nocte) and highdose (300 mg q.d.s.) ranitidine. Patients were assessed after 2 weeks of treatment and, if unhealed, after a further 2 weeks of therapy. The therapeutic gain in ulcer healing at the 2‐week endoscopy of the higher dose over the lower dose of ranitidine was 22% (68%vs 46%, P < 0.001). The cumulative ulcer healing rates at the 4‐week endoscopy were 88% and 92% for the standard and high‐dose ranitidine groups, respectively (N.S.). By 2 weeks, 61% of patients treated with standard ranitidine therapy and 79% of those receiving 300 mg ranitidine q.d.s. were pain‐free (P < 0.01). A further 2 weeks of therapy enabled 88% and 97% of patients (N.S.) to become pain‐free on these two regimens, respectively. The drug regimens were equally well tolerated. Thus higher‐dose ranitidine can significantly accelerate the healing of duodenal ulcer with improvement in pain relief.
Effects of cisapride on ano‐rectal sphincter function
Authors: ENCK P. , ARPING H. G. , ENGEL S. , BIELEFELDT K. , ERCKENBRECHT J. F.
Published: July 2010

To investigate the effects of cisapride, a motility‐inducing agent, on anorectal sphincter functions, standard manometry was performed in 10 healthy male volunteers after 5 days on a 20‐mg dose of cisapride in a placebo‐controlled double‐blind randomized crossover fashion. All subjects kept stool diaries during the experiment. Cisapride significantly increased stool frequency by adding soft and liquid stools; in addition, anal resting pressure was reduced with cisapride in seven of the 10 subjects; mean resting pressure decreased by 16%, while all other measurements were not altered. This suggests that cisapride may act directly on the smooth muscle of the internal anal sphincter. It also supports the view that enhanced defaecation in chronic constipation induced by cisapride may not be achieved by propulsive motor activity in the colon but also by a decreased anal sphincter tone.
Acute treatment of benign gastric ulcer with once‐daily bedtime dosing of cimetidine compared with placebo
Authors: FRANK W. O. , YOUNG M. D. , PALMER R. , ROCKHOLD F. , KARLSTADT R. , MOUNCE W. , O'CONNELL S.
Published: July 2010

This multicentre, double‐blind study evaluated the efficacy of cimetidine 800 mg nocte compared to placebo for ulcer healing and pain relief in patients with endoscopically confirmed, benign gastric ulcers treated for up to 8 weeks. Cimetidine accelerated ulcer healing throughout the study. More cimetidine‐treated patients (35 of 82, 43%) than placebotreated patients (26 of 79, 33%) had healed ulcers after 4 weeks of therapy. Similarly, after 6 and 8 weeks of treatment, cimetidine continued to have superior healing rates, 76% (59 of 78, P= 0.02) and 91% (69 of 76, P= 0.02) heal rates for cimitidine recipients compared with 58% (42 of 73) and 74% (52 of 70) for placebo. For every week of the study except the second, a greater proportion of cimetidine‐treated patients were free of daytime and night‐time pain than placebo‐treated patients; the differences were statistically significant for night‐time pain. Adverse reaction profiles were similar for the cimetidine and placebo groups. In conclusion, cimetidine 800 mg nocte was comparably safe and significantly more effective than placebo in accelerating healing and relieving pain in the treatment of acute, benign gastric ulcer.
Coated oral 5‐aminosalicylic acid versus placebo in maintaining remission of inactive Crohn's disease
Authors:   INTERNATIONAL MESALAZINE STUDY GROUP
Published: July 2010

