misoprostol and Intestinal-Diseases

Recent advances in small-bowel endoscopy such as capsule endoscopy have shown that non-steroidal anti-inflammatory drugs (NSAIDs) frequently damage the small intestine, with the prevalence rate of mucosal breaks of around 50% in chronic users. A significant proportion of patients with NSAIDs-induced enteropathy are asymptomatic, but some patients develop symptomatic or complicated ulcers that need therapeutic intervention. Both inhibition of prostaglandins due to the inhibition of cyclooxygenases and mitochondrial dysfunction secondary to the topical effect of NSAIDs play a crucial role in the early process of injury. As a result, the intestinal barrier function is impaired, which allows enterobacteria to invade the mucosa. Gram-negative bacteria and endogenous molecules coordinate to trigger inflammatory cascades via Toll-like receptor 4 to induce excessive expression of cytokines such as tumor necrosis factor-α and to activate NLRP3 inflammasome, a multiprotein complex that processes pro-interleukin-1β into its mature form. Finally, neutrophils accumulate in the mucosa, resulting in intestinal ulceration. Currently, misoprostol is the only drug that has a proven beneficial effect on bleeding small intestinal ulcers induced by NSAIDs or low-dose aspirin, but its protection is insufficient. Therefore, the efficacy of the combination of misoprostol with other drugs, especially those targeting the innate immune system, should be assessed in the next step.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Aspirin; Capsule Endoscopy; Gastrointestinal Hemorrhage; Humans; Intestinal Diseases; Intestine, Small; Misoprostol; Peptic Ulcer

Our knowledge of the mechanism by which aspirin and traditional NSAIDs work and damage the gastrointestinal mucosa, recently markedly improved, has suggested a number of measures for the prevention of the NSAID-induced GI lesions. Among these, perhaps the most innovative approach seems to be the nitric oxide-releasing NSAIDs or compounds, like amtolmetin guacyl, that work by increasing the endogenous biosynthesis of NO selectively at gastric mucosa level. Further data, stemming from large RCTs and confirming the results of experimental studies and the initial clinical experiences, are needed to better define the true clinical impact of this approach.

Topics: Age Factors; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Cytoprotection; Duodenal Ulcer; Female; Gastrointestinal Diseases; Glycine; Helicobacter Infections; Helicobacter pylori; Histamine H2 Antagonists; Humans; Intestinal Diseases; Male; Middle Aged; Misoprostol; Pyrroles; Risk Factors; Stomach Ulcer; Sucralfate; Ulcer

There is no known preventive agent against nonsteroidal anti-inflammatory drug (NSAID) induced small-intestinal injury.. To evaluate by capsule endoscopy whether coadministration of prostaglandin (PG) can prevent small-intestinal damage induced by short-term NSAID treatment.. Single-blind, randomized, controlled trial.. All procedures were performed at Nippon Medical School.. Thirty-four healthy male volunteers.. All subjects were randomly assigned to 2 groups: an NSAID-control group, who underwent NSAID (diclofenac sodium, 25 mg 3 times daily) and omeprazole (20 mg once daily) treatment, and an NSAID-PG group, who received PG (misoprostol, 200 microg 3 times daily) in addition to the same NSAID-omeprazole treatment. Eligible subjects, 15 per group, underwent capsule endoscopy before and 14 days after treatment.. The number of mucosal breaks at capsule endoscopy.. NSAID treatment significantly increased the mean (SD) number of mucosal breaks per subject, from a basal level of 0.1 +/- 0.3 up to 2.9 +/- 6.3 lesions in the NSAID-control group (P = .012). In contrast, there was no significant change in the mean number of mucosal breaks before and after PG cotreatment (P = 0.42). Thus, the mean number of posttreatment mucosal breaks per subject was significantly higher in the NSAID-control group than in the NSAID-PG group (P = .028). There was a significant increase in the percentage of subjects in the NSAID-control group, with at least 1 mucosal break after treatment (from 6.7% to 53.3%), whereas there was no change in the incidence of mucosal breaks in the NSAID-PG group, which remained at 13.3%. (P = .002).. Single-center, open-label study.. PG cotherapy reduced the incidence of small-intestinal lesions induced by a 2-week administration of diclofenac sodium.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Capsule Endoscopy; Diclofenac; Humans; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Male; Middle Aged; Misoprostol; Omeprazole; Prostaglandins E, Synthetic; Proton Pump Inhibitors; Single-Blind Method; Young Adult

Intestinal mucosal barrier dysfunction caused by disease and/or chemotherapy lacks an effective treatment, which highlights a strong medical need. Our group has previously demonstrated the potential of melatonin and misoprostol to treat increases in intestinal mucosal permeability induced by 15-min luminal exposure to a surfactant, sodium dodecyl sulfate (SDS). However, it is not known which luminal melatonin and misoprostol concentrations are effective, and whether they are effective for a longer SDS exposure time. The objective of this single-pass intestinal perfusion study in rats was to investigate the concentration-dependent effect of melatonin and misoprostol on an increase in intestinal permeability induced by 60-min luminal SDS exposure. The cytoprotective effect was investigated by evaluating the intestinal clearance of

Topics: Animals; Intestinal Diseases; Intestinal Mucosa; Intestines; Melatonin; Misoprostol; Permeability; Rats

A healthy intestinal barrier prevents uptake of allergens and toxins, whereas intestinal permeability increases following chemotherapy and in many gastrointestinal and systemic diseases and disorders. Currently, there are no approved drugs that target and repair the intestinal epithelial barrier while there is a medical need for such treatment in gastrointestinal and related conditions. The objective of this single-pass intestinal perfusion study in rats was to investigate the preventive cytoprotective effect of three mucosal protective drugs-melatonin, misoprostol, and teduglutide-with different mechanisms of action on an acute jejunal injury induced by exposing the intestine for 15 min to the anionic surfactant, sodium dodecyl sulfate (SDS). The effect was evaluated by monitoring intestinal clearance of

Topics: Animals; Drug Combinations; Edetic Acid; Intestinal Diseases; Intestinal Mucosa; Intestines; Male; Melatonin; Misoprostol; Perfusion; Permeability; Phenobarbital; Rats; Rats, Wistar; Sodium Dodecyl Sulfate

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Aspirin; Humans; Intestinal Diseases; Intestine, Small; Misoprostol

To investigate the preventive effect of misoprostol against non-steroidal anti-inflammatory drug (NSAID)-induced intestinal injury in mice.. NSAID-induced intestinal injury model was established through diclofenac sodium. Sixty specific-pathogen-free (SPF) BABL/c male mice were randomly divided into the following five groups: normal, model and three misoprostol groups with different concentrations (200, 400, 800 μg/kg). Misoprostol was given to aforementioned three misoprostol groups by gavage once a day for 6 days. In the fourth day afternoon, 5 mg/kg (10 mL/kg) diclofenac was fed to all mice by gavage except for normal group. On the seventh day, all mice were sacrificed and intestinal permeability was detected using FITC labeled dextran. The intestinal tissues were taken for detecting the mRNA and protein expressions of intestinal glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and tumor necrosis factor alpha (TNF-α) through HE staining, reverse transcription PCR and Western blotting, respectively.. Compared with the normal group, intestinal mucosa in the model group was seriously damaged and intestinal permeability significantly increased. The intestinal mucosal villus degeneration, necrosis, shedding, and inflammatory cell infiltration occurred in the model group. Yet, intestinal mucosal injury in different misoprostol groups was less severe. Their intestinal mucosal permeability was improved. The expressions of GRP78 protein and TNF-α, CHOP mRNAs on intestine were significantly reduced compared with those of the model group.. Misoprostol has preventive effect against NSAID-induced intestinal diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Endoplasmic Reticulum Chaperone BiP; Gene Expression Regulation; Heat-Shock Proteins; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Male; Mice; Mice, Inbred BALB C; Misoprostol; Permeability; RNA, Messenger; Transcription Factor CHOP; Tumor Necrosis Factor-alpha

Antisecretory drugs such as histamine H₂-receptor antagonists and proton pump inhibitors are commonly used for the treatment of upper gastrointestinal mucosal lesions induced by nonsteroidal anti-inflammatory drugs (NSAIDs). However, it has recently been reported that these drugs exacerbate NSAID-induced small intestinal lesions in rats. Unfortunately, there are few effective agents for the treatment of this complication. We examined the effects of mucosal protective agents (MPAs) (misoprostol, irsogladine, and rebamipide) and mucin of porcine stomach on diclofenac-induced intestinal lesions and the exacerbation of the lesions by ranitidine or omeprazole. The effects of the drugs on intestinal motility and mucus distribution/content were also examined. Male Wistar rats (180-220 g) were used. Each drug was administered orally under fed conditions. Diclofenac (1-10 mg/kg) produced multiple lesions in the small intestine dose-dependently. Both ranitidine (30 mg/kg) and omeprazole (100 mg/kg) significantly increased the intestinal lesions induced by low doses (3 and 6 mg/kg) of diclofenac. Misoprostol (0.03-0.3 mg/kg), irsogladine (3-30 mg/kg), and rebamipide (30-300 mg/kg), as well as mucin (30-300 mg/kg) inhibited the formation of intestinal lesions caused by a high dose (10 mg/kg) of diclofenac alone and prevented the exacerbation of diclofenac-induced lesions by antisecretory drugs. Diclofenac (10 mg/kg) markedly increased the intestinal motility and decreased the mucosal mucus, and the decrease of mucus was significantly inhibited by the MPAs. These results indicate the usefulness of the MPAs for the treatment of intestinal lesions induced by NSAIDs alone or by coadministration with antisecretory drugs, and suggest that mucus plays an important role in the protection of intestinal mucosa by the MPAs.

