Recent studies have suggested that some patients may not obtain the full benefits of aspirin's antiplatelet effects. An international roundtable of experts was held November 6, 2004, in New Orleans, Louisiana, to address the concept of aspirin resistance and its clinical implications. Panelists discussed various definitions and possible mechanisms of aspirin resistance, along with several tests currently available to measure platelet function. They recommended that until the clinical importance of these tests is known, physicians should continue to prescribe low-dose aspirin therapy for individuals at high risk for cardiovascular events and patients currently taking aspirin should continue to comply with their prescribed therapy.

This systematic review examines the evidence for commonly employed strategies of managing patients with recurrent ulcer disease after acid-reducing operations. Particular attention is given to recent evidence relating Helicobacterpylori (H. pylori) and nonsteroidal anti-inflammatory drugs (NSAIDs) to ulcer recurrence after operative therapy. MED LINE word searches of the literature from 1966 to 2001 identified 895 articles that cross-reference the terms “peptic ulcer disease (PUD),” “surgery,” and “recurrence.” Articles were selected for systematic review of evidence relating incomplete vagotomy, NSAIDs, and H. pylori to postoperative ulcer recurrence and evidence supporting common medical and surgical strategies. The relationship between incomplete vagotomy and recurrent ulcer disease is suggested by randomized controlled trials and well-designed prospective case series. The evidence that NSAID use is an important pathogenic factor in recurrent ulcer disease includes the relationship between NSAIDs and primary PUD, the occurrence of NSAID-induced ulcers in patients taking proton pump inhibitors, and case series demonstrating virulent ulcer disease in patients taking aspirin despite prior acid-reducing operations. The relationship between H. pylori infection and postoperative ulcer recurrence remains uncertain despite multiple controlled trials and well-designed case series that have documented high rates of H. pylori infection in postoperative patients. The initial management of patients with recurrent ulcer disease after acid-reducing operations consists of a protein pump inhibitor or a histamine-2 receptor antagonist and antibiotics directed at H. pylori, if present. Evidence for this regimen includes prospective randomized trials demonstrating the efficacy of cimetidine in healing ulcers after acid-reducing operations and prospective, randomized studies documenting the efficacy of histamine-2 receptor antagonists and protein pump inhibitors in the management of patients with primary PUD. The critical role that H. pylori infection plays in primary PUD and the minimal risks associated with H. pylori eradication strongly support the initiation of antibiotic therapy when H. pylori is present. The principal indication for operative management of recurrent PUD is the occurrence of ulcer complications that cannot be managed by medical or endoscopic means. The operative management of patients with failed acid-reducing operations is based on ulcer recurrence rates and morbidity and mortality rates in randomized and nonrandomized prospective trials of patients with primary PUD and retrospective case series of patients undergoing remedial operative procedures after various failed acid-reducing operations.

Aspirin's antithrombotic effect is mediated predominately by inhibition of platelet cyclooxygenase-1, leading to a decline in serum thromboxane A(2) concentrations. We performed a placebo-controlled, randomized, double-blind trial to determine whether aspirin could be given at 3-day intervals and still achieve potent serum thromboxane inhibition. One hundred nine healthy men and women with no recent exposure to aspirin and no contraindications to its use participated. Subjects received 325 mg, 81 mg, or 40 mg of plain aspirin every third day, with placebo on other days; 81 mg of aspirin every day; or placebo every day. Serum concentrations of thromboxane B-2 (the metabolite of thromboxane A(2)) were measured at 3-day intervals during a 31-day treatment period, as well as 4, 7, and 14 days after treatment ended. Serum thromboxane B-2 concentrations were nearly identical during treatment with 325 mg of aspirin every third day or 81 mg of aspirin per day (86% inhibition [84%, 89%] and 85% inhibition [73%, 96%], respectively). An aspirin dose of 81 mg every third day was nearly as potent (74% inhibition [70%, 79%]), whereas 40 mg of aspirin every third day achieved only 50% inhibition (40%, 60%). Every-third-day low-dose aspirin regimens (325 and 81 mg) deserve comparison with daily low-dose aspirin regimens in controlled clinical trials because the former regimens could prove to have equal efficacy with reduced toxicity.

