[What should be our criteria in the choice of drugs?].
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Drug Costs↗
Biomedical subjects
A Uribe
Publications and source records attributed to A Uribe.
Indomethacin accelerates clearance of labeled cells and increases DNA synthesis in gastrointestinal mucosa of the rat.
Sprague-Dawley rats treated with placebo, parenteral indomethacin, or oral prostaglandin E2 for six days were given an intraperitoneal injection of [3H] methyl-thymidine and killed at 45 min and 96 hr after labeling. Treatments were continued until death. The dpm/DNA index was determined in mucosal scrapings of the stomach, duodenum, and jejunum and used to estimate DNA synthesis (45 min) and the clearance of labeled cells (96 hr). Indomethacin increased the DNA synthesis in both the duodenal and jejunal mucosa (P less than 0.05). In comparison to the controls, the clearance of labeled cells from the antral, duodenal, and jejunal mucosa was accelerated by indomethacin treatment, whereas the elimination of labeled cells from the antral and jejunal mucosa was slowed by PGE2 treatment (P less than 0.05). DNA synthesis of the antral mucosa was significantly reduced by PGE2 (P less than 0.05). The cyclooxygenase blocker did not affect the cell kinetic parameters of the oxyntic mucosa. The plasma levels of somatostatin were significantly higher both in PGE2- and indomethacin-treated rats than in controls (P less than 0.05). It is concluded that indomethacin treatment increases the cell losses from the epithelial surface, which in turn trigger a compensatory trophic reaction. It is suggested that an important physiological action of endogenous prostaglandins is to regulate the outflow of cells from the superficial zones of the epithelium. Finally, this study disclosed the presence of hitherto unknown regulatory mechanisms that promote cell proliferation in the gastrointestinal mucosa despite inhibition of the synthesis of endogenous prostaglandins.
Animals↗
Fluorescamine-induced membrane permeability in mitochondria.
1. Addition of fluorescamine (75 microM) to mitochondria induced an increase in membrane permeability. 2. The leakiness of the inner mitochondrial membrane is characterized by extensive release of accumulated Ca2+, collapse of the transmembrane potential, mitochondrial swelling and efflux of matrix proteins, among them, malate dehydrogenase. 3. These effects were diminished by supplementing the media with 1 mM phosphate, and partially prevented by Mg2+. 4. These results indicate that the primary amino groups of membrane components contribute, partially, to the maintenance of the permeability barrier in mitochondria.
Animals↗
The characteristics of mitotic figures in jejunal mucosa of patients with celiac disease.
The morphologic characteristics of the mitotic figures present in the jejunal mucosa of 23 pediatric patients having gluten enteropathy were recorded. Of the 851 mitoses found, 4.9% were in prophase, 39.9% in prometaphase, 29.5% in metaphase, 22.3% in anaphase, and 3.3% in telophase. Of the 851 mitoses found, 98.8% were considered to be morphologically normal and the remaining 1.2% were considered atypical. The occurrence of atypical mitoses in the jejunal mucosa of pediatric patients was unexpected. However, because jejunal adenocarcinomas in celiac patients are known to be rare, the plausible explanation for the present findings is that the occurrence of atypical mitoses may mirror morphologic variations from the normal mitotic pattern occurring in a rapidly proliferating mucosa, such as that of patients with gluten enteropathy.
Celiac Disease↗
Oral prostaglandin E2 influences the enterochromaffin-like and somatostatin cell populations in the oxyntic mucosa of the rat.
Our aim was to study the effects of long-term oral administration of different doses of prostaglandin E2 (PGE2) and of a synthetic analogue on the endocrine cells and on selected epithelial cells of the rat oxyntic mucosa. The endocrine cells were visualized by immunohistochemical staining and by the Sevier-Munger method. Quantification of the mucosal cells was performed at a light-microscopic level using stereological methods. The highest dose of 15-R-15-methylprostaglandin E2 (MePGE2) increased the total volume of enterochromaffin-like (ECL) cell profiles whereas no changes were observed after treatment with PGE2. On the other hand, the total mucosal volume of chromogranin A-immunoreactive cells was significantly reduced by both doses of natural PGE2. The highest dose of PGE2 increased the total volume of somatostatin-immunoreactive cells. The serotonin-immunoreactive cells were very few and unaffected by treatments. E2 prostaglandins induced hyperplasia and hypertrophy of epithelial cells. A selective trophic action on the mucous but not on the parietal cells was observed. The area of the parietal cells was increased in rats treated with the analogue. The gastric acid content was increased in rats treated with the highest doses of E2 prostaglandins. The plasma level of somatostatin was significantly increased in rats given MePGE2 and the highest dose of PGE2. The cell population of chromogranin A-immunoreactive cells did not reach the levels of the NECL cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
E2 prostaglandins modulate cell proliferation in the small intestinal epithelium of the rat.
