Denis M. McCarthy

Nonsteroidal Anti-inflammatory Drugs and Peptic Ulcer Disease

Evidence has accumulated that nonsteroidal anti-inflammatory drugs (NSAIDs) cause clinically important gastroduodenal ulcers. The pathogenesis, which involves the impairment of mucosal resistance to injury in an acid-peptic environment, is multifactorial and controversial. Ulcers caused by NSAIDs can occur either in mucosa inflamed because of infection with Helicobacter pylori or in histologically normal mucosa. The use of these drugs has been linked to an unexpectedly high incidence of ulcer complications, and a history of peptic ulcer disease is common in such cases. Nonsteroidal anti-inflammatory drugs thus appear both to exacerbate an underlying peptic diathesis and to cause de novo ulcers. The association between the use of these drugs and ulcer complications is supported by ulcer prevalence data from cross-sectional studies, and by data from case-controlled and cohort studies, and from randomized, experimental trials. Drug-induced gastric ulcers have been prevented by misoprostol, but not by H2 blocker therapy. Several therapies have been reported to promote ulcer healing despite continued use of NSAIDs, but adequate controlled trials have not been done. Small gastric and duodenal ulcers readily heal, whereas larger gastric ulcers require vigorous and prolonged therapy. The relative efficacies of various therapies in preventing ulcers, healing ulcers, or preventing complications remain to be established.

Secretin and Calcium Provocative Tests in the Zollinger-Ellison Syndrome: A Prospective Study

STUDY OBJECTIVE To evaluate criteria of positivity for and usefulness of both the secretin and calcium gastrin-provocative tests in patients with the Zollinger-Ellison syndrome. DESIGN Prospective trial in consecutive patients. SETTING Referrals to a clinical research center. PATIENTS Consecutive sample of 80 patients with the Zollinger-Ellison syndrome. INTERVENTION Kabi-secretin (2 U/kg body weight) given by intravenous bolus and calcium gluconate (10%) (54 mg/kg.h [5 mg/kg.h of calcium]) given by continuous intravenous infusion for 3 hours. Serum gastrin measured at -15, and -1 minutes before, and 2, 5, 10, 15, 20, and 30 minutes after secretin, or every 30 minutes for 3 hours during the calcium infusion. Serum calcium and serum gastrin were measured simultaneously during the calcium infusion. MEASUREMENTS AND MAIN RESULTS There was no significant difference in the responses of patients with different extents or locations of the tumor, presence or absence of multiple endocrine neoplasia, type-I, or with fasting gastrin less than or greater than 1000 pg/mL. In patients with fasting gastrin of less than 1000 pg/mL, the sensitivity of the secretin test using the criterion of an increase in gastrin of at least 110 pg/mL was 93% (CI, 76% to 99%) and for an increase of 200 pg/mL it was 85% (CI, 66% to 96%), (P greater than 0.05). With the calcium infusion test, the sensitivity using the criterion of an increase of 395 pg/mL was 43%, (CI, 23% to 66%) and for an increase of 50% was 74% (CI, 52% to 90%), (P less than 0.01). The calcium infusion test was positive in 33% of patients with a negative secretin test. With the secretin test, 75% of patients had a positive response by 5 minutes, 95% by 10 minutes, 100% by 15 minutes, and 6% only at 2 minutes. With calcium infusion, patients had positive responses at 120 to 180 minutes. CONCLUSIONS The secretin test is preferred over the calcium test because of its greater sensitivity and simplicity. The recommended criteria are a 200 pg/mL increase for the secretin test and a 395 pg/mL increase for the calcium test. The calcium test should be reserved for patients having a negative secretin test, gastric acid hypersecretion, and a strong clinical suspicion of the Zollinger-Ellison syndrome.

Lansoprazole treatment of patients with chronic idiopathic laryngitis: a placebo-controlled trial

