Metabolic bone disease in patients with inflammatory bowel disease.
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Bone Diseases, Metabolic↗
Biomedical subjects
I Bjarnason
Publications and source records attributed to I Bjarnason.
Gastrointestinal toxicity of non-steroidal anti-inflammatory drugs: the effect of nimesulide compared with naproxen on the human gastrointestinal tract.
This overview includes theories and evaluation of non-steroidal anti-inflammatory drug (NSAID)-induced gastrointestinal toxicity. Factors in damage include microvascular aspects, neutrophil recruitment, mucosal prostaglandins, gastrointestinal secretions and bacteria. We have proposed an extensive simplified framework that includes an important local initiating effect which may involve NSAID accumulation, interaction with surface phospholipids, events that alter cellular ATP, and local/systemic effects of cyclooxygenase (COX) inhibition. COX-2-selective drugs are desirable not only because they spare COX-1 and so avoid gastrointestinal toxicity, but also because COX-2-selective agents are only weakly acidic and therefore avoid substantial accumulation in the gastric mucosa. Short-term endoscopy studies of NSAIDs are important initially to evaluate human gastroduodenal tolerability. They show that injury increases with the amount of NSAIDs even though the lowest therapeutic doses inhibit gastric COX almost completely, and that the more-acidic NSAIDs tend to cause greater gastric damage. Long-term endoscopy studies involve NSAID ingestion for at least 3 months. A main question is the extent to which the ulcers seen cause symptoms, substantial bleeding and/or perforation. Measurement of serious outcomes is thought by many to be the best assessment of gastrointestinal safety, but studies find marked variations even with the same drug. Damage to the small intestine by NSAIDs is even more frequent than to the upper gastrointestinal tract, but is difficult to evaluate. Conventional acidic NSAIDs increase the permeability of human small intestine, probably by a non-prostaglandin mechanism, but nimesulide does not do so, possibly because of its very weak acidity.
Animals↗
Intestinal absorption and permeability in paediatric short-bowel syndrome: a pilot study.
BACKGROUND: Sugar absorption tests are an effective, noninvasive way to assess intestinal permeability. The role of intestinal barrier integrity in complications and outcome of short-bowel syndrome is not known. The purpose of the study was to evaluate whether such tests provide information on the status of intestinal mucosa of these patients. METHODS: Six children with short-bowel syndrome--median age, 12 months, and median small bowel length at birth, 30 cm--had a sugar test with 3-o-methyl-D-glucose, D-xylose, D-rhamnose, and melibiose approximately 2 months after operation. The melibiose/L-rhamnose ratio was used as an index of permeability, and percentages of 3-o-methyl-D-glucose and D-xylose absorbed were used as indices of absorption. Parenteral nutrition requirement, bowel length, liver disease, recent sepsis, and bacterial overgrowth were recorded. RESULTS: Three patients had increased permeability, and all of them had had a recent episode of sepsis and severe liver disease. All subjects had malabsorption of 3-o-methyl-D-glucose, and five of six had malabsorption of D-xylose and L-rhamnose. The absorption of 3-o-methyl-D-glucose correlated with bowel length (r2 = 0.78; P = 0.04), whereas the absorption of D-xylose correlated with parenteral requirement (r2 = 0.66; P = 0.04) at that time. CONCLUSIONS: Increased permeability was observed in three of six patients with short-bowel syndrome associated with a recent episode of sepsis and severe liver disease. Other indices of malabsorption correlated significantly with different clinical features of the disease. A prospective larger scale study in a homogeneous population is indicated to assess at multiple points during the disease course whether the test can be helpful in the management of these patients.
3-O-Methylglucose↗
Intolerance of the dirty intestine.
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Antigen Presentation↗
Small intestinal transit, absorption, and permeability in patients with AIDS with and without diarrhoea.
