The impact of low-dose aspirin on endoscopic gastric and duodenal ulcer rates in users of a non-selective non-steroidal anti-inflammatory drug or a cyclo-oxygenase-2-selective inhibitor.

BACKGROUND: The effect of low-dose aspirin on endoscopic ulcer incidence in cyclo-oxygenase-2-selective inhibitor or non-selective non-steroidal anti-inflammatory drug users remains controversial. AIM: To compare prospectively the incidence of endoscopic ulcers in healthy subjects receiving low-dose aspirin plus celecoxib or naproxen. METHODS: In this double-blind, placebo-controlled, 1-week study, subjects (50-75 years) were randomized to receive aspirin 325 mg o.d. plus either celecoxib 200 mg o.d., naproxen 500 mg b.d., or placebo. Baseline and end of study endoscopies were performed. The primary end point was incidence of one or more gastric and duodenal ulcers. RESULTS: A lower incidence of gastric and duodenal ulcers was seen in celecoxib/aspirin-treated subjects (19%) vs. naproxen/aspirin (27%; RR: 0.63, 95% CI: 0.44-0.92). Both naproxen/aspirin and celecoxib/aspirin groups demonstrated a higher incidence of gastric and duodenal ulcers vs. placebo/aspirin (8%; RR: 3.7, 95% CI: 1.8-7.6 and RR: 2.6, 95% CI: 1.2-5.8, respectively). CONCLUSIONS: Fewer endoscopic ulcers were observed in patients treated with celecoxib/aspirin vs. naproxen/aspirin. However, celecoxib/aspirin was associated with a significantly higher incidence of gastric and duodenal ulcers than aspirin alone. Further studies are required to determine the generalizability of these findings in the aspirin users and to determine the appropriate strategy to minimize risk in susceptible patients.

Endoscopic studies of gastric and duodenal injury after the use of ibuprofen, aspirin, and other nonsteroidal anti-inflammatory agents.

The toxic effects of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) were endoscopically evaluated in several studies conducted between 1975 and 1983 and involving 843 normal volunteers. Anti-inflammatory doses of acetylsalicylic acid (2,400 and 3,900 mg/day) consistently produced significantly more mucosal injury than did any of the newer NSAIDs. Buffering did not reduce the degree of damage. Little or no mucosal injury was seen with placebo, "pro drugs," enteric-coated aspirin, or 1,200 mg/day of ibuprofen (Motrin, Upjohn). However, varying degrees of generally dose-dependent mucosal injury were evident with larger doses of ibuprofen, naproxen, tolmetin sodium, and indomethacin. The amount of mucosal damage after 2,400 mg/day of ibuprofen did not increase when 4,800 mg daily was administered. Duodenal injury corresponded to gastric injury, but it was generally less severe. Short-term studies of one to three days indicated that ibuprofen produced little or no injury when given at a dose of 2,400 mg for one day or 1,600 mg/day for three days. No relation was noted between subjective symptoms and endoscopic findings.

Effects of fenbufen, indomethacin, naproxen, and placebo on gastric mucosa of normal volunteers. A comparative endoscopic and photographic evaluation.

The effects of fenbufen (1,000 mg a day), indomethacin (150 mg a day), naproxen (750 mg a day), and placebo on gastric mucosa were determined by endoscopy and recorded photographically. One hundred normal subjects, randomly divided into equal, parallel-treatment groups, were given the drugs in divided daily doses for seven consecutive days. The results revealed that the effects of fenbufen on gastric mucosa were significantly (p less than or equal to 0.05) less than those of either naproxen or indomethacin and not statistically different from those observed with placebo.

Effects of flurbiprofen and aspirin on the gastric and duodenal mucosa. An endoscopic comparison.

A single-blind, randomized endoscopic tolerance study was conducted to compare daily doses of flurbiprofen (Ansaid, Upjohn) at 100, 150, and 200 mg per day with 2,600 mg of aspirin per day. Ten normal volunteers were enrolled in each of the flurbiprofen groups, and five were enrolled in the aspirin group. Analysis of the mean gastric mucosal injury scores obtained on day eight revealed statistically significant lower mean scores (p = 0.05) in the 100-mg and 150-mg flurbiprofen treatment groups when compared with the 200-mg flurbiprofen group and the aspirin group. No significant differences were found between any of the treatment groups in duodenal mucosal injury scores. Mean scores for gastric mucosal injury in the three groups receiving flurbiprofen showed a definite dose relationship. The aspirin-treated subjects had significantly decreased uric acid levels (p = 0.006) and a significantly higher incidence of tinnitus (p = 0.04) compared with the flurbiprofen treatment groups. There was a poor correlation between subjective symptomatology and endoscopic pathologic findings.

