Fred E. Silverstein

Misoprostol Reduces Serious Gastrointestinal Complications in Patients with Rheumatoid Arthritis Receiving Nonsteroidal Anti-Inflammatory Drugs: A Randomized, Double-Blind, Placebo-Controlled Trial

Approximately 14 million patients in the United States regularly take nonsteroidal anti-inflammatory drugs(NSAIDs) for various types of arthritis [1] for relief of pain, stiffness, and other symptoms. However, these benefits are obtained at a price. Use of NSAIDs is associated with various gastrointestinal side effects. Minor side effects such as nausea, dyspepsia, anorexia, abdominal pain, flatulence, and diarrhea may affect 10% to 60% of patients [2]. Symptomatic ulcers and potentially life-threatening ulcer complications such as upper gastrointestinal bleeding, perforation, and gastric outlet obstruction are reported in 2% to 4% of patients who take NSAIDs for a year [3]. The chance of hospitalization or death from a gastrointestinal adverse event is 1.3% to 1.6% per year in patients with rheumatoid arthritis [4]. These infrequent but potentially serious gastrointestinal side effects of NSAIDs have become a major health care problem because of the many patients at risk [5]. General physicians and rheumatologists caring for patients with symptoms of chronic arthritis may be reluctant to abandon using NSAIDs, which help most of these patients, in order to protect the few who may develop serious complications from use of these drugs. On the other hand, gastroenterologists see fewer patients for arthritis but many with serious gastrointestinal complications. Life-threatening events such as perforation or serious hemorrhage from NSAID-induced ulcers, which often develop with little or no warning [6], are a real problem because of the many patients at risk. Various agents have been used in attempts to reduce the incidence of NSAID-induced gastrointestinal lesions. In one endoscopic study, cimetidine at a dose of 300 mg four times a day showed no benefit in healing NSAID-related lesions compared with placebo, and 400 mg at bedtime provided no benefit in preventing these lesions compared with placebo [7]. Antacids (magnesium-aluminum hydroxide, 10 to 20 mL as needed to a dose as high as 60 mL daily) and sucralfate have recently been reported to reduce dyspeptic symptoms in arthritic patients receiving NSAIDs in whom gastropathic lesions (but not ulcers) were shown endoscopically [8, 9]. The surface-active antiulcer drug sucralfate was ineffective in preventing ulcers in persons receiving NSAIDs [10, 11], and the histamine-2-receptor antagonist ranitidine did not prevent gastric ulcers but did reduce the frequency of duodenal ulcers [12, 13]. Results of preliminary studies indicate that the effects of omeprazole parallel those of ranitidine [14]. A recent study [15] in achlorhydric patients showed that NSAID-induced ulcers develop in the absence of gastric acid. In contrast, several clinical trials have shown that the incidence of endoscopically visible erosions and ulcers associated with NSAID use can be reduced by cotherapy with the synthetic prostaglandin misoprostol [16-19]. However, it was not proved that preventing endoscopic lesions would prevent clinically serious complications of NSAID-induced gastrointestinal ulcers [20]. Our objective was to determine whether concurrent therapy with misoprostol reduces the incidence of serious upper gastrointestinal complications in older patients with chronic rheumatoid arthritis who are taking NSAIDs. Because most patients taking NSAIDs do not routinely have endoscopy, we investigated the incidence of these complications during clinical care as actually practiced. A second goal was to better define which patients were at increased risk for development of serious NSAID-induced upper gastrointestinal complications. Methods Patients Ambulatory patients at least 52 years of age who had chronic rheumatoid arthritis, defined by American College of Rheumatology criteria [21], and who were expected to be taking 1 of 10 specified NSAIDs at predefined minimum doses for 6 months were sought from practices of family medicine, internal medicine, or rheumatology. Of these practices, 661 in the United States and 3 in Canada enrolled at least one patient between July 1991 and August 1993. For all patients, a medical history was elicited, a physical examination was done, and a modified Health Assessment Questionnaire that included eight items on activities of daily living was administered [22]. Patients were excluded if they had had active peptic ulcer disease within 30 days of study enrollment; were taking or expected to need antiulcer medication (histamine-2 blockers, sucralfate, omeprazole) or any experimental medication during the study; had the Zollinger-Ellison syndrome, pyloric or duodenal obstruction, previous gastric resection or vagotomy, gastroesophageal reflux disease, varices, or cirrhosis; had a history of inflammatory bowel disease, upper gastrointestinal tract malignancies, hepatitis, alcoholism, or bleeding diathesis; were estimated to have a life expectancy