A randomized, double‐blind, placebo‐controlled multicentre study was undertaken to evaluate the safety and efficacy of coated, oral 5‐aminosalicylic acid (Mesasal/Claversal; 5‐ASA) in maintaining remission of inactive Crohn's disease for up to 12 months. A total of 248 patients were entered from eight countries, of which 206 adhered to the protocol and were included in the analysis. The patients had Crohn's disease for an average of 5 years, with their disease clinically inactive for at least 1 month prior to entry into the study, and for an average of over 12 months previously. Thirty per cent of patients had had a previous resection, 16% of patients had been treated with sulphasalazine, while none of those analysed received glucocorticosteroids. Treatment consisted of 500 mg 5‐ASA t.d.s. or placebo. ‘Relapse’was defined as the first occurrence of Best's Crohn's Disease Activity Index > 150, which had increased 60 points from the pre‐trial index. The cumulative life‐table relapse estimate was lower in 5‐ASA patients compared to placebo (22.4% us 36.2%, respectively, Log rank test P = 0.0395). The 12‐month relapse estimate in the 5‐ASA group was also lower in patients with ileal disease (8.3% for 5‐ASA and 31.0% for placebo, P = 0.0535) and in patients with previous bowel resections (14.2% us 47.0%, P = 0.0436). The incidence of side‐effects was similar in both treatment groups. It is concluded that 5‐ASA was significantly superior to placebo in preventing relapse of Crohn's disease; this effect was most apparent in patients with disease restricted to the ileum and in patients with previous bowel resection. 5‐ASA was well‐tolerated, as demonstrated by a low incidence of adverse events.
Colonic transit in man is slowed by ondansetron (GR38032F), a selective 5‐hydroxytryptamine receptor (type 3) antagonist
Authors: GORE S. , GILMORE I. T. , HAIGH C. G. , BROWNLESS S. M. , STOCKDALE H. , MORRIS A. I.
Published: July 2010

Ondansetron (GR38032F) is a selective antagonist of 5‐hydroxytryptamine (5‐HT) type 3 receptors. This randomized, doubleblind, cross‐over study was undertaken to evaluate and compare the effect of ondansetron with placebo on gastrointestinal transit in 10 healthy male volunteers. There were no significant differences between the effects of placebo and ondansetron on gastric emptying or mouth‐to‐caecum transit time. However, significant differences in mean whole‐gut transit time were observed, that is 54.8 h with ondansetron and 32.1 h with placebo. Therefore, 5‐HT3 receptors may be involved in the regulation of colonic transit and ondansetron may prove useful as an anti‐diarrhoeal agent.
A comparison of two doses of nizatidine versus placebo in the treatment of reflux oesophagitis
Authors: QUIK R. F. P. , COOPER M. J. , GLEESON M. , HENTSCHEL E. , SCHUETZE K. , KINGSTON R. D. , MITCHELL M.
Published: July 2010

Three‐hundred and twenty‐five patients with endoscopically verified oesophagitis entered a double‐blind, randomized multicentre study that compared 300 mg nizatidine b.d., 300 mg nocte and placebo. The 6‐ and 12‐week treatment responses were studied. Healing was defined as complete epithelialization of all oesophageal lesions. The healing rates were 40% in the 300 mg nizatidine b.d. group, 30% in the 300 mg nocte group and 26% in the placebo group at 6 weeks. The corresponding figures after 12 weeks of treatment were 50%, 44% and 34%, respectively. The healing rates were significantly different (P< 0.05) between the high‐dose nizatidine group and placebo only, both at 6 and 12 weeks. Despite a trend at both 6 and 12 weeks in favour of 300 mg nizatidine nocte compared to placebo, this was not significantly different. The most important factor for the outcome, apart from the treatment group, was the pre‐entry severity of oesophagitis. The differences observed between treatment groups in healing rates, symptomatic relief, and antacid consumption appear to result mainly from the patients with
Single intravenous administration of the H+, K+‐ATPase inhibitor BY 1023/SK&F 96022—inhibition of pentagastrin‐stimulated gastric acid secretion and pharmacokinetics in man
Authors: SIMON B. , MÜLLER P. , BLIESATH H. , LÜHMANN R. , HARTMANN M. , HUBER R. , WURST W.
Published: July 2010

The effects of the H+, K+‐ATPase inhibitor BY 1023/SK&F 96022 on pentagastrin‐stimulated acid secretion have been studied in healthy male volunteers (n= 12). The gastric acid response to submaximal pentagastrin‐stimulation (0.6 μg/h/kg b.w.) was dose‐dependently inhibited. A single dose of 5 mg decreased acid output by 22% while after 60 mg and 80 mg secretion was almost completely abolished.

A good dose linearity was observed for AUC (0, >) and Cmax over the dose range from 5 to 80 mg. Elimination half‐life, total clearance and volume of distribution of the parent compound were independent of the dose.

