The effect of nabumetone and indomethacin on gastric mucosal function.
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Adult↗
Biomedical subjects
W D Rees
Publications and source records attributed to W D Rees.
Comparison of indomethacin and the prodrugs, fenbufen and nabumetone, on human gastric morphology and blood flow.
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Butanones↗
Mechanisms of gastroduodenal protection by sucralfate.
Over the past 5-10 years, a number of studies have shown that topical sucralfate enhances a number of gastric and duodenal mechanisms, e.g., the "mucus-bicarbonate barrier," mucosal hydrophobicity, mucosal blood flow, cell viability, and local production of prostaglandins, as well as endogenous mediators of tissue injury and repair. It seems likely that the complex actions of sucralfate are in part related to direct interaction between the drug or its components (aluminum, sucrose, and sulfate) and gastric mucosal tissues, and in part related to effects of the drug on the various mucosal mediators of tissue injury and repair. Local actions may play a role in accelerating healing of ulcer-damaged mucosa, but this does not explain the protective actions of sucralfate on normal mucosa. Thus sucralfate appears to enhance the protective function of the "mucus-bicarbonate" barrier by actions on both components. This may depend in part on an interaction with the unstirred layer overlying gastric epithelium. Sucralfate has also been shown to increase the hydrophobicity of mucus gel. There is little doubt that sucralfate increases local production and release of protective prostaglandins (PGs), but the precise role played by these agents in mediating mucosal protection and in chronic ulcer healing remains uncertain. Currently, the mechanism of action of sucralfate on vascular integrity remains unknown and the role of PGs in this protective function is unclear. There is little evidence that epidermal growth factor plays any role in mediating mucosal protection by sucralfate, but it may be important in its ulcer-healing action. Sucralfate has been shown to be truly "cytoprotective" in that it protects isolated epithelial cells from damage by noxious agents. In animals treated with sucralfate, the surface epithelial cells were disrupted, but necrotic lesions in the deep proliferative zone were virtually absent. It seems likely that investigations of the actions of sucralfate and its components will move ever closer to defining the target cells, the intracellular events, and the mediators that bring about its protective and ulcer-healing activity.
Animals↗
Sarcosine kinetics in pigs by infusion of [1-14C]sarcosine: use for refining estimates of glycine and threonine kinetics.
To investigate in vivo the interconversion between glycine (Gly) and its N-methyl product sarcosine (Sar), [1-13C]Gly and [1-14C]Sar were infused into hourly fed pigs receiving diets with low- and high-threonine levels. An open two-pool model was developed to calculate Sar demethylation (DM) and Gly methylation (GM). During [1-14C]Sar infusion, intracellular Gly specific radioactivities (SA) in the liver and kidney were higher than plasma Gly SA, suggesting that demethylation of Sar occurred in those tissues. DM estimated by using hippuric acid (HA) as the production pool had a mean value of 1.55 mumol.kg-1.h-1, similar to the Sar production rate (mean 1.85 mumol.kg-1.h-1). GM was undetectable (less than 0.5 mumol.kg-1.h-1). These results suggest that, in fed pigs, Sar is produced mainly from choline catabolism and is degraded only to Gly in liver and kidney. On the assumption that Sar degradation gave rise only to Gly, the production rate of Gly (Gly PR) was calculated from [1-13C]Gly and [1-14C]Sar infusions using either the primary pools (plasma Gly and HA, respectively) or the secondary pools (HA and plasma Gly, respectively). The results were explained by a liver-plasma Gly exchange model. The whole body Gly irreversible loss, i.e., direct loss from plasma and liver, was calculated from this model to be 832 +/- 58 mumol.kg-1.h-1, showing that the estimation of Gly PR with [1-13C]Gly infusion and plasma Gly enrichment (599 +/- 56 mumol.kg-1.h-1) was a significant underestimate of the true value.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Dyspepsia in general practice.
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Antacids↗
The effects of indomethacin on gastroduodenal morphology and mucosal pH gradient in the healthy human stomach.