Placebo-controlled, randomized, evaluator-blinded endoscopy study of risedronate vs. aspirin in healthy postmenopausal women.

BACKGROUND: Bisphosphonates are effective treatments for osteoporosis. Since some primary amino bisphosphonates are associated with oesophageal injury, we conducted a study of the upper gastrointestinal effects of risedronate, a pyridinyl bisphosphonate. METHODS: Healthy, postmenopausal women received risedronate 5 mg (n=26), aspirin 2600 mg (n=27), or placebo (n=27) daily for 14 days and underwent endoscopy at baseline, Day 8 and Day 15. RESULTS: Oesophageal erosions were noted in one subject in the aspirin group, two in the placebo group, and none in the risedronate group, and an ulcer in one aspirin-treated subject. Gastric erosions and ulcers were observed most frequently in the aspirin group. Gastric ulcers were noted in eight subjects in the aspirin group, one in the placebo group, and none in the risedronate group (P=0.010, placebo vs. aspirin; P=0.002, risedronate vs. aspirin). Duodenal erosions and ulcers were observed in the aspirin group only. Gastroduodenal erosion scores of three or more occurred more frequently in the aspirin than in the risedronate and placebo groups (P < 0.001). CONCLUSIONS: Risedronate 5 mg was not associated with oesophageal or gastroduodenal ulcers in healthy, postmenopausal women, a population representative of patients who will receive risedronate in the clinical setting.

Effect of enprostil on the gastroduodenal mucosa of healthy volunteers.

Enprostil is a synthetic dehydro-prostaglandin E2 with gastroduodenal ulcer-healing and mucosal-protective properties. One hundred and three healthy volunteers were randomized to receive capsules of enprostil 35 micrograms b.d. (the clinically recommended dose), enprostil 70 micrograms b.d., or placebo b.d. All underwent endoscopic assessment of the gastroduodenal mucosa, scored using a 0-4 scale, at baseline and on Days 3, 7, 14, 21 and 28 of dosing. Mean and median maximum scores demonstrated a dose response, and the mean maximum scores were statistically significantly higher for both enprostil groups on each endoscopy day when compared with placebo. The majority of enprostil-treated subjects had petechial haemorrhages. The proportion of volunteers with small white-based mucosal breaks (erosions) was significantly higher for the fundus in the enprostil 70-microgram group on Days 21 and 28 when compared with placebo, but there were no significant differences between treatment groups for any area on the other study days. The 70-microgram dose was associated with significantly more gastrointestinal adverse events than the 35-microgram dose, which was similar to placebo. There were no significant differences between groups for large white-based mucosal breaks (ulcers). We conclude that oral enprostil produced gastric mucosal petechial haemorrhages, primarily in the fundus of the stomach. Gastric mucosal petechial haemorrhages are probably without clinical significance because they are very common in the general population (10-15%) and do not progress to erosions and ulcers.

Specific inhibition of cyclooxygenase-2 with MK-0966 is associated with less gastroduodenal damage than either aspirin or ibuprofen.

BACKGROUND: Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxygenase), MK-0966 (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity. AIM: To compare the effect on the upper gastrointestinal mucosae of a high dose of MK-0966 with that of conventional doses of ibuprofen and aspirin. METHODS: Healthy subjects (n = 170; age range 18-54 years) with endoscopically normal gastric and duodenal mucosa were randomized to either MK-0966 250 mg q.d. (n = 51), ibuprofen 800 mg t.d.s. (n = 51), aspirin 650 mg q.d.s. (n = 17), or placebo (n = 51) in this 7-day, double-blind, parallel-group study. The mucosae were evaluated by endoscopy using a predefined scale; scores could range from 0 to 4. The primary end-point was the percentage of subjects who developed a mucosal score >/= 2 (i.e. the development of one or more erosions). To evaluate COX-1 activity, serum thromboxane B2 levels were determined in a subset of the population. RESULTS: The percentage of subjects who developed a mucosal score >/= 2 in the MK-0966 group (12%) was significantly lower (P < 0.001) than that in the ibuprofen (71%) and aspirin (94%) groups, and was similar to that in the placebo group (8%). Only ibuprofen and aspirin significantly (P < 0.0001) reduced baseline thromboxane B2 levels. All treatments were generally well tolerated. CONCLUSIONS: In this acute short-term endoscopic study, MK-0966 250 mg q.d. (a dose at least 10 times higher than that demonstrated to reduce the signs and symptoms of osteoarthritis) produced significantly less gastrointestinal mucosal damage than either ibuprofen 800 mg t.d.s. or aspirin 650 mg q.d.s. and was comparable to placebo in this regard.

A controlled endoscopic study comparing the toxic effects of sulindac, naproxen, aspirin, and placebo on the gastric mucosa of health volunteers.

Sixty volunteers were endoscopically evaluated to compare gastric mucosal injury following oral administration of sulindac, naproxen, aspirin, or placebo for two consecutive seven-day periods. A single-blind technique was utilized wherein the endoscopist was unaware which drug each volunteer had received. The following dosages were employed for the two study periods: sulindac, 150 and 200 mg, b.i.d., naproxen, 250 and 375 mg, b.i.d., and aspirin, 650 and 975 mg, q.i.d. The only subject who developed a frank ulcer with mucosal bleeding was in the sulindac group, however volunteers taking sulindac demonstrated statistically less significant mucosal injury on endoscopic examination than those receiving naproxen or aspirin.

Gastroscopic evaluation of the effect of aspirin and oxaprozin on the gastric mucosa.

Oxaprozin, a new long-acting, antiinflammatory agent, and aspirin were compared utilizing gastroscopic evaluation and photography of the gastric mucosa in a double-blind, crossover study in normal volunteers. Submucosal hemorrhages or mucosal bleeding was observed in seven of eight subjects on aspirin and in only two of eight on oxaprozin (P = 0.061). Adverse effects were experienced by seven of eight subjects after the aspirin treatment period--tinnitus in five and gastrointestinal symptoms in four. Only one patient had mild diarrhea on oxaprozin. The incidence of adverse effects was found significantly higher with aspirin therapy (P less than 0.001). No laboratory abnormalities of clinical significance were attributed to either drug administration. Results after ten days of treatment show that oxaprozin in therapeutic dose levels (1200 mg once a day) produces significantly fewer changes in the gastric mucosa than aspirin (975 mg administered four times a day, total daily dose 3.9 Gm) in the same subjects, who received both drugs in this double-blind, crossover experiment with a four-week washout period between treatments.

The effects of flurbiprofen, aspirin, cimetidine, and antacids on the gastric and duodenal mucosa of normal volunteers. An endoscopic and photographic study.

This 7-day, single blind, randomized endoscopic tolerance study compared daily doses of 100, 150 and 200 mg flurbiprofen with 2600 mg aspirin. After seven days the flurbiprofen 100 and 150 mg groups had significantly less gastric irritation than the flurbiprofen 200 mg and aspirin groups. Flurbiprofen showed a linear dose-response relationship with respect to gastric injury and serum drug levels. Four subjects each on aspirin and flurbiprofen with the most severe injuries continued on their medications plus cimetidine and antacids for four more weeks. Both drug groups showed clinical improvement in the gastroduodenal area. In conclusion, flurbiprofen and aspirin therapy can be tolerated in the presence of gastroduodenal irritation by concomitantly administering cimetidine and antacids.

Corrosive injury to the stomach: the natural history and role of fiberoptic endoscopy.

Most physicians recognize that the ingestion of lye is associated with severe esophageal damage. It is much less widely known that gastric injury is the predominant finding when acid is ingested. We are reporting on five patients who had severe gastric damage after ingestion of diluted sulfuric acid (three cases), capsules of potassium hydroxide, and Clinitest tablets (one case each). Fiberoptic endoscopy was used to localize the extent and severity of injury and to follow the evolution of the damage. The extent and location of injury varied with the amount and type of agent ingested. Acid ingestion resulted in severe gastritis, which eventually led to antral stenosis and gastric outlet obstruction requiring operative intervention in two cases. Potassium hydroxide capsules produced diffuse esophagitis, gastritis, and a non-healing large gastric ulcer. Clinitest tablets produced distal esophagitis and stricture and antral damage leading to gastric outlet obstruction which required operative intervention. These cases demonstrate the natural history of corrosive injury to the stomach and the value of fiberoptic endoscopy in the management of this problem.

