The ulcerogenic gastrointestinal side-effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the more serious complications in patients taking these drugs. It is known that prostaglandin (PG) deficiency plays a critical role in the pathogenesis of NSAID-induced gastric injury. The results presented in the article suggest that NSAIDs at ulcerogenic doses induce an increase in glucocorticoid production, which in turn helps the gastric mucosa to resist the harmful action of NSAID treatment. The gastroprotective action of glucocorticoids during NSAID treatment may be provided by their maintenance of glucose homeostasis, gastric blood flow and mucus secretion and their attenuation of enhanced gastric motility and microvascular permeability. We conclude that glucocorticoids produced in response to NSAIDs are natural defensive factors in maintaining the gastric mucosa integrity during PG deficiency caused by NSAIDs.

Of all the arachidonic acid metabolites, only prostaglandin E (PGE) has been shown to have a clear role in the regulation of cellular and humoral immune responses. In cellular immune responses such as T cell proliferation, lymphokine production, and cytotoxicity, PGE usually acts as a feedback inhibitor of the response. This is also true of macrophage and natural killer cytotoxicity. In some instances PGE is responsible for cellular activation rather than inhibition. This is clearest in the control of humoral immunity, where PGE production is a necessary component in the generation of some type of T suppressor cells. Disturbances in immune function found in several human conditions and diseases have been linked to changes in PGE mediated immunoregulation. Either increased production of PGE or increased sensitivity to PGE results in depressed cellular immunity. Conversely drugs which inhibit PGE production act as stimulants of cellular immune function in vitro and in vivo.

We enrolled 61 neonates of 600 to 1250 gm birth weight with evidence of low-grade intraventricular hemorrhage at 6 to 11 hours of age in a prospective, randomized, placebo-controlled trial to test the hypothesis that indomethacin (0.1 mg/kg given intravenously at 6 to 12 postnatal hours and every 24 hours for two more doses) would prevent extension of intraventricular hemorrhage. Twenty-seven infants were assigned to receive indomethacin; 34 infants received saline placebo. There were no significant differences between the two groups in birth weight, gestational age, sex, Apgar scores, percentage of infants treated with surfactant, or distribution of hemorrhages at the time of the first cranial sonogram (echo-encephalogram). Within the first 5 days, 9 of 27 indomethacin-treated and 12 of 34 saline solution-treated infants had extension of their initial intraventricular hemorrhage (p = 1.00). Four indomethacin-treated and three saline solution-treated infants had parenchymal extension of the hemorrhage. Indomethacin was associated with closure of a patent ductus arteriosus by the fifth day of life (p = 0.003). There were no differences in adverse events attributed to indomethacin. We conclude that in very low birth weight infants with low grade intraventricular hemorrhage within the first 6 postnatal hours, prophylactic indomethacin therapy promotes closure of the patent ductus arteriosus and is not associated with adverse events, but does not affect the cascade of events leading to parenchymal involvement of intracranial hemorrhage.

Inhibition of prostaglandin synthesis constricts the ductus arteriosus in fetal lambs in utero. We administered the inhibitors, aspirin or indomethacin to 18 premature infants with patent ductus arteriosus, and assessed the effects clinically and by echocardiography (left atrial/aortic-root ratio). After aspirin (20 mg per kilogram, every six hours for four doses) the ductus closed permanently in one infant within 24 hours; in another, constriction occurred with clinical improvement, and the third did not respond. In five infants given 0.3 mg per kilogram of indomethacin, complete closure occurred within one day; two of them, who received three doses had an elevated serum creatinine for one week. In one infant the ductus reopened, requiring a second dose of indomethacin 11 days after the first. Ten infants received 0.1 mg per kilogram of indomethacin, and closure occurred within 24 to 30 hours in eight. One had a soft murmur for four days, and one did not respond to two doses of indomethacin. A murmur reappeared after three to seven days in three infants but only one required further treatment. In infants receiving a single dose of 0.3 mg per kilogram, or one or more doses of 0.1 mg per kilogram, renal function was unaltered.

The prostaglandins affect smooth-muscle tone of the ductus arteriosus. Patent ductus often complicates the clinical course of prematurely born infants with respiratory-distress syndrome. In the present study, a single oral or rectal dose of a potent inhibitor of prostaglandin synthesis, indomethacin, was administered to six consecutive premature infants with the syndrome who would otherwise have undergone surgical ligation of the patent ductus. Within 24 hours all the clinical symptoms and physical, echocardiographic and radiographic signs attributable to substantial left-to-right shunting through a patent ductus arteriosus dramatically and permanently disappeared. A transient reduction in renal function was observed in two infants in whom sustained ill-effects did not occur. The observation that constriction and closure of the patent ductus arteriosus may be induced pharmacologically raises important possibilities for the improved treatment of the respiratory-distress syndrome.

