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Aim of this overview was to evaluate the main clinical trials with lansoprazole published from 1997 to 1999 in English-language journals, regarding gastroesophageal reflux disease, peptic ulcer, NSAID-induced ulcer, and ZES. Results of clinical trials for therapy and prevention of lesions/symptoms have been evaluated separately. In direct comparisons, lansoprazole alone (not combined with antibiotics) proves to be equieffective to other PPI and more effective than H2-RA in both therapy and prevention of GERD, peptic ulcer (a part from anti-Hp regimens) and NSAID-induced ulcer. Among Hp-eradicating regimens in patients with peptic ulcer or functional dyspepsia, lansoprazole-based triple therapy is equal in efficacy to other PPI-based or RBC-based triple therapies and, in any case, significantly better than dual therapies. The in vitro anti-Hp activity of lansoprazole, more marked than with other PPI, does not seem to effort clinical advantages. Safety of lansoprazole is largely satisfactory and no different from other PPI and H2-RA.

The improved knowledge of the mechanism by which NSAIDs work and damage the gastrointestinal (GI) mucosal suggested a series of measures for the prevention of NSAIDs-induced GI lesions, apart from the use of those proved to be less toxic. PPI have now been definitively shown to be more effective in the relief of symptoms and in the healing and prevention of ulcers/erosions than H2-antagonists and also better tolerated than misoprostol. Other more innovative approaches include selective and highly selective COX-2 inhibitors, NSAIDs containing NO or stimulating the gastric endogenous biosynthesis of NO, and chiral NSAIDs. Clinical usefulness of other compounds, including NSAIDs associated with zwitterionic phospholipids or fibroblast growth factor, is still under investigation.

The aim of this randomized, multicenter, double-masked, parallel-group study was to compare the efficacy of lansoprazole with that of omeprazole monotherapy in duodenal ulcer healing and prevention of relapse. A total of 251 patients with duodenal ulcer were treated with either lansoprazole 30 mg/d (n = 167) or omeprazole 40 mg/d (n = 84). Patients with healed ulcers were then randomly allocated to 12 months of maintenance therapy with lansoprazole 15 mg/d (n = 74), lansoprazole 30 mg/d (n = 71), or omeprazole 20 mg/d (n = 73). Healing rates at 4 weeks (intent-to-treat analysis) were 93.9% (95% confidence interval [CI], 90.2% to 97.6%) with lansoprazole and 97.5% (95% CI, 93.7% to 100%) with omeprazole; there were no significant differences between groups. Endoscopic relapse rates after 6 months were 4.5% (95% CI, 0% to 10.6%) with lansoprazole 15 mg, 0% with lansoprazole 30 mg, and 6.3% (95% CI, 1.5% to 12.5%) with omeprazole 20 mg, compared with 3.3% (95% CI, 0% to 8.2%), 0%, and 3.5% (95% CI, 0% to 8.8%), respectively, at 12 months. Again, there were no significant differences between groups. The incidence of adverse events during acute treatment was 6.0% and 7.1% in the lansoprazole and omeprazole groups, respectively; during maintenance therapy, the incidences were 12.2% (lansoprazole 15 mg), 5.6% (lansoprazole 30 mg), and 11.0% (omeprazole 20 mg). Within treatment groups, pain was significantly ameliorated after the acute phase but not after maintenance therapy (P < 0.05); no differences were observed between groups. Gastrin values increased significantly after acute therapy (P < 0.05), persisted at these increased levels during maintenance therapy, and returned to normal after 6-month follow-up. Both lansoprazole and omeprazole were highly effective and well tolerated in the treatment of duodenal ulcer; relapse rates were similar for all doses studied. Thus no additional benefit is to be gained from using a proton-pump inhibitor at a dose > 15 mg lansoprazole to prevent relapse.

While the correlation between Helicobacter pylori and peptic ulcer is accepted worldwide, the role of Hp in functional dyspepsia is still a debatable issue. Therefore, Hp eradication in all dyspeptic patients has both supporters and opponents. In contrast, anti-Hp regimens are increasingly well defined, most convincing treatments being triple therapies consisting of one proton pump inhibitor (PPI) or ranitidine bismuth citrate (RBC) plus two antimicrobials. Duration of anti-Hp regimens varies from 2 weeks (more usually adopted in USA) and 1 week (more usually adopted in Europe). Due to the short and simple anti-Hp triple therapies, side effects prove to be few and negligible and patient compliance is significantly better. By contrast, Hp resistance to extensively used antimicrobials, such as metronidazole and clarithromycin, is more than an emerging problem causing significantly lower eradication rates. Very recent data indicate that RBC-based triple therapy is much less affected by the helicobacterial resistance, and is also effective in non-responders to a PPI-based triple therapy.

