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Biomedical subjects

R A Erickson

Publications and source records attributed to R A Erickson.

At least 37 records · Page 2Linked to original sources
PubMed1992

Effect of difluoromethylornithine (DFMO) on NSAID-induced intestinal injury in rats.

Combination therapy with difluoromethylornithine (DFMO) and a nonsteroidal antiinflammatory drug (NSAID) has been proposed for the chemoprevention of colonic neoplasia. The purpose of this study was to examine whether DFMO would affect NSAID-mediated intestinal injury. Male Sprague-Dawley rats were gavaged with 20 mg/kg of indomethacin, after seven days of exposure to drinking water with or without 2% DFMO. The rats were killed 24 or 48 hr later, and the small intestine removed for macroscopic and microscopic quantitation of intestinal injury by computerized image analysis. Seven days of DFMO alone had no effect on overall mucosal thickness, but did increase the depth of proximal intestinal crypts. Forty-eight hours after indomethacin, DFMO treatment decreased the number of indomethacin-induced ulcers and percent of the surface area ulcerated. However, DFMO also decreased the mucosal thickness, villus height, and crypt depth in indomethacin-treated rats. Thus although DFMO decreases macroscopic intestinal ulceration by indomethacin, the reduction in villus and crypt height suggests that it also impairs the mucosa's ability to recover from microscopic indomethacin-induced damage. This study shows DFMO does impact NSAID-mediated intestinal injury and therefore human trials with combinations of DFMO and NSAIDs should include monitoring for small intestinal injury.

Animals↗
PubMed1992

16,16-Dimethyl prostaglandin E2 reduces bile acid-mediated intestinal vascular injury in rats.

To examine the effects of prostaglandin on bile acid-mediated intestinal vascular injury, male rats were given 50 mg/kg of fluorescein isothiocyanate (FITC)-stained dextran 70 or 25 mg/kg of Evans Blue intravenously. Before intestinal injury with 45-minute perfusion of 5 mmol/L chenodeoxycholic acid, rats received 16,16-dimethyl prostaglandin E2 (5 micrograms/kg intravenously or 0.5 micrograms/mL or in the perfusate for 15 minutes or vehicle). FITC-dextran clearance from the blood to the intestinal lumen and tissue Evans Blue content were used as measures of intestinal vascular injury. Morphological mucosal injury was assessed by transmission electron microscopy and quantitative histological analysis. Chenodeoxycholic acid perfusion caused villous denudation and shortening of and ultrastructural damage to villous venules. Functional vascular injury was evidenced by a 10-fold increase in the rate of FITC-dextran blood-to-lumen clearance and a 3-4-fold increase in tissue Evans Blue content. Pretreatment with either intravenous or intraluminal 16,16-dimethyl prostaglandin E2 reduced FITC-dextran clearance by 70%-80% and tissue Evans Blue content by 50%. However, only luminal prostaglandin reduced superficial mucosal morphological injury, possibly because of differences in the local concentrations of 16,16-dimethyl prostaglandin E2 or chenodeoxycholic acid or because of superficial mucosal protection and injury being, at least in part, independent of mucosal microvascular injury and protection.

16,16-Dimethylprostaglandin E2↗
PubMed1991

Chronic omeprazole treatment increases duodenal susceptibility to ethanol injury in rats.

To test whether omeprazole would increase the susceptibility of the duodenum to damage, 200 to 250-g male Sprague-Dawley rats were given 10 mg/kg of omeprazole (Losec) by gavage every morning for 29 days. Control rats were given gavage buffer alone. After fasting overnight, half the rats received 10 mg/kg indomethacin intraperitoneally; then all rats were given 2 ml of 50% ethanol by gavage. Three hours later the rats were killed and the stomach and duodenum removed and histologic injury to the duodenal mucosal was quantitated. In omeprazole pretreated rats, gavage with ethanol resulted in a significant twofold worsening of duodenal injury. Pretreatment with indomethacin to decrease endogenous prostaglandin production resulted in more severe ethanol-induced duodenal injury in both groups; however, there were no longer statistically significant differences between the omeprazole and control groups. Measurement of duodenal mucosal synthesis of prostaglandin E2 showed no difference between the omeprazole and control groups. Thus chronic administration of omeprazole appears to increase the susceptibility of the duodenal mucosa to ethanol injury in rats. The mechanism of this effect is as yet unknown but does not appear to be prostaglandin-mediated.