OBJECTIVE:Previous uncontrolled studies suggested a therapeutic benefit for treating gastroesophageal reflux disease (GERD) among patients with laryngitis. The present study is the first randomized, placebo-controlled, double-blind study of gastric acid suppression among patients with laryngitis in the United States.METHODS:Patients diagnosed with idiopathic chronic laryngitis were randomized to receive either lansoprazole 30 mg p.o. b.i.d. or a matching placebo for 3 months. Before randomization, all patients underwent upper endoscopy, dual probe ambulatory 24-h esophageal pH-metry, and laryngoscopy, as well as completing a symptom questionnaire for GERD and laryngitis. The primary outcome of treatment was the complete resolution of laryngeal symptoms.RESULTS:A total of 22 patients with symptoms and signs of chronic laryngitis were enrolled, 20 of whom completed the study. At baseline, there were no significant differences between the two groups with regards to GERD symptoms, erosive esophagitis, proximal and distal esophageal pH-metry, or laryngeal signs and symptoms. In an intention-to-treat analysis, six patients in the lansoprazole group (50%) and only one patient (10%) in the placebo group achieved a complete symptomatic response, p = 0.04. Apart from receiving lansoprazole, there were no significant differences between responders and nonresponders in any of baseline esophageal or laryngeal signs and symptoms.CONCLUSIONS:Empirical treatment with lansoprazole is efficacious in relieving symptoms of laryngitis compared to placebo. Such treatment can be considered as a first-line option in managing patients with idiopathic chronic laryngitis.

Nonsteroidal Antiinflammatory Drug-Induced Ulcers: Management by Traditional Therapies

Endoscopic distinction between ulcers and erosions is difficult. Consequently, existing literature, which must be taken at face value, may be misleading. Nevertheless, from published studies most gastric and duodenal ulcers associated with nonsteroidal antiinflammatory drugs appear to heal on antacids or H2-antagonists. Sucralfate appears useful for duodenal but not gastric ulcers. Continuing nonsteroidal antiinflammatory drugs does not prevent or delay healing of duodenal or small gastric ulcers; their effects on large gastric ulcers remain uncertain. Thus far, only full doses of H2-antagonists, or their combinations with antacids, have been shown to heal ulcers and prevent recurrences. Ulcer recurrences and complications have occurred in small numbers of patients on maintenance doses of H2-antagonists. Available antiulcer drugs (antacids, H2-antagonists, sucralfate) reduce severe acute injury when taken before or with nonsteroidal antiinflammatory drugs. They also reduce ulcerlike symptoms due to nonsteroidal antiinflammatory drugs. Inexplicably, chronic prophylaxis with H2-antagonists for 4 wk or more appears ineffective in preventing gastric ulcers, although duodenal injury is reduced. As the efficacy of available prophylactic therapy (H2-antagonists, sucralfate, and antacids) has not been established, routine use in all cases seems unjustified at present.

Colonoscopy after golytely preparation in acute rectal bleeding

Thirty-five consecutive patients with acute hematochezia, negative gastric aspirates, and negative sigmoidoscopy underwent urgent colonoscopy after Golytely purgation. Mucosal visualization was excellent. Colonic bleeding lesions were identified in 24 of 35 patients, and hemorrhage originating proximal to the ileoceal valve was documented in three of these 35 patients. Therapeutic endoscopic electrocautery, employed in 12 of 35 patients, was effective in 11. The peroral preparation was well tolerated, and there were no complications of the preparation or of colonoscopy. The data suggest that urgent colonoscopy following Golytely purgation is a safe, sensitive, and specific diagnostic procedure that provides an opportunity for early nonoperative treatment of acute colonic hemorrhage.

Adverse effects of proton pump inhibitor drugs: clues and conclusions

Purpose of review To review evidence relating to the strength of associations that have appeared in largely observational studies, between high-dose or long-term use of proton pump inhibitor drugs and certain possibly attributable side-effects, which emerge from studies confounded by other variables. In retrospective studies not designed to assess safety, evidence of causality is generally lacking. Recent findings The associations of fractures of hip, wrist, forearm and other sites appear weak and only slightly higher than the risks in control populations matched for age. They may increase with drug exposure, but probably do so only in individuals in whom other risk factors are also operational (smoking, alcohol, poor nutrition, steroids, etc.). The risks of Clostridium difficile colitis, other enteric infections, small bowel bacterial overgrowth and possibly spontaneous bacterial peritonitis also appear increased. Impaired gastric secretion may adversely affect the absorption of various nutrients, but their clinical impact is ill defined. Potentially more important are the consequences of hypergastrinemia, including rebound hypersecretion of acid, and possible development of various cancers, including carcinoid tumors. Effects of other drugs, including clopidogrel, on metabolism are reviewed, but clouded by uncertainties. Summary The safety of long-term PPI administration needs serious prospective study.