Our knowledge of the mechanism by which aspirin and traditional NSAIDs work and damage the gastrointestinal mucosa, recently markedly improved, has suggested a number of measures for the prevention of the NSAID-induced GI lesions. Among these, perhaps the most innovative approach seems to be the nitric oxide-releasing NSAIDs or compounds, like amtolmetin guacyl, that work by increasing the endogenous biosynthesis of NO selectively at gastric mucosa level. Further data, stemming from large RCTs and confirming the results of experimental studies and the initial clinical experiences, are needed to better define the true clinical impact of this approach.

Background: Although injection treatments for ulcer haemostasis seem to be effective, recurrent bleeding remains a serious problem. Large randomised clinical trials are required to show differences between treatment modalities for gastrointestinal bleeding. The aim of this study was to compare the safety and efficacy of repeated endoscopic injection of fibrin glue (FG) with that of single endoscopic injection of polidocanol in the prevention of recurrent bleeding., Methods: 854 patients with active gastroduodenal bleeding (spurting, oozing), or ulcers with a visible non-bleeding vessel, were randomly assigned one of three endoscopic treatments: single application of polidocanol 1%, single application of FG, or daily repeated application of FG until the visible vessel had disappeared. All patients were pretreated with local injection of epinephrine (1/10,000), and had daily repeat endoscopies until the vessel observed at initial endoscopy was no longer visible., Findings: Recurrent bleeding rates among the 790 patients in whom the rates could be assessed were 58 (22.8%) of 254 in the polidocranol group, 51 (19.2%) of 266 in the FG-single group, and 41 (15.2%) of 270 in the FG-repeated group. The difference between FG-repeated treatment and polidocanol was significant (p = 0.036). Treatment failed, making other treatments (including surgery) necessary, in 34 (13.0%) of 261 in the polidocanol group, 34 (12.4%) of 274 in the FG-single group, and 21 (7.7%) of 274 in the FG-repeated group. The difference between FG-repeated treatment and polidocanol was significant (p = 0.046). The 30-day-mortality rates were low in all three treatment groups (polidocanol 4.7%; FG-single treatment 5.3%, FG-repeated treatment 4.3%). The safety profiles of the three treatment strategies were similar., Interpretation: Repeated injection with FG glue is significantly more effective than injection with polidocanol 1% in the treatment of bleeding from gastroduodenal ulcers.

A substantial body of studies (controlled, cohort and case-control studies) now confirm the long established impression that there is an increased prevalence of gastric and duodenal ulcer and of associated complications in subjects treated with aspirin (ASA) or with non-steroidal anti-inflammatory drugs (NSAIDs). The overall percentage of ulcers/erosions in patients treated with ASA ranges from 10 to 50% with a relative risk of bleeding ranging from 1.8 to 15%. The overall relative risk of ulcers/erosions in NSAIDs-treated subjects is around 3%, with complications detectable in 2.4% of cases. The risk of lesions and complications associated with ASA/NSAIDs is more marked in patients aged over 65, in those with a previous history of ulcer (both symptomatic and silent), in those treated with substantial doses or with combinations of NSAIDs and in those concomitantly using anticoagulants and/or steroids. The epidemiological data highlight the importance of implementing ASA/NSAIDs therapy only when strictly necessary as well as the advisability of adopting as broad a range of measures as possible to reduce the tissue-damaging effects of these pharmacological agents.

The aims of medical therapy in chronic pancreatitis are mainly to relieve the recurrent pain and to correct any malabsorption secondary to digestive insufficiency resulting from deficient exocrine pancreatic function. The treatment of the pain initially involves the use of dietary measures and analgesic drugs. The results of the use of pancreatic extracts and somatostatin reported in the literature are controversial, as are those of coeliac plexus block. Of unquestionable efficacy, at least in the short to medium term, are surgical decompression interventions in patients, with pain refractory to these measures and who present significant dilation of Wirsung's duct at ERCP. Endoscopic decompression constitutes an alternative to surgical decompression. In view of the transitory results of endoscopic decompression, which, in any event, should be implemented only by endoscopists possessing the necessary experience and expertise, the use of this technique may perhaps be targeted at carefully selected patients to be submitted to surgical decompression. As far as maldigestion is concerned, which occurs only when the pancreatic functional deficit reaches 90% or more, replacement therapy with pancreatic extracts must be resorted to. Multi-Unit Dose preparations are to be preferred, consisting in gastro-protected microspheres measuring not more than 2 mm in diameter and containing high doses of lipase, since at least 30,000 I.U. of lipase are required in the post-prandial phase for reasonably satisfactory correction of the steatorrhoea. Should this fail to prove effective, it is good policy to add antisecretory drugs (H2-antagonists, proton-pump inhibitors).