Animals↗
PubMed1991

The effect of portal hypertension on indomethacin-induced small intestinal ulceration in the rat.

The purpose of this study was to determine whether portal hypertension potentiates intestinal ulceration induced by indomethacin. Portal hypertension was produced in male Sprague-Dawley rats by two-staged ligation of the portal vein. Sham-operated rats were used as controls. The rats were given 20 mg/kg of indomethacin intragastrically, 7 and 14 days, respectively, after complete portal vein ligation. Forty-eight and 72 h after indomethacin, portal pressures were measured and the whole small intestine removed for quantitative measurement of the percent of the mucosa ulcerated by computerized image analysis. There were no differences in the area of ulceration between the portal hypertensive and sham-operated rats at either 7 or 14 days, despite the presence of significant portal hypertension. Portal hypertension does not appear to potentiate small intestinal ulceration induced by indomethacin in rats.

Animals↗
PubMed1991

Is the small intestinal epithelium truly "tight" to inulin permeation?

In this study, we evaluated the "leakiness" of intestinal epithelium through examination of small intestinal absorption of inulin in vivo by perfusing rat jejunum with 10 microM inulin. In physiological conditions, we found significant absorption of inulin at a rate of 44.6 nmol.100 cm-1.h-1 or absorption of 14.7%.100 cm-1.h-1 of the amount perfused. Increasing water flux by changing the luminal osmolarity resulted in linear (y = 31.1 + 2.4x, r = 0.97) increase in absorption of inulin, indicating a significant convective component of inulin absorption. There was large permeation of inulin at net water secretion and at zero net water fluxes (31.1 nmol.100 cm-1.h-1), indicating significant absorption of inulin by diffusive movement as well. The small intestinal tissue retention of inulin occurred rapidly within the first 15 min of perfusion, and the total tissue retention remained unchanged thereafter at approximately 10.8 nmol/100 cm. 16,16-Dimethylprostaglandin E2 decreased water flux, whereas cyclooxygenase inhibitors, indomethacin and acetylsalicylate, increased water flux. Inulin absorption closely paralleled changes in water flux induced by these agents. Taurocholate also caused parallel decrease in water and inulin absorption. Varying the resistance of unstirred water layer with changing luminal flow rate, the addition of mucolytic agent acetylcysteine, or alterations of luminal pH did not affect water or inulin absorption. We conclude that inulin permeates the small intestinal epithelium in significant amounts under normal physiological conditions, presumably through the paracellular pathways utilizing aqueous channels.

16,16-Dimethylprostaglandin E2↗
PubMed1990

Cimetidine reduces bile acid-mediated small intestinal mucosal injury in rats in vivo.

Whether cimetidine has protective effects on the gastrointestinal mucosa independent of its ability to reduce gastric acid secretion is still controversial. To study this, rats had small intestinal mucosal injury induced in vivo by perfusion with 5 mM chenodeoxycholic acid. Control rats were compared to rats receiving either intraperitoneal or intravenous pretreatment with 50 mg/kg cimetidine or intraluminal pretreatment with 0.5 mM cimetidine. Mucosal injury was assessed by measuring villus tip epithelial cell denudation by computerized quantitative morphology. Intraperitoneal cimetidine reduced the average denudation/villus (micrometers) caused by 45-min perfusion with chenodeoxycholic acid: control = 39.1 +/- 7.7 (SEM), intraperitoneal cimetidine = 20.8 +/- 3.5 (P less than 0.05). Additionally, both intraluminal and intravenous cimetidine reduced villus denudation caused from 30 min perfusion with chenodeoxycholic acid: control = 62.5 +/- 5.8, intravenous cimetidine = 42.6 +/- 4.7 (P less than 0.05), intraluminal cimetidine = 44.6 +/- 7.2 (P less than 0.05). The observation that reduced mucosal injury is observed in an in vivo model that is independent of gastric acid supports the conclusion that cimetidine indeed has acid-independent protective properties.

Animals↗
PubMed1990

Effect of portal hypertension on in vivo bile acid-mediated small intestinal mucosal injury in the rat.

This study's purpose was to determine whether portal hypertension adversely affects small intestinal mucosal injury. Portal hypertension was produced in male Sprague-Dawley rats by two-stage ligation of the portal vein. Sham-operated rats were used as controls. Two weeks later, intestinal injury was produced by in vivo perfusion with 5 mM chenodeoxycholic acid for 30 min. Intestinal injury was assessed by quantitative morphometry and by measuring intestinal water and mannitol absorption. Portal hypertension resulted in more injury in the distal perfused intestine as manifested by increased villus tip denudation [portal hypertensive 52.5 +/- 9.6 (SEM) vs controls 28.1 +/- 5.7 microns, P = 0.05). Additionally there was a significant decrease in the unperfused duodenal villus height in portal hypertensive rats (portal hypertensive 755 +/- 22 vs controls 848 +/- 28 microns, P less than 0.02). Portal hypertension had no significant effect on the increase in mannitol absorption or water secretion caused by chenodeoxycholic acid perfusion. This study suggests that portal hypertension alters small intestinal mucosa and increases susceptibility to injury.

Absorption↗
PubMed1990

16,16-Dimethyl prostaglandin E2 induces villus contraction in rats without affecting intestinal restitution.

In a previous study we found that 16,16-dimethyl prostaglandin E2 protects the small intestine against chenodeoxycholic acid injury in the rat. One possible explanation for prostaglandin's protective action may be that prostaglandin-induced villus contraction accelerates mucosal restitution. This hypothesis was tested in rats by perfusing intestinal segments in vivo in a single-pass fashion with 0.125-0.5 micrograms/L of 16,16-dimethyl prostaglandin E2. These studies showed a dose-dependent, reversible contraction of intestinal villi and crypts. To test the effect of this contraction on mucosal restitution, standardized intestinal injury was produced in indomethacin-pretreated rats perfused in vivo with 5 mmol/L chenodeoxycholic acid. The rats were then perfused with bile acid-free buffer containing either 0.5 microgram/mL of 16,16-dimethyl prostaglandin E2 or vehicle. This study showed that despite decreasing villus height after bile acid injury, 16,16-dimethyl prostaglandin E2 did not significantly affect the rate of morphologic (assessed by villus denudation) or functional (assessed by mannitol and water absorption) restitution of the injured intestinal mucosa. Thus, although 16,16-dimethyl prostaglandin E2 causes villus contraction, this effect does not result in more rapid restitution of the injured intestinal mucosa and is not a likely mechanism for prostaglandin-mediated protection of the intestinal mucosa.

16,16-Dimethylprostaglandin E2↗
PubMed1990

Intraperitoneal injection induces prostaglandin-mediated protection from bile acid intestinal mucosal injury in rats in vivo.

The production of endogenous prostaglandins by the gastrointestinal mucosa can be induced by many processes. Whether the commonly used technique of intraperitoneal injection alone can also induce significant endogenous prostaglandin-mediated mucosal injury induced in vivo by perfusion for 45 min with 5 mM chenodeoxycholic acid. 10 control rats received 1 ml/kg of normal saline subcutaneously on abdomen tree hours before exposure to chenodeoxycholic acid. Another group of 10 rats received 1 ml/kg of saline intraperitoneally before injury. Mucosal injury was assessed histologically by measuring villus tip epithelial cell denudation by computerized quantitative morphology. Injury was assessed functionally by measuring water and mannitol absorption from the lumen. To examine the role of endogenous prostaglandins in this phenomenon, the above experiment was repeated with 10 and 12 rats respectively by replacing the saline with 10 mg/kg injections of indomethacin. Intraperitoneal injection of saline reduced the average denudation/villus caused by chenodeoxycholic acid: Subcutaneous = 100.8 microns +/- 14.7 (SEM). Intraperitoneal = 65.1 +/- 6.4 (p less than 0.5). Parallel reductions were noted in the increase in water secretion and mannitol absorption caused by chenodeoxycholic acid. All of these differences were reversed by exchanging indomethacin for saline. This study suggests there exists a mechanism by which the simple act of performing an intraperitoneal injection induces endogenous intestinal mucosal protection. That this protection is negated by pretreatment with indomethacin suggests it is prostaglandin mediated.

Animals↗
PubMed1990

Intestinal morphometry and bile acid-induced mucosal injury in chronic experimental renal failure.

To examine whether the intestinal mucosa in uremia is more prone to injury, we studied acute intestinal mucosal injury in rats with experimental chronic renal failure (RF) and sham-operated and starved control animals. Intestinal injury was produced by perfusing intestinal segments in vivo with 5 mmol/L chenodeoxycholic acid. Histologic specimens were then taken from the proximal and distal perfused and unperfused intestinal segments. Quantitative morphometry was done with computerized image analysis, and samples of the unperfused intestine were assayed for protein and DNA content. Chronic RF did not significantly affect the functional or morphologic injury caused by chenodeoxycholic acid. However, it was noted that RF rats had consistently taller villi and deeper crypts in all the samples studied. The protein content and the ratio of DNA to protein was similar among the three groups. The mechanism of the increase in villus height and crypt depth in the RF rats was not related to increases in tissue water content or to alterations in protein or DNA content, and the mechanism thus remains unexplained. This study clearly demonstrates, however, that the intestinal mucosa of rats with chronic renal insufficiency is not more susceptible to mucosal injury by bile acids than is the mucosa of appropriate control animals.

Animals↗
PubMed1988

Oral chenodeoxycholic acid increases small intestinal permeability to lactulose in humans.

In animals, chenodeoxyholic acid (chenodiol) causes significant small intestinal mucosal injury which is paralleled by increased intestinal permeability. The objective of this study was to determine whether chenodiol increases small intestinal mucosal permeability in humans. This was assessed in a before-after trial by collecting urine from nine fasted healthy male volunteers for 3 h after oral intake of an isotonic solution containing 1 g mannitol, 5 g L-rhamnose and 10 g lactulose, all nondigestible sugars. After at least 72 h, this was repeated 1 h after taking 750 mg of chenodiol orally. The amount of each sugar excreted in the urine was quantified by high performance liquid chromatography. Chenodiol doubled the percent urinary excretion of lactulose from 0.21 +/- 0.12 (SD) to 0.42% +/- 0.25 (p less than 0.02) and the ratio of lactulose to mannitol or to rhamnose [0.012 +/- 0.005 to 0.027 +/- 0.013 (p less than 0.01) and 0.045 +/- 0.022 to 0.087 +/- 0.039 (p less than 0.05), respectively]. Oral administration of 750 mg chenodiol is associated with increased small intestinal permeability to lactulose in humans, supporting the possibility that this drug may also cause acute small intestinal mucosal injury.

Administration, Oral↗
PubMed1988

Effect of 16,16-dimethyl PGE2 and indomethacin on bile acid-induced intestinal injury and restitution in rats.

Topically administered 16,16-dimethyl prostaglandin E2 reduced bile acid-induced small intestinal mucosal injury; however, the time course of restitution after such injury and whether either exogenous or endogenous prostaglandins affect this restitution are unknown. To explore these questions, mucosal injury was produced in 50 cm small intestinal segments of anesthetized male Sprague-Dawley rats perfused in vivo for 0, 5, 15, 30, or 45 minutes with buffer containing 5 mmol/L chenodeoxycholic acid, and to assess mucosal restitution, additional rats were perfused for 45 minutes with chenodeoxycholic acid followed by 15, 30, 60 or 120 minutes with chenodeoxycholate-free buffer. The above studies were then repeated in rats receiving either intraperitoneal indomethacin (10 mg/kg) or 15 minutes of preperfusion with buffer containing 1.4 mumol/L (0.5 microgram/ml) 16,16-dimethyl prostaglandin E2. Prostaglandin pretreatment reduced and indomethacin pretreatment increased significantly the morphologic (as measured by quantitative histology) and functional (as measured by mannitol and water absorption) mucosal injury caused by chenodeoxycholic acid. However, neither pretreatment had a major impact on the time course of functional or morphologic mucosal restitution, with nearly complete restitution occurring within 1 hour. Thus, although both endogenous and exogenous prostaglandins have a significant impact on bile acid-induced small intestinal mucosal injury, this effect is not caused by an acceleration of the rate of mucosal restitution.