Groups of Sprague-Dawley rats were administered 1 mg/kg indomethacin subcutaneously, indomethacin subcutaneously plus 200 micrograms/kg oral 15-R-15 methyl-prostaglandin E2 (MePGE2) or oral MePGE2 twice daily for 10 days. The animals were treated with antibiotics to prevent mortality. Two control groups were used: control 1 was given placebo and control 2 was treated with antibiotics. All rats were killed 4 h after injection of a metaphase blocker, and the proliferative activity of the distal small intestine was examined in histological sections by means of the cumulative mitotic index (MI). A reduction in the number of villous cells was observed in the rats given antibiotics (p < 0.05 vs. control 1). The small intestinal villi of the rats treated with indomethacin had fewer cells than those of both control groups (p < 0.05) whereas the crypts contained more cells (p < 0.05) and had a higher MI than those of the controls (p < 0.05 vs. controls 1 and 2). These changes were reverted by the prostaglandin analogue. The number of cells of the small intestinal crypts and the cumulative MI in the rats who received indomethacin and the prostaglandin analogue were similar to controls, and they were significantly lower than the values observed in the animals treated with indomethacin (p < 0.05). The animals treated with the prostaglandin analogue and placebo developed a marked hyperplasia of the small intestinal villi (p < 0.05 vs. both control groups), but the atrophy of the villi induced by indomethacin was not prevented by simultaneous administration of the analogue.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Somatostatin cells in the oxyntic mucosa of hypo- or hypergastrinemic rats.
The present report describes the long-term effects of antrectomy, antrum exclusion, portacaval shunt, omeprazole treatment, or the combination of omeprazole treatment and portacaval shunt on the number and density of somatostatin cells in the oxyntic mucosa of the rat. Antrectomy, which is associated with hypogastrinemia, raised the number and density of the somatostatin cells, whereas antrum exclusion and omeprazole treatment, which are associated with hypergastrinemia, reduced the number and density of the somatostatin cells. Portacaval shunt, which is associated with hypogastrinemia, increased both the number and the density. Omeprazole treatment of portacaval--shunted rats suppressed or even reversed the somatostatin cell hyperplasia after portacaval shunt alone. From these findings it is unlikely that gastrin stimulates the proliferation of somatostatin cells in the oxyntic mucosa. In fact, there seems to be an inverse relationship between the serum gastrin concentration and the somatostatin cell number.
Animals↗
Trophic doses of E2 prostaglandins do not influence the exocrine and endocrine pancreas in the presence of high levels of plasma somatostatin.
The aim of the present investigation was to study the effect of a long-term and a short-term treatment regimen with 15-R-15-methyl prostaglandin E2 and natural prostaglandin E2 (PGE2) on the endocrine cell populations of the rat pancreas. Graded oral doses of the analogue (5 and 50 micrograms/kg) and PGE2 (5000 micrograms/kg) were given twice daily for 4 weeks. The pancreas was carefully excised and weighed. Sections from randomly taken pancreatic biopsy specimens were processed for immunohistochemistry or hematoxylin and eosin staining before quantitative estimations were made, using stereologic methods. The total pancreatic volumes of insulin-, glucagon-, polypeptide P-, somatostatin-, and chromogranin A-immunoreactive cells were not affected by E2 prostaglandins. Neither the total volume of the islets of Langerhans nor that of the pancreatic cell nuclei was affected. The size of pancreatic cell nuclei was the same in the groups. The plasma levels of the antitrophic peptide somatostatin were significantly increased in rats treated with doses of both the analogue and PGE2 (p less than 0.05). In an additional short-term study rats were given oral placebo or 5000 micrograms/kg PGE2 twice daily for 5 days. The total endocrine pancreatic volume was not affected by PGE2. As in the long-term study, natural PGE2 did not affect the total pancreas volume or the total volume of pancreatic cell nuclei. These findings indicate that E2 prostaglandins produce no changes in the exocrine or endocrine pancreas in a dose range known to induce hyperplasia in the gastrointestinal epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Distribution of control of oxidative phosphorylation in mitochondria oxidizing NAD-linked substrates.