Non-organic dyspepsia, although not frequently reported, is still a disorder which is difficult to classify in nosographic and physiopathological terms, a fact which inevitably influences the indications for its treatment. Non-pharmacological treatment of non-organic dyspepsia includes changes in dietary and behavioural habits which, even if established on empirical grounds, play a far from ancillary role. When considered appropriate, pharmacological treatment must be formulated solely on the basis of controlled clinical trials vs placebo given the well-known significance of the placebo effect in this and other so-called "functional" diseases. The therapeutic strategies which are most subject to verification are based on the one hand on the neutralisation or inhibition of gastric acid secretion and, on the other, on the improvement of gastrointestinal motility. Surprisingly, the widely used antacid drugs are among those which have been less well studied and show the lowest efficacy. Among the anti-secretory drugs, pirenzepine is approximately 25% more effective than placebo. H2-antagonists, the drugs which have been most closely studied both in terms of the number of trials and the size of the sample populations studied, produce contradictory results. However, a meta-analysis of the trials shows an overall 18% improvement in efficacy compared to placebo. The overall results of studies on prokinetic compounds are "good" in meta-analytical terms, with an improved efficacy of 50% compared to placebo. This is not necessarily due to the superiority of prokinetic compared to anti-secretory drugs and can be explained by the reduced placebo effect in trials using prokinetic drugs or a greater presence in the latter of dyspepsia which is physiopathologically correlated to motor discord. Among the future drugs still being studied, it is particularly worth mentioning fedotozine, a specific K opioid receptor agonist which appears to have provided extremely interesting results in preliminary studies. The role of barrier drugs, such as sucralfate and colloidal bismuth, continues to remain unclear and in particular the latter might be of increased use if evidence of a relationship between Helicobacter pylori and non-organic dyspepsia were reinforced; this relationship may in fact not exist in all dyspeptic patients but only in a subgroup. Lastly, the problem of the duration of pharmacological treatment still remains unsolved, as do the questions of whether longterm treatment should be conceived once acute symptoms have disappeared and whether it is possible to hypothesise differentiated pharmacological treatment depending on the clinical variants of functional dyspepsia which have been defined with greater attention over the course of the past decade.

Maintenance treatment with antisecretory agents, and above all with H2-RA, is a therapeutic option still largely favoured by physicians. However, in the last decades the pathogenetic role of Helicobacter pylori (Hp) in duodenal and gastric ulcer has met with increasingly convincing confirmation. Actually, Hp eradication brings about a dramatic and persistent decrease in ulcer relapse rate. At present, there is a general agreement that Hp-positive patients, with ulcer whether ab initio or recurrent, need to be treated with anti-Hp regimens. The first choice therapy, according to some clinicians, should be the classic triple therapy (colloidal bismuth, metronidazole and tetracicline or amoxicillin) associated or not with a proton pomp inhibitors (PPI) or H2-RA. Though supported by other gastroenterologists, dual therapy with a PPI plus amoxicillin raises some perplexity due to the unpredictable variability of the results. Non-bismuth triple therapy, consisting in 2 antimicrobial and 1 antisecretory agent, for which a duration of only 1 week would seem sufficient even at low dosage, is currently meeting with greater favour. The FDA approval is probably imminent for 2 anti-Hp regimens consisting in clarithromycin plus a PPI or the complex salt ranitidine-bismuth citrate.

During a period of 24 months, 115 patients with symptomatic gallbladder stones (77 females, 38 males; median age 46 years, range 22-87) were treated by extracorporeal shock wave lithotripsy with a Lithostar Plus. Concomitant bile acid dissolution therapy (ursodeoxycholic acid + chenodeoxycholic acid 7.5 mg/kg/day each or tauroursodesoxycholic acid 5-10mg/kg/day) was administered until 3 months after total fragment clearance. Complete clearance of all fragments was obtained after 6, 9, 12, 18 and 24 months in, respectively, 30, 45, 51, 62 and 72%. Life table analysis of the subgroups showed significantly better clearance results in patients with fragments < 5mm at the first extracorporeal shock wave lithotripsy session (67%) than in patients with larger fragments (39%) (p < 0.01). Patients with solitary stones < 20mm cleared their fragments better (58%) at 12 months than those with multiple stones (49%), but the differences were not statistically significant. Stone recurrence was 6% at 1 year and was lower in patients with solitary stones (3%) than in those with multiple stones (12%). Major side effects consisted in 2 cases of mild acute pancreatits and 19% of biliary colics.

Chronic gastritis may favour the development of gastric cancer more as a condition than as precancerous lesion. Since, in most cases, it is pathologically correlated with Helicobacter pylori infection, it is reasonable to postulate at least an indirect role for this organism in the pathogenesis of gastric cancer. H. pylori, however, is only one of the risk factors involved, in that additional factors (excess salt, cigarette smoking, deficiency of foodstuffs with an antioxidizing effect) may facilitate the malignant transformation of chronic atrophic gastritis into intestinal-type gastric cancer. Gastric carcinogenesis therefore presents itself as a multifactorial, multistage process, furthered by the occurrence of precancerous lesions which are usually interrelated (type-III intestinal metaplasia, severe dysplasia) and by functional alterations such as achlorhydria, which, though it is not enough in itself to cause gastric cancer, promotes abnormal intragastric bacterial development, a condition which may be followed by abnormal intragastric formation of cancerogenous nitroso compounds. The existence of a close correlation between both gastric cancer and H. pylori infection and low socio-economic and hygienic status of the population lends further strength to the hypothesis that an "H. pylori factor" is involved in gastric carcinogenesis. Consequently, to reduce the risk of gastric cancer, various strategies have been devised to prevent H. pylori infection (improvement in socio-environmental conditions, anti-H. pylori vaccine) and/or to eradicate the organism (by means of therapeutic regimens including antimicrobial agents, which, however, can be implemented only in patients who have not developed diffuse atrophy and/or dysplasia, in whom H. pylori may no longer be detectable). Definitive proof of the real extent of the relationship between H. pylori and gastric cancer and of the efficacy of therapeutic and preventive measures can be provided only by controlled trials in populations with a high prevalence of chronic non-atrophic gastritis which are difficult to organize.

