Lanza Score Research Articles

Celecoxib, a cyclooxygenase-2 inhibitor, improved upper gastrointestinal lesions in rheumatoid arthritis patients as assessed by endