Low-dose misoprostol for the prevention of low-dose aspirin-induced gastroduodenal injury.

INTRODUCTION: The harmful effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastric mucosa and the prophylactic effects of misoprostol are both dose-dependent. AIM: To investigate whether a low-dose of misoprostol is sufficient to prevent gastric mucosal injury caused by low-dose aspirin. METHODS: We conducted a double-blind placebo controlled parallel group endoscopic study in 32 evaluable volunteers. The main outcome measure was erosive injury (ulcers and superficial erosions) in the gastric mucosa over 28 days. RESULTS: Most subjects developed erosions on aspirin 300 mg daily. This was significantly reduced by misoprostol 100 microg daily. (Odds ratio 0.18, 95% CI: 0.07-0.48). There were no drug-related or gastrointestinal adverse events in subjects receiving misoprostol. CONCLUSION: Misoprostol 100 microg daily can prevent low-dose aspirin induced gastric mucosal injury without causing identifiable adverse effects.

Protection against aspirin-induced human gastric mucosal injury by bosentan, a new endothelin-1 receptor antagonist.

BACKGROUND: Gastric ulceration induced by aspirin and by non-steroidal anti-inflammatory drugs (NSAIDs) is a major clinical problem. The mechanism of injury is unclear. There is evidence that NSAID-induced injury may cause endothelin activation. Endothelin-induced vasoconstriction has been shown to be capable of causing gastric ulceration. AIM: To investigate whether acute gastroduodenal injury induced in humans by aspirin can be prevented by the endothelin-1 antagonist, bosentan. METHODS: Eighteen healthy volunteers each received 5 x 900 mg aspirin every 12 h on three separate occasions (with either placebo, bosentan 700 mg or misoprostol 400 mg). Treatment order was randomized by Latin square design. Subjects were endoscoped and erosions counted before and 90 min after the first and last dose of aspirin. Plasma concentrations of bosentan were measured up to 5 h post-dose. RESULTS: There was a significant reduction in the mean number of erosions in the aspirin plus bosentan and aspirin plus misoprostol groups after the first dose of aspirin, compared with controls (aspirin plus placebo) (P<0.05). This was not sustained after the fifth dose of aspirin in the aspirin plus placebo and aspirin plus bosentan groups, but was still present in the aspirin plus misoprostol group. The mean plasma concentration of bosentan measured 3.5 h post-dose fell from 4510 (95% CI: 2791-6230) ng/mL after the 1st dose to 2508 (95% CI: 1733-3283) ng/mL after the 5th dose (P = 0.02). CONCLUSION: Endothelin receptor antagonism by bosentan can protect the gastric mucosa against aspirin damage. After five doses, bosentan levels fell, possibly because of enzyme induction, and protection was no longer evident. Further investigation is needed to assess whether higher doses would be effective.

Effect of sucralfate on aspirin induced mucosal injury and impaired haemostasis in humans.

BACKGROUND: Sucralfate does not have potent anti-ulcerogenic actions in users of non-steroidal anti-inflammatory drugs (NSAIDs). However, sucralfate may influence intragastric haemostasis favourably. AIM: To investigate separately the effects of sucralfate on acute gastric and duodenal injury and on changes in intragastric bleeding induced by aspirin. METHOD: On three occasions, 24 healthy volunteers received three days' treatment with aspirin 900 mg twice daily together with placebo, sucralfate 2 g twice daily or sucralfate 1 g four times daily. Injury was assessed endoscopically and bleeding by spontaneous and biopsy induced bleeding intragastric washings. Ex vivo prostaglandin E2 (PGE2) synthesis and serum thromboxane were measured by using radioimmunoassay. RESULTS: Aspirin significantly inhibited ex vivo gastric mucosal PGE2 synthesis, reduced serum thromboxane, caused gastric erosions, and increased spontaneous and biopsy induced bleeding. Sucralfate had no significant effects on endoscopic injury but sucralfate 1 g four times daily significantly reduced spontaneous and biopsy induced bleeding. Similar trends were seen with sucralfate 2 g twice daily but the results were less consistent. CONCLUSION: Sucralfate does not affect aspirin induced acute gastric mucosal injury but reduces aspirin associated intragastric bleeding.

Healing with basic fibroblast growth factor is associated with reduced indomethacin induced relapse in a human model of gastric ulceration.