Placebo, defined as any therapeutic procedure, without any specific activity, given deliberately to have an effect on a patient, symptom, syndrome or disease, has a great impact in the evaluation of drug response. The possible pathways via which the possible effect brings about clinical and physiological changes remain unknown, but a humoral mechanism seems to be implicated in some placebo effects (e.g. placebo-induced analgesia). The placebo effect depends on many factors, including the type of patient, the personality of the physician, the doctor-patient relationship and the type and even the colour of the drug preparation. Placebo control is important particularly when the disease is characterized by frequent spontaneous periods of acute exacerbation and remission. Functional (such as dyspepsia and irritable bowel syndrome) and organic (such as peptic ulcer and inflammatory bowel disease) gastrointestinal diseases have got great benefit from placebo-controlled clinical trials. In such trials the more effective the placebo is, the more difficult it will be to demonstrate the efficacy of active drug in statistical terms. Nevertheless, provided the use of placebo be ethical for a given condition, placebo-controlled trials are the only objective way of assessing correctly drug response in patients.

The authors examine the relationship between Helicobacter pylori and gastric ulcer therapy, analyzing both the data suggesting that eradication of the organism renders the gastric mucosa less susceptible to development of gastric ulcer and the substantial body of evidence to the contrary. They review the results reported in clinical trials with colloidal bismuth subcitrate, antimicrobial agents (furazolidone), and combinations of antiulcer and antimicrobial agents (H2-antagonist + cefixime, H2-antagonist + metronidazole). Also analyzed is the relationship between Helicobacter pylori eradication and ulcer recurrence; only one study is available on this aspect, and the limited evidence it provides in favour of a prophylactic effect of eradication therapy is not entirely convincing. The authors conclude that there is no reasonable case for the dogmatic assumption that eradication of Helicobacter pylori facilitates either acute healing or long-term prophylaxis of gastric ulcer, though certain subgroups of gastric ulcer patients may benefit from eradication therapy.

Despite the fact that reflux esophagitis is a multifactorial disease, inhibition of gastric acid secretion is the mainstay of medical treatment, both for moderate and severe cases. Antisecretory agents lower the acidity of the refluxate, thus decreasing its aggressive effect, which favors the mucosal healing process. The greater the acid inhibition, the greater will be the mucosal repair. This is the reason for a therapeutic gain for H2-receptor antagonists over anticholinergics and antacids, and for proton pump inhibitors over H2-receptor antagonists. The most recently developed proton pump inhibitor, lansoprazole, at doses of 15, 30, or 60 mg/day for 4 and 8 weeks of treatment, has proven to be significantly more effective than placebo (one multicenter study involving 292 patients) or ranitidine (three multicenter studies involving 653 patients) in terms of mucosal healing and symptom relief. In two comparative trials with omeprazole 20 mg vs lansoprazole 30 mg (in a total of 349 evaluable patients) healing rates were found to be similar, but in one trial the relief of heartburn proved to be significantly more pronounced in patients receiving lansoprazole who also used fewer antacids. The frequency of adverse events was comparable in the two treatment groups. Reflux esophagitis is a chronic condition and after stopping antisecretory treatment, including lansoprazole, most patients relapse in terms of symptoms and endoscopical lesions, which suggests the need for long-term treatment. However, a strategy for long-term control of reflux esophagitis remains to be defined (lower daily dose, alternate-day standard dose, or concomitant prokinetic drugs?). The safety of proton pump inhibitors given for prolonged periods also needs to be more thoroughly evaluated.

Histamine H2-receptor antagonists at conventional doses have proved only partly efficacious in the treatment of reflux oesophagitis. The aim of this study, therefore, was to compare the efficacy of high doses of nizatidine (300 mg b.i.d.) versus placebo in 117 patients with grade I and II oesophagitis. After 6 weeks' treatment, 70.6% of nizatidine-treated patients showed complete endoscopic healing against 25.4% of placebo-treated subjects (p less than 0.001). After 12 weeks, the respective healing rates were 77.5% and 47.4% (p less than 0.01). Nizatidine also proved significantly more effective than placebo in improving overall symptoms (p less than 0.05). Antacid intake was significantly greater in the placebo group (p less than 0.001). Both treatments were well tolerated. In conclusion, this study demonstrates that nizatidine at the dose of 300 mg b.i.d. for 6-12 weeks constitutes an effective treatment for patients with reflux oesophagitis.