Aspirin causes peptic ulcers predominately by reducing gastric mucosal cyclooxygenase (COX) activity and prostaglandin synthesis. Because aspirin circulates for only a few hours, we hypothesized that aspirin's inhibitory effect on gastric COX activity must be prolonged. We performed a placebo-controlled experiment in healthy humans to determine the duration of inhibition of aspirin on gastric mucosal COX activity (PGE(2) and PGF(2 alpha) synthesis rates). Recovery of gastric COX activity after stopping aspirin was slow and linear. Seventy-two hours after 325-mg aspirin, gastric COX activity was still reduced by 57% (P< 0.001). Duration of inhibition of gastric COX activity was estimated to be 7-8 days after 325-mg aspirin and 5 days after 81-mg aspirin. Recovery of gastric prostaglandin synthesis after 325-mg but not after 81-mg aspirin occurred at slower rates in subjects with Helicobacter pylori-associated gastritis than in those with normal histology. In conclusion, aspirin inhibits gastric COX activity for much longer than predicted from its pharmacokinetic profile, explaining why aspirin at widely spaced intervals is ulcerogenic.

Large clinical trials such as the second International Study of Infarct Survival routinely gave patients with myocardial infarction a chewed aspirin, yet there are no data to show whether chewing of aspirin is better, or worse, than swallowing a whole tablet. We performed a randomized, placebo-controlled study to determine whether chewing aspirin or administering it in solution accelerates its absorption and antiplatelet activity. On separate days, 12 fasting volunteers ingested 325 mg of buffered aspirin, either by chewing a tablet for 30 seconds before swallowing it with 4 ounces of water, swallowing a whole tablet with 4 ounces of water, or drinking 4 ounces of Alka Seltzer. Frequent blood samples were obtained for serum aspirin, salicylate, and thromboxane B2 (TxB2) concentrations. With all formulations of aspirin, serum TxB2 decreased 50% when the plasma aspirin concentration reached approximately 1,000 ng/ml. A 50% and 90% decrease in serum TxB2 occurred more quickly after chewing a tablet than after a tablet was swallowed whole. For example, the t 50% for serum TxB2 inhibition was 5.0 +/- 0.6 minutes with the chewed tablet versus 12.0 +/- 2.3 minutes when the tablet was swallowed (p = 0.01). A 50% decrease in serum TxB2 occurred 7.6 +/- 1.2 minutes after Alka Seltzer solution (p = 0.04 vs chewing a tablet; p = 0.13 vs swallowing a whole tablet). Chewing an aspirin tablet is the most effective way of accelerating absorption of aspirin into the blood and shortening the time required for an antiplatelet effect.

Gastric acid secretion, gastrin release, gastric emptying, and gastroesophageal acid reflux were measured in asymptomatic individuals before and after elimination of Helicobacter pylorigastritis. After basal gastric acid secretion and serum gastrin concentrations were measured, meal-stimulated gastric acid secretion and gastrin release were assessed during in vivo intragastric titration to pH 3. Experiments were repeated 4 wk after treatment with lansoprazole, amoxicillin, and clarithromycin. Esophageal pH was also monitored for 24 h before and after therapy. Basal gastric acidity increased ∼20 mmol/l in subjects whose infection was eradicated ( P < 0.05) but not in those with persistent infection. Basal and meal-stimulated gastric acid secretion did not change after H. pylorieradication, despite a 41% reduction in meal-stimulated gastrin release ( P < 0.05). Gastroesophageal acid reflux increased two- to threefold after successful treatment ( P < 0.05) but did not change in subjects with persistent infection. Thus elimination of H. pylori gastritis increases gastric acidity, probably by reducing nonparietal alkaline secretion, and this may facilitate gastroesophageal acid reflux.

Oral aspirin blocks cyclooxygenase in platelets, lowering serum thromboxane concentrations. Oral aspirin also blocks cyclooxygenase in the gastrointestinal mucosa, lowering prostaglandin production and increasing the risk of gastrointestinal ulceration and bleeding. Aspirin placed on the skin also inhibits cyclooxygenase in platelets, but aspirin absorption through skin is slow, which may minimize the gastrointestinal effects. Our objectives in this study were 1) to compare the pharmacokinetic and pharmacodynamic effects of cutaneous and oral aspirin in healthy volunteers and 2) to compare the effects of cutaneous aspirin on gastroduodenal mucosal prostaglandin E2 and F2 alpha content and on mucosal damage, using endoscopy. The bioavailability of cutaneous aspirin was 4%-8% that of oral aspirin. Cutaneous aspirin (750 mg/day for 10 days) significantly lowered serum thromboxane (by 85%) and gastric and duodenal prostaglandins (by 49%-71%); placebo had no effect. Moreover, cutaneous aspirin, but not placebo, resulted in significant gastric mucosal injury. These findings demonstrate that even tiny amounts of aspirin in the blood (2 microM) have inhibitory effects on prostaglandin production in the human stomach and duodenum that result in gastric mucosal damage, even without direct exposure of the stomach to aspirin.

