Hedva Marcus

Naloxone is protective against indomethacin-induced intestinal ulceration in the rat

Naloxone, an opiate antagonist, was reported to protect against stress ulcers in dogs and rats. We studied its possible protective effect against indomethacin-induced intestinal ulceration in the rat. Naloxone was indeed found to possess a marked protective effect on the intestinal mucosa (ulcer index 73.3 +/- 13.6 vs. 273.8 +/- 21.8, p less than 0.001). Naloxone was found to elevate basal intestinal mucosal prostaglandin E2 (p less than 0.001) and cyclic adenosine monophosphate levels (p less than 0.005) but was unable to overcome the inhibition of prostaglandin E2 caused by indomethacin. An increase of cyclic adenosine monophosphate levels was seen, however, even in the presence of indomethacin, suggesting that cyclic adenosine monophosphate, but not prostaglandins, may play a role in the protective effect of naloxone.

Ferritin-Bearing Lymphocytes in the Diagnosis of Breast Cancer

Four hundred forty‐seven women attending a breast clinic because of either suspicious lesions, anxiety about breast cancer, follow‐up after the removal of a benign breast lesion, or a family history of breast cancer had a routine test for percentage of ferritin‐bearing lymphocytes (FBL) in their peripheral blood. Among patients who received surgery following physical examination in the clinic and/or mammography, the test was positive in 40 of the 45 (89%) with Stage I; II carcinoma, 3 of 3 with Stage IV carcinoma, and only in 29 of the 97 (37%) with benign breast disease. The possible reasons for the poorer detection rate in Stage III carcinoma are discussed. The test, however, identified 2 cases of Stage I carcinoma, 1 of breast lymphoma, and 12 with premalignant lesions in those who were found normal on physical examination and mammography. Ferritin‐bearing lymphocyte results tended to become negative after surgical removal of the lesion, and became positive on recurrence of the tumor and appearance of metastases. The detection rate was maximized by combining the FBL test with the clinical modes of detection.

Sucralfate Is Protective against Indomethacin-induced Intestinal Ulceration in the Rat

The therapeutic effects of sucralfate on ulcerated gastric and duodenal mucosa is well known. There is, however, very little information about its effect on the mucosa of the small intestine. We studied the possible protective effect of sucralfate against indomethacin-induced intestinal ulceration in the rat. Sucralfate was found to possess a marked protective effect on the intestinal mucosa (ulcer index 23.16 +/- 6.58 vs. 225 +/- 36.37; p less than 0.001). Sucralfate elevated basal mucosal prostaglandin E2 generation (p less than 0.001), and partially overcame the inhibition of prostaglandin E2 synthesis caused by indomethacin (p less than 0.03), but had no effect on mucosal cAMP level. The effect of sucralfate on prostaglandin E2 content might partially explain its protective effect on the intestinal mucosa.

Effect of sucralfate on experimental colitis in the rat

The therapeutic effect of sucralfate on ulcerated gastric and duodenal mucosa is well known. There is, however, almost no information about its activity in colitis. Experimental colitis was produced in rats by rectal instillation of 1 ml of 10 percent acetic acid, and 1.5 ml of a 20 percent suspension of sucralfate was then administered every 12 hours for various lengths of time. Study animals and appropriate controls were killed after 3, 7, 10, or 14 days. The distal colons were studied macroscopically and histologically. Colonic prostaglandin E2 levels were measured in animals killed after 3, 7, 10, or 14 days. The macroscopic score was significantly improved 10 and 14 days after induction of colitis, although the histologic appearence was unchanged. Acetic acid administration increased and sucralfate treatment reduced prosta-glandin E2 levels in colitic animals on days 3 and 7, but not later. The present study supports a role for sucralfate in the treatment of colitis, but further studies on the mechanism of its effect and on its clinical activity are indicated.

The effect of opiates on the intestinal immune response to cholera toxin in mice

We studied the effect of opiates on the intestinal immunoglobulin A response in mice. C57BL mice were orally immunized by two doses of 10 micrograms of cholera toxin, 2 weeks apart. Experimental groups received subcutaneous injections of morphine, either 10 or 20 mg/kg/day, in two divided doses. Morphine was given for 4 days, starting 1 day prior to each cholera toxin dose. Intestinal secretions were collected by lavage 1 week after the last cholera toxin dose, and assayed for specific anticholera toxin antibody and total immunoglobulin A. Results were expressed as units of anticholera toxin per nanogram immunoglobulin A. It was found that morphine, 20 mg/kg/day, reduced the response from 30.9 +/- 3.11 to 9.78 +2- 1.42 units/ng (M +/- SEM; p less than 0.0001). 10 mg/kg/day of morphine slightly reduced the immune response to 21.38 +/- 3.51 units/ng (M +/- SEM), but failed to achieve statistical significance. Naloxone administration prior to morphine injections abolished the inhibitory effects of morphine. Morphine administration had no effect on the response to a booster dose of cholera toxin 3 months after the initial cholera toxin immunization and morphine administration. It is concluded that morphine has a significant inhibitory effect on the intestinal immune response, but does not effect long-term mucosal immunological memory. The effect is probably mediated by a specific opiate receptor, as it is blocked by naloxone. This effect may have clinical implications.

Oxygen radical scavengers are protective against indomethacin-induced intestinal ulceration in the rat.

Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used and may cause small intestinal inflammation and damage. Reactive oxygen metabolites are involved in various gastrointestinal inflammatory processes, but there is little information about their role in small intestinal mucosal damage induced by NSAIDs. We studied the effect of the oxygen radical scavengers superoxide dismutase (SOD), catalase (CAT), and allopurinol (ALLO) on indomethacin (INDO)-induced intestinal ulceration in the rat. Ulceration was produced by s.c. injection of 30 mg/kg of INDO 30 min after refeeding 24 h-fasted rats. Total ulcer area was measured 24 h after INDO administration. Study groups each consisted of eight animals which received either i.p. CAT, SOD, or both together, at a dosage of 5,000 U/kg each. All drugs were divided into five doses, given once an hour over a 4-h period, starting at the time of INDO injection. Another group received 100 mg/kg ALLO in two doses. Total ulcer area was reduced by SOD from 228 +/- 12 (sq mm, mean +/- SEM) to 153 +/- 12 (p < 0.001), by CAT to 179 +/- 13 (p < 0.01), and by both together to 95 +/- 5 (p < 0.0001). ALLO administration reduced the total ulcer area to 176 +/- 7 (p < 0.003). The protective effect of oxyradical scavengers supports the hypothesis that oxygen radicals are involved in the pathogenesis of INDO-induced small intestinal ulceration in the rat.

L-dopa is protective against indomethacin-induced small intestinal ulceration in the rat: Possible role of an α-2-adrenergic mechanism

Dopaminergic agents ameliorate experimentally induced gastroduodenal mucosal injury, but there is no information about their effect on small intestinal mucosa. We studied the effect of L-dopa and related substances on indomethacin-induced intestinal ulceration in the rat. Ulceration was produced by s.c. injection of 30 mg/kg indomethacin, 30 min after refeeding fasted rats. Total ulcer area was measured 24 hrs after indomethacin administration. L-dopa, 5 mg/kg given in two divided doses 5 h apart, starting 30 minutes before administration of indomethacin, was found to protect the small bowel mucosa against indomethacin- induced damage (ulcer area 122 +/- 5.5 vs 224.2 +/- 5.4 mm2, mean +/- SEM, p less than 0.006). Administration of 5 mg/kg haloperidol, a dopa antagonist, did not abolish the protective effect of L-dopa. On the other hand, yohimbine, an alpha-2-adrenoreceptor antagonist, almost completely abolished the protective effect (180.4 +/- 5.3 vs 122 +/- 5.5, p less than 0.004). Clonidine 20 micrograms/kg, an alpha-2-adrenoreceptor agonist, closely mimicked the protective effect of L-dopa (141.5 +/- 10.9 vs 224.2 +/- 5.4, p less than 0.006). All drugs were give i.p. in two divided doses, at the same schedule as described for L-dopa. The results demonstrate that L-dopa has a protective effect on indomethacin-induced small bowel injury in the rat. The protective effect is probably mediated through stimulation of alpha-2-adrenoreceptors.

Therapeutic Effect of Colloid Bismuth Subcitrate in Experimental Colitis in the Rat

Colloid bismuth subcitrate (CBS) has a protective effect on ulcerated gastric and duodenal mucosa. To investigate its effect on large intestinal mucosal injury, we used acetic acid-induced colitis in the rat. Colitis was produced in male Wistar rats by rectal instillation of 1 ml of 10% acetic acid followed immediately by 1.5 ml of NaCl 0.9% (saline) enema. 1.5 ml of saline containing 240 mg of CBS or saline alone were then administered rectally every 24 h for 5 days. Another group of animals received CBS only. On the sixth day the distal colon was examined macroscopically and histologically using a 0 (normal) to 3 (necrosis) score. Prostaglandin E2 (PGE2) was measured by RIA (ng/mg protein). CBS significantly reduced both macroscopic and microscopic scores from 2.09 to 1.25 (p < 0.02) and from 2.4 to 1.08 (p < 0.02) respectively. It also induced a significant reduction in PGE2 from 1.6 to 0.57 (p < 0.004) in the inflamed colonic mucosa. The significant protective effect of topical CBS, which is accompanied by a reduction of PGE2, indicates that CBS may have a role in the treatment of colitis.

Pentagastrin Protects the Proximal Small Intestine against Indomethacin-induced Ulcers in the Rat

The possible protective effects of pentagastrin on indomethacin-induced small intestinal ulceration were investigated in rats. Ulcers were induced by subcutaneous injection of 30 mg/kg indomethacin, 30 min after refeeding rats fasted for 24 h. Administration of pentagastrin at a dose of 250 or 400 micrograms/kg i.p., 3 h prior to refeeding, reduced total ulcer area from 27.6 +/- 6.5 to 7.2 +/- 1.97 mm2 (mean +/- SEM; p less than 0.02) in the proximal small intestine only. Cyclic adenosine monophasphate, but not prostaglandin E2 levels were significantly raised by 250 micrograms/kg pentagastrin (0.15 +/- 0.05 vs. 0.38 +/- 0.07 pmol/mg protein; mean +/- SEM; p less than 0.02) in the same intestinal segment.

Total parenteral nutrition-associated cholestasis after selective damage to acinar zone 3 hepatocytes by bromobenzene in the rat

Total parenteral nutrition is known to cause cholestasis, but the hepatic site of this effect has not been determined. The purpose of our study was to observe the effect of TPN on bile flow and bile salt secretion rate in rats after selective damage to acinar zone 3. Bromobenzene, 3.8 mmol/kg, was injected i.p., and the animals were studied 48 hours later. Experimental groups received either parenteral nutrition or saline for 2 hours. Bromobenzene caused selective damage to acinar zone 3 hepatocytes, and reduced baseline bile flow (23.99 +/- 1.09 vs 37.2 +/- 1.66, mean +/- SEM, microliter/min/kg, p < 0.001). Bromobenzene had no effect on bile salt secretion rate. Total parenteral nutrition decreased bile flow in the bromobenzene treated groups, despite the selective hepatic damage to acinar zone 3 (20.54 +/- 1.07 vs 23.28 +/- 1.63, mean +/- SEM, p < 0.001). Total parenteral nutrition reduced bile salt secretion rate in healthy animals, but this reduction was not seen in bromobenzene treated rats. Our results suggest that bile flow reduction in response to total parenteral nutrition is mediated through an effect on acinar zones 1 and 2, as this reduction is still observed after zone 3 destruction by bromobenzene. Zone 3 hepatocytes may be involved in the effect of parenteral nutrition on bile salt secretion, as the reduction in secretion rate seen in healthy animals was not observed in bromobenzene treated rats.