Anti-ulcer Therapy Research Articles

Antiulcer Therapy in Nsaid Gastropathy: A Rheumatologist's Perspective

Nonsteroidal anti-inflammatory drug (NSAID) gastropathy can now be recognized as an iatrogenic problem separate from classic acid peptic disease. Thus, the cost benefits of particular NSAID use is impacted by the hidden costs of common NSAID toxicity as well as gastroprotective measures necessary in those gastro-damaged by chronic NSAID use. Appropriate cytoprotective measures exist for serious gastropathy. A basis for selection of gastroprotective interventions also is available for that subset at greatest risk from continued, necessary NSAID therapy with associated potential putative consequences. Accepting this requires recognition that natural protective adaptation can fail in the face of such NSAID therapy and that the chronic gastric pathophysiology induced may be silent and ultimately catastrophic in outcome. Common symptomatic measures with H2 blockade antacid agents are contrasted with cytoprotective potential of prostaglandin analogs and sucralfate as potentially more specific responses.

Future Prospects for Anti-Ulcer Therapy: Acid Inhibitors versus Mucosal Protectives

Present histamine H2 antagonists together with omeprazole would appear to satisfy completely the range of medical needs for anti-secretory drugs. With the possible exception of gastrin antagonists, future developments in anti-secretory therapy are likely to present marketing rather than scientific challenges. The mechanism of action of protective drugs is largely unknown, so that no rationale exists on which to base the search for improved compounds in this category. Indeed, much of the clinical attraction for this approach has disappeared as a result of the disappointing clinical performance of prostaglandin analogues. Anti-secretory therapy is likely to dominate the anti-ulcer market, although protective drugs could assume importance in the event of long-term toxicity problems occurring in man, comparable to those found during animal carcinogenicity tests with potent, long-acting inhibitors. Opportunity exists in the future for the development of agents that act by increasing wound healing, since the qu...

Prostaglandins, H2-receptor antagonists and peptic ulcer disease.

Peptic ulcer develops when offensive factors overwhelm defensive processes in the gastroduodenal mucosa. Offensive factors include NSAIDs, hydrochloric acid-peptic activity, bile reflux, and some products of the lipoxygenase pathway such as leukotriene B4; whereas defensive processes are largely mediated by prostaglandins through poorly understood mechanisms uniformly termed cytoprotection. Cytoprotection, a physiological process working through the products of arachidonic acid metabolism, may result from the net effect of the protective actions of prostaglandins versus the damaging actions of leukotrienes. Some prostaglandins also have antisecretory effects. Therefore the peptic ulcer healing effects of prostaglandin analogues, all of which have significant antisecretory activity, may be more due to their antisecretory effects than primarily to their effects on mucosal defences. Certain drug-induced gastroduodenal lesions, e.g. NSAID-induced ulcers, which are often unresponsive to H2-receptor antagonists, have been healed and their recurrence prevented by the use of PGE1 and PGE2 analogues. All the prostaglandin analogues investigated to date in humans have the potential for inducing abortion, an important side effect which may limit their worldwide use. The optimal prostaglandin analogue for ulcer healing should not induce abortion and should be potently cytoprotective. The predominant damaging agent in the development of peptic ulcer disease is gastric hydrochloric acid. Thus, the worldwide established efficacy and safety of H2-receptor antagonists such as cimetidine, ranitidine, famotidine and most recently of roxatidine acetate suggest that these agents have become the standard by which other forms of anti-ulcer therapy should be judged.

…but protective agents have an important role in antiulcer therapy

…but protective agents have an important role in antiulcer therapy

The role of eicosanoids in the gastrointestinal tract.