The drug was well tolerated up to the highest dose of 80 mg. No clinically relevant influence was found on either laboratory screen or cardiovascular parameters.
Omeprazole in the treatment of peptic ulcers resistant to H2‐receptor antagonist
Authors: GUERREIRO A. S. , NEVES B. C. , QUINA M. G.
Published: July 2010

Thirty patients with peptic ulcers resistant to at least 8 weeks of continuous therapy with full‐dose H2‐receptor antagonists alone or followed by other anti‐ulcer drugs, were treated with the gastric proton pump inhibitor omeprazole (40 mg), administered orally once daily for up to 8 weeks. The study design was non‐comparative and open; healing was verified by endoscopy. After only 2 weeks of treatment, 21 out of 23 (91%) duodenal ulcer patients were healed, as well as 2 out of 2 patients with both duodenal and gastric ulcer and 1 out of 3 patients with prepyloric ulcer. After 4 weeks, all duodenal ulcers, 1 out of 2 gastric ulcers and 2 out of 3 pre‐pyloric ulcers were healed. A further month of therapy healed the gastric ulcer to give an overall healing rate of 97% and leaving only one patient (pre‐pyloric ulcer) unhealed at the end of the study.

Of 19 patients suffering ulcer symptoms at entry, only two patients reported any symptoms at 2 weeks and one of these (who remained unhealed) continued to have symptoms throughout the study. One patient reported mild asthenia; otherwise, no clinical or biochemical side‐effects were recorded. It is concluded that omeprazole is highly effective in healing refractory peptic ulcers.
Effect of repeated oral administration of BY 1023/SK&F 96022 – a new substituted benzimidazole derivative – on pentagastrin‐stimulated gastric acid secretion and pharmacokinetics in man
Authors: SIMON B. , MÜLLER P. , MARINIS E. , LÜHMANN R. , HUBER R. , HARTMANN R. , WURST W.
Published: July 2010

Pentagastrin stimulated gastric secretion was measured in 12 healthy male subjects after repeated once daily oral administration of 20 and 40 mg BY 1023/SK&F 96022 – a new substituted benzimidazole derivative.

Twenty milligrams inhibited acid output compared with placebo by 24% (2.5–3.5 h) and 26% (24.5–25.5 h) after the first oral intake. Inhibition increased to 56% and 50%, respectively, after the seventh oral dose. Forty milligrams inhibited acid output by a mean of 51% (2.5 to 3.5 h) and 52% (24.5–25.5) after the first oral intake. After the seventh dose mean inhibition rose to 85% and 66%, respectively.
Effect of mefenamic acid on bowel transit time in healthy adult volunteers
Authors: RASHID M. U. , BATEMAN D. N.
Published: July 2010

The effect of mefenamic acid on bowel transit time was investigated. Seven healthy adult male subjects of age 39 ± 2.4 years (mean ± S.E.M.) received placebo or mefenamic acid (500 mg t.d.s) orally in randomized order for five days, with a 7‐day washout between studies. On the third morning after starting the drug they had a meal containing Redi‐Brek and baked beans with radio‐opaque markers. Small bowel transit time was measured using breath hydrogen, and whole gut transit time was measured using radio‐opaque markers. The small bowel transit times were 160 min (median) with placebo and 50 min with mefenamic acid (P< 0.05). The percentages of appearance of marker in stool within 24 h were 24.9 ± 11.8 (mean± S.E.M.) with placebo and 48.9±11.7 with mefenamic acid (P< 0.05). The times of appearance of twenty‐fifth marker in stool were 41.0±4.4h with placebo and 26.9±3.2h with mefenamic acid (P< 0.05). The total weights of faeces in 72 h were 500.9±96.2 g with placebo and 657.1 ± 118.8 g with mefenamic acid (P< 0.05). Mefenamic acid in therapeutic doses (500 mg t.d.s.) accelerated bowel transit time in healthy subjects.
Combined gastric and oesophageal 24‐hour pH monitoring and oesophageal manometry in patients with reflux disease, resistant to treatment with omeprazole.
Authors: KLINKENBERG‐KNOL E. C. , MEUWISSEN S. G. M.
Published: July 2010