BACKGROUND: Diarrhoea in AIDS is associated with anorexia and weight loss. The importance of gastrointestinal transit in such symptoms has not been addressed. AIMS: To assess jejunal to caecal transit times in subjects with AIDS related diarrhoea and weight loss and correlate these with measures of absorptive capacity and intestinal permeability. METHODS: Jejunal to caecal transit times were assessed in 20 seronegative controls and 60 HIV seropositive subjects from serum analysis of 3-O-methyl-D-glucose and sulphapyridine after ingestion of the monosaccharide and sulphasalazine in aqueous solution. The method also allows an estimation of gastric emptying times for liquids. Intestinal absorptive capacity and permeability were assessed by a combined test using 3-O-methyl-D-glucose, D-xylose, L-rhamnose, and lactulose. RESULTS: Gastric emptying was significantly delayed in all groups of patients with AIDS. Mean jejunal to caecal transit times were not significantly different between controls (246 (62) minutes) and patients without diarrhoea (AIDS, well: 278 (103) minutes; AIDS, wasting: 236 (68) minutes), cytomegalovirus colitis (289 (83) minutes), pathogen negative diarrhoea (192 (100) minutes), or microsporidiosis (190 (113) minutes), although 30% of patients had values below the control range. Patients with cryptosporidiosis differed significantly from controls (135 (35) minutes, p<0.0001), seven of 10 having rapid transit times. Absorptive capacity was reduced and intestinal permeability significantly increased in AIDS, but did not correlate significantly with transit times. CONCLUSION: Small bowel transit is accelerated in many patients with AIDS, particularily in protozoal diarrhoea, but is not the sole explanation for malabsorption of monosaccharides.
AIDS-Related Opportunistic Infections↗
High prevalence of NSAID enteropathy as shown by a simple faecal test.
BACKGROUND: The diagnosis of non-steroidal anti-inflammatory drug (NSAID) induced enteropathy is difficult, requiring enteroscopy or the use of four day faecal excretion of (111)In labelled white cells. AIMS: To assess faecal calprotectin (a non-degraded neutrophil cytosolic protein) as a method for diagnosing NSAID enteropathy. METHODS: Single stool faecal calprotectin concentrations were compared with the four day faecal excretion of (111)In labelled white cells in 47 patients taking NSAIDs. The prevalence and severity of NSAID enteropathy was assessed using this method in 312 patients (192 with rheumatoid arthritis, 65 with osteoarthritis, 55 with other conditions) taking 18 different NSAIDs. RESULTS: The four day faecal excretion of (111)In white cells correlated significantly with faecal calprotectin concentrations. In the group of 312 patients on NSAIDs faecal calprotectin concentrations were significantly higher than in controls, the prevalence of NSAID enteropathy being 44%. The prevalence and severity of NSAID enteropathy was independent of the particular type or dose of NSAID being taken or other patient variables. CONCLUSIONS: Assay of faecal calprotectin provides a simple practical method for diagnosing NSAID enteropathy in man. Forty four per cent of patients receiving these drugs had NSAID induced enteropathy when assessed by this technique; 20% of these had comparable levels of inflammation to that previously reported in patients with inflammatory bowel disease.
Adolescent↗
Forthcoming non-steroidal anti-inflammatory drugs: are they really devoid of side effects?
Non-steroidal anti-inflammatory drugs are the most prescribed of the anti-rheumatic drugs. The frequency and severity of their side effects on the gastrointestinal tract is a major health issue. A part of the toxicity of conventional non-steroidal anti-inflammatory drugs is due to their "topical" effect as well as their inhibition of cyclo-oxygenase-1. It has been suggested that the emergence of highly specific and selective cyclo-oxygenase-2 inhibitors will lead to significant decrease in gastrointestinal damage while maintaining or even improving therapeutic efficacy. Here I review the strength and weaknesses of conventional methods for assessing gastric and small intestinal safety of non-steroidal anti-inflammatory drugs. The available safety data for a range of cyclo-oxygenase-2 selective agents (meloxicam, nimesulide, celecoxib and vioxx) is reviewed. Short term endoscopy studies show minimal damage with these drugs and there is some data to suggest, at least for celecoxib and vioxx, that long term ingestion is not associated with significant gastric damage. Serious outcome studies are not available, but there is a suspicion that meloxicam may not be devoid of toxicity. Short term studies assessing intestinal permeability, which appear to give predictive information on the longer term small intestinal tolerability, show that meloxicam increases intestinal permeability while neither nimesulide or vioxx do so. Furthermore nimesulide does not cause non-steroidal anti-inflammatory drug-enteropathy when taken short term. So far the more selective cyclo-oxygenase-2 inhibitors are living up to their promise.