Exploring the role of eicosanoids in the gastrointestinal tract entails fundamental problems of methodology and interpretation. Most important are the difficulties inherent in the choice of an experimental design which prevents non-specific stimulation of eicosanoid formation, because any perturbation of cell membranes will initiate eicosanoid synthesis. In addition to cyclic nucleotides, prostaglandins may serve as intracellular mediators for the stimulus of secretion coupling via intracellular free calcium in the gastrointestinal epithelial cells. By contrast, the effects of supraphysiological doses of prostaglandins parallel those of cyclic AMP-dependent secretagogues such as VIP, which increases calcium through activation of the mucosal adenylatecyclase. The question of whether patients develop gastric or duodenal ulcers as a result of a prostaglandin deficiency remains open. The synthetic prostaglandin analogues available commercially for anti-ulcer therapy appear to be unable to accelerate the healing of peptic ulcers unless they are administered in anti-secretory doses, and are unlikely to have a substantial effect on patients with bleeding from ulcerative lesions in the gastro-duodenal mucosa. Prostaglandins of the E type mediate, at least partly, the diarrhoea associated with a large number of clinical conditions and various pharmacological agents. Several types of secretory diarrhoea respond to drugs that inhibit prostaglandin biosynthesis. Whether eicosanoids are mediators, or merely epiphenomena, of inflammation in ulcerative colitis and Crohn's disease remains unclear. Improved knowledge of their functional role of eicosanoids has nevertheless allowed a reinterpretation of the rationale behind current therapy. Uncontrolled formation of eicosanoids may not only be the source of diarrhoea in colonic inflammation, but may also be critical for cell proliferation and the development of dysplasia in long-standing disease.

Enhanced Bleeding With Cefoxitin or Moxalactam

Most cases of beta-lactam-associated coagulopathy occur in patients with other risk factors. This study analyzed temporally related clinical bleeding events in 1493 patients who received one antibiotic for at least three days. Univariate and multivariate analyses controlled for condition variables (nutritional status, renal, hepatic, or hematologic dysfunction, intensive care unit stay) and treatment variables (use of antiplatelet agents, anticoagulants, vitamin K, antitumor chemotherapy or antiulcer therapy, steroids) that could have been associated with bleeding independently. Rates of bleeding ranged from 0% (chloramphenicol sodium succinate, vancomycin hydrochloride, erythromycin lactobionate) to 8.2% (cefoxitin) to 22.2% (moxalactam disodium). Multiple logistic regression analyses revealed that only moxalactam (odds ratio, 9.9) and cefoxitin (odds ratio, 2.1) exhibited significantly higher likelihoods of bleeding than other agents. This study statistically confirms increased risk of bleeding with moxalactam, heretofore reported only anecdotally. Cefoxitin may carry risks greater than previously believed.

Anti-ulcer therapy. Past to present.

Until 1950 the clinical treatment of peptic ulcer disease relied on dieting and antacids. However, recent controlled studies suggest that the natural course of peptic ulcer disease is not affected by diet. Antacids are primarily used to relieve distress, although high- and low-dose antacid regimens have been reported to promote duodenal ulcer healing. Initial favorable reports following the introduction of synthetic anticholinergic drugs have not been confirmed. Pirenzepine is an anticholinergic compound with a specific action on the muscarinic receptors of the parietal cells. Although pirenzepine appears effective in peptic ulcer, the results obtained in different centers have not been uniform. Sucralfate and tripotassium dicitrato bismuthate both act locally by coating the ulcer crater, the latter agent also liberating prostaglandins. Most prospective studies suggest that both drugs are effective when compared with placebo. Carbenoxolone heals 70% of gastric ulcers but is less effective against duodenal ulcers, and has a high incidence of side-effects. Treatment of peptic ulcer in the 1980s has been dominated by the advent of the H2-blockers, cimetidine and ranitidine. Peptic ulcer healing rates are similar with both drugs, and the main problem is how often and how much should be given in order to provide acceptable healing and to prevent ulcer recurrence. Other H2-blockers are being tested and they may be more effective either by healing more ulcers or healing them earlier. The clinical treatment of peptic ulcers will in future be advanced by the addition of two new classes of drugs, the prostaglandins and the benzimidazole derivatives, which are currently being investigated and appear extremely promising.

Gastric acid secretion and gastrin production in the short bowel syndrome.

Excess gastric acid secretion and gastrin production may occur in patients with the short bowel syndrome but the two measurements have never been made simultaneously in man in response to a food stimulus. Using the technique of intragastric titration, this was carried out in eight patients after extensive small bowel resection resulting mainly from vascular occlusion and in eight matched normal control subjects. Basal acid output and peak acid output in response to pentagastrin was also measured separately. Although peak and integrated serum gastrin concentrations were significantly greater in patients (450 +/- SE 109 pg/ml; 113 +/- 2.9X10(-3) pg/ml/min) compared with control subjects (174 +/- 98 pg/ml; 6.1 +/- 2.0X10(-3) pg/ml/min p less than 0.05), no concomitant increase in acid secretion was shown either during intragastric titration or in response to pentagastrin. These findings indicate that there is no rationale for treating these patients with long term anti-ulcer therapy.