The objective of this study was to characterize the mechanisms of acute and chronic intestinal mucosal injury and inflammation induced by subcutaneously injected indomethacin (Indo). One injection of Indo (7.5 mg/kg) produced acute injury and inflammation in the distal jejunum and proximal ileum that were maximal at three days and completely resolved within one week. Two daily subcutaneous injections of Indo produced a more extensive and chronic inflammation that lasted in an active form in more than 75% of the rats for at least two weeks. Epithelial injury, as measured by enhanced mucosal permeability, was significantly elevated only at one day in the acute model (one injection) but was persistently elevated in the chronic model (two injections). Bile duct ligation completely attenuated increased mucosal permeability in the acute model, however, depletion of circulating neutrophils had no effect. Neither Indo (0-0.1 mg/ml) nor normal bile was cytotoxic to cultured rat intestinal epithelial cells; however, they synergistically promoted significant cytotoxicity. Bile collected from rats treated with Indo was cytotoxic towards the epithelial cells in a dose-dependent manner. Sulfasalazine and metronidazole (100 mg/kg/day, both) attenuated enhanced mucosal permeability in the chronic model. Massive bacterial translocation into the mesenteric lymph nodes, liver, and spleen following two injections of Indo was significantly attenuated by metronidazole. We conclude that:(1) a single injection of Indo produces acute intestinal mucosal injury and inflammation that resolve completely within three to seven days, whereas two daily injections of Indo produce both acute and chronic injury and inflammation,(2) enterohepatic circulation of Indo is important in promoting the acute phases of injury and inflammation,(3) circulating neutrophils do not play a role in the pathogenesis of this model, and (4) endogenous bacteria play an important role in exacerbating and/or perpetuating the chronic phases of injury and inflammation.

Indomethacin is a potent agent in the treatment of premature labor, but its use has been limited because of concern about its constrictive effects on the fetal ductus arteriosus. To study these effects we used serial fetal echocardiography in 13 pregnant women in premature labor who received indomethacin according to three different dose schedules, ranging from 100 to 175 mg per day, for a maximum of 72 hours. The gestational ages of the fetuses ranged from 26.5 to 31.0 weeks. The detection of ductal constriction in 7 of the 14 fetuses by echocardiography led to the discontinuation of indomethacin. Three fetuses also had tricuspid regurgitation. There was no statistically significant difference between the mean (+/- SEM) gestational age of the fetuses with ductal constriction and that of those without constriction (29.3 +/- 0.59 and 28.4 +/- 0.52, respectively). There was no relation between serum indomethacin levels in the mothers and ductal constriction. In all seven fetuses affected, ductal constriction had resolved by the time they were restudied 24 hours after the discontinuation of indomethacin. Persistent fetal circulation was not detected in any of the 11 neonates studied after delivery. Indomethacin used to treat premature labor appears to cause transient constriction of the ductus arteriosus in some fetuses, even after short-term use.

Eicosanoids may be important factors for tumor cell proliferation, metastatic formation, and development of cancer cachexia. The present study has evaluated the effect of anti-inflammatory treatment on tumor progression in clinical cancer. Patients (n = 135) with insidious or overt malnutrition due to generalized malignancy (various kinds of solid tumors) and an expected survival of more than 6 months were randomized by a computer-based algorithm to receive placebo, prednisolone (10 mg twice daily), or indomethacin (50 mg twice daily) p.o. until death. Patient groups were stratified in the randomization procedure for sex, tumor type, stage, nutritional state, and previous tumor treatment, and biochemical, physiological, and some functional variables (Karnowsky index, fatigue and pain score). A majority of these variables was then registered during the follow-up. Indomethacin and prednisolone treatment maintained Karnowsky index, while placebo-treated patients experienced a decreased index. Indomethacin-treated patients suffered less pain and consumed less additional analgetics compared to the other patient groups. Indomethacin prolonged mean survival compared to placebo-treated patients from 250 +/- 28 days to 510 +/- 28 days (P < 0.05). Survival analysis on observations from all patients treated with either indomethacin or prednisolone demonstrated a significantly prolonged survival by anti-inflammatory treatment compared to placebo treatment (log rank, P < 0.03). The results suggest that not only may prostaglandin synthesis inhibition offer palliative support to patients with solid advanced cancer, but it may also impact on pathways that ultimately determine outcome.

Renal function is known to be abnormal in patients with cirrhosis. Diminished cortical blood flow due to active renal vasoconstriction is present. Renal prostaglandins, potent vasodilators, could be released by the kidney in an attempt to maintain renal blood flow. This possibility was investigated by measuring the effect of indomethacin, an inhibitor of prostaglandin synthetase, in patients with alcoholic liver disease. Administration of indomethacin reduced the effective renal plasma flow (ERPF) and creatinine clearance by 23% and 19%, respectively (P less than 0.001), and increased serum creatinine by 29%(P less than 0.001). The response to indomethacin was variable (fall in ERPF (+)7.8% to (-)67%), but was greatest in patients with ascites. Eighty percent of ascitic patients had a greater than 15% fall in ERPF after administration of indomethacin compared with 20% of nonascitic patients (P less than 0.025). An infusion of prostaglandin A1 in 13 patients corrected the decrease in ERPF and creatinine clearance that had followed the administration of indomethacin. The administration of indomethacin caused a significant fall in plasma renin activity, 8.2 +/- 2.5 to 3.6 +/- 1.4 ng/ml/hr (P less than 0.025). The fall in plasma renin activity occurred when ERPF was depressed maximally, suggesting that endogenous prostaglandins exert more control over renin release than does ERPF. Prostaglandins appear to be an important factor in maintaining renal blood flow in patients with cirrhosis and sodium retention.

125Iothalamate and 131I-hippuran clearances, sodium excretion and plasma renin activity (PRA) before and during indomethacin administration in an oral dose of 3 x 50 mg/day were studied in volunteers with a normal or reduced kidney function, as well on non-sodium-restricted as on sodium-restricted diet. Indomethacin induced a temporary sodium and water retention and a decrease in glomerular filtration rate. It also lowered PRA. The latter phenomenon did not depend on sodium retention and was present within 2 h after an oral dose of 50 mg. The results may be explained by indomethacin-induced inhibition of prostaglandin synthesis.