The relationship between Helicobacter pylori (HP) and gastric ulcer therapy is examined by analyzing both the data that suggest that eradication of HP renders the gastric mucosa less susceptible to development of gastric ulcer as well as the substantial body of evidence that does not support this contention. The results reported in clinical trials with colloidal bismuth citrate, antimicrobial agents (furazolidone), and combinations of anti-ulcer and antimicrobial agents (H2-antagonist+cefixime, H2-antagonist+metronidazole) are reviewed. Also analyzed is the relationship between HP eradication and ulcer recurrence. Only one study is available on this aspect, and the limited evidence it provides in favour of a prophylactic effect of eradication therapy is not entirely convincing. The authors conclude that there is no reasonable case for the dogmatic assumption that eradication of HP facilitates either acute healing or long-term prophylaxis of gastric ulcer, though certain subgroups of gastric ulcer patients may benefit from eradication therapy.

According to the traditional view gastric acid and pepsin are a sine qua non for ulcer development. Acid suppression, however, is far from being the only successful therapeutic approach, and similar healing rates are achieved by drugs with substantially different mechanisms of action--antacids, H2-antagonists, antimuscarinics, cytoprotective and site-protective agents--thus denoting a multifactorial pathogenesis. Even with the antisecretory compounds, the relationship between gastric acid and ulcer healing gives rise to perplexity: antacids prove effective at widely varying doses; pirenzipine and H2-blockers, which are clinically equieffective, differ considerably in antisecretory efficacy; H2-antagonist studies on early vs late postprandial dosing yield contradictory clinical results; morning and bedtime single administrations of H2-antagonists prove equiactive on ulcer healing, leading to a reappraisal of the alleged importance of nocturnal acidity. Ulcer sealants such as colloidal bismuth and sucralfate prove as effective as H2-antagonists despite their total lack of antisecretory activity, thereby apparently undermining the primary pathogenetic role of acid. However, with the spectacular 100% healing rates achieved by the protonpump blocker, omeprazole, the wheel has come full circle, and gastric acid appears to re-emerge as a primary element in pathogenesis. Specific therapy, based on the predominant pathogenetic factor involved, is likely to be a feasible proposition, but, at present, remains little more than a remote possibility.

The clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with significant adverse effects on the integrity of the gastrointestinal (GI) mucosa. A unique, double-blind, placebo-controlled, randomized, multicentre study investigated the prophylactic co-therapy with misoprostol, a novel PGE1 analog, for the prevention of the NSAID-induced gastric and duodenal mucosal lesions. The study also investigated whether the co-therapy with misoprostol could interfere with the anti-rheumatic action of the NSAIDs using detailed rheumatological assessments. Patients with osteoarthritis or rheumatoid arthritis had to be free of symptoms and significant erosive and/or haemorrhagic lesions of the upper GI tract. The patients were randomized to co-therapy with misoprostol or its matching placebo. Follow-up endoscopy and symptoms assessment were carried out within 4 weeks and compared to pre-study findings. Misoprostol significantly reduced (p less than 0.01) the incidence of erosive and/or haemorrhagic gastric and duodenal mucosal lesions. Misoprostol also reduced the proportion of patients with epigastric pain (p less than 0.01). Misoprostol was well tolerated and did not interfere with the anti-rheumatic activity of the administered NSAID. We conclude that misoprostol is safe and effective in the protection against NSAID-induced gastric and duodenal mucosal lesions and symptoms.

Less attention has been devoted to the effects of antisecretory agents on pepsin secretion than to those on gastric acid secretion, particularly in human subjects. Moreover, comparison of the various trials is far from being simple and straightforward owing to the fact that the studies available present substantial variability in terms of types of subjects (controls, DU patients), gastric secretion (basal, stimulated), type of stimulation (pentagastrin, histamine, insulin, meals, sham feeding) antisecretory drug administration route (oral, i.v.) and considered parameters (concentration, output). This review of the published data reveals that all antisecretory agents reduce pepsin output, regardless of their sometimes very different mechanism of action. Despite this, there are differences in antisecretory effects according to the agent used to stimulate gastric secretion. Even within a single drug class (H2-antagonists, prostaglandins) there may be differences depending on the potency of the compound used.

We conducted a double-blind randomized treatment study on patients affects by non-ulcer dyspepsia in whom multiple biopsy specimens showed active gastritis. Patients were given either 3 g/day of sucralfate (n = 39) or 600 mg/day of sulglycotide (n = 50) for 6 wk, a glycopeptide isolated from pig duodenum constituents. Endoscopy was carried out at baseline and at the end of treatment. We took biopsies from the gastric body (twice) and antrum (six times) at each endoscopy in order to determine grade and extent of gastritis and Helicobacter pylori colonization. Both treatments induced a marked regression of active gastritis (sucralfate group: p less than 0.05 and p less than 0.0001, respectively, in body and in antrum; sulglycotide group: p less than 0.01 and p less than 0.001, respectively). Conversely, Helicobacter pylori colonization remained unchanged at the end of the treatments. At baseline, a close relationship was found between grade of active inflammation in each biopsy and Helicobacter pylori density. After therapy, the association was lost in each treatment group. These results suggest that there can be a remission of active gastritis in patients with non-ulcer dyspepsia even without changes in Helicobacter pylori colonization. This result can be achieved by enhancing the protective properties of the gastric mucosa.

According to the traditional view, gastric acid and pepsin are a sine qua non for ulcer development. Acid suppression, however, is far from being the only successful therapeutic approach, and similar healing rates are achieved by drugs with substantially different mechanism of action antacids, H2-antagonists, antimuscarinics, cytoprotective and site-protective agents-thus denoting a multifactorial pathogenesis. Even with the antisecretory compounds, the relationship between gastric acid and ulcer healing gives rise to perplexity: antacids prove effective at widely varying doses; pirenzipine and H2-blockers, which are clinically equieffective, differ considerably in antisecretory efficacy; H2-antagonist studies on early vs late postprandial dosing, yield contradictory clinical results; morning and bedtime single administration of H2-antagonists prove equiactive on ulcer healing, leading to a appraisal of the alleged importance of nocturnal acidity. Ulcer sealants such as colloidal bismuth and sucralfate prove as effective as H2-antagonists despite their total lack of antisecretory activity, thereby reapparently under-mining the primary pathogenetic role of acid. However, with the spectacular 100% healing rates achieved by the proton-pump blocker, omeprazole, the wheel has come full circle, and gastric acid appears to re-emerge as a primary element in pathogenesis. Specific therapy, based on the predominant pathogenetic factor involved, is likely to be a feasible proposition, but, at present, remains little more than a remote possibility.

Peptic ulcers fail to heal in up to 10% of patients after 8 weeks of therapy with H2-receptor antagonists largely owing to the multifactorial pathogenesis of the disease. Site-protective agents may heal the ulcers in many, but not all, of these non-responders. In ulcers which prove particularly refractory to therapy, only powerful gastric acid inhibition of the type best achieved with omeprazole is capable of healing most, and sometimes even 100% of patients in the short term. Powerful inhibition of gastric acid secretion proves clinically advantageous, in terms both of symptom relief and endoscopic lesions, in severe reflux oesophagitis, characterized, as it is, by erosive and ulcerative lesions. Strong inhibition of acid secretion is, of course, also indicated in Zollinger-Ellison syndrome, the treatment of which has already been revolutionized by the use of H2-antagonists, usually given in very high doses, and appears to have made yet another step forward with the advent of omeprazole thanks to the particularly marked potency and duration of action of this benzimidazole derivative. Powerful inhibition of acid secretion thus seems possible both with high-dose H2-antagonists and, most notably, with omeprazole. Though fully justified in certain classic conditions such as refractory ulcer, erosive-ulcerative oesophagitis and Zollinger-Ellison syndrome, massive antisecretory blockade would not appear to be suitable for indiscriminate use, especially long-term.

Nineteen healthy volunteers were studied to investigate whether or not muscarinic receptors of different exocrine glands could be distinguished from one another by the use of pirenzepine. A simultaneous evaluation of lacrimation, salivation and gastric secretion was carried out, bethanechol (80 micrograms/kg/hr) being used as a stimulant and pirenzepine (10 or 5 mg i.v.) as an inhibitor. Bethanechol increased salivation significantly and the volume of gastric juice, and non-significantly increased lacrimation and total acid output. Pirenzepine abolished the hypersecretion induced by bethanechol, and decreased the basal level of the exocrine secretions, to approximately the same extent. These experiments seem to demonstrate that if there is a difference among the muscarinic receptors of lacrimal, salivary and gastric oxyntic glands, pirenzepine is unable to discriminate them from one another, at least under the experimental conditions of this investigation.

171 duodenal ulcer patients were treated for four weeks with either ranitidine or placebo under double-blind conditions. 40 patients (monocentre study) received ranitidine (40 mg), or placebo t.d.s. with meals and 80 mg at bedtime. 131 patients (multicentre study) received ranitidine (150 mg), or placebo b.d. In the monocentre study endoscopy after 4 weeks of treatment showed complete healing in 83.3% of the ranitidine patients and 30.4% of those on placebo (P less than 0.01%). In the multicentre study the healing percentages were 79.4% and 30.4%, respectively (P less than 0.001). In both trials pain and antacid consumption decreased in patients taking ranitidine more than in patients on placebo. After 4 weeks in the double blind studies 13 of the 15 patients with unhealed ulcer in the monocentre study and 51 of 54 patients in the multicentre study received open treatment with ranitidine for another 4 week period. The overall healing percentages by the 8th week of treatment with ranitidine were 94.4% and 93.6% respectively. No serious side effects, or haematological changes were observed during the treatment with ranitidine.

The aim of the present study was to investigate the effectiveness of ranitidine in the treatment of duodenal ulcer. Fourty patients with endoscopically proven pyloric or duodenal ulcer were treated with ranitidine 40 mg t.d. with meals and 80 mg nocte, or identical placebo tablets under double-blind conditions. Endoscopy after four weeks of treatment revealed complete healing in 15 out of 18 (83.3%) ranitidine-treated patients and in 5 out of 17 (29.4%) of the placebo patients (P less than 0.01). Ulcer symptoms were significantly less in ranitidine-treated patients, while the difference in antacid consumption between the two groups was found to be only arithmetical. No side effects or significant hematological or biochemical abnormalities were found. Four-week treatment with 200 mg of ranitidine daily seems to correspond to that of 6-8 weeks with 1-1, 6 g of cimetidine.

According to the most recent definition, "placebo" is any substance devoid of specific activity, which nevertheless is given in order to obtain an effect. It is used to advantage in identifying active drugs (controlled clinical trials). It has an effect which is usually (though not always) favourable and has its own pharmacology closely resembling that of active substances. In view of the consistency of the placebo effect, any substance tried in the treatment of the various diseases of the alimentary tract must prove superior to placebo in order to be considered an "active" substance. It is only on the basis of this criterion that we may accept the risk of side-effects which, though they may be slight, are nevertheless unjustified if the drugs we are administering are inactive. This drug vs placebo comparison classically takes the form of so-called "double-blind" controlled studies, but for digestive diseases these are far less numerous than the many unreliable, uncontrolled studies available. Generally, the use of a placebo control has led to the elimination of numerous substances characterized by purely alleged efficacy, and to the identification of efficacious compounds or acceptable therapeutic trends. In peptic ulcer, controlled studies vs placebo have also contributed towards the acquisition and definition of useful pathophysiological, clinical and therapeutic notions.(ABSTRACT TRUNCATED AT 250 WORDS)

93 publications concerning drug-induced pancreatitis are reviewed. A confirmed causal relationship between drug and acute pancreatitis so far exists only for 8 compounds: azathioprine, chlorothiazide, furosemide, sulfonamides, tetracycline, estrogens, valproic acid and L-asparaginase. There is less convincing, but still suggestive, evidence for a causal relationship with 5 other drugs, namely: corticosteroids, chlorthalidone, ethacrynic acid, phenformin and iatrogenic hypercalcemia. Due to inadequate or contradictory evidence, the link between a number of additional drugs and acute pancreatitis is considered possible, conditional or doubtful. Finally, the scant literature concerning the pathogenesis and histological lesions of drug-induced pancreatitis is briefly reviewed.

The purpose of the present study was to compare the effectiveness of pirenzepine and carbenoxolone in accelerating the healing of chronic gastric ulcer. Sixty-six out-patients with endoscopically proven gastric ulcer, without major systemic diseases, were admitted to the study. Patients were randomly allocated to either pirenzepine, 50 mg three times a day for 6 weeks, or carbenoxolone, 100 mg three times a day for one week followed by 50 mg three times a day for the remaining five weeks. At 6 weeks, the ulcers had healed in 20 out of 34 patients (59%) treated with pirenzepine, and in 15 out of 29 patients (52%) treated with carbenoxolone. Symptomatic improvement was similar with both drugs. Some major side effects (oedema, hypokalaemia and hypertension) occurred in approximately 30% of patients treated with carbenoxolone; of those receiving pirenzepine 25% complained of minor symptoms (e.g. dry mouth, headache, tachycardia). It is concluded that pirenzepine and carbenoxolone are of similar, but rather limited, efficacy in speeding the healing of chronic gastric ulcer, but show important differences with respect to tolerability.

34 patients were treated with cimetidine and placebo in a double blind trial and 42 were treated with cimetidine alone. Criteria investigated were the pain response, consumption of antacids when required and especially the endoscopically demonstrated scarring of the duodenal ulcer. Compared with placebo, cimetidine is capable of soothing pain and also reducing the consumption of antacids more quickly and to a greater extent. The differences are statistically significant. Complete anatomical healing of the ulcer was established in the double blind study in 80% of the patients in the cimetidine group and in 40% of the placebo group. Similar results were also shown in the group which received cimetidine alone.