of less than 8 months or had do-not-resuscitate status; were women of child-bearing potential; or could not tolerate misoprostol or any prostaglandin. The following were the minimum NSAID doses (mg/d) allowed: aspirin, 2000; diclofenac, 100; flurbiprofen, 200; ibuprofen, 1200; indomethacin, 75; ketoprofen, 150; naproxen, 750; piroxicam, 20; sulindac, 200; or tolmetin, 1200. Patients were allowed to receive more than one NSAID. Intervention Eligible patients were randomly assigned to receive either misoprostol or placebo in the form of 200- micrograms tablets from coded bottles supplied by the manufacturer. Patients were randomly assigned in blocks of four, so that in each block, half the patients would receive misoprostol and half would receive placebo. Because blocks were assigned to investigators, patients were randomly assigned within the individual centers. Investigators were not informed about the randomization procedure but were told only that the study was randomized and double-blind. Patients were instructed to begin taking half a tablet with meals and at bedtime each day for 10 days and then, if the drug was tolerated, to increase the dose to a whole tablet four times a day for the rest of the study. If the drug was not tolerated, the patients were instructed to reduce the dose back to half a tablet four times a day. Patients could continue therapy with arthritis disease-modifying agents (such as gold or corticosteroids) and were allowed to take antacids that did not contain magnesium. Patients purchased their own arthritis medications or antacids and reported their consumption when seen monthly for examination and counts of study medication tablets. Physicians were instructed to watch closely for clinical signs of gastrointestinal bleeding or other possible gastrointestinal complications, to inquire about symptoms, and to investigate suspicious episodes by appropriate clinical procedures. Outcome Measures All suspicious events, regardless of presumed cause, were to be reported, along with all available patient data, to the study medical officer (HWD) and then to an external review committee. This committee consisted of a gastroenterologist (FS), a rheumatologist (Kenneth Brandt, MD, Indiana University), and an epidemiologist (Marie Griffin, MD, MPH, Vanderbilt University). The committee determined, without unblinding the randomization code, whether the patient had upper gastrointestinal bleeding; other ulcer complications; or a problem such as hemorrhoids, diverticulitis, colon polyps, or cancer. It developed definitions of what were considered to be complications related to NSAID use and categories of such complications. The committee reached consensus and assigned such events to one of the following categories of definite upper gastrointestinal complications: 1. perforated ulcer, proved at surgery; 2. gastric outlet obstruction caused by proven ulceration and stricture, proved by endoscopy; 3. hematemesis, with endoscopically proven gastric or duodenal ulceration or erosion; 4. active or recent visualized bleeding from endoscopically proven ulceration or erosion; 5. melena, with endoscopically proven ulceration or erosion; 6. heme-positive stool, with endoscopically proven ulceration or erosion, plus either a) a decrease in hematocrit of at least 0.05 or b) orthostatic change in the pulse rate (from sitting to standing) of at least 20 beats per minute or decrease in systolic blood pressure of at least 20 mm Hg and a decrease in diastolic blood pressure of 10 mm Hg; 7. hematemesis, without endoscopically proven ulceration or erosion; and 8. melena, with heme-positive stool and without endoscopically proven ulceration or erosion. The committee also defined categories of events not involving clinically significant bleeding: 9. report of melena with no other data; 10. heme-positive stools, with endoscopically proven ulceration or erosion and without active bleeding; and 11. report of melena and heme-negative stools when the stools were tested. Sample Size Calculation and Statistical Methods The placebo group was expected to have an incidence of serious NSAID-induced upper gastrointestinal complications of about 2% per year or about 1% during the 6-month study period. We estimated that the misoprostol group might have 40% to 50% fewer complications and that 60% to 70% of patients would complete the study. Given an less than 0.05 and power greater than 0.80, we planned in the protocol to assess the number of such complications observed, without unblinding the study, after 7500 patients had been followed. We did this to confirm the incidence assumptions and adjust the study size if necessary. We used the Fisher exact test to compare occurrence of events in the treatment groups. To identify risk factors, we evaluated the relation between the occurrence of serious upper gastrointestinal complications and patient characteristics using logistic regression. Supplementary time-to-event analyses were done using the log-rank test and Kaplan-Meier curves. The study was supported by a grant from G.D. Searle & Co. Data c