The flux control distribution of the net rate of state 3 respiration was determined in heart and kidney mitochondria incubated with low concentrations of pyruvate (0.5 mM) or 2-oxoglutarate (1 mM), and in conditions that led to activation of NAD-linked dehydrogenases, i.e., high substrate or Ca2+ concentrations. Control of flux was exerted by the ATP/ADP carrier (flux control coefficient, ci = 0.37) and Site 1 of the respiratory chain (ci = 0.28) when dehydrogenase activity was low. Control of the process shifted to the ATP synthase (ci = 0.32) and the Pi carrier (Ci = 0.27) when dehydrogenases were activated by high pyruvate and high Ca2+. The changes in the control exerted by the ATP/ADP carrier and the ATP synthase were not due to changes in the transmembrane potential, nor to a modification of intramitochondrial ATP/ADP ratios. Applying the summation theorem of the control analysis, it was found that at low Ca2+ and pyruvate concentrations the dehydrogenases shared the control of state 3 respiration with other steps. The NAD-linked dehydrogenases did not exert any significant control at high Ca2+ or high pyruvate concentrations.
Animals↗
Diagnostic laparoscopy.
Laparoscopy is a unique procedure which can be used in diagnostic or therapeutic situations involving intra-abdominal pathology. Until recently, open laparotomy has been the preferred method for such evaluations. The following cases indicate the increased sensitivity, specificity, safety, and cost effectiveness of laparoscopy in diagnostic situations.
Abdominal Neoplasms↗
Colonic ulcerations in Wegener's granulomatosis.
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Aged↗
Endogenous prostaglandins as regulators of cell proliferation.
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Cell Division↗
Prostaglandin E2-induced hyperplasia of the rat antral epithelium is followed by a secondary inhibition of the mitotic activity.
The aim of the study was to examine the mitotic activity in the antral and duodenal epithelium of Sprague-Dawley rats given trophic doses of E2 prostaglandins during a prolonged period of time. Natural prostaglandin E2 (dose range: 0.2-5.0 mg.k-1) and 15 (R) 15 methyl prostaglandin E2 (dose range: 0.03-2.0 mg.kg-1) were administered for 11 days, and mitoses were arrested with vincristine for 4 h before estimation of the cumulative mitotic index. A dose-related hyperplasia of the antral glands was observed after treatment with prostaglandin E2 and the synthetic analogue (p less than 0.05). The proliferative zone was enlarged in rats treated with high doses of the analogue but natural prostaglandin E2 did not affect the limits of the proliferative zone. A dose-related reduction of the mitotic index was observed in animals treated with prostaglandin E2 despite the presence of hyperplastic changes. All doses of the analogue induced antral hyperplasia without affecting the mitotic index except in rats given the highest dose who had a significantly lower mitotic index than controls (p less than 0.05). Hyperplasia of both crypts and villi was observed in the duodenum of rats given high doses of E2 prostaglandins (p less than 0.05) whereas the mitotic index and the growth fraction were not affected by treatments. It is concluded that hyperplasia by prostaglandins is developed in absence of changes of the mitotic activity. The observed reduction of the mitotic index is interpreted as a secondary phenomenon, possibly mediated by a regulatory mechanism of cell proliferation which is triggered to reduce further epithelial growth. It is suggested that prostaglandin E2 might influence such regulatory mechanisms.
Administration, Oral↗
Retroperitoneal approach for repairs of abdominal aortic aneurysms.
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Aorta, Abdominal↗
Oral E2 prostaglandins affect endocrine cell populations in the gastric antrum of the rat.
The aim of the present study was to investigate antral endocrine cell populations and tissue and circulating hormone levels following a 4-week oral regimen with prostaglandin E2 (25, 250 and 5000 micrograms/kg-1 b.i.d.) or a stable methyl analogue (5 and 50 micrograms kg-1 b.i.d.). Epithelial hyperplasia of the gastric antrum was observed with the highest dose of prostaglandin E2 and both doses of the analogue, as evaluated by stereological methods and conventional cell count. The treatments significantly affected the endocrine cell population. Somatostatin-immunoreactive cells were increased in proportion to the increased epithelial cellularity and plasma levels of somatostatin were increased in parallel. The tissue content of somatostatin-like immunoreactivity differed according to the extraction procedure used, and was significantly higher than controls in specimens extracted in neutral water. In the neutral extracts an immunoreactive somatostatin of unidentified molecular structure dominated quantitatively over somatostatin 14 and 28, which were the major components in acetic acid extracts. The serotonin-immunoreactive cell population was also significantly increased by natural prostaglandin E2 and the analogue but the gastrin cell population was not significantly affected by treatments. Accordingly, no significant changes were observed in tissue or plasma gastrin levels. It is concluded that the epithelial hyperplasia of the antral epithelia produced by E2 prostaglandins is associated with selective changes of endocrine cell populations. The changes were proportional to the increases of epithelial cellularity and required quantitative determination of the total antral volume to be detected.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Initial kinetic changes of prostaglandin E2-induced hyperplasia of the rat small intestinal epithelium occur in the villous compartments.