Combined oesophageal and gastric 24‐hour pH monitoring and oesophageal manometry were performed in 19 patients with resistant reflux oesophagitis after short‐term therapy with omeprazole (40 to 60 mg daily) or during maintenance treatment with omeprazole (20 to 80 mg daily). Omeprazole's effects on acidity were analysed as well as any possible influence on oesophageal motility. A pH in the stomach of below 4 was present during considerable periods of time (in 27 of 29 measurements), particularly during the night. As a consequence, pathological gastro‐oesophageal reflux occurred, particularly in the supine period. Insuficiency of the lower oesophageal sphincter was present in all but one patient; decreased or virtually absent motility of the oesophagus was found in 63 % of the patients. Combined intragastric and intra‐oesophageal pH monitoring, with oesophageal manometry, may contribute to the management of patients with reflux disease resistant to treatment with omeprazole. The present study emphasizes the need to individualize therapy in patients with refractory gastro‐ oesophageal reflux disease.
Pharmacokinetics of a 5‐aminosalicylic acid enteric‐coated tablet in patients with Crohn's disease or ulcerative colitis and in healthy volunteers
Authors: NORLANDER B. , GOTTHARD R. , STRÖM M.
Published: July 2010

An Eudragit‐L coated oral 5‐aminosalicylic acid (5‐ASA; mesalazine) product (Mesasal), has been formulated to deliver 5‐ASA to the distal small bowel and colon for the treatment of inflammatory bowel disease. The purpose of this study was to compare the pharmacokinetic profile of this drug between two patient groups, with either inflamed small or large bowel and with volunteers.

Two carefully selected patient groups (one with nine patients suffering from Crohn's disease restricted to the small intestine, and one with ten patients suffering from total ulcerative colitis) and a group of ten volunteers received two 250 mg Mesasal tablets in the morning, on a fasting stomach. Plasma 5‐ASA and acetyl‐5‐ASA concentrations were followed for 48 h, and urine and faecal excretion for 72 h. There was a great variation in most pharmacokinetic parameters within each group. Numerically, however, the data suggests a somewhat higher systemic absorption in patients with Crohn's disease than in healthy volunteers or patients with ulcerative colitis. The location of the inflammatory process might have some influence on the pharmacokinetics of 5‐ASA in inflammatory bowel disease.
Topical and systemic availability of 5‐amino‐salicylate: comparisons of three controlled release preparations in man
Authors: CHRISTENSEN L. A. , FALLINGBORG J. , ABILDGAARD K. , JACOBSEN B. A. , SANCHEZ G. , HANSEN S. H. , BONDESEN S. , HVIDBERG E. F. , RASMUSSEN S. NØRBY
Published: July 2010

The bioavailability of three pure 5‐aminosalicylic (5‐ASA) preparations (Asacol, Claversal, and Pentasa) was studied in 8 ileostomy patients and 12 normal subjects after 6 days of treatment with 2000 mg 5‐ASA. The local bioavailability, reflected by the 5‐ASA concentration was thereby measured at two clinically relevant areas of the gut: at the entrance to, and the exit from the colon. Estimates of the systemic bioavailability were obtained from the urinary excretions and the plasma values of 5‐ASA and Acetyl‐5‐ASA (Ac‐5‐ASA) during the three regimens. The three preparations studied are designed to release 5‐ASA at different levels in the intestine, but there was no significant difference in the 5‐ASA concentrations in the ileostomy effluents (Asacol 1.8 mmol/L, Claversal 3.4 mmol/L, Pentasa 2.0 mmol/L, median values). However, we found a smaller urinary excretion of 5‐ASA and Ac‐5‐ASA (5.2%vs Claversal 27.9% and Pentasa 23.0%, median values of ingested daily dose) and a lower concentration of Ac‐5‐ASA in the ileostomy effluents after Asacol treatment (0.8 mmol/L, median value) which indicates a more distal release from this preparation compared with Claversal (2.4 mmol/L, median value) and Pentasa (5.5 mmol/L, median value). In normal subjects a higher faecal water concentration of 5‐ASA was found after Asacol (9.8 mmol/L, median value) compared with Claversal (5.0 mmol/L, median value), whereas no difference between the faecal water concentrations of Ac‐5‐ASA was found (Asacol 21.5 mmol/L, Claversal 21.6 mmol/L, median values). This can be explained by a larger systemic absorption of 5‐ASA from Claversal, and accordingly Claversal treatment resulted in the largest urinary excretion of 5‐ASA and Ac‐5‐ ASA (43.7% us Asacol 35.6% and Pentasa 31.6 %, median values of ingested daily dose). The high Ac‐5‐ASA concentration in the ileostomy effluents and in the faeces after Pentasa, and the low plasma values, indicate a slow 5‐ASA release from this preparation throughout the small and large intestine. The results of the study indicate that Asacol is released in the distal part of the small intestine, that Pentasa is gradually released in the small and large intestine, and that Claversal shows an intermediate release pattern.
Prospective evaluation of omeprazole treatment in reflux oesophagitis refractory to H2‐receptor antagonists
Authors: KOOP H. , HOTZ J. , POMMER G. , KLEIN M. , ARNOLD R.
Published: July 2010