Topics: Alanine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Diclofenac; Dose-Response Relationship, Drug; Gastric Mucins; Gastrointestinal Agents; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Male; Misoprostol; Mucus; Omeprazole; Protective Agents; Proton Pump Inhibitors; Quinolones; Ranitidine; Rats; Rats, Wistar; Sus scrofa; Triazines

A case of a 40-year-old man with chronic anaemia because of nonspecific ulcerating and stenosing enteropathy is presented. The diagnosis was made on the basis of capsule endoscopy, histology of resected ileum and no use of NSAIDs. He showed a clinical response to treatment with misoprostol, and therefore, he was investigated for a possible impairment in eicosanoid biosynthesis compared with healthy controls. No deficient synthesis of prostacyclin, prostaglandin E2 and thromboxane was found on examination of metabolites in blood and urine. This suggests a normal release of arachidonic acid from phospholipids. Ex-vivo cyclooxygenase (COX) assays showed normal COX-1 and COX-2 activities. The clinical response to treatment with the prostaglandin E1 analogue misoprostol suggests a defective prostaglandin E synthesis in the intestinal mucosa.

Topics: Adult; Anemia, Iron-Deficiency; Humans; Intestinal Diseases; Male; Misoprostol; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Ulcer

Topics: Anti-Inflammatory Agents, Non-Steroidal; Capsule Endoscopy; Humans; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Misoprostol; Prostaglandins E, Synthetic

Small bowel ulceration is an increasingly recognised complication of therapy with non-steroidal anti-inflammatory drugs (NSAID). The ulceration is a potent site of blood loss contributing to unexplained iron deficiency anaemia in patients with arthritis. No drug is currently available to treat NSAID small bowel ulcers.. We have retrospectively examined the effect of therapy with the prostaglandin E1 analogue misoprostol on the anaemia of patients with enteroscopically proven NSAID small bowel enteropathy.. All of the patients had proven iron deficiency anaemia. Eleven patients received misoprostol and ten received no treatment. Haemoglobin in the misoprostol-treated group rose significantly from median (range) 9.1 (6.2-10.6) g/dL (95% confidence intervals 8.76, 10.13) to 10.6 (6.5-16.8) g/dL (95% confidence intervals 10.06, 11.82); P = 0.004). Those patients who did not receive misoprostol had no significant change in their haemoglobin: 9.1 (7.5-10.6) g/dL to 8.1 (5.6-14.7) g/dL (P = N.S.).. Misoprostol therapy was associated with an improvement in the anaemia in patients with proven NSAID enteropathy.

Topics: Adult; Aged; Anemia, Iron-Deficiency; Anti-Inflammatory Agents, Non-Steroidal; Female; Humans; Intestinal Diseases; Male; Middle Aged; Misoprostol; Retrospective Studies; Rheumatic Diseases; Ulcer

SC-53450 is a new polybutadiene-based polymer system with an acid labile diisopropyl silyl ether linker to which the active isomer of misoprostol (SC-30249) is attached covalently at position C-11. It was studied in rats and dogs to define its profile of gastrointestinal effects relative to misoprostol-hydroxypropyl methylcellulose (HPMC) and the systemic availability of prostaglandin from the polymer. Results of rat studies indicate that SC-53450 has a spectrum of mucosal protective activity similar to misoprostol-HPMC, being protective against indomethacin-induced gastric, cysteamine/indomethacin-induced duodenal and indomethacin-induced lower small bowel damage. SC-53450, in contrast to misoprostol-HPMC, was not diarrheagenic in the rat when administered intragastrically. The observation that SC-53450 is more than 4 times more potent than misoprostol-HPMC suggests the possibility of sustained gastric availability of the prostaglandin SC-30249. SC-53450 exhibited gastric antisecretory activity in histamine-stimulated gastric fistula dogs and protected against acidified aspirin-induced gastric damage in normal fasted beagles. Rat and dog experiments indicate that little, if any, polymer-derived prostaglandin is available systemically, suggesting SC-53450 will have reduced abuse potential in abortion induction. SC-53450 is a potential candidate to replace the present misoprostol formulation in the marketplace for the prevention of nonsteroidal anti-inflammatory drug-induced gastric damage.

Topics: Animals; Antacids; Aspirin; Biological Availability; Butadienes; Depression, Chemical; Diarrhea; Dogs; Drug Carriers; Ethanol; Female; Gastric Mucosa; Hypromellose Derivatives; Indomethacin; Intestinal Diseases; Male; Methylcellulose; Misoprostol; Polymers; Rats; Rats, Inbred Strains; Stomach Diseases

The influence of misoprostol pretreatment (100 micrograms/loop intraluminally) on small intestinal damage induced by acetic acid was evaluated in anesthetized rabbits. In this model injury was induced by intraluminal administration into loops of distal small intestine, of a solution of calcium gluconate (50 mg/ml) and acetic (200 mM). After 3 hr damage was associated with increase in loop fluid volume, loop fluid protein levels and epithelial permeability to 51Cr-EDTA, all of which were attenuated by misoprostol pretreatment. Similar protective effects were noted 45 min after the insult, suggesting that misoprostol may be therapeutically useful in conditions where the epithelial barrier is compromised.

Topics: Acetates; Animals; Edetic Acid; Epithelium; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Male; Misoprostol; Proteins; Rabbits

Topics: Alprostadil; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Humans; Intestinal Absorption; Intestinal Diseases; Intestine, Small; Misoprostol