GASTROENTEROLOGY 1999;117:1505-1506

Background & Aims: The safety of low-dose daily aspirin therapy in the gastrointestinal tract is uncertain. Our objectives were to evaluate the long-term effects of very low daily aspirin doses in the gastrointestinal tract and effects on platelet-derived serum thromboxane levels in volunteers. Methods: Subjects were randomized to receive 10 mg (n = 8), 81 mg (n = 11), or 325 mg (n = 10) aspirin daily for 3 months. Before administration of aspirin, all subjects underwent gastroduodenoscopy, and most underwent proctoscopy for assessment of mucosal injury and prostaglandin content. After 1.5 and 3 months, subjects again underwent gastroduodenoscopy and, at 3 months, another proctoscopy. Results: Each aspirin dose (even 10 mg) significantly reduced gastric mucosal prostaglandin levels, to similar to 40% of the baseline value. All three doses also induced significant gastric injury, and 325 mg caused duodenal injury. Three subjects developed gastric ulcers, 1 while taking 10 mg/day of aspirin. Furthermore, aspirin at 81 mg/day and 325 mg(day (but not 10 mg/day) significantly reduced duodenal mucosal prostaglandin levels to similar to 40% of the baseline value. Only 325 mg of aspirin per day significantly reduced rectal mucosal prostaglandin levels to similar to 60% of the baseline value. Serum thromboxane levels were inhibited 62%, 90%, and 98% with 10, 81, and 325 mg of aspirin. Conclusions: The findings explain aspirin's predominant gastric toxicity and question the safety of even 10 mg of aspirin daily.

Helicobacter pylori gastritis is common, but effects on gastric secretion are not well understood. We measured basal and pentagastrin-stimulated gastric acidity, pepsin activity, and fluid output, as well as serum gastrin concentrations and H. pylori antibody levels, before and after treatment of H. pylori gastritis in 28 men and women. Subjects were studied before and 1 and 3 mo after a course of bismuth, metronidazole, and tetracycline. Elimination of H. pylori gastritis, accomplished in 14 subjects, increased basal and pentagastrin-stimulated gastric acidity (by 15 meq/l) and basal acid output significantly (by 2.1 meq/h 1 mo after therapy). Elimination of H. pylori had an opposite effect on pepsin secretion, significantly decreasing pepsin output by 30%. Elimination of H. pylori significantly reduced nonparietal fluid output by 35%, without affecting fluid output from parietal cells. Serum gastrin and H. pylori antibody levels declined significantly after elimination of H. pylori. None of these changes was observed in 14 subjects whose H. pylori gastritis was resistant to antimicrobial therapy. In summary, eradication of H. pylori infection increases gastric acidity by reducing nonparietal gastric secretion from peptic and other cells.

CONTEXTThe role of serologic testing to confirm cure of Helicobacter pylori infection after antimicrobial therapy is not completely defined.OBJECTIVETo determine the utility of serologic testing in confirming cure of H pylori infection more than 1 year after therapy.DESIGNA prospective, before-after interventional trial.SETTINGAn outpatient clinical research laboratory in an academic, urban Veterans Affairs medical center.PARTICIPANTSTwenty-three otherwise healthy men and women with active H pylori infection demonstrated by gastric biopsy and with positive H pylori serologic findings.INTERVENTIONA 14-day course of bismuth, tetracycline, and metronidazole.MAIN OUTCOME MEASURESDetermination of IgG serum antibodies to H pylori at baseline, 1 month, 3 months, and approximately 18 months after completion of therapy compared with serial gastric mucosal biopsy specimens with stains for H pylori and for histologic examination as the criterion standard.RESULTSFifteen (65%) of 23 subjects were cured of their H pylori infection as assessed by gastric biopsy, with elimination of gastritis; median antibody levels declined from 92.5 U/mL at baseline to undetectable levels at 18 months. The other 8 subjects (35%) were not cured and had persistent gastritis at 18 months; median antibody levels declined from 130.6 U/mL at baseline to 89.7 U/mL at 18 months. Sensitivity and specificity of seroconversion (from a positive to negative test result) in detecting cure of H pylori infection were 60% and 100%, respectively.CONCLUSIONUndetectable antibody levels beyond the first year of therapy accurately confirm cure of H pylori infection in initially seropositive healthy subjects, with reasonable sensitivity.