The efficacy of omeprazole therapy (40 mg daily) in H2‐blocker refractory severe reflux oesophagitis (Grade II‐IV; Savary and Miller classification) was investigated in 61 patients. Mean duration of reflux disease and preceding H2‐antagonist treatment were 4.3 years and 15 months, respectively. Healing rates at 4, 8 and 12 weeks were 48%, 80% and 92%, respectively. There was a correlation between severity of oesophagitis and duration of omeprazole therapy necessary for healing. Three patients (5%) required higher dosages than 40 mg for healing. Symptomatic responses paralleled healing. It is concluded that omeprazole is a highly effective drug for severe reflux oesophagitis not responding to H2‐blocker treatment and that 40 mg daily is the optimal dose.
The effect of intravenous doxofylline or aminophylline on gastric secretion in duodenal ulcer patients
Authors: LAZZARONI M. , GROSSI E. , PORRO G. BIANCHI
Published: July 2010

The aim of this study was to compare the effects upon gastric secretion of therapeutic doses of aminophylline, with doxofylline, a new xanthine derivative proposed for the treatment of chronic asthma.

Twelve patients with endoscopically‐proven healed duodenal ulcer were studied twice under double‐blind conditions in cross‐over experiments. In a 1‐hour infusion, six patients received either 240 mg aminophylline i.v. or 200 mg doxofylline i.v., and six received either 240 mg aminophylline i.v. or 400 mg doxofylline i.v.

Compared with basal gastric secretion, for the hour after the infusion 240 mg aminophylline i.v. stimulated gastric acid output by a mean 213% (P< 0.01) and mean pepsin output by 129% (P< 0.01). Intravenous doxofylline did not stimulate a significant increase of either acid or pepsin output (200 mg: acid output + 4%, pepsin output + 10%; 400 mg: acid output + 25%, pepsin output + 27%).

These findings suggest that doxofylline, unlike aminophylline, has a low secretagogue activity and it may be more suitable for asthmatic patients with peptic ulcer disease.
Helicobacter pylori infection treated with a tripotassium dicitrato bismuthate and metronidazole combination
Authors: WEIL J. , BELL G. D. , POWELL K. , MORDEN A. , HARRISON G. , GANT P. W. , JONES P. H. , TROWELL J. E.
Published: July 2010

Seventy‐two patients with H. pylori infection in their antral mucosa took part in the study. Forty‐three received metronidazole 400 mg t.d.s. for two weeks, plus De‐Nol tabs 2 b.d. for four weeks, and the remaining 29 patients received metronidazole 400 mg t.d.s. for two weeks plus De‐Nol liquid 5 ml q.d.s. for four weeks. Seven of 57 H. pylori isolates were found to have pre‐treatment metronidazole resistance. Success, in terms of eradication of H. pylori, was assessed using a one‐month post‐treatment 14C urea breath test.

Successful eradication of H. pylori was achieved in 72% and 79%, respectively, of the metronidazole/De‐Nol tablet and metronidazole/De‐Nol liquid groups. These figures increased to 87% and 84%, respectively, if the patients whose organisms were known to be metronidazole‐sensitive were considered in isolation. H. pylori was successfully eradicated in only one of seven patients with a metronidazole‐resistant organism.
Controlled study of the effects of intravenous famotidine on intragastric pH in bleeding peptic ulcers
Authors: FULLARTON G. M. , MACDONALD A. M. , MANN S. G. , McCOLL K. E. L.
Published: July 2010

As blood coagulation and platelet aggregation are abolished at pH < 5.4 the failure of antisecretory drugs to promote haemostasis in bleeding peptic ulcers may reflect inadequate pH control. This study examined the ability of famotidine, a potent, long‐acting H2 blocker to maintain intragastric pH above 5.4 in patients presenting with bleeding peptic ulcers. Twenty patients with acute upper gastrointestinal haemorrhage confirmed endoscopically to be related to peptic ulceration (17 duodenal, 3 gastric ulcers), were entered into the study within 24 h of presentation. Each patient was randomly allocated to receive either intravenous famotidine (n= 10) administered as a 10 mg bolus followed by a constant infusion of 3.2 mg/h or similarly administered placebo (n= 10). All patients remained fasted over the 22‐h study period. Their median intragastric pH values ranged from 6.8 to 7.9 (median 7.1) in the famotidine group and from 1.1 to 6.9 (median 1.6) in the placebo group (P < 0.001). Over this same period intragastric pH was > 6 for 64%‐100% (median 98%) of the recording time in the famotidine group compared with 0%‐93% (median 13%) in the placebo group (P < 0.001).

We conclude that intravenous famotidine can maintain intragastric pH > 6 in fasting patients with acute upper gastro‐intestinal bleeding from peptic ulceration. This provides a rational basis for further studies assessing its clinical efficacy in such patients.
Short report: a double‐blind placebo‐controlled trial of omeprazole on characteristics of gastric emptying in healthy subjects
Authors: RASMUSSEN L. , ØTER‐JØRGENSEN E. , QVIST N. , KRAGLUND K. , HOVENDAL C. , PEDERSEN S. A.
Published: July 2010

The aim of the study was to investigate a possible effect of omeprazole on the characteristics of the gastric emptying of liquid and solid in healthy subjects. The study was performed as a double‐blind crossover study and the gastric emptying studies were performed after 10 days of treatment with placebo or omeprazole 40 mg o.m. Omeprazole was without effect on the characteristics of liquid emptying or the lag phase of solid. It does, however, decrease the emptying rate of solid as the omeprazole group had a median half‐time duration of the linear emptying period which had twice the duration of the corresponding figure in the placebo group.
Review article: stomach wars—a mucosal defence initiative
Authors: MATTHEWS J. B. , GARNER A.
Published: July 2010

A model is presented which attempts to unify many of the processes identified in recent years as contributing to the maintenance of mucosal integrity in the stomach. Two concepts, namely acid disposal and rapid repair of superficial injury, are highlighted as being of particular physiological significance. The mechanisms involved in protection of the normal mucosa against luminal aggressors (e.g. acid/pepsin, ethanol, aspirin) must be distinguished from the factors which influence the healing of a pre‐existent ulcer. In this context, the relatively neglected topic of wound healing in the gastric mucosa is considered, and the implications for current therapeutic strategies and for the discovery of new anti‐ulcer drugs are explored.
Ranitidine in the treatment of duodenal ulcer disease: relationship between antisecretory effect and ulcer healing rate
Authors: McISAAC R. L. , DIXON J. S. , MILLS J. G. , WOOD J. R.
Published: July 2010

The relationship between drug‐induced suppression of intragastric acidity and the rate of duodenal ulcer healing was examined using data for a single drug, ranitidine, from 156 clinical trials involving 16362 patients together with data on acid suppression from 37 studies of intragastric acidity in 630 subjects. In these studies ranitidine was given in doses ranging from 150 mg to 1200 mg per day administered in 9 different dosage regimens. The overall percentage of patients whose duodenal ulcers healed at 2 and 4 weeks on the different regimens was highly correlated with the percentage suppression of 24‐hour intragastric acidity induced by different regimens. Thus the therapeutic benefit of a given ranitidine dosage regimen in healing duodenal ulcers relates directly to its antisecretory effect.