The National ASGE Survey on Upper Gastrointestinal Bleeding: II. Clinical prognostic factors

Data about the risks of upper endoscopy in patients with upper gastrointestinal bleeding was gathered as part of a prospective national survey of the ASGE membership. Endoscopic complications occurred in 21 of 2320 endoscopies (0.9%). These included 12 major (perforation, aspiration, bleeding) and 9 minor (mucosal tear, medication reaction, transient cardiac or pulmonary episode) complications. There were 3 deaths attributable to major complications of the procedure. These fatalities all occurred in patients with severe major underlying illnesses. Although these results indicate a higher complication rate than earlier retrospective ASGE surveys on endoscopy, they are comparable to other available data about the risks of endoscopy in the specific group of patients with upper gastrointestinal bleeding.

Transmission of Infection by Gastrointestinal Endoscopy and Bronchoscopy

Spurred in part by the acquired immunodeficiency syndrome (AIDS) epidemic, both health care workers and the lay public have become keenly interested in preventing the iatrogenic transmission of infections. Recently, reports of the transmission of infections via contaminated endoscopes have generated concern. We review the reported evidence of infections transmitted by flexible gastrointestinal and pulmonary endoscopes, the circumstances surrounding transmission of these infections, and recommended means to prevent such transmission. Methods We identified all relevant English-language articles published between 1966 and July 1992 through prominent review articles and a MEDLINE search (keywords: endoscopy, bronchoscopy, infections, transmission, and disinfection). We also manually searched bibliographies of identified articles to find additional sources. The entire search yielded 265 articles, all of which were reviewed in depth. General Considerations Flexible endoscopy is a common clinical procedure; an estimated 8.7 million gastrointestinal and 580 000 pulmonary flexible endoscopies were done in the United States in 1989 [1]. The risk for transmitting infections via these procedures depends on three factors: exposure of the endoscope to microorganisms, cleaning and disinfection procedures, and instrument design. Depending on the origin of the contaminating microorganisms, transmission of infection can be categorized as either patient-to-patient or environment-to-patient (Figure 1). During a procedure, an endoscope can be contaminated with whatever organisms are contained in patient secretions. Environmental contamination typically results from flushing or cleaning the endoscope with contaminated solutions. Whether contamination of the endoscope persists depends on the quantity and nature of the microorganisms. Some microbes are inherently more resistant to disinfectants (Figure 2), the efficacy of which depends on type, concentration, and duration of exposure. If patient material, such as blood, feces, or secretions, remains on or in the endoscope after cleaning, the effectiveness of subsequent disinfection diminishes. Figure 1. Nosocomial transmission of microorganisms via endoscopes. Figure 2. Resistance of microorganisms to disinfectants. Because endoscopes are made of fragile, heat-sensitive materials, they are routinely decontaminated by high-level disinfection, not sterilization [2]. Gastrointestinal endoscopes, with their multiple internal channels and valves (Figure 3), are more complex than the single-channeled bronchoscopes. In general, the more complex the instrument, the more crevices, joints, or surface pores there are and, hence, the more problematic cleaning and disinfection becomes [2]. Figure 3. Cross-section of typical gastrointestinal endoscope. Transmission of Specific Microorganisms Salmonella Infections Salmonella infections occur frequently in the United States; for example, more than 41 000 culture-positive patients were reported to the Centers for Disease Control (CDC) in 1989[3]. A chronic asymptomatic carrier state, defined by the continued fecal excretion of Salmonella organisms for more than 1 year, develops in approximately 3% of persons after S. typhi infection (typhoid fever) [4] and in fewer than 1% of persons after nontyphoidal Salmonella infection [5]. Both acutely infected persons and chronic carriers are thus potential sources of endoscopic contamination. Many disinfectants, including glutaraldehyde, phenolics, and iodophors, effectively kill salmonellae [2]. Transmission of Salmonella infections by endoscopy has occurred with many serotypes, including S. agona, S. kedougou, S. newport, S. oranienburg, S. oslo, S. typhi, and S. typhimurium [6-14]. Of the 84 patients reported to have developed such infections, 6 patients developed septicemia and 1 patient died. In most cases, the disinfectant (hexachlorophene, cetrimide, chlorhexidine, or quaternary ammonium compounds) used to clean the endoscopes had relatively little microbiocidal activity against salmonellae. In one outbreak, investigators identified inadequately disinfected colonic biopsy forceps as the source of infection [9]. Pseudomonas Infections Pseudomonas aeruginosa flourishes in warm, damp environments. Typical environmental reservoirs include respiratory equipment, sinks, and water bottles [15]. Most acute P. aeruginosa infections, which often involve the lungs, are nosocomially acquired. Among healthy adults, P. aeruginosa can