Animals↗
The effect of tacrolimus (FK506) on intestinal barrier function and cellular energy production in humans.
BACKGROUND & AIMS: The maintenance of the intestinal mucosal barrier may be energy dependent. Tacrolimus is a potent immunosuppressive drug that decreases mitochondrial adenosine triphosphate production and increases intestinal permeability in animals. METHODS: Twelve liver graft recipients receiving tacrolimus, 9 healthy volunteers, and 5 liver graft recipients not receiving immunosuppression underwent a combined absorption-permeability-mitochondrial function test using 5 g lactulose, 1 g L-rhamnose, 0.5 g D-xylose, 0.2 g 3-O-methyl-D-glucose, 1 mg/kg 2-keto[1-13C]isocaproic acid ([13C]KICA), and 20 mg/kg L-leucine. The respiratory quotient and resting energy expenditure were measured by indirect calorimetry. Tacrolimus pharmacokinetic profiles and levels of endotoxin and IgM and IgG endotoxin core antibodies were determined. RESULTS: Tacrolimus inhibited the decarboxylation of [13C]KICA, the resting energy expenditure, and the respiratory quotient in an exposure-dependent manner, suggesting an inhibition of mitochondrial respiration. Tacrolimus inhibited intestinal absorptive capacity in an exposure-dependent manner. Tacrolimus-treated patients had an increased intestinal permeability and significantly higher endotoxin levels compared with healthy volunteers. CONCLUSIONS: Tacrolimus inhibits cellular energy production in humans at clinically relevant doses. This is associated with an increased intestinal permeability, endotoxemia, and an impaired intestinal absorptive capacity.
Adolescent↗
Effects of indomethacin on mitochondrial ATP synthesis.
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Adenosine Triphosphate↗
Effects of indomethacin on mitochondrial oxygen uptake in intestine.
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2,4-Dinitrophenol↗
In vitro evidence for mitochondrial effects of indomethacin.
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Animals↗
Comparison of indomethacin and nimesulide, a selective cyclooxygenase-2 inhibitor, on key pathophysiologic steps in the pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in the rat.
BACKGROUND: The predicted gastrointestinal tolerability of specific cyclooxygenase-2 inhibitors could be due to either a lack of 'topical' irritation and/or lack of effect on cyclooxygenase-1. METHODS: Key pathophysiologic steps (in vitro and in vivo uncoupling, intestinal prostanoid levels (prostaglandin E, thromboxane B2, and 6-keto-prostaglandin F1alpha), intestinal permeability (51Cr-ethylenediaminetetraacetic acid), inflammation (faecal excretion of a granulocyte marker protein), and ulcer counts) in enteropathy induced by nonsteroidal anti-inflammatory drugs were assessed after administration of indomethacin, 10 mg/kg, and 15 (roughly equipotent), 30, and 60 mg/kg of the preferential cyclooxygenase-2 inhibitor nimesulide. RESULTS: Indomethacin uncoupled oxidative phosphorylation at lower concentrations than nimesulide in vitro. Indomethacin was associated with electron microscopy changes suggestive of uncoupling in 60%-70% of enterocytes examined, whereas nimesulide affected 10%-30% of enterocytes, depending on the dose. Indomethacin increased intestinal permeability and caused inflammation and ulcers with 71%-96% reductions in prostanoid levels. Nimesulide at 15 mg/kg caused no damage, whereas 30 and 60 mg/kg nimesulide were associated with significant decreases in mucosal prostanoids (46%-75%), but only the 60-mg/kg dose caused a transient increase in intestinal permeability. However, at none of the doses did nimesulide cause intestinal inflammation or ulcers. CONCLUSIONS: These results endorse the idea that selective cyclooxygenase-2 inhibitors may be associated with some gastrointestinal tolerance due to their selectivity for cyclooxygenase-2, inhibiting cyclooxygenase-1 at only very high doses, and reduced topical irritation.
Animals↗
Intestinal permeability and inflammation in patients on NSAIDs.
BACKGROUND: The frequency with which non-steroidal anti-inflammatory drugs (NSAIDs) increase small intestinal permeability and cause inflammation is uncertain. AIMS: To examine small intestinal permeability and inflammation in a large number of patients on long term NSAIDs. METHODS: Sixty eight patients receiving six different NSAIDs for over six months underwent combined absorption-permeability tests at three different test dose osmolarities (iso-, hypo-, and hyperosmolar). Two hundred and eighty six patients on 12 different NSAIDs underwent indium-111 white cell faecal excretion studies to assess the prevalence and severity of intestinal inflammation. RESULTS: The iso- and hyperosmolar tests showed significant malabsorption of 3-0-methyl-D-glucose, D-xylose, and L-rhamnose. Intestinal permeability changes were significantly more pronounced and frequent with the hypo- and hyperosmolar as opposed to the iso-osmolar test. Sequential studies showed that four and nine patients (of 13) developed inflammation after three and six months treatment with NSAIDs, respectively. There was no significant difference (p>0.1) in the prevalence (54-72%) or severity of intestinal inflammation in the 286 patients taking the various NSAIDs apart from those on aspirin and nabumetone, these having no evidence of intestinal inflammation. There was no significant correlation between the inflammatory changes and age, sex, dose of NSAID, length of disease, or NSAID ingestion. CONCLUSIONS: Intestinal permeability test dose composition is an important factor when assessing the effects of NSAIDs on intestinal integrity. All the conventional NSAIDs studied were equally associated with small intestinal inflammation apart from aspirin and nabumetone which seem to spare the small bowel.
Adult↗
Enantiomers of flurbiprofen can distinguish key pathophysiological steps of NSAID enteropathy in the rat.
BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage by a non-prostaglandin (PG) dependent "topical" action and by inhibiting cyclooxygenase. AIMS: To discriminate between these two effects by studying some key pathophysiological steps in NSAID enteropathy following administration of (R)- and (S)-flurbiprofen, the racemic mixture, and an uncoupler, dinitrophenol. METHODS: The effects of dinitrophenol, racemic, (R)-, and (S)-flurbiprofen on mitochondria were assessed in vitro and on key pathophysiological features of small intestinal damage in vivo (ultrastructure by electron microscopy, mucosal prostanoid concentrations, intestinal permeability, inflammation, and ulcer count) in rats. RESULTS: All the drugs uncoupled mitochondrial oxidative phosphorylation in vitro, caused mitochondrial damage in vivo, and increased intestinal permeability. Dinitrophenol and (R)-flurbiprofen caused no significant decreases in mucosal prostanoid concentrations (apart from a decrease in thromboxane (TX) B2 concentrations following (R)-flurbiprofen) while racemic and (S)- flurbiprofen reduced mucosal prostanoids significantly (PGE, TXB2, and 6-keto-PGF1alpha concentrations by 73-95%). Intestinal inflammation was significantly greater following administration of (S)-flurbiprofen and racemate than with dinitrophenol and (R)-flurbiprofen. No small intestinal ulcers were found following dinitrophenol or (R)-flurbiprofen while both racemic and (S)-flurbiprofen caused numerous ulcers. CONCLUSIONS: Dinitrophenol and (R)-flurbiprofen show similarities in their actions to uncouple mitochondrial oxidative phosphorylation in vitro, alter mitochondrial morphology in vivo, increase intestinal permeability, and cause mild inflammation without ulcers. Concurrent severe decreases in mucosal prostanoids seem to be the driving force for the development of severe inflammation and ulcers.
Animals↗
Non steroidal anti-inflammatory drugs, cyclooxygenase selectivity and gastrointestinal toxicity.
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Animals↗
Reduced bone density in patients with inflammatory bowel disease.
BACKGROUND: Reduced bone mineral density in patients with inflammatory bowel disease is thought to be due to disturbances in calcium homeostasis or the effects of corticosteroid treatment. AIMS: To assess the prevalence and mechanism of reduced bone mineral density in 79 patients with inflammatory bowel disease (44 with Crohn's disease, 35 with ulcerative colitis) who did not have significant risk factors for low bone densities. METHODS: Dual x ray absorptiometry was used to measure bone mineral density and serum and urinary markers of osteoblast (alkaline phosphatase, procollagen 1 carboxy terminal peptide and osteocalcin) and osteoclast (pyridinoline, deoxypyridinoline, and type 1 collagen carboxy terminal peptide) activities to assess bone turnover. RESULTS: There was a high prevalence of low bone mineral density (prevalence of T scores < -1.0 from 51%-77%; T scores < -2.5 (osteoporosis) from 17%-28%) with hips being more often affected than vertebrae (p < 0.001). Reduced bone mineral density did not relate to concurrent or past corticosteroid intake, or type, site, or severity of disease. Whereas calcium homeostasis was normal, bone markers showed increased bone resorption without a compensatory increase in bone formation. CONCLUSIONS: The greater prevalence of reduced hip bone mineral density, as opposed to vertebral, mineral density and the pattern of a selective increase in bone resorption contrasts with that found in other known causes of metabolic bone disease.
Absorptiometry, Photon↗
Intestinal tolerability of nitroxybutyl-flurbiprofen in rats.
BACKGROUND: Nitric oxide derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) are thought to be much less ulcerogenic than their parent compounds. AIM: To compare the effect and potency of flurbiprofen and nitroxybutyl-flurbiprofen to uncouple mitochondrial oxidative phosphorylation (an early pathogenic event in NSAID enteropathy), increase intestinal permeability (transitional stage), and cause macroscopic small intestinal damage. METHODS: In vitro uncoupling potency was assessed using isolated coupled rat liver mitochondria and in vivo by electron microscopy of rat small intestinal mucosa (two hours after the drugs). A dose-response study with flurbiprofen (single doses of 5, 10, 20, and 40 mg/kg) and equimolar doses of nitroxybutyl-flurbiprofen was performed; assessing their effect on intestinal permeability (at 18-20 hours), with 51Cr EDTA, and the number of pointed (< 5 mm) and longitudinal (> 5 mm) small intestinal ulcers at 24 hours. RESULTS: Flurbiprofen, but not nitroxybutyl-flurbiprofen, stimulated coupled respiration in vitro. Both drugs, however, uncoupled in vivo; in the case of nitroxybutyl-flurbiprofen possibly because hydrolysis of its ester bond released free flurbiprofen. Intestinal permeability was uniformly and equally increased with both drugs compared with controls. The number of small intestinal ulcers, pointed and longitudinal, was significantly reduced with nitroxybutyl-flurbiprofen apart from the number of longitudinal ulcers with the highest dose. CONCLUSIONS: These studies show that nitroxybutyl-flurbiprofen is associated with significantly less macroscopic damage in the small intestine than flurbiprofen but was associated with mitochondrial damage in vivo and caused similar increases in permeability of the small intestine, suggesting that its beneficial effect is on the later pathogenic stages of the damage.
Animals↗
Mitochondrial damage: a possible mechanism of the "topical" phase of NSAID induced injury to the rat intestine.
BACKGROUND: The "topical" effect of non-steroidal anti-inflammatory drugs (NSAIDs) seems to be an important cause of NSAID induced gastrointestinal damage. AIM: To examine the possible mechanism of the "topical" phase of damage in the small intestine. METHODS: Electron microscopy and subcellular organelle marker enzyme studies were done in rat small intestine after oral administration of indomethacin (doses varied between 5 and 30 mg/kg). The effect of conventional and non-acidic NSAIDs on rat liver mitochondrial respiration was measured in vitro in a Clarke-type oxygen electrode. RESULTS: The subcellular organelle marker enzymes showed mitochondrial and brush border involvement within an hour of indomethacin administration. Electron microscopy showed dose dependent mitochondrial changes following indomethacin administration consistent with uncoupling of oxidative phosphorylation (or inhibition of electron transport) which were indistinguishable from those seen with the uncoupler dinitrophenol. Parenteral indomethacin caused similar changes, but not in rats with ligated bile ducts. A range of NSAIDs, but not paracetamol or non-acidic NSAIDs which have a favourable gastrointestinal tolerability profile, uncoupled oxidative phosphorylation in vitro at micromolar concentrations and inhibited respiration at higher concentrations. In vivo studies with nabumetone and aspirin further suggested that uncoupling or inhibition of electron transport underlies the "topical" phase of NSAID induced damage. CONCLUSION: Collectively, these studies suggest that NSAID induced changes in mitochondrial energy production may be an important component of the "topical" phase of damage induction.
Acetaminophen↗