Novel non-steroidal anti-inflammatory drugs: what we have learned from animal studies.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) is frequently associated with serious adverse effects related to the inhibition of cyclooxygenase (COX) in tissues where prostanoids exert physiological effects, such as gastric mucosal defence, renal homeostasis and platelet aggregation. The discovery of a second COX isoform (COX-2) specifically induced in pathological tissues led to the development of selective COX-2 inhibitors, believed to have an improved safety profile compared to traditional NSAIDs. Animal studies, however, have revealed a protective role for the COX-2 enzyme in the stomach, kidney, heart, vasculature and reproductive system, and therefore, the safety of COX-2 selective inhibitors needs to be reassessed. On the other hand, new therapeutic indications have emerged as a result of the role played by COX-2 overexpression in cancer or Alzheimer's disease. A second approach aimed at obtaining safer NSAIDs is based on the gastroprotective effects of nitric oxide (NO). Traditional NSAIDs chemically linked to NO-releasing moieties retain the therapeutic efficacy, but not the adverse effects, of the parent NSAIDs. Moreover, additional therapeutic applications in cardiovascular diseases, Alzheimer's disease and cancer have been suggested. Animal data, however, need to be confirmed in large clinical trials. Finally, the increase in endogenous NO via a selective increase in inducible NO synthase in the gastric mucosa is the mechanism underlying the good gastric tolerability and the gastroprotective effects of the non-selective NSAID amtolmetin guacyl, documented to date in the rat.

[Lansoprazole: an analysis of the clinical trials in the 3 years of 1997-1999]. / Lansoprazolo: analisi delle esperienze cliniche nel triennio 1997-1999.

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.

Randomised trial of single and repeated fibrin glue compared with injection of polidocanol in treatment of bleeding peptic ulcer.

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.

Chronic gastritis, intestinal metaplasia, dysplasia and Helicobacter pylori in gastric cancer: putting the pieces together.

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.

Treatment of gastroesophageal (acid) reflux with lansoprazole: an overview.

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.

Misoprostol prevents NSAID-induced gastroduodenal lesions in patients with osteoarthritis and rheumatoid arthritis.

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.

Effects of sucralfate and sulglycotide treatment on active gastritis and Helicobacter pylori colonization of the gastric mucosa in non-ulcer dyspepsia patients.

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.

Powerful gastric acid inhibition: when is it justified?

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.

Management of chronic pancreatitis. Focus on enzyme replacement therapy.

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.

Cisapride versus placebo in reflux esophagitis. A multicenter double-blind trial.

In a 6 to 12-week double-blind trial, the effect of cisapride (10 mg q.i.d.) was compared with that of placebo in 63 patients with esophagitis confirmed by endoscopy and/or biopsy. In only one patient (3%) in the cisapride group but in 43% of the placebo patients (p = 0.001), symptoms had not improved after 6 weeks. Forty patients continued treatment until week 12. At that time, control endoscopy showed a significantly (p = 0.005) higher rate of healing (no erosions, ulcers, or bleeding mucosa) in the cisapride patients (63%) than in the placebo patients (12%). At week 12, only three of the 21 cisapride patients still had moderate reflux symptoms, whereas eight of the 19 placebo patients had moderate or severe symptoms (p less than 0.05). Cisapride patients also took significantly (p less than 0.001) less antacids during the trial. These results show that cisapride, 10 mg q.i.d., heals esophagitis lesions and greatly reduces associated symptoms. The treatment was well tolerated.

Omeprazole vs. ranitidine in the short-term treatment of duodenal ulcer: an Italian multicenter study.

A double-blind, double-dummy, randomized Italian multicenter trial was carried out to compare the efficacy and safety of omeprazole 20 mg in the morning and ranitidine 150 mg b.i.d. in short-term treatment of acute duodenal ulcer. One hundred and twenty-one patients (61 in the omeprazole and 60 in the ranitidine group) with endoscopically proven active duodenal ulcer, completed the study. The healing rates after 2, 4 and 6 weeks were 66, 97 and 100%, respectively, with omeprazole and 53, 85 and 92%, respectively, with ranitidine. The difference was statistically significant (p less than 0.05) at weeks 4 and 6. Night and day pain were markedly reduced during both treatments, as also antacid consumption. Both drugs were well tolerated, and the adverse events were infrequent and moderate. In our experience, omeprazole 20 mg once daily seems to be superior to ranitidine 150 mg b.i.d. in the short-term treatment of duodenal ulcer.

Short-term treatment of reflux oesophagitis with ranitidine 300 mg nocte. Italian multicentre study.

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.

Comparison of once-daily bedtime administration of famotidine and ranitidine in the short-term treatment of duodenal ulcer. A multicenter, double-blind, controlled study.

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.

CA 19-9 assay in differential diagnosis of pancreatic carcinoma from inflammatory pancreatic diseases.

Levels of a new carbohydrate antigen CA 19-9, which is a monosialoganglioside identified by a monoclonal antibody raised against colorectal carcinoma cells, were compared to carcinoembryonic antigen and tissue polypeptide antigen assays in 250 sera from patients with different pancreatic diseases including acute pancreatitis, chronic pancreatitis, and pancreatic cancer. All three tumoral markers were elevated at the onset of an acute pancreatic attack in a few patients. All but five patients with chronic pancreatitis displayed normal levels with each of the three markers; in two of these five cases an extraintestinal cancer was later discovered. CA 19-9 displayed higher sensitivity and predictive value of a negative result than the other two markers. The best operational characteristic of CA 19-9 was its high predictive value for a positive test which suggests a "ruling in" usage of it for pancreatic cancer diagnosis. CA 19-9 assay was of extreme value in disclosing both localized and metastatic pancreatic cancer while the other two markers were more often positive in the latter case. Of 71 cancer patients with positive markers, only four would have escaped a right diagnosis by assaying CA 19-9 alone.

Prospective evaluation of the diagnostic efficacy of CA 19-9 assay as a marker for gastrointestinal cancers.

Levels of a new carbohydrate antigen, CA 19-9, which is a monosialoganglioside identified by a monoclonal antibody raised against colorectal carcinoma cells, were compared to conventional CEA assays in 615 sera from healthy controls, patients with benign gastrointestinal disorders, and patients with cancers of gastrointestinal or extragastrointestinal origin. Whereas CEA levels were higher in smokers, CA 19-9 values were independent of the smoking history. CA 19-9 was undetectable in lymphoma and myeloma patients, but some patients with extraintestinal epithelial cancers expressed this antigen in serum. For benign and malignant gastrointestinal diseases, CA 19-9 displayed higher sensitivity, specificity, and predictive values than CEA. CA 19-9 was elevated as frequently as CEA in patients with metastatic pancreatic cancer, but in patients with localized disease, CA 19-9 was elevated more often than was CEA. In colorectal cancer, patients with and without metastases were detected at similar rates by both assays. It is concluded that CA 19-9 is a marker of epithelial cancers, does not vary with the smoking status, and is superior to CEA in detecting gastrointestinal malignancies, especially those arising from the pancreatic gland.

Comparison of pirenzepine and carbenoxolone in the treatment of chronic gastric ulcer. A double-blind endoscopic trial.

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.