This study was performed to further identify the sequence of cell kinetics that occurs in the development of gastric and intestinal epithelial hyperplasia after orally administered prostaglandins of the E series. A high-dose, short-treatment schedule was used to examine the initial effects on kinetic parameters in the rat small intestinal epithelium. Groups of rats were killed after a single dose of oral prostaglandin E2 at 1 h after in vivo labeling with [methyl-3H]thymidine and during continued treatment at 6, 12, 24, 48, 72, and 96 h. As evidenced by autoradiography, the earliest change produced by prostaglandin E2 was an increased cellularity of the villous compartment (p less than 0.05 after 24 h). There was no change of labeling index of the villous compartment or of the leading edge of labeled cells within 24 h. At 48 h, the increased cellularity was accompanied by a significantly elevated labeling index of the villi. Throughout the study period no significant differences were observed between groups in the number of cells or labeling indices in the jejunal crypts, or in cellular input from the crypts to the villi. Epithelial turnover time in the placebo and treatment groups was 69 and 71 h, respectively. To exclude the possibility that prostaglandin E2 initially affects cell birth rate and mean cell cycle time, a metaphase blocker was given after 4 days of treatment in a second study. Animals were killed after 0, 0.5, 1.0, 1.5, and 2.5 h. The rate of entry into mitoses was 8.1% cells/h in controls compared with 8.2% cells/h in treated rats. The distribution of mitoses within crypts was identical in the two groups and the mean cell cycle time was 13.6 and 13.2 h, respectively. Also in this study there were trophic changes of the villi. It is concluded that the hyperplasia produced by oral prostaglandin E2 starts in the villi of the small intestine and is initiated by reduced cell exfoliation from the villous tips. Previously recorded retention of cellular elements in villi and crypts, increased cellularity of the proliferative compartments, and reduced mitotic index are secondary events.
Animals↗
Effects of prostaglandin E2 on disease activity, gastric secretion and intestinal permeability, and morphology in patients with rheumatoid arthritis.
The effects of oral natural prostaglandin E2 (PGE2) on symptoms, disease activity, and gastrointestinal functions in rheumatoid arthritis (RA) were studied in an open pilot trial. Twelve patients, six taking and six not taking non-steroidal anti-inflammatory drugs (NSAIDs), received 1 mg natural PGE2 three times a day for six weeks. The treatment was tolerated well and the only side effect noted was slightly looser stools in three patients. Half of the patients reported subjective improvement and none had aggravation of symptoms. The Ritchie articular index and several biochemical inflammation markers decreased and were significantly reduced at the end of the treatment period. The thickness of the small intestinal mucosa increased during the PGE2 treatment. The intestinal permeability pattern, measured by urinary excretion of polyethylene glycols (PEG 400), differed between the patients taking and not taking NSAIDs. The initially high urinary PEG 400 excretion values in the patients taking NSAIDs decreased and the initially low excretion values in patients not taking NSAIDs increased during the PGE2 treatment. The jejunal contents became sterile in 5/6 patients not taking NSAIDs and remained sterile in 1/6 patients taking NSAIDs at the end of the treatment. The treatment period was associated with a reduction of lactobacilli in patients not treated with NSAIDs. Thus the treatment appeared to decrease disease activity and to improve small intestinal functions in patients with RA, findings that need confirmation in a controlled trial.
Adult↗
Alternating proliferative capacity in the rat gastrointestinal mucosa. Effects of E2 prostaglandins and indomethacin.
Having previously observed an apparent uneven distribution of proliferating cells in the gastric corporic mucosa of the rat, we examined the mitotic distribution along 8-mm sections of gastric and jejunal epithelia. Metaphases were arrested with vincristine to facilitate mitotic count, and the effects of treatment with a prostaglandin E2 analogue and a cyclooxygenase blocker were examined. Clusters of mitotic figures alternating with non-proliferating areas were observed in the gastric corporic epithelium of control rats. During 4 h mitotic activity was absent over 21% of the corporic mucosa. Extending the examined area to about 240 glands reduced substantially the error of mitotic counts. An uneven distribution of mitoses was found in the antral and jejunal epithelium, but areas without proliferating cells were uncommon. Treatment with the prostaglandin E2 analogue reduced the number of mitosis-free areas in the gastric corpus to 13%, and clusters were less easily identified. The total mitotic count was unaffected by treatment. In the jejunum prostaglandin increased the absolute number of mitoses. The mitotic span was also increased, reflecting the uneven distribution. Indomethacin produced the opposite effects to the prostaglandin analogue, including reduction of epithelial height. Of the gastric corporic mucosa 35% was non-proliferating during the observation period, but the clustering phenomenon was still apparent. Absence of dose relationship was attributed to ulcerogenic actions of high doses of indomethacin. It is concluded that mitoses are unevenly distributed in the upper gastrointestinal epithelium of the rat and that safe estimates of mitotic count require examination of large corporic areas.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