sulindac and Gastrointestinal-Hemorrhage

Gastric injury resulting from nonsteroidal anti-inflammatory drugs is thought to require direct contact of the drug with the gastric mucosa. An inactive form of a drug (as a prodrug) should protect against mucosal damage. Because sulindac sulfoxide has little effect on prostaglandin synthesis until it is reduced to sulindac sulfide after absorption, we performed a double-blind, crossover endoscopic study in 15 normal subjects to compare the prodrug sulindac sulfoxide (200 mg b.i.d.), the active sulfide metabolite sulindac sulfide (100 mg b.i.d., which yields similar sulfide blood concentrations), a positive control (aspirin, 650 mg q.i.d.), and a negative control (placebo). Each drug was taken for 1 week and gastric mucosa were endoscopically assessed before and after 2, 5, and 7 days of dosing. Aspirin predictably damaged the gastric mucosa, whereas the effects of sulindac sulfoxide and sulindac sulfide could not be distinguished from those of the placebo. We conclude that sulindac sulfoxide as a prodrug is not directly responsible for the reduced severity of gastric mucosal lesions. Both sulindac sulfoxide and sulindac sulfide are poorly soluble in acid gastric contents and the reduced damage may relate to the inability of high concentrations of the drug to enter gastric mucosal cells.

Topics: Administration, Oral; Adult; Aspirin; Double-Blind Method; Gastric Mucosa; Gastrointestinal Hemorrhage; Gastroscopy; Humans; Indenes; Male; Random Allocation; Sulindac

We have examined concurrent gastric secretory rates and bleeding by a gastric wash technique during treatment with naproxen, sulindac, and placebo. Twelve subjects, in each of 4 treatment periods, took either placebo, sulindac 200 mg, naproxen 250 mg, or naproxen 375 mg, twice a day for four days. Of the resultant 192 days (12 subjects, 4 drugs, 4 days/drug), two thirds of all days showed bleeding at a rate less than 0.5 ml/day; this low rate of bleeding was seen with all treatments. In spite of this minor bleeding, we were able to show statistically significantly less bleeding with placebo than with drugs; placebo never resulted in a maximum rate of bleeding for any subject. Distinctions between drugs on the basis of bleeding, however, were not possible. Correlations between outputs of acid and chloride were not significantly affected by any of these drugs. In contrast to previous results with aspirin, no correlation between rates of bleeding and gastric secretion could be established. The low water solubility of these drugs at the pH of gastric contents may account for their causing very little bleeding. In effect, the greater the gastric secretion of acid the less the absorption through the gastric mucosa.

Topics: Aspirin; Gastric Acid; Gastric Mucosa; Gastrointestinal Hemorrhage; Humans; Indenes; Intestinal Absorption; Male; Naproxen; Placebos; Sulindac

Unlike other nonsteroidal antiinflammatory agents, benoxaprofen has only minor antiprostaglandin synthetase activity. This property may explain the lack of gastric irritation seen in animal studies. To evaluate gastric irritation in man, benoxaprofen was compared with aspirin, naproxen, ibuprofen, sulindac, and indomethacin by measuring fecal blood loss with chromium-51 tagged red blood cells in randomized double-blind crossover and parallel studies. Benoxaprofen produced significantly less blood loss than aspirin, naproxen, or indomethacin, and less blood loss than ibuprofen or sulindac. Benoxaprofen also caused the fewest gastrointestinal complaints.

Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Aspirin; Benzoxazoles; Clinical Trials as Topic; Double-Blind Method; Gastrointestinal Hemorrhage; Humans; Indomethacin; Melena; Naproxen; Propionates; Prostaglandins; Sulindac; Time Factors

Newer nonsteroidal antiinflammatory agents (NSAI's) such as ibuprofen, neproxen, fenoprofen, and tolmetin have broadened the therapeutic choice and increased the chances of providing optimum arthritis control, but require careful assessment of the possibilities for unwanted drug effects when long-term therapy is required. A review of the literature on the gastrointestinal effects of the promising newer NSAIs, as compared with the older agents, aspirin, indomethacin, and phenylbutazone, is presented, highlighting animal toxicology and human adverse reaction surveillance data and the evidence for various suggested pathophysiological mechanisms.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Aspirin; Clinical Trials as Topic; Diclofenac; Double-Blind Method; Drug Evaluation; Fenoprofen; Gastric Mucosa; Gastritis; Gastrointestinal Hemorrhage; Gastroscopy; Humans; Ibuprofen; Ketoprofen; Naproxen; Phenylbutazone; Registries; Sulindac; Tolmetin

We report the first case in a preterm infant given oral sulindac for treatment of symptomatic patent ductus arteriosus who subsequently developed severe acute haemorrhagic gastritis leading to disseminated intravascular coagulation, massive pulmonary haemorrhage and death. The postmortem examination suggested that the mechanism was likely a direct irritant insult causing ischaemia on the gastric mucosa. Although sulindac is supposed to be a renal-sparing non-steroidal anti-inflammatory prodrug associated with minimal renal and gastrointestinal adverse effects, clinicians should be alerted to this potential life-threatening complication in preterm infants. Until the question of safety could be adequately addressed, the use of sulindac for ductal closure should remain experimental.

Topics: Cyclooxygenase Inhibitors; Diseases in Twins; Ductus Arteriosus, Patent; Fatal Outcome; Gastritis; Gastrointestinal Hemorrhage; Humans; Infant, Newborn; Infant, Premature; Irritants; Sulindac

To assess the relative rate or upper gastrointestinal (UGI) tract bleeding associated with nonsteroidal anti-inflammatory drugs (NSAIDs), we performed a retrospective cohort study using 1980 billing data from all Medicaid patients in the states of Michigan and Minnesota. The rate of UGI tract bleeding in the 30 days following each drug exposure was examined in the 88,044 patients dispensed only one of seven NSAIDs. The rate of UGI tract bleeding differed significantly among users of these drugs. Stratification and logistic regression were used to adjust for multiple potential confounding factors, without substantive changes in the results. An alcohol-drug interaction was found. Sulindac users had the highest rate of UGI tract bleeding, and it was the only drug statistically different from ibuprofen. When the average daily dose of sulindac received was divided by the maximum recommended daily dose, it was notably higher than those for other drugs. Repeated analyses using data from 1982 confirmed these results. We conclude that there are significant and consistent differences in the incidence of UGI tract bleeding associated with the use of NSAIDs in this population.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Drug Prescriptions; Female; Gastrointestinal Hemorrhage; Humans; Male; Retrospective Studies; Sulindac