Conclusion.The study supports the previous suggestion that patients with FD responding to acid secretion inhibitors have a characteristic gastroesophageal reflux pattern with a high number of reflux episodes.1.

PURPOSE: Both isoforms of cyclo-oxygenase, COX-1 and COX-2, are inhibited to varying degrees by all of the available nonsteroidal anti-inflammatory drugs (NSAIDs). Because inhibition of COX-1 by NSAIDs is linked to gastrointestinal ulcer formation, those drugs that selectively inhibit COX-2 may have less gastrointestinal toxicity. We measured the extent to which NSAIDs and other anti-inflammatory or analgesic drugs inhibit COX-1 and COX-2 in humans.SUBJECTS AND METHODS: Aliquots of whole blood from 16 healthy volunteers were incubated ex vivo with 25 antiinflammatory or analgesic drugs at six concentrations ranging from 0 (control) to 100 mu M (n = 5 for each). Blood was assayed for serum-generated thromboxane B-2 synthesis (COX-1 assay) and for lipopolysaccharide-stimulated prostaglandin E-2 synthesis (COX-2 assay). In addition, gastric biopsies from the same volunteers were incubated with each drug ex vivo and mucosal prostaglandin E-2 synthesis measured.RESULTS: Inhibitory potency and selectivity of NSAIDs for COX-1 and COX-2 activity in blood varied greatly. Some NSAIDs (eg, flurbiprofen, ketoprofen) were COX-1 selective, some (eg, ibuprofen, naproxen) were essentially nonselective, while others leg, diclofenac, mefenamic acid) were COX-2 selective. Inhibitory effects of NSAIDs on gastric prostaglandin E-2 synthesis correlated with COX-1 inhibitory potency in blood (P <0.001) and with COX-1 selectivity (P <0.01), but not with COX-2 inhibitory potency. Even COX-2 "selective" NSAIDs still had sufficient COX-1 activity to cause potent inhibitory effects on gastric prostaglandin E-2 synthesis at concentrations achieved in vivo.CONCLUSION: No currently marketed NSAID, even those that are COX-2 selective, spare gastric COX activity at therapeutic concentrations. Thus, all NSAIDs should be used cautiously until safer agents are developed. (C) 1998 by Excerpta Medica, Inc.

Little is known about the effect of age on gastric alkaline and nonparietal secretion. Using a previously validated technique, we prospectively measured gastric HCO3- and nonparietal volume secretion, as well as secretion of H+, Na+, K+, and Cl-, in 114 healthy human beings over a wide age range(18-82 years). Each subject had normal oxyntic mucosal histology, was on no medication known to affect gastric secretion, and was studied under both basal (fasting) conditions and following stimulation of gastric H+ secretion by pentagastrin. There was a significant (p < 0.05) decline in gastric HCO3-, Na+, and nonparietal fluid secretion with advancing age, but not in H+, K+, Cl- or parietal fluid secretion. As a consequence of reduced gastric HCO3- and nonparietal fluid secretion, mean H+ concentrations in gastric juice increased significantly with advancing age. Thus, in healthy subjects with normal gastric histology, advancing age was associated with a significant decline in gastric HCO3-, Na+, and nonparietal fluid secretion, resulting in an increase in gastric acidity (H+ concentration).

H. pylori (Hp) strains which possess the cytotoxin associated gene product (Cag A) elicit more gastric inflammation than Cag A neg. strains.PURPOSE: To correlate the presence of serum antibodies to Cag A with the histologic severity of fundic gastritis, basal (BAn) and peak (PAn) acid output, and fasting serum gastrin.METHODS: 81 healthy volunteers underwent serum collection and nasogastric (NG) intubation.BAn and PAn (pentagastrin 6ug/kg) were determined, following which fundic mucosa was biopsied under fluoroscopic guidance via forceps placed through the NG tube.Biopsies were classified for severity of gastritis and presence of Hp by a blinded pathologist.Serum IgG to Hp and Cag A antibodies were determined blindly from coded specimens by ELISA.RESULTS: