Am J Med

Constitutional symptoms and health-related quality of life in patients with symptomatic HIV disease.

Year 1998
Cunningham WE. Shapiro MF. Hays RD. Dixon WJ. Visscher BR. George WL. Ettl MK. Beck CK.
Department of Medicine, University of California at Los Angeles, USA.
PURPOSE: To assess the severity of constitutional symptoms in persons with human immunodeficiency virus (HIV) infection, and their relationship to health-related quality of life (HRQOL). PATIENTS AND METHODS: Two hundred five HIV-infected patients (93% male, 26% African American, 28% Latino, 39% white, 7% other ethnicity) with diarrhea, fever, or weight loss were studied at a county hospital and a Veterans Administration hospital in southern California. Consenting subjects were administered a battery that included 11 scales measuring various aspects of health-related quality of life and detailed questions about six constitutional symptoms or symptom complexes (myalgias, exhaustion, anorexia/nausea/vomiting, night sweats, fever, and weight loss) as well as about other manifestations of HIV disease. RESULTS: Constitutional symptoms except weight loss were all strongly related to all measures of quality of life. On 0 (worst) to 100 (best) point scales, mean scores ranged from 34 (for individuals having all five symptoms other than weight loss) to 78 (for those with none) for physical function, 43 to 79 for emotional well-being, and 36 to 73 for social function. Adjustment for helper T-lymphocyte counts, duration of illness, and demographic characteristics did not diminish these associations. CONCLUSION: The presence, number, and severity of constitutional symptoms in HIV disease is strongly related to health-related quality of life in symptomatic HIV-infected individuals. Identifying and treating these very common symptoms has the potential to improve quality of life in these patients.

The impact of gastroesophageal reflux disease on health-related quality of life.

Year 1998
Revicki DA. Wood M. Maton PN. Sorensen S.
MEDTAP International, Inc., Bethesda, Maryland 20814, USA.
BACKGROUND: Gastroesophageal reflux disease (GERD) affects health-related quality of life. METHODS: We enrolled 533 adults with a history of heartburn symptoms for at least 6 months of moderate to severe heartburn in 4 of the 7 days before study entry. Patients were treated with ranitidine 150 mg twice a day for 6 weeks and Gelusil antacid tablets as needed. We measured physician-rated symptoms and the Medical Outcomes Study short-form 36 (SF-36) Health Survey at baseline and after 6 weeks of treatment. Baseline results were compared with normative data for the US population and for patients with selected chronic diseases. Treatment response was defined as no episode of moderate to severe heartburn for 7 days. Statistical significance was set at P

Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs.

Year 1998
Cryer B. Feldman M.
Department of Medicine, Dallas Department of Veterans Affairs Medical Center, Texas 75216, USA.
PURPOSE: Both isoforms of cyclo-oxygenase, COX-1 and COX-2, are inhibited to varying degrees by all of the available nonsteroidal anti-inflammatory drugs (NSAIDs). Because inhibition of COX-1 by NSAIDs is linked to gastrointestinal ulcer formation, those drugs that selectively inhibit COX-2 may have less gastrointestinal toxicity. We measured the extent to which NSAIDs and other anti-inflammatory or analgesic drugs inhibit COX-1 and COX-2 in humans. SUBJECTS AND METHODS: Aliquots of whole blood from 16 healthy volunteers were incubated ex vivo with 25 antiinflammatory or analgesic drugs at six concentrations ranging from 0 (control) to 100 microM (n = 5 for each). Blood was assayed for serum-generated thromboxane B2 synthesis (COX-1 assay) and for lipopolysaccharide-stimulated prostaglandin E2 synthesis (COX-2 assay). In addition, gastric biopsies from the same volunteers were incubated with each drug ex vivo and mucosal prostaglandin E2 synthesis measured. RESULTS: Inhibitory potency and selectivity of NSAIDs for COX-1 and COX-2 activity in blood varied greatly. Some NSAIDs (eg, flurbiprofen, ketoprofen) were COX-1 selective, some (eg, ibuprofen, naproxen) were essentially nonselective, while others (eg, diclofenac, mefenamic acid) were COX-2 selective. Inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated with COX-1 inhibitory potency in blood (P < 0.001) and with COX-1 selectivity (P < 0.01), but not with COX-2 inhibitory potency. Even COX-2 "selective" NSAIDs still had sufficient COX-1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo. CONCLUSION: No currently marketed NSAID, even those that are COX-2 selective, spare gastric COX activity at therapeutic concentrations. Thus, all NSAIDs should be used cautiously until safer agents are developed.

Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome.

Year 1998
Termanini B. Gibril F. Sutliff VE. Yu F. Venzon DJ. Jensen RT.
Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
BACKGROUND AND AIMS: Long-term treatment with H(+)-K(+)-adenotriphosphatase (ATPase) inhibitors, such as omeprazole or lansoprazole, for severe gastroesophageal reflux disease is now widely used. Whether such treatment will result in vitamin B12 deficiency is controversial. We studied whether long-term treatment with omeprazole alters serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. METHODS: In 131 consecutive patients treated with either omeprazole (n = 111) or histamine H2-receptor antagonists (n = 20), serum vitamin B12 and folate levels and complete blood counts were determined after acid secretion had been controlled for at least 6 months. These studies were repeated yearly. Serum vitamin B12 and folate levels were correlated with the type of antisecretory drug and the extent of inhibition of acid secretion. RESULTS: The mean duration of omeprazole treatment was 4.5 years, and for H2-receptor antagonists 10 years. Vitamin B12 levels, but not serum folate levels or any hematological parameter, were significantly (P = 0.03) lower in patients treated with omeprazole, especially those with omeprazole-induced sustained hyposecretion (P = 0.0014) or complete achlorhydria (P < 0.0001). In 68 patients with two determinations at least 5 years apart, vitamin B12 levels decreased significantly (30%; P = 0.001) only in patients rendered achlorhydric. The duration of omeprazole treatment was inversely correlated with vitamin B12 levels (P = 0.013), but not folate levels. Eight patients (6%) developed subnormal B12 levels during follow-up. CONCLUSIONS: Long-term omeprazole treatment leads to significant decreases in serum vitamin B12 but not folate levels. These results suggest patients with Zollinger-Ellison syndrome treated with H(+)-K(+)-ATPase inhibitors should have serum vitamin B12 levels monitored. Furthermore, these results raise the possibility that other patients treated chronically with H(+)-K(+)-ATPase inhibitors may develop B12 deficiency.

Epidemiology of nonsteroidal anti-inflammatory drug-associated gastrointestinal injury.

Year 1998
Griffin MR.
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Nonaspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently used drugs in many countries. Use of the majority of NSAIDs increases with age, primarily for symptoms associated with osteoarthritis and other chronic musculoskeletal conditions. Population-based studies have shown that, on any given day, 10-20% of elderly people (> or = 65 years old) have a current or recent NSAID prescription. Over a 6-month period in Alberta, Canada, 27% of elderly people were prescribed NSAIDs. Furthermore, in Tennessee (USA), 40% of elderly people received at least one NSAID prescription annually, and 6% had NSAID prescriptions for > 75% of the year. NSAIDs cause a wide variety of side-effects. The most clinically important side-effects are upper gastrointestinal tract dyspepsia, peptic ulceration, hemorrhage, and perforation, leading to death in some patients. Gastrointestinal side-effects are common; the most common NSAID-associated side-effect is epigastric pain/indigestion. Gastrointestinal side-effects are also a frequent reason both for withdrawal of NSAIDs and for co-treatment with another drug. Indeed, in two population-based studies of people aged > or = 65 years, the use of agents to prevent peptic ulcers or relieve dyspepsia was nearly twice as common in regular NSAID users (20-26%) than in non-NSAID users (11%). In Alberta, Canada, it has been estimated that NSAID use accounts for 28% of all prescriptions for anti-ulcer drugs in people aged at least 65 years. Many studies have now shown that NSAIDs increase the risk of peptic ulcer complications by 3-5-fold, and in several different populations it has been estimated that 15-35% of all peptic ulcer complications are due to NSAIDs. In the United States alone, there are an estimated 41,000 hospitalizations and 3,300 deaths each year among the elderly that are associated with NSAIDs. Factors that increase the risk of serious peptic ulcer disease include older age, history of peptic ulcer disease, gastrointestinal hemorrhage, dyspepsia, and/or previous NSAID intolerance, as well as several measures of poor health.

Variability in risk of gastrointestinal complications with different nonsteroidal anti-inflammatory drugs.

Year 1998
Garcia Rodriguez LA.
Centro Espanol de Investigacion Farmacoepidemiologica, Universidad Complutense de Madrid, Spain.
Exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) is known to increase substantially the risk of upper gastrointestinal bleeding and/or perforation. A meta-analysis of the available epidemiologic studies has shown that there are wide differences between individual drugs in the risk of inducing gastrointestinal complications. Of the NSAIDs in common use, ibuprofen and diclofenac were found to be associated with the lowest relative risk; indomethacin, naproxen, sulindac, and aspirin were associated with intermediate risk; and azapropazone, tolmetin, ketoprofen, and piroxicam were associated with higher risk. Some of these apparent differences in toxicity may, however, be dose related. The low risk of gastrointestinal complications associated with ibuprofen appears to be attributable to the low doses that are prescribed routinely in clinical practice. Higher doses of ibuprofen were associated with relative risks similar to those of naproxen and indomethacin. Thus, as first-line treatment, patients should be prescribed the lowest effective dose of an NSAID that appears to be associated with a comparatively low risk. This should substantially reduce the morbidity and mortality from serious gastrointestinal complications that are associated with the use of these drugs.

Does Helicobacter pylori status affect nonsteroidal anti-inflammatory drug-associated gastroduodenal pathology?

Year 1998
Malfertheiner P. Labenz J.
Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University of Magdeburg, Germany.
There are two lines of thought regarding the interrelationship between the damaging effects of Helicobacter pylori and those of nonsteroidal anti-inflammatory drugs (NSAIDs) on the gastroduodenal mucosa. First, both pathogenic factors exert a damaging effect on the mucosa, and therefore an additive, or even synergistic, effect occurs, leading to aggravation of mucosal damage. Second, mutual antagonism exists, leading to one of the pathogenic factors actually deriving some protection from the damaging potential of the other. Microscopically, H. pylori- and NSAID-associated gastritis are recognized as two separate entities. Furthermore, pathologically, the mechanisms of mucosal damage of the two factors have important differences; for example, H. pylori increases the synthesis of prostaglandins, whereas NSAIDs inhibit prostaglandin synthesis. The role of H. pylori infection in patients with NSAID-associated peptic ulcers has been addressed recently in two large, randomized, multicenter trials. From these studies, it appears that antisecretory drugs are more effective in H. pylori-positive peptic ulcer patients taking NSAIDs than in H. pylori-negative patients taking these drugs. The studies, however, do not provide any evidence that H. pylori infection reduces the pathogenic effects of NSAIDs. Other studies, however, have shown protection against NSAID-associated gastroduodenal damage in H. pylori-negative patients. Thus, there are no firm conclusions on the role of H. pylori infection in patients with NSAID-associated peptic ulcers. Based on the available data, however, practical considerations and guidelines are listed.

Mechanisms of ulcer healing and effects of nonsteroidal anti-inflammatory drugs.

Year 1998
Schmassmann A.
Gastrointestinal Unit, Inselpital, University Hospital, Bern, Switzerland.
Ulceration of the gastroduodenal mucosa occurs frequently in humans, particularly in patients with a history of peptic ulcer disease. In order for healing to occur, mucosal damage stimulates secretion of growth factors in the adjacent mucosa and ulcer bed. Peptic ulcer healing is accomplished by the filling of the mucosal defect with cells that migrate from the ulcer margin and by connective tissue, including microvessels originating from granulation tissue. Peptic ulcer healing is accelerated both in humans and experimental models by gastric acid inhibition, which enhances cell migration and maturation of the granulation tissue. In experimental models, peptic ulcer healing can also be accelerated by oral administration of basic fibroblast growth factor, which increases angiogenesis in the ulcer bed, or by nitric oxide-releasing compounds, which improve gastric blood flow. Clinical and experimental data indicate that traditional nonsteroidal anti-inflammatory drugs (NSAIDs) delay the healing of peptic ulcers by interfering with the action of growth factors, decreasing epithelial cell proliferation in the ulcer margin, decreasing angiogenesis in the ulcer bed, and slowing maturation of the granulation tissue. In order to reduce the gastroduodenal side-effects of NSAIDs, selective cyclo-oxygenase (COX)-2 inhibitors have been developed, which inhibit the inducible COX-2 isoform in inflammatory tissue but have only limited effect on the constitutive COX-1 isoform in the stomach. It has been reported that the selective COX-2 inhibitor L-745,337 has a reduced liability for gastrointestinal ulceration. In our chronic experimental gastric ulcer model in rats, however, delay of gastric ulcer healing with L-745,337 was comparable to that with ordinary NSAIDs. It has also been reported that nitric oxide-releasing NSAIDs have a low relative risk of gastrointestinal ulceration but, again, in our chronic gastric ulcer model, nitric oxide did not reverse NSAID-induced deleterious effects on ulcer healing. In contrast, the proton pump inhibitor omeprazole has been shown to reverse NSAID-induced deleterious effects on gastric ulcer healing in our model. Comparable results have also been reported in humans. Histologic analysis has shown that omeprazole reverses the effects of NSAIDs on cell proliferation, angiogenesis, and maturation of the granulation tissue. In conclusion, only highly effective gastric acid inhibition reliably reverses NSAID-induced delay of gastric ulcer healing.