16,16-Dimethylprostaglandin E2↗
PubMed1987

Impact of endoscopy on mortality from occult cancer in radiographically benign gastric ulcers. A probability analysis model.

Endoscopy is commonly used in the management of patients with radiographically benign gastric ulcers to detect occult malignancy. Clinical studies examining the cost-effectiveness of using endoscopy in such patients, however, have not been done. To address this issue using probability analysis, a probability tree was designed incorporating the possible clinical courses of patients with radiographically benign gastric ulcers managed with and without endoscopy, and probability estimates for each course were derived by compiling data from the literature. Probability and sensitivity analysis was used to compare the impact on overall mortality rate and cost-effectiveness of six commonly practiced methods of using endoscopy to manage patients with radiographically benign gastric ulcers: (1) all follow-up by upper gastrointestinal x-ray only; (2) endoscopy for nonhealing ulcers only; (3) endoscopy for all ulcers before medical therapy with all follow-up by upper gastrointestinal x-ray; (4) endoscopy for all ulcers after an initial trial of medical therapy; (5) endoscopy for all ulcers before therapy and for nonhealers; (6) endoscopy before therapy, and all follow-up by endoscopy. This analysis predicts that the greatest decrease in mortality rate occurs when endoscopy is used before medical therapy and for all follow-up, reducing the estimated number of deaths per 1000 patients with radiographically benign gastric ulcers from 36.7 with follow-up by upper gastrointestinal x-ray only to 27.2. However, initial endoscopy with all subsequent follow-up by upper gastrointestinal x-ray increased the overall death rate by only a small amount, to 28.0, and was consistently the most cost-effective method, requiring 116 endoscopies and approximately 60,000 diagnostic dollars per additional 5-yr survivor.

Cost-Benefit Analysis↗
PubMed1987

16,16-Dimethyl prostaglandin E2 reduced chenodeoxycholate-induced small intestinal mucosal injury in the rat.

To determine whether prostaglandin may protect the small intestinal mucosa against bile acid-induced injury, we perfused in vivo rat jejunal segments with 5 mmol/L chenodeoxycholate with and without topical pretreatment with 2.6 mumol/L (1 microgram/ml) 16,16-dimethyl prostaglandin E2. Mucosal injury by chenodeoxycholate and its time sequence was assessed by using mannitol absorption and quantitative histology after 5, 15, 30, and 45 minutes of chenodeoxycholate perfusion. Forty-five-minute perfusion with chenodeoxycholate increased mannitol absorption from 0 to 0.9 nmol/min/cm, whereas prostaglandin pretreatment reduced this increase threefold (P less than 0.001). The increase in mannitol absorption coincided with progressive denudation of epithelial cells from intestinal villi. After 45 minutes exposure to chenodeoxycholate, an average of 50 micron of the cross-sectional surface of the villi tips was denuded of epithelial cells compared with only 25 micron denuded with prostaglandin pretreatment (P less than 0.01). These data indicate that topical administration of 16,16-dimethyl prostaglandin E2 reduces both the functional and morphologic small intestinal mucosal injury caused by chenodeoxycholate.

16,16-Dimethylprostaglandin E2↗
PubMed1986

Why have controlled trials failed to demonstrate a benefit of esophagogastroduodenoscopy in acute upper gastrointestinal bleeding? A probability model analysis.

Numerous prospective randomized trials have failed to demonstrate a benefit attributable to early diagnostic esophagogastroduodenoscopy (EGD) in acute upper gastrointestinal bleeding (UGIB). The clinical implications of these studies have received extensive editorial comment and analysis. We have employed a probability model to further analyze the reasons why these studies have failed to demonstrate an impact of EGD on UGIB. The clinical course of each bleeding lesion can be predicted from the literature. For each lesion, the mortality associated with early specific intervention afforded by an early specific diagnosis can be compared with the mortality of intervention delayed by applying EGD only to those patients who have a complicated course marked by continued bleeding or rebleeding. Using optimistic assumptions that would tend to overstate the impact of EGD, this analysis estimates the maximum decrease in overall mortality in any of these trials afforded by early diagnostic EGD to be 1.2% which would require randomization of over 5000 patients to demonstrate this benefit in a prospective trial.

Acute Disease↗