colonize many body sites, as evidenced by isolation from throat (0% to 7%), sputum (2%), and stool (3% to 24%). Hospitalized patients, as well as patients with certain chronic lung diseases, have higher colonization rates [16]. Potential sources of endoscope contamination with Pseudomonas species thus include environmental reservoirs, acutely infected patients, and colonized patients. Like Salmonella species, P. aeruginosa is susceptible to glutaraldehyde, phenolics, and iodophors [2]. Most P. aeruginosa infections transmitted by endoscopy occurred after endoscopic retrograde cholangiopancreatography and resulted from environment-to-patient transfer of organisms. In all cases, the investigators isolated P. aeruginosa from some part of the endoscope. These infections resulted in bacteremia in 45 patients, of whom 4 died [17-26]. Most infections were caused by the use of an inadequate disinfectant [21, 22], contamination of an inner channel [18, 20], or incomplete drying of the endoscope channels before overnight storage [23, 26]. One epidemic, however, occurred despite the use of glutaraldehyde after each procedure and ceased only after replacement of the endoscope [19]. The first reports of bronchoscopic transmission of P. aeruginosa involved patients who developed Pseudomonas pneumonia [27, 28]. In a subsequent report, investigators cultured P. aeruginosa from the bronchoscopic washings of 11 patients; 1 patient, who was immunosuppressed, developed severe pneumonia [29]. The investigators isolated P. aeruginosa from the aspiration-irrigation channel of the bronchoscope, and the outbreak continued until they sterilized the bronchoscope with ethylene oxide. Mycobacteria Approximately 22 000 new cases of active tuberculosis occur in the United States each year [30], and an estimated 10 to 15 million persons carry Mycobacterium tuberculosis in its dormant phase [31]. After many years of decline, the incidence of tuberculosis in the United States began increasing dramatically in 1986 [30], predominantly because of an increasing number of cases in HIV-infected patients [32]. Infections with mycobacteria commonly found in the environment, such as M. avium-intracellulare complex, M. chelonae, and M. fortuitum, have also recently increased [33]. Unfortunately, studies determining the sensitivity of mycobacteria to various disinfectants are conflicting. In general, cetrimide, chlorhexidine, and iodophors are considered unreliable. Glutaraldehyde is widely accepted as a mycobactericidal agent, but the time required for disinfection remains undefined [34-36]. In the first reports of the bronchoscopic transmission of M. tuberculosis, the investigators, who disinfected the bronchoscopes with iodophor, advocated using a more effective disinfectant such as glutaraldehyde [37, 38]. In three subsequent cases, the patients developed clinically apparent M. tuberculosis infection despite rigorous cleaning and disinfection of the bronchoscope; the suction valve, with its spring-operated sleeve, seemed the most likely source of contamination [39]. The investigators tested this hypothesis by contaminating bronchoscopes with M. fortuitum; after they routinely cleaned and disinfected the instrument, M. fortuitum remained in all valves. Among other mycobacteria, M. chelonae has most commonly been associated with endoscopic transmission. In a large outbreak, M. chelonae was isolated from bronchial washings, brushings, or sputum in 72 patients [40]. Two patients developed clinical disease and one patient died. After recognizing the outbreak, the investigators changed from glutaraldehyde disinfection of the bronchoscopes to ethylene oxide sterilization. Nevertheless, they continued to isolate M. chelonae from clinical specimens until they discovered punctured suction channels in two of the bronchoscopes; M. chelonae was isolated from slimy material in the interior of both instruments. Hepatitis B Virus On average, more than 300 000 cases of primary hepatitis B virus (HBV) occur each year in the United States [41], and approximately 5% to 10% of patients develop persistent HBV infection. The estimated number of chronic HBV carriers in the United States ranges from 750 000 to 1 000 000 [42]. In infected persons, hepatitis B surface antigen (HBsAg) has been found in various body fluids, including serum, feces, bile, and saliva [43]. The inability to culture HBV has limited the evaluations of its environmental stability and its susceptibility to disinfectants. Alternative approaches include measuring the presence of HBsAg or inoculating chimpanzees. A study in chimpanzees showed that HBV-contaminated inanimate objects, if not properly cleaned and disinfected, can harbor and transmit the virus for up to 1 week [44]. Most of the commonly used disinfectant and sterilization procedures, however, inactivate HBV [45, 46]. Two studies have shown the potential for the endoscopic transmission of HBV. In one study, iodophor-isopropyl alcohol removed HBsAg from surfaces of endoscopes used in four HBsAg-positive patients, but not from the cytology brushes or biopsy forceps [47]. In the other study, an endoscope and a biopsy forceps were immersed for 15 minutes in gastric juice containing 1.0% serum and Iodine-125-HBsAg, and, despite subsequent disinfection with chlorhexidine and cetrimide for 15 to 20 minutes, they were both positive for Iodine-125-HBsAg [48]. One group of investigators documented the endoscopic transmission of HB