Why proton pump inhibition should heal and protect against nonsteroidal anti-inflammatory drug ulcers.

Year 1998
Dent J.
Department of Gastrointestinal Medicine, Royal Adelaide Hospital, North Terrace, Australia.
Several lines of evidence provide support for the potential of gastric acid-inhibitory therapy in the management of nonsteroidal anti-inflammatory drug (NSAID)-associated gastroduodenal injury. Studies on the rat stomach have shown that the acute mucosal injury produced by both aspirin and indomethacin can be prevented by elevation of the pH of the gastric contents of >4.0. The pH-dependent pattern of mucosal injury is best explained by the very low activity of gastric pepsin above pH 4.0. This view is supported by studies of experimental esophagitis, which indicate that the pH-activity curve of gastric pepsin approximates the aggressiveness of acid-pepsin mixtures to the esophageal mucosa. Healthy human volunteer studies have shown that elevation of intragastric pH with omeprazole greatly reduces, or abolishes, aspirin-associated gastric microbleeding. A small amount of clinical data also support the view that elevation of gastric pH with acid-inhibitory therapy is a promising option for both the treatment of established NSAID-associated chronic peptic ulcer, even during continued NSAID use, and for prophylaxis against the develop of chronic gastric and duodenal ulcers during NSAID therapy. These data indicate consistently that the benefits from gastric acid-inhibitory therapy are proportional to the degree of elevation of gastric pH by therapy. This dose-response relationship suggests that proton pump inhibition has the potential to achieve superior results in patients who have, or who are at risk of, NSAID-associated peptic ulcer, when compared with agents that inhibit gastric acid secretion to lower levels than seen with proton pump inhibition.

New data on healing of nonsteroidal anti-inflammatory drug-associated ulcers and erosions. Omeprazole NSAID Steering Committee.

Year 1998
Yeomans ND.
Department of Medicine, The University of Melbourne, Western Hospital, Victoria, Australia.
A total of 1,456 patients were available for the All Patients Treated analysis of two large, randomized, double-blind, multicenter, controlled studies (Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-Associated Ulcer Treatment [ASTRONAUT] and Omeprazole versus Misoprostol for NSAID-Induced Ulcer Management [OMNIUM]). These studies examined the efficacies of omeprazole, 20 and 40 mg once daily (both studies), ranitidine, 150 mg twice daily (ASTRONAUT), and misoprostol, 200 microg four times daily (OMNIUM), for the healing of gastric ulcer, duodenal ulcer, or erosions, and the relief of dyspeptic symptoms. At entry, patients were receiving, and continued to receive, nonsteroidal anti-inflammatory drugs (NSAIDs), and had a gastric or duodenal ulcer, and/or >10 erosions in the stomach or duodenum at initial endoscopy. Patients were randomized to blinded treatment for 4/8 weeks until treatment success, which was defined as the healing of ulcer(s),

Progress in prophylaxis against nonsteroidal anti-inflammatory drug-associated ulcers and erosions. Omeprazole NSAID Steering Committee.