BACKGROUND: Acid stable basic fibroblast growth factor (bFGF) promotes angiogenesis and healing of gastric ulcers in rats and reduces subsequent non-steroidal anti-inflammatory drug (NSAID) induced relapse. AIMS: To test in a double blind, placebo controlled, three way crossover study whether bFGF promotes healing and reduces subsequent relapse in a human model of gastric ulceration. SUBJECTS: Twelve healthy volunteers. METHODS: Subjects took aspirin 900 mg twice daily (days 1-3) with bFGF 0.1 mg twice daily or cimetidine 400 mg twice daily or placebo (days 1-14) and then indomethacin 50 mg thrice daily (days 15-21). Endoscopy was performed on days 1, 4, 8, 15, and 22 during each treatment period. Eight antral biopsy specimens were taken on day 1 and the number of unhealed biopsy induced mini-ulcers and NSAID induced erosions counted during subsequent endoscopies. RESULTS: Basic FGF and cimetidine were protective against aspirin and indomethacin induced duodenal (but not gastric) injury compared with placebo. There was significant relapse of biopsy induced mini-ulcers after indomethacin only in the placebo group (0 (0-0) before v 1 (0-4.5) after; p > 0.05). TGP-580 was detected in serum of one volunteer. CONCLUSIONS: Healing with bFGF (and cimetidine) was associated with reduced NSAID induced ulcer relapse in this model of gastric ulceration.

Nitric oxide donating compounds stimulate human colonic ion transport in vitro.

BACKGROUND: Nitric oxide (NO) has been recently implicated as a possible mediator of bowel inflammation and has also been shown to stimulate electrogenic chloride secretion in rat and guinea pig intestine. This study therefore investigated the effect on two NO donors, sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) on human colonic ion transport. METHODS: Changes in short circuit current (delta SCC) in response to nitric oxide donating compounds were measured in muscle stripped normal human colon mounted in Ussing chambers. The ion species and intracellular mechanisms responsible for delta SCC evoked by SNP were investigated. RESULTS: Basolateral SNP caused a progressive rise in delta SCC over the range 10(-7) to 10(-4)M (ED50 = 2.5 x 10(-5)M). SNAP 10(-4)M also evoked a qualitatively similar delta SCC compared with SNP 10(-4)M. Basolateral SNP evoked a greater delta SCC than apical and this was significantly attenuated by bumetanide 10(-4)M (52.9 +/- 10.1%) and in chloride free media (68.3 +/- 7.3%). delta SCC response to SNP was not significantly changed by basolateral 4-acetamido-4'-isothio-cyano-2,2'disulphonic acid stillbene (SITS 10(-3)M) an inhibitor of sodium/bicarbonate exchange, or apical amiloride 10(-5)M an inhibitor of sodium absorption. SNP induced delta SCC was also significantly reduced by piroxicam (mean (SEM)) 10(-5)M (57.9 (11.9)%), nordihydroguaretic acid 10(-4)M (48.0 (12.9)%), tetrodotoxin (TTX 10(-6)M, 52.3 (9.1)%), and practically abolished by TTX and piroxicam together (96.8 (3.3)%). CONCLUSION: NO donors stimulate human colonic ion transport in vitro. For SNP, increased delta SCC is at least due in part to chloride secretion, and the response seems to be transduced through enteric nerves and by local prostanoid synthesis. This study provides evidence that NO may be another important mediator of ion transport in human colon.

Effect of allopurinol, sulphasalazine, and vitamin C on aspirin induced gastroduodenal injury in human volunteers.

BACKGROUND: The mechanisms of aspirin induced gastroduodenal injury are not fully understood. Aspirin induces the release of reactive oxygen metabolites in animal models, which may contribute to mucosal injury. AIMS: To investigate the effects of aspirin administered with placebo or antioxidants on gastric mucosal reactive oxygen metabolite release and gastroduodenal injury in human volunteers. SUBJECTS: Fourteen healthy volunteers participated in the study (seven male; mean age 27 years, range 20-40). METHODS: In a double blind, randomised, crossover study, volunteers received aspirin 900 mg twice daily and either placebo, allopurinol 100 mg twice daily, sulphasalazine 1 g twice daily or vitamin C 1 g twice daily for three days. Injury was assessed endoscopically and by quantifying mucosal reactive oxygen metabolite release by measuring chemiluminescence before and after each treatment. The effect on prostanoids was determined by measuring ex vivo antral prostaglandin E2 (PGE2) synthesis and serum thromboxane B2 (TXB2). RESULTS: No drug reduced any parameter of gastric injury but vitamin C reduced duodenal injury assessed by Lanza score (p < 0.005). Chemiluminescence increased after aspirin both with placebo (p < 0.05) and vitamin C (p < 0.05). Post-treatment chemiluminescence was lower in subjects taking allopurinol (p < 0.05) or sulphasalazine (p < 0.005) than in those taking placebo with aspirin. CONCLUSIONS: In this study, aspirin induced gastric injury was associated with reactive oxygen metabolite release. This was reduced by sulphasalazine and allopurinol, although macroscopic injury was not affected. Vitamin C, however, was shown to have a previously unrecognised protective effect against aspirin induced duodenal injury.

Low dose aspirin: selective inhibition of rectal dialysis thromboxane B2 in healthy volunteers.