Histologic correlates of gastrointestinal ultrasound images.

Endoscopic ultrasound imaging has potential for improving the diagnosis of gastrointestinal disease. However, the anatomic correlates of gastrointestinal ultrasound images have not been precisely defined. We have compared ultrasound images with the corresponding histologic sections of 81 specimens of resected and postmortem, normal and diseased gastrointestinal tissue. The five layers seen on ultrasound images of the normal gastrointestinal tract correspond to (1) superficial mucosa, (2) deep mucosa, (3) submucosa plus the acoustical interface between the submucosa and muscularis propria, (4) muscularis propria minus the acoustical interface between the submucosa and muscularis propria, and (5) serosa and subserosal fat. This interpretation takes into consideration the echoes produced by the tissue layers and the echoes produced by the interfaces between layers. Abnormal findings on ultrasound images of neoplastic and inflammatory diseases correspond to histologic tissue structure. When properly interpreted, ultrasound images of the gastrointestinal wall can provide potentially useful diagnostic information.

Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor.

OBJECTIVE:The aim of this study was to assess the rate of upper gastrointestinal (UGI) ulcer complications (bleeding, perforation, or gastric outlet obstruction) associated with celecoxib, a specific COX-2 inhibitor, compared with the rate associated with nonspecific, nonsteroidal anti-inflammatory drugs (NSAIDs).METHODS:A pooled analysis was conducted of 14 multicenter, double-blind, randomized, controlled trials (RCTs) and a separate analysis of one long-term open label trial that assessed the efficacy and safety of celecoxib for symptomatic treatment of arthritis. The RCTs enrolled 11,008 patients with osteoarthritis or rheumatoid arthritis treated for 2–24 wk; the long-term open label trial enrolled 5,155 patients receiving celecoxib for a maximum of 2 yr. In the RCTs, patients were randomly assigned to receive placebo (n = 1,864; 208 patient-years), celecoxib 25–400 mg b.i.d. (n = 6,376; 1,020 patient-years), or a comparator NSAID (n = 2,768; 535 patient-years); NSAIDs were naproxen 500 mg b.i.d., diclofenac 50 or 75 mg b.i.d., or ibuprofen 800 mg t.i.d.). In the long-term, open-label trial, patients received celecoxib 100–400 mg b.i.d. for up to 2 yr (n = 5,155; 5,002 patient-years). The principal outcome measure of this analysis was development of a UGI ulcer complication, which was prospectively defined as bleeding, perforation, or gastric outlet obstruction. Ulcer complications were assessed and adjudicated by persons blinded to the patients treatment assignment or the study in which the patient participated.RESULTS:In the RCTs, UGI ulcer complications occurred in no placebo patients (0 of 1,864 patients), in 2 of 6,376 celecoxib patients (0.03%), and in 9 of 2,768 patients receiving an NSAID (0.33%), corresponding to annual incidences of 0.20% for celecoxib (p > 0.05vs placebo) and 1.68% for NSAIDs (p = 0.002vs celecoxib and placebo). In the long-term open-label trial, nine UGI ulcer complications occurred, for an incidence of 0.17% and an annualized incidence of 0.18%.CONCLUSIONS:The incidence of UGI ulcer complications associated with celecoxib was 8-fold lower than with nonspecific NSAIDs. The incidence of ulcer complications observed in celecoxib-treated patients was similar to that in patients receiving placebo in the RCTs, and to that in non-NSAID users reported in the literature.