Year 1998
Hawkey CJ.
Division of Gastroenterology, University Hospital, Queen's Medical Centre, Nottingham, United Kingdom.
Four large clinical studies have shown that omeprazole, 20 mg once daily, is effective in preventing the significant gastroduodenal consequences of nonsteroidal anti-inflammatory drugs (NSAIDs). In the Scandinavian Collaborative Ulcer Recurrence (SCUR) study, patients were randomized (without initial endoscopy) to receive omeprazole or placebo for up to 3 months. Of the patients treated with omeprazole, 24.7% experienced treatment failure, compared with 50.0% of those on placebo. Fewer patients in the omeprazole group than in the placebo group developed a peptic ulcer (4.7% versus 16.7%, respectively) or dyspeptic symptoms (8.2% versus 20.0%, respectively). In the Omeprazole versus Placebo as Prophylaxis of Ulcers and Erosions from NSAID Treatment (OPPULENT) study, patients were also randomized to receive omeprazole or placebo. The estimated probability of remaining in remission for 6 months while receiving omeprazole was 0.78, compared with 0.53 for placebo. Fourteen (16.5%) patients on placebo developed peptic ulcer(s), compared with three (3.6%) patients on omeprazole. The Omeprazole versus Misoprostol for NSAID-Induced Ulcer Management (OMNIUM) study consisted of a healing and a prophylactic phase. Patients who successfully completed the healing phase were re-randomized to receive omeprazole, misoprostol, or placebo for up to 6 months. In patients receiving omeprazole, 36.5% experienced treatment failure, compared with 48.6% of those on misoprostol, and 67.7% of those on placebo. Omeprazole and misoprostol appeared to be equally effective in preventing gastric ulcer; by contrast, omeprazole was highly effective in preventing duodenal ulcer, when compared with misoprostol and placebo. The Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-Associated Ulcer Treatment (ASTRONAUT) study also consisted of a healing and a prophylactic phase. Patients who successfully completed the healing phase were re-randomized to receive omeprazole or ranitidine for up to 6 months. In patients receiving omeprazole, 26.2% experienced treatment failure, compared with 37.7% of those on ranitidine. The percentages of patients with a peptic ulcer relapse were 5.7% for omeprazole and 19.5% for ranitidine. The data show that omeprazole is an effective and well-tolerated agent for both primary and secondary (maintenance) prophylaxis in patients receiving NSAIDs.

Management of nonsteroidal anti-inflammatory drug-associated lesions: a cost-effectiveness perspective.

Year 1998
Jonsson B. Wahlqvist P.
Stockholm School of Economics, Sweden.
Results are presented from a cost-effectiveness analysis of the acute healing phases of two new clinical studies. Acute treatment with omeprazole, 20 mg once daily, is compared with misoprostol, 200 microg four times daily, or ranitidine, 150 mg twice daily, in patients with nonsteroidal anti-inflammatory drug (NSAID)-associated gastroduodenal lesions (gastric ulcer, duodenal ulcer, and/or >10 erosions in either the stomach or duodenum). The cost-effectiveness comparisons indicate that omeprazole is cost-effective when compared with ranitidine in the treatment of gastric ulcers, duodenal ulcers, and erosions only, and that omeprazole is cost-effective when compared with misoprostol in the treatment of gastric ulcers and duodenal ulcers. In patients with erosions only, misoprostol is cost-effective when compared with omeprazole. When assessing the uncertainty of these estimates, a definite conclusion can be made in only two comparisons: omeprazole is cost-effective when compared with ranitidine in the treatment of gastric ulcers, and misoprostol is cost-effective when compared with omeprazole in the treatment of erosions only. However, the clinical studies were not powered for assessing the cost-effectiveness of the treatment alternatives, which impedes the uncertainty assessment. The determinants of the cost-effectiveness of prophylactic strategies are also discussed, as well as the need for further studies that include relevant outcome measures and a design that reflects actual clinical practice.

Practical management: a keypad-based interactive session.

Year 1998
Hawkey CJ.
Division of Gastroenterology, University Hospital, Queen's Medical Centre, Nottingham, United Kingdom.
If controlled therapeutic, epidemiologic, and pathologic data are to be put rationally into clinical practice, they need to be evaluated against real clinical scenarios. This was done by presenting the symposium delegates with a clinical case and then asking management questions, which were answered using a keypad system.

Gastrointestinal bleeding in the hospitalized patient: a case-control study to assess risk factors, causes, and outcome.

Year 1998
Terdiman JP. Ostroff JW.
Department of Medicine, University of California, San Francisco, USA.
PURPOSE: To determine the risk factors, etiology, and outcome of clinically important gastrointestinal bleeding that occurs after hospital admission (nosocomial gastrointestinal bleeding). PATIENTS AND METHODS: Cases consisted of consecutive patients who developed gastrointestinal bleeding more than 24 hours after admission to the hospital. Cases were compared with two control populations: a set of hospitalized patients without gastrointestinal bleeding matched with cases for age, gender, and length of stay; and all patients admitted to the hospital with clinically important gastroduodenal ulcer bleeding during the study period. Case and controls were compared with respect to risk factors for gastrointestinal bleeding and outcomes. Data were obtained through a comprehensive review of medical records. RESULTS: Clinically important nosocomial gastrointestinal bleeding occurred in 67 inpatients after a mean hospital length of stay of 14 +/- 10 days. The majority (64%) of the patients were not hospitalized in the intensive care unit at the onset of the bleeding. Seventy-two percent of the patients who developed bleeding had been receiving some form of bleeding prophylaxis. In a multivariate analysis, a prior intensive care unit stay (odds ratio 2.5; 95% confidence interval 1.0 to 6.1; P