AIM: To investigate the degree and selectivity of rectal thromboxane inhibition by low dose aspirin and there by investigate the contribution of platelet thromboxane to rectal thromboxane. METHODS: The study was a randomized double-blind placebo controlled crossover study. Twelve healthy volunteers were studied, each over four separate study periods with two weeks wash-out between each period. Changes in levels of thromboxane (TX) B2, prostaglandin (PG) E2 and leukotriene (LT) B4 in rectal dialysates were measured in response to 5 days oral low dose aspirin therapy in one of three once-daily formulations (plain 75 mg, plain 300 mg or enteric coated 300 mg), and compared to placebo. For each study period, rectal dialysates (4 h duration) were obtained at baseline and twice more after 5 days of aspirin or placebo therapy. Dialysate levels of thromboxane B2, leukotriene B4, prostaglandin E2, and serum thromboxane B2 were measured by radioimmunoassay. RESULTS: Dialysate thromboxane B2 levels were consistently inhibited by low dose aspirin (overall results of all formulations, 75 to 300 mg daily) from 1.06 ng/ml (geometric mean, 95% CI: 0.79-1.43 ng/ml) on placebo, by 29% (95% CI: 11-40%) to 0.75 ng/ml (0.56-1.01 ng/ml) (P = 0.046) on aspirin. In the absence of aspirin the level of prostaglandin E2 was 1.47 ng/ml (0.97-2.23 ng/ml) and in the presence of aspirin was not significantly changed. The dialysate level of leukotriene B4 was 0.45 ng/ml (0.34-0.61 ng/ml) in the absence of aspirin and there was no significant change on low dose aspirin. Serum thromboxane was inhibited by 80% to 20% of placebo values by plain aspirin 75 mg, by 95% by plain aspirin 300 mg, and by 82% by enteric coated aspirin 300 mg, respectively (P < 0.01). These results show that 29% of the rectal thromboxane, but none of the rectal prostaglandin E2 or leukotriene B4 is inhibited by low dose aspirin. We infer that 34% of the rectal thromboxane B2 is platelet-derived in our volunteers. CONCLUSION: Low dose aspirin will selectively inhibit a proportion of rectal thromboxane and may have prophylactic therapeutic potential in inflammatory bowel disease.

High dose eicosapentaenoic acid ethyl ester: effects on lipids and neutrophil leukotriene production in normal volunteers.

1. A 93% pure ethyl ester of eicosapentaenoic acid was investigated for tolerability and biochemical effects on neutrophil leukotriene synthesis and plasma lipoproteins when given in high dose. Six healthy volunteers received 6 g eicosapentaenoic acid ethyl ester daily for 6 weeks, followed by a 4 week wash-out and then 18 g daily for 6 weeks. 2. There was inhibition of neutrophil leukotriene B4 and 5-hydroxyeicosatetraenoic acid synthesis, with no significant differences between low and high dose. 3. There was a dose dependent increase in leukotriene B5 and 5-hydroxyeicosatetraenoic acid acid synthesis. 4. Plasma triglycerides were reduced maximally on 6 g daily, with no greater suppression at 18 g daily. 5. Plasma cholesterol was only suppressed significantly at 18 g daily. 6. The 6 g daily dose was well tolerated but the 18 g daily dose produced diarrhoea and steatorrhoea.

Evidence that adaptive cytoprotection in rats is not mediated by prostaglandins.

We investigated the proposition that adaptive cytoprotection (enhanced gastric mucosal integrity) caused by exposure to 20% ethanol in rats is mediated by endogenous prostaglandin synthesis. Experiments were performed both without and with indomethacin sufficient to inhibit ex vivo release of prostaglandin E2 by 56% +/- 9% (2.5 mg/kg) or 86% +/- 4% (10 mg/kg). Twenty percent ethanol significantly reduced both macroscopic and histologic signs of injury caused by subsequent exposure to 100% ethanol whether or not the rats were pretreated with indomethacin. Twenty percent ethanol itself caused extensive superficial disruption of the surface epithelium, so that about half of the mucosa was covered by desquamated debris, but did not stimulate prostaglandin release. We conclude that adaptive cytoprotection still occurs after doses of indomethacin sufficient to cause a profound depression of prostaglandin E2 release. The possibility that it could be due to formation of a protective covering of surface debris is worth further investigation.

Gastric mucosal protection with selective inhibition of thromboxane synthesis.

Because thromboxane synthesis enhances gastric mucosal damage we have investigated whether the thromboxane synthesis inhibitor dazmegrel might be protective to the mucosa. Dazmegrel at a dose of 1 and 5 mg per rat (4.8 and 23.8 mg/kg) significantly reduced the damage caused by acidified taurocholate. In parallel experiments dazmegrel exerted a selective and dose dependent inhibition of ex vivo thromboxane synthesis by gastric fragments over the dose range in which protection was observed. As dazmegrel can be given to man, these experiments suggest that investigation of mucosal protection would be justified.