Experimental evaluation of an endoscopic ultrasound probe: In vitro and in vivo canine studies

We developed an endoscopic echo probe that can be passed via the biopsy channel of a flexible fiberoptic or video endoscope with a 3.5-mm channel. The probe moves along the gastrointestinal wall under direct endoscopic vision. The translational scanning action is sensed by a position potentiometer and combines with the ultrasonic B-mode echoes to produce a cross-sectional image of the wall. The system uses an ultrasound frequency of 20 MHz to produce high-resolution images. The device was used to image canine gastrointestinal tissue in vitro and in vivo during endoscopy. Ultrasound images of the gut wall correlate with histologic structure. This probe overcomes some of the problems associated with the combined ultrasound endoscopes now in use. Use of the probe with video endoscopy allows the endoscopic and ultrasound images to be displayed side by side, simplifying coordination of application of the two techniques.

Method and apparatus for endoscopic blood flow detection by the use of ultrasonic energy

A system for endoscopic detection of blood flow is disclosed. A catheter is sized to pass through the biopsy channel of an endoscope and includes an elongated catheter tube of flexible material and an ultrasonic probe carried by the catheter tube adjacent its tip. Depending on the application, the ultrasonic field provided by the ultrasonic probe may be either transverse or parallel to the longitudinal axis of the catheter tube and may be either highly directional, omnidirectional, or sectorial. The ultrasonic probe is coupled to a pulsed Doppler circuit (FIG. 16) by an isolation circuit (FIG. 20) that provides electrical isolation and RFI suppression. The Doppler circuit is designed to enhance close proximity detection of blood flow, to limit the range of the probes ultrasonic field, and to distinguish between arterial blood flow, venous blood flow, and vessel wall motion.

National ASGE survey on upper gastrointestinal bleeding: complications of endoscopy.

Data about the risks of upper endoscopy in patients with upper gastrointestinal bleeding was gathered as part of a prospective national survey of the ASGE membership. Endoscopic complications occurred in 21 of 2320 endoscopies (0.9%). These included 12 major (perforation, aspiration, bleeding) and 9 minor (mucosal tear, medication reaction, transient cardiac or pulmonary episode) complications. There were 3 deaths attributable to major complications of the procedure. These fatalities all occurred in patients with severe major underlying illnesses. Although these results indicate a higher complication rate than earlier retrospective ASGE surveys on endoscopy, they are comparable to other available data about the risks of endoscopy in the specific group of patients with upper gastrointestinal bleeding.

Misoprostol Reduces Gastroduodenal Injury From One Week of Aspirin: An Endoscopic Study

Misoprostol is a synthetic prostaglandin E1 analogue that inhibits gastric acid production and may augment mucosal defense. A double-blind trial examined the effect of misoprostol on the endoscopic appearance of gastroduodenum at the end of 1 wk of aspirin ingestion. One hundred thirty healthy subjects were randomized to take either 50, 100, or 200 micrograms of misoprostol, or placebo along with 975 mg of aspirin four times daily. Fewer subjects developed acute endoscopic gastric ulcers in the group taking any dose of misoprostol compared with the placebo group (1% vs. 43%). No subject taking the 100- or 200-micrograms dose of misoprostol developed an acute endoscopic duodenal ulcer compared with 13% of subjects taking placebo (p less than 0.05). Significantly fewer subjects developed gastric erosions and significantly fewer subjects developed duodenal erosions in each of the three groups taking misoprostol compared with the placebo group (p less than 0.01). There were fewer subjects with a gastric erosion (p less than 0.05) and fewer subjects with a duodenal erosion (p less than 0.05) in the group taking the 200-micrograms dose compared with the group taking the 50-micrograms dose of misoprostol. Gastrointestinal symptoms causing a modification in usual activities were infrequent but there was significantly more diarrhea in the 200-micrograms misoprostol group. There was no correlation between endoscopic scores and symptoms in any group. We conclude that misoprostol can protect the normal gastroduodenum from acute ulceration and reduce the chance of erosion after 1 wk of aspirin ingestion.

A Reproducible Animal Model of Acute Bleeding Ulcer—The “Ulcer Maker”

An instrument has been developed which creates an experimental model of an acute bleeding gastric ulcer. The diameter and depth of these gastric ulcers are reproducible. The instrument can be used endoscopically or at laparotomy. Using this ulcer model nonsurgical modalities for the treatment of upper gastrointestinal bleeding can be compared in a controlled manner. This standard experimental model may also facilitate comparison of results among different research groups.