Moderate reduction of gastric acid secretion in the treatment of peptic ulcer disease.

Duodenal ulceration is presumed to be induced and maintained by imbalance between aggressive and defensive factors. Development of drugs for correction of this imbalance has recently concentrated on maximum inhibition of acid secretion e.g. via H2-receptor antagonists but has led to re-evaluation of antacids and antimuscarinics. It has been shown that about the same percentage of ulcers can be healed using low antacid doses or antimuscarinics (e.g. pirenzepine) or doses of H2-receptor antagonists which do not inhibit acid secretion maximally as can be healed using higher doses of H2-receptor antagonists. Avoidance of the intragastric bacterial overgrowth and its consequences and the disturbance of the acid-gastrin feedback mechanism which may follow maximum gastric acid suppression could provide a rationale for use of anti-ulcer therapy based on moderate reduction of gastric acid secretion.

A study of the inhibitory effects of SCH 28080 on gastric secretion in man.

1 SCH 28080 (2-methyl-8-(phenyl methoxy) imidazo-(1-2-a) pyrine-3-acetonitrile) is a novel drug unrelated to existing anti-ulcer agents. 2 The effect of placebo and increasing doses of the drug on gastric acid output and peptic activity was examined in four healthy men, in the resting state and following pentagastrin stimulation. 3 Significant inhibition of gastric acid secretion and peptic activity occurred with the 50 mg dose in both the stimulated and unstimulated states. Approximately 90% inhibition of acid output was achieved with the 200 mg dose. 4 Antisecretory activity of SCH 28080 is confirmed in man. This drug or an analogue may have potential in anti-ulcer therapy.

Tracheostomy for Acute Respiratory Failure

The effects of tracheostomy were evaluated in 17 patients moribund due to severe respiratory failure. When tracheostomy was added to the previous therapy, which included intermittent positive pressure breathing, there was dramatic improvement in their condition. This is attributed to the more effective application of ventilatory assistance, the improved clearing of the airway, and the decrease in dead space ventilation. Earlier tracheostomy would have been advantageous in several instances. Thirteen of these patients were discharged from the hospital, and restored to their previous level of respiratory competence. Eight have survived without need for continuing ventilatory assistance for periods up to 64 months at the time of this report. Mortality was considerably higher in five others on whom tracheostomy was refused and in 12 who did not have detailed respiratory management postoperatively. The common complications of tracheostomy are largely preventable. Cardiac arrhythmia during tracheostomy and during the period of correction of blood gas levels is an insufficiently recognized cause of morbidity and mortality. Apparatus that fully controls ventilation may produce unduly rapid carbon dioxide washout and necessitates careful observation of the arterial blood carbon dioxide tension, pH, blood electrolytes and electrocardiogram. Death due to massive hemorrhage secondary to peptic ulcers occurred in two of our patients. Thus, it would seem advisable to prescribe anti-ulcer therapy in patients with respiratory failure. Severe chronic pulmonary insufficiency may require permanent tracheostomy.

Peptic esophagitis with duodenal ulcer

This disease is apparently one that afflicts men in the older age groups. In the group under consideration, duodenal ulcer or gastric ulcer (and in one case a previous peptic ulcer of the esophagus) were constantly associated. From this feature, the location of the lesion in the lower third of the esophagus and the hyperchlorhydria in most cases, the conclusion seems inescapable that this disease is peptic in origin. The response to medical and surgical antiulcer therapy is striking. What the ultimate, detailed mechanism of peptic esophagitis is seems purely conjectural at present. Reflux may result from the hypersecretion associated with duodenal ulcer or from an unexplained decrease in the tone of the cardial sphincter. Perhaps the characteristic nocturnal hypersecretion with the patient in the horizontal position leads to a prolonged bathing of the lower esophagus by the highly acid gastric contents. As a result, localized peptic esophagitis occurs in the lower esophagus with a spastic narrowing. The disease is characterized by a long history of duodenal or gastric ulcer with a subsequent shorter history of esophageal symptoms. The chief symptoms are dysphagia, heartburn, regurgitation, substernal pain and loss of weight. The complications are stenosis, hemorrhage and perforation. There is no evidence that this is a precancerous disease. The response to medical therapy and mechanical dilatation is usually good. In a small percentage of the patients, surgical therapy is necessary. This condition is important not only as a disease entity but also in the differential diagnosis from carcinoma of the lower end of the esophagus.