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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

Background : Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxy- genase), 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

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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.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.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 (P0.001).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.

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.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.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.The percentage of subjects who developed a mucosal score/= 2 in the MK-0966 group (12%) was significantly lower (P0.001) 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 (P0.0001) reduced baseline thromboxane B2 levels. All treatments were generally well tolerated.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.

The effect on the gastroduodenal mucosa of alcohol combined either with aspirin or ibuprofen was studied in 60 normal volunteers. The volunteers were divided into six groups comprised of 10 subjects receiving ibuprofen, placebo, or aspirin with or without alcohol. Medications consisted of 1) three 325-mg aspirin tablets, or three identical placebo tablets, 2) one 600-mg ibuprofen tablet, and 3), three ounces of 100 proof vodka diluted in 6 ounces of orange juice, or alcohol placebo made by diluting 3 ounces of water in orange juice. All subjects received 4 doses over a 24-hr period and underwent endoscopic examination the following morning. The gastroduodenal mucosa was graded according to a 0 to 4 + scale. Aspirin caused considerably greater duodenal and gastric damage than did either ibuprofen or placebo. The addition of alcohol to all drugs increased the damage seen in the stomach but not to a significant degree; this effect was slightly more pronounced with ibuprofen than with placebo or aspirin and approached significance (0.1 greater than p greater than 0.05). These results are compatible with alcohol being a mild damaging agent or a potentiating agent for damage from other drugs.

Forty endoscopically normal healthy subjects were randomized to receive either BID salsalate (3500 mg/day) or BID naproxen (750 mg/day) for 14 days followed by repeat endoscopic examination. Gastroduodenal lesions were found in 55% (11/20) of the subjects taking naproxen, and 10% (2/20) of those taking salsalate (p = 0.002). Twenty-five percent (5/20) of the subjects taking naproxen and none of the subjects taking salsalate were noted to have severe gastric injury (p = 0.003). There was no difference between the 2 groups in subjective gastrointestinal system adverse experiences. Overall, 95% (19/20) of subjects taking salsalate reported at least 1 adverse experience compared with 60% (12/20) of those taking naproxen (p = 0.02). This was due primarily to the higher number of subjects taking salsalate reporting reversible tinnitus or hearing loss. There was no significant treatment difference in adverse experiences reported for any other organ system. The results of our study support previous observations in patients with rheumatoid arthritis that salsalate produces less gastroduodenal mucosal toxicity than the widely used antiinflammatory agent, naproxen.

Forty-five normal volunteers were divided into 3 equal groups, each receiving indomethacin or placebo once daily in he evening as a capsule or suppository for 10 days. The dose of indomethacin was 50 mg for the first 5 days and 100 mg for the second 5 days. Endoscopic evaluation of the gastric mucosa was carried out on days 1, 6 and 11. It was found that indomethacin capsules caused significantly more gastric irritation than indomethacin suppositories (p less than .01) or placebo (p less than .0001). No significant difference was found in the incidence of gastric injury observed in the indomethacin suppository and placebo groups.

To assess the effects of various nonsteroidal antiinflammatory drugs on gastroduodenal mucosa, 72 normal men were administered either etodolac, indomethacin, ibuprofen, naproxen, or placebo for 7 days. Gastric and duodenal mucosa were scored before and after treatment by direct endoscopy and evaluation of photographs taken during endoscopy. Subjects treated with indomethacin, ibuprofen, and naproxen had significantly worse direct gastric scores, and those treated with indomethacin and naproxen also had significantly worse direct duodenal scores, when compared with pre-treatment and placebo scores. Subjects given either of 2 doses of etodolac had gastric and duodenal scores comparable to pretreatment and placebo scores. The direct gastric scores of the etodolac groups were significantly better than the scores of subjects receiving indomethacin, ibuprofen and naproxen. Similar results were obtained when endoscopy photographs were scored.