Nonsteroidal Anti-inflammatory Drug-Related Gastrointestinal Toxicity: Definitions and Epidemiology

Nonsteroidal anti-inflammatory drug (NSAID)-associated gastrointestinal (GI) toxicity is a broad topic encompassing symptoms as well as severe GI complications. GI bleeding and perforation are the 2 overlapping components that account for the majority of deaths and disability associated with these drugs. Abnormal gastric endoscopic profiles as well as symptoms such as heartburn, pain, and dyspepsia are common in NSAID users, but no correlation has been found between these factors and the occurrence of the more severe complications; therefore, neither symptoms nor endoscopic observations can necessarily be considered reliable predictors of future outcomes. Confounding factors can increase the risk of complications, and specific NSAIDs vary in the magnitude and type of risk attending their use. Recent studies have focused on the contribution of nonprescription NSAIDs to total complications, and combined with evidence suggesting that the risk is greatest during the first month of NSAID use, it is apparent that NSAID toxicity is an acute as well as a chronic problem.

H2-Histamine Receptor Blocking Agents in the Zollinger-Ellison Syndrome: Experience in Seven Cases and Implications for Long-Term Therapy

H2-Histamine receptor blocking agents metiamide and cimetidine were assessed in seven patients with Zollinger-Ellison syndrome (serum gastrin greater than 300 microgram/ml, basal acid output greater than 15 meq/h, ratio of basal acid output to maximal acid output greater than 0.5). Intravenous or oral administration of the drugs lowered acid secretion by at least 70% in all cases. Subsequent treatment of six patients for 3 to 15 months (oral therapy) and one patient for 1 month (intravenous therapy) showed that the drugs abolished symptoms in all seven, abolished diarrhea in five, allowed ulcer healing in six, and were well tolerated without adverse effects in seven. No patient failed to respond to the drug, although one died from tumor progression and two required total gastrectomy for complex reasons. The results indicate that patients with Zollinger-Ellison syndrome can be managed medically and, in light of current mortality trends, gain little from the extra risks attending total gastrectomy.

GERD 2003 - A Consensus on the Way Ahead

Gastroesophageal reflux disease (GERD) has in recent times become an important public health issue owing to the considerable health care resources utilized in its management, its deleterious effect on quality of life and the increasing prevalence of a relatively rare complication of reflux disease – esophageal adenocarcinoma. We review here the major current challenges in the field of reflux disease and its complications, and provide some approaches that may be useful in management. The issues to be faced include the very limited comprehension of the reasons behind the increasing prevalence of the disease, difficulties in correlating symptoms with objective data of pathological gastroesophageal reflux and the relatively unsophisticated tools we are employing to investigate the underlying pathophysiology. It is certain that the lack of well-defined and characterized methodologies to compare the effects of therapy require the development of more effective questionnaire-type analytic tools. In regard to treatment, there is little doubt that the widely prescribed proton pump inhibitors have dose-equivalent efficacy and are the most highly effective agents capable of suppressing acid, controlling many of the symptoms of GERD and healing erosions. Nevertheless, many patients continue to experience symptoms on withdrawal or at night. Pharmacological agents that can effectively increase lower esophageal sphincter pressure or promote motility are as yet unavailable. Although the introduction of laparoscopic techniques has resulted in a modest revival in surgical intervention using a variety of ‘wrap-type’ operations, the indications are few and the procedure is associated with a significant morbidity and even mortality especially if the expertise of the surgeon is an issue. Endoscopic techniques of regulating reflux are at this time experimental and not applicable to the general population. Intestinal metaplasia in the lower esophagus is probably very common. Whether and how to, first, screen for, and then, perform surveillance in Barrett’s esophagus remains highly problematic and contentious.

Healing of peptic ulcers during continuing anti-inflammatory drug therapy in rheumatoid arthritis.

To evaluate the effect of anti-inflammatory drug therapy on ulcer healing, we studied retrospectively patient records listing the dual diagnoses of rheumatoid arthritis and peptic ulcer (1953-1975). Forty-three ulcers (23 gastric and 20 duodenal) occurred in 41 subjects. Evaluation of ulcer healing was possible in 35 patients, 27 of whom had continued on anti-inflammatory drug therapy while being treated for ulcer disease and eight who did not. In 21 of the 27 patients the ulcer healed; in six the ulcer failed to heal, including one who died from gastric carcinoma. Fourteen of the 21 patients whose ulcer healed were taking both aspirin and corticosteroids; in all eight patients who stopped taking anti-inflammatory drugs, the ulcers (eight gastric, one duodenal) healed. In six patients no evaluating was possible because the outcome of ulcer therapy was unknown. The numbers of patients not studied, unlisted or unretrieved are unknown, though probably small, and while no data are available on controls drawn from the same population or on the rates of spontaneous ulcer healing and recurrence in this population, our study nevertheless establishes that ulcer healing does occur in many patients with rheumatoid arthritis despite continued treatment with salicylate, corticosteroid, or other anti-inflammatory drugs.