To define further the injury and the mechanisms of mucosal injury induced by indomethacin, the effect of 28-day continuous administration of oral indomethacin on gastroduodenal morphology, gastric histology, and the protective mucus-bicarbonate barrier overlying gastroduodenal mucosa in humans was studied. In the studies, indomethacin caused acute gastroduodenal damage in 100% of cases, with maximal damage at 24 hours of administration. With continued intake this damage resolves, although a minority (two study subjects) progressed to discrete ulceration. Why these two subjects failed to adapt is unknown. Biopsy specimens taken during the studies showed no significant changes in inflammatory or regenerative features, and thus failed to shed any light on this process of adaptation to damage. Mucosal pH gradient studies showed a significant increase in juxtamucosal pH at the time of maximal damage (24 hours); this is thought to represent passive diffusion of alkali from damaged mucosa. In conclusion, mucosal adaptation to acute damage by indomethacin occurs in humans. The mechanisms through which the mucosa adapts in this intriguing way remain unknown.
Adaptation, Physiological↗
Opioid needs of terminal care patients: variations with age and primary site.
The records of 1383, terminal cancer patients have been reviewed to determine whether opioid requirements vary in a consistent pattern with age and with site of primary cancer. Opioid requirements are shown to decrease with age in a regular pattern and from early adult life. Opioid requirements also differ significantly with site of primary cancer and there appears to be a discernible pattern of opioid need for different cancers. Patients with sexually related cancer have the highest opioid requirements, irrespective of sex. When the sexually determined cancers are excluded, the analgesic needs of men and women are not significantly different (P = 0.191).
Adult↗
A molecular biological approach to reducing dietary amino acid needs.
Rapid developments in transgenic animal technology make it possible to consider introducing new metabolic capabilities into animals, using genes from other species. Lysine and threonine are both essential amino acids in mammals, and are commonly the first and second limiting amino acids, respectively, for protein accretion in pigs and poultry fed cereal based diets. Here we consider the potential for transgenic animals with microbial biosynthetic pathways for these amino acids.
Amino Acids, Essential↗
Lysine oxidation by rat hepatocytes: effect of serum from pigs given a high or low lysine diet.
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Animals↗
Effect of bismuth subcitrate and sucralfate on rat duodenal and human gastric bicarbonate secretion in vivo.
Acid and alkali secretion have been examined together with prostaglandin E2 production in response to two mucosal protective drugs, colloidal bismuth subcitrate and sucralfate. Doses of colloidal bismuth subcitrate in the therapeutic range (120 and 1200 mg) had no effect on alkali secretion or luminal PGE2 output when perfused into the stomach of human volunteers. Similarly, in the anaesthetised rat, neither gastric acid nor duodenal alkali secretions were influenced by iv (12 mg/kg) or topical (120 mg/ml) administration of colloidal bismuth subcitrate. In contrast, perfusion of the human stomach with 1 g sucralfate stimulated bicarbonate output by 50%, a response which was unaffected by indomethacin (25 mg/h). A rise of 64% in gastric PGE2 output after sucralfate was, however, prevented by indomethacin pretreatment. Alkali secretion by rat duodenum was also increased by sucralfate but the response depended on the basal secretory rate. Low basal secretors (less than 3 mumol) showed a 75% stimulation whereas rats with high basal secretory rates (greater than 3 mumol) showed no significant response. All duodenal preparations regardless of basal secretory rate showed a stimulation of bicarbonate output with topical PGE2. The results suggest that enhancement of gastroduodenal bicarbonate secretion may play a role in the protective action of sucralfate but is unlikely to explain mucosal protection by colloidal bismuth subcitrate.
Adolescent↗
Quantitative partition of threonine oxidation in pigs: effect of dietary threonine.
Kinetic aspects of threonine (Thr) metabolism were examined in eight pigs fed hourly with a diet containing either 0.68% (LT group) or 0.81% (HT group) of Thr (wt/wt), corresponding to 10 and 30% Thr excess, respectively, compared with an "ideal" diet. Primary production (PR) and disposal (DR) rates were obtained for Thr, glycine (Gly), and 2-keto-butyrate (KB) after a 12-h continuous infusion of L-[U-14C]-Thr together with [1-13C]Gly and a 6-h continuous infusion of [1-14C]KB. Transfer of Thr into secondary pools was also monitored, and from these the rates of Thr oxidation through the catabolic pathways of L-Thr 3-dehydrogenase (DR(Thr-Gly)) and threonine dehydratase (DR(Thr-KB)) were estimated. For the LT group the results were (mumol.kg-1.h-1) PR(Thr) 314 +/- 3, PR(Gly) 551 +/- 24, PR(KB) 41 +/- 3, DR(Thr-Gly) 22 +/- 2, and DR(Thr-KB) 7 +/- 1. For the HT group they were PR(Thr) 301 +/- 23, PR(Gly) 598 +/- 55, PR(KB) 39 +/- 4, DR(Thr-Gly) 32 +/- 2, and DR(Thr-KB) 8 +/- 1. The increase in Thr intake (14 mumol.kg-1.h-1, P less than 0.01) induced a commensurate increase in the sum of DR(Thr-Gly) and DR(Thr-KB) (14 mumol.kg-1.h-1, P less than 0.001) when liver was used as the precursor pool. This was mainly due to the increased DR(Thr-Gly) (13 mumol.kg-1.h-1, P less than 0.01); the change in DR(Thr-KB) was not statistically significant. By comparison of intracellular-to-plasma ratios of specific activities (or enrichments) for different tissues with each type of infusion, liver was shown to be the major site of production of Gly and KB from Thr. These data suggest that in fed growing pigs a 30% excess of Thr in the diet does not alter the partition of Thr oxidation, since 80% of Thr oxidation occurs through the L-Thr 3-dehydrogenase pathway for both LT and HT groups.
Amino Acids↗
Effect of sucralfate on human gastric bicarbonate secretion and local prostaglandin E2 metabolism.
The protective and ulcer-healing properties of sucralfate on gastroduodenal mucosa are well established. In this study, the possible mode of action of sucralfate in humans has been explored by examining its effect on gastric bicarbonate secretion and luminal prostaglandin E2 (PGE2) output from the intact stomach. The gastric output of bicarbonate and PGE2 has been calculated using a perfusion technique before, during, and after perfusion with sucralfate (8 mg/ml) in eight healthy volunteers. A significant increase in bicarbonate output occurred during the period of sucralfate perfusion returning to basal values during the post-sucralfate period. Pretreatment with indomethacin (25 mg/hour) failed to influence this secretory response. Luminal PGE2 output was significantly increased in the post-sucralfate perfusion period only. These changes were caused mainly by an increase in gastric secretory volume with insignificant increases in concentrations of bicarbonate and PGE2. These results suggest that stimulation of gastric bicarbonate secretion and PGE2 output by sucralfate may play a role in its protective actions.
Adolescent↗
Effect of enprostil on amphibian gastroduodenal and human gastric bicarbonate secretion.
The protective and ulcer healing properties of prostaglandins are well established. We have explored the possible mode of action of enprostil, a synthetic dehydroprostaglandin E2, on amphibian gastroduodenal mucosal bicarbonate secretion in vitro and on human gastric bicarbonate secretion in vivo. Addition of enprostil (10(-6) M) to the luminal solution of isolated amphibian gastric mucosa produced a 28% increase in bicarbonate secretion without a change in transmucosal potential difference. The same concentration of enprostil added to the luminal solution of isolated amphibian duodenal mucosa produced a 37% increase in bicarbonate secretion and was associated with a rise in transmucosal potential difference. The gastric output of bicarbonate from the human stomach has been calculated using a perfusion technique before, during, and after perfusion with enprostil (35 micrograms) in six healthy volunteers. A significant 78% increase in bicarbonate secretion occurred during the period of enprostil perfusion, falling to normal during the postenprostil period. These changes were caused mainly by an increase in gastric secretory volume with insignificant increases in bicarbonate concentration. These results suggest that stimulation of gastroduodenal bicarbonate secretion by enprostil may play a role in its protective actions.
Adult↗
Effect of bismuth subcitrate on amphibian gastroduodenal bicarbonate secretion.
The ulcer healing and cytoprotective properties of colloidal bismuth (De-Nol) are well established although its mode of action is unclear. We have examined the action of bismuth subcitrate, the active ingredient of De-Nol, on gastroduodenal bicarbonate secretion by isolated amphibian mucosa. Addition of bismuth subcitrate (10(-6) to 10(-4) M) to the luminal solution produced a dose dependent increase in bicarbonate secretion from both gastric and duodenal mucosae without a change in transmucosal potential difference. The magnitude of this stimulation was greater for gastric than duodenal mucosae at all dose ranges. A second bismuth salt, bismuth oxynitrate, produced similar increases in bicarbonate secretion from gastric mucosae. Pretreatment of gastric mucosa with the cyclooxygenase inhibitor, indomethacin (10(-5) and 10(-4) M), did not abolish the secretory response to bismuth subcitrate. Similar treatment with the chloride transport inhibitor, 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) (10(-3) M) prevented the secretory response to bismuth subcitrate.