Ibuprofen, a commonly proscribed nonsteroidal anti-inflammatory drug that is also available in many countries, including the United States, without a prescription, is known to cause hemorrhage and erosion of the gastroduodenal mucosa. This study was conducted to compare the efficacy of 200, 100, and 50 micrograms of misoprostol and placebo administered qid for 6 days, with a final dose on the morning of the 7th day, in the prevention of gastric and duodenal lesions induced by the concurrent administration of 800 mg of ibuprofen qid. A total of 120 healthy subjects with endoscopically normal gastric and duodenal mucosae were enrolled in the study. The endoscopic examination was repeated 2 h after the final dose on day 7, and the mucosae were graded on a 0 to 4+ scale. In the stomach, all three misoprostol groups were significantly more protective than placebo and did not differ significantly from each other. In the duodenum, the endoscopic scores of the 200- and 100-micrograms misoprostol groups, but not the 50-micrograms group differed significantly from placebo. The 200- and 100-microgram groups did not differ significantly from each other, but both differed from the 50-micrograms group for duodenal mucosal injury. Subjective symptoms thought to be primarily attributable to the NSAID (e.g., pain, indigestion/heartburn and nausea) were recorded by each subject in a diary. Subjects in the 200-micrograms misoprostol group attained the greatest degree of mucosal protection and had a significantly higher incidence of indigestion/heartburn and abdominal pain than the placebo group. One can conclude that misoprostol in both antisecretory (200- and 100-micrograms) and non-antisecretory (50-micrograms) doses protects the gastric mucosa from injury from high anti-inflammatory doses of ibuprofen (3200 mg/day). Only the antisecretory doses (100 and 200 micrograms qid) were effective in the duodenum, suggesting that acid suppression is necessary for mucosal protection to occur in the duodenum.

In a series of previous studies, we showed that misoprostol protects the gastric and duodenal mucosae against ulceration seen with the administration of both aspirin and the nonsteroidal antiinflammatory drug tolmetin. The purpose of this study was to confirm, in addition, that misoprostol protects the mucosae against aspirin-induced damage and, for the first time, to compare its cytoprotective properties with those of sucralfate. Thirty healthy volunteers were randomized into three equal groups receiving either misoprostol 200 micrograms, sucralfate 1 g, or placebo, co-administered with 650 mg of aspirin, four times a day for 7 days. All subjects had endoscopically normal mucosae on entry and were reendoscoped 2 h after a single final dose on day 7. The mucosae were graded on a 0-4 scale as follows: 0 = normal, 1 = single hemorrhage or erosion, 2 = 2-10 hemorrhages or erosions, 3 = 11-25 hemorrhages or erosions, 4 = more than 25 hemorrhages or erosions or an invasive ulcer of any size. Utilizing a previously established criterion of a score of 2 or less as a clinically significant degree of protection to the gastric mucosae, we found that the success rate for misoprostol was 100% (10/10), compared to 20% (2/10) for sucralfate and 0% (0/10) for placebo. Misoprostol was statistically significantly superior to both sucralfate (p = 0.0001) and placebo (p = 0.00001), with 95% confidence intervals on the difference in success rates between misoprostol and sucralfate and between misoprostol and placebo of (44%; 100%) and (61%; 100%), respectively. In the duodenum, nine of 10 subjects taking misoprostol showed no damage (0 grade), whereas this was seen in only five sucralfate and three placebo patients. Misoprostol was significantly superior to placebo (p = 0.020) and marginally superior to sucralfate (p = 0.141) with confidence intervals of (29%; 91%) and (-5%; 67%), respectively. Adverse experiences were minor and did not differ in the three groups.

Twenty-five normal volunteers were randomized into five equal parallel groups. Groups I received ibuprofen (2,400 mg./day); group II received tolmetin (2,000 mg./day); group III received indomethacin (150 mg./day); group IV received naproxen (750 mg./day) and group V received placebo (four tablets daily). All drugs were given on a q.i.d. basis except naproxen which was given b.i.d. The doses selected represented the manufacturer's highest recommended dosage for the treatment of arthritic disorders. A single-blind technic was used in which the investigators were unaware of which drug each volunteer was taking. Upper gastrointestinal endoscopy and photography were carried out before and after seven days of administration of each medication. Gastric and duodenal mucosal injury was graded on a 0-4 + scale. Three of the four drugs studied produced essentially equal gastric and duodenal mucosal injury with tolmetin producing the most damage followed by naproxen and indomethacin. Ibuprofen produced gastric mucosal injury equivalent to that seen with naproxen and indomethacin but no duodenal mucosal injury was seen with this drug. Extremely poor correlation was found between subjective symptomatology and endoscopic findings.