The goals of treatment with pancreatic extracts in patients with chronic relapsing pancreatitis are twofold: pain relief and control of maldigestion caused by exocrine pancreatic insufficiency. Experience with the use of pancreatic enzymes for analgesic purposes suggests that the less severe the pain, the greater the analgesic effect of these enzymes. However, the number of trials, as well as the number of patients treated, is fairly small and more studies in larger patient populations are needed. The use of pancreatic enzymes for maldigestion owing to exocrine pancreatic insufficiency which is secondary to chronic pancreatitis, pancreatectomy, cystic fibrosis, or GI bypass surgery incurs several problems. These problems are primarily caused by gastric inactivation of the enzymes, low enzyme activity of many commercial preparations and/or poor patient compliance. Treatment with conventional enzyme products (powdered extracts, enteric-coated tablets or capsules) has been disappointing. At best, results were inconsistent, showing a high degree of individual variation. The introduction of enzyme preparations in the form of pH-sensitive enteric-coated microspheres in hard gelatin capsules represents a significant advance. These microspheres are superior to conventional enzyme preparations in improving the symptoms of pancreatic insufficiency, particularly steatorrhea, where low doses of microspheres are as effective as large doses of conventional enzyme preparations. Steatorrhea, however, is rarely completely resolved. In cases refractory to therapy, treatment with the combination of pH-sensitive enteric-coated microspheres and H2-antagonists or prostaglandins has met with some success.

A multicentre study involving 9 Italian institutions was carried out to compare the efficacy and safety of ranitidine 150 mg b.i.d. and ranitidine 300 mg nocte in the treatment of reflux oesophagitis. 117 patients with histologically proven oesophagitis were randomly allocated to two comparable treatment groups. Efficacy and reliability were evaluated by clinical and laboratory tests at the beginning of the study, and at 3 and 6 weeks; endoscopy and biopsies were performed at the beginning and at 6 weeks. Treatment with ranitidine for 6 weeks led to total disappearance of gastro-oesophageal reflux symptoms in 60% of patients, with percentages of partial improvement varying between 85% and 95% of cases. Improvement in the results of endoscopic examination was 85%, of which 55% were cured. Microscopic examination revealed an improvement of 36% and 44%, with a cure rate of 18% and 26% respectively. With regard neither to the regression of symptoms nor to the macroscopic and microscopic inflammation of the oesophageal mucosa did statistical examination show significant differences in the therapeutic efficacy of ranitidine 150 mg b.i.d. or 300 mg nocte for treatment of reflux oesophagitis.

A multicenter, double-blind, randomized, controlled study was conducted in 234 duodenal ulcer patients to compare the efficacy and safety of the H2-receptor antagonists famotidine and ranitidine in the treatment of duodenal ulcer. Patients received 40 mg famotidine (119 patients) or 300 mg ranitidine (115 patients) once daily at bedtime for 4 weeks. If ulcer lesions persisted, treatment was extended to 6 weeks. Efficacy was assessed by relief of symptoms and endoscopic findings of ulcer healing. Safety was determined on the basis of reports of side effects, results of laboratory tests, and, in selected patients, changes in plasma levels of hormones. The 4- and 6-week healing rates achieved with famotidine were 76% and 91%, respectively, and with ranitidine they were 76% and 87%, respectively; the differences in healing rates for the two drugs were not statistically significant. Similarly, both drugs provided satisfactory relief of pain and dyspeptic symptoms. However, famotidine produced significantly (P less than 0.05) greater relief of postprandial fullness and heartburn. The incidence of untoward effects was low in both treatment groups, and abnormal results in laboratory tests were observed in only one patient, a chronic alcoholic receiving famotidine, who withdrew from the study because of a slight elevation in serum transaminase levels. One patient in the ranitidine treatment group dropped out of the study because of a generalized urticarial rash; however, a causal relationship between drug and effect could not be established. The authors conclude that famotidine may be regarded as the best alternative to ranitidine in the treatment of duodenal ulcer.

Secretin (1 CU/Kg) plus Caerulein (100 ng/Kg) or Cholecystokinin (1 or 2 IvyU/Kg) were given by rapid intravenous injection (Schedule 1) or by continuous infusion (Schedule 2) to 63 control subjects (C) and 69 patients affected by chronic pancreatitis (CP). Duodenal juice was collected for two and four 30-minute periods in schedule 1 and schedule 2, respectively. Volume, bicarbonate, and enzyme content were measured. Secretin-Daerulein, by rapid intravenous injection, showed a strong overlapping between C and CP values and led to some side-effects. Secretin-Caerulein by continuous intravenous infusion gave almost identical results as the Secretin-Cholecystokinin.

A comparative evaluation of ERCP and the bicarbonate output 30 min after stimulation of the pancreas with secretin and cholecystokinin-pancreozymin, was carried out in 124 patients, of whom 65 were affected by proven chronic pancreatitis (PCP), and 59 by only suspected chronic pancreatitis (SCP). In PCP patients the false negative results were 14.7% and 21.5%, respectively. In 5 of the PCP patients with false negatives on ERCP and functional test a normal result of both the procedures was found. ERCP and bicarbonate output were found to be abnormal in 12% and 40%, respectively of 59 patients with SCP. In 30 SCP subjects both procedures gave a normal result, and only in two cases were results abnormal. A correct classification of the SCP patients with pathological bicarbonate secretion and normal ERCP seems quite impossible. The diagnostic usefulness of ERCP results is preeminent but the of carrying out both types of investigation together may give complementary information in the evaluation of pancreatic disorders.