Animals↗
Oesophageal ulcer caused by warfarin.
Oesophageal injury is a well recognized complication of certain oral medications but warfarin has not been implicated previously. We present a case of an oesophageal ulcer occurring in a patient with mitral regurgitation taking warfarin, and demonstrate a delayed oesophageal tablet transit time.
Drug Administration Schedule↗
Mechanisms of gastric damage by non-steroidal anti-inflammatory drugs.
All non-steroidal anti-inflammatory drugs (NSAIDs) used in the treatment of rheumatic diseases may cause gastrointestinal mucosal injury. The mechanisms by which these agents damage mucosa are not fully understood, although, reduction of mucosal defence by the depletion of endogenous, protective prostaglandins has been deemed important. NSAIDs have been shown to decrease the magnitude of the mucus-bicarbonate barrier, disrupt the epithelial cell layer, reduce the surface hydrophobicity of epithelial cells and to diminish mucosal blood flow. Such effects render the mucosa more susceptible to damage by acid, pepsin, bile salts and alcohol. In addition, direct mucosal injury may be caused by the physiochemical properties of NSAIDs, being weak acids. There is now increasing evidence that gastroduodenal mucosa adapts to acute damage by these drugs with mucosal injury recovering during continued administration. The mechanisms governing such adaptation remain unknown and require further investigation.
Adaptation, Physiological↗
Overview of gastroduodenal mucosal protection.
The ability of the gastric mucosa to resist autodigestion has been recognized for over 200 years. Since these early observations, several components of gastroduodenal defense against injury from damaging luminal contents have been identified. The first line of defense is the thick layer of mucus gel into which bicarbonate is secreted by the underlying epithelial cells. The "mucus-bicarbonate" barrier sustains a pH gradient between the lumen and cell surface such that epithelial cells are maintained at pH 7 to 8, despite the presence of intraluminal acid. The epithelial cells form a second line of defense; since the pH gradient may be overwhelmed by physiologic concentrations of intraluminal acid, this mechanism may be important in maintaining mucosal integrity. The physical properties of the apical cell membrane and intercellular junctions and the presence of surface-active phospholipids on the membrane may be responsible for preventing hydrogen ions (H+) from diffusing into the mucosa by providing a physical barrier to their movement. Furthermore, epithelial cells are capable of rapid turnover and migration and may breach a defect in the epithelium within hours. The aftermath of mucosal damage may generate a further defense mechanism: a thick layer of mucus containing sloughed epithelial cells together with passive movement of bicarbonate-rich fluid from the damaged mucosa. This may prevent exposure of undamaged cell nests to acid and thus aid re-epithelialization. Finally, mucosal blood flow plays a vital role in maintaining epithelial integrity. Studies have shown that increasing or decreasing mucosal blood flow will, respectively, reduce or enhance susceptibility to damage. Although the precise physiologic control mechanisms for mucosal protection have not been defined, there is evidence that local endogenous prostaglandin metabolism may play an important role [4]. The release of neurotransmitters and hormones may also contribute to or modulate the defense mechanisms.
Anti-Inflammatory Agents, Non-Steroidal↗
Stimulation of amphibian gastroduodenal bicarbonate secretion by sucralfate and aluminium: role of local prostaglandin metabolism.
The present studies were designed to explore the possible mode of protective and ulcer healing actions of sucralfate by examining its effect on gastroduodenal bicarbonate secretion by isolated amphibian mucosa. Luminal sucralfate (0.5 g/l) significantly increased bicarbonate secretion by fundic and antral mucosa without influencing transmucosal potential difference. Significant stimulation of duodenal bicarbonate secretion occurred only at 1.0 g/l without change in potential difference. Aluminium, a component of sucralfate, produced similar increases in bicarbonate secretion, while the sucrose and sulphate components were without effect. Pretreatment of mucosae with the cyclooxygenase inhibitor, indomethacin (10 5M) did not abolish the secretory response to sucralfate or aluminium. The results suggest that stimulation of gastroduodenal bicarbonate secretion, possibly by the aluminium moiety of sucralfate, may play a role in its protective and ulcer healing actions.
Aluminum↗