Etodolac, a new nonsteroidal anti-inflammatory drug: gastrointestinal microbleeding and endoscopic studies.

A review of the literature is presented on the gastrointestinal effects of etodolac, a new nonsteroidal anti-inflammatory drug (NSAID), as evaluated in both microbleeding and endoscopic studies. In four microbleeding studies, gastrointestinal blood loss in healthy subjects was estimated by a 51Cr-erythrocyte labeling method before drug treatment, after 7 days of treatment with NSAIDs including etodolac, and 1 week after the last day of treatment. In these 7-day studies, the gastrointestinal blood loss seen with etodolac (600 to 1200 mg/day) was similar to that seen with placebo and significantly (p less than 0.05) less than that seen with aspirin (2600 mg/day), naproxen (750 mg/day), ibuprofen (2400 mg/day), or indomethacin (200 mg/day). Naproxen, ibuprofen, and indomethacin caused mean daily blood losses in excess of 1 ml/day over baseline values. The increase with aspirin was 4 to 5 ml/day. In contrast, the greatest mean daily increase in blood loss with etodolac therapy was 0.2 ml. In a 4-week study of etodolac (600 and 1000 mg/day) and piroxicam (20 mg/day) given to patients with osteoarthritis or rheumatoid arthritis, blood loss seen with etodolac was comparable to that seen with placebo and significantly less than that seen with piroxicam. Gastrointestinal irritation was also assessed by endoscopy after 1 week of NSAID or placebo treatment. Endoscopy scores after etodolac treatment (up to 1200 mg/day) were similar to scores at baseline and after placebo and were significantly lower than scores following treatment with aspirin (3900 mg/day), indomethacin (200 mg/day), ibuprofen (2400 mg/day), or naproxen (100 mg/day). The effects of etodolac (600 or 1000 mg/day) and diclofenac (150 mg/day) were not different from each other or from baseline. These data indicate that etodolac, in these studies, did not cause clinically significant gastrointestinal microbleeding or visible gastric injury. By the criteria used in these studies, etodolac is less irritating to the gastrointestinal tract than aspirin, indomethacin, ibuprofen, naproxen, or piroxicam, and compares favorably with diclofenac.

Prevention of NSAID-related ulcers.

The use of NSAIDs constitutes a significant risk for gastrointestinal bleeding and other ulcer complications. However, if they prove clinically effective in relieving arthritic symptoms, the new COX-2 selectively inhibiting NSAIDs may ultimately solve the problem of gastrointestinal toxicity with NSAIDs.

A review of mucosal protection by synthetic prostaglandin E analogs against injury by non-steroidal anti-inflammatory agents.

Non-steroidal anti-inflammatory agents (NSAIDs) damage the gastric mucosa both in normal volunteers and in arthritic patients. Four large studies have been done in our laboratory comparing the prostaglandin E analog misoprostol against placebo, cimetidine, and sucralfate. These studies showed that misoprostol protected the stomach significantly better than cimetidine or sucralfate. In the duodenum, misoprostol and cimetidine were equally effective. Comparison of secretory and anti-secretory doses of misoprostol reveal duodenal protection with the former but not with the latter, but gastric protection with both doses, suggesting that cytoprotective mechanisms other than acid suppression exist in the stomach in subjects taking prostaglandins. Adequately controlled and blind studies reported in the literature in arthritic patients are also reviewed, and it would appear that prostaglandins offer the best currently available method of providing mucosal protection for patients taking NSAIDs.

A review of gastric ulcer and gastroduodenal injury in normal volunteers receiving aspirin and other non-steroidal anti-inflammatory drugs.

Studies in normal volunteers from our laboratory and by other investigators have demonstrated that non-steroidal anti-inflammatory agents (NSAIDs) can significantly damage the gastroduodenal mucosa. This damage is maximal with plain and buffered aspirin products. The injury produced by non-aspirin NSAIDs in anti-inflammatory doses is less than with aspirin but depends primarily on the dosages used. Pro-drugs and enteric-coated aspirin tend to produce less injury. The incidence of gastric ulcer in 1064 normal volunteers studied in our laboratory over a period of 7 years is reviewed. Seventy-two (6.7%) normal subjects developed a gastric ulcer after 7 days of therapy with anti-inflammatory doses of these drugs. The largest number of ulcers were seen with plain and buffered aspirin, and the lowest number with the lower anti-inflammatory doses of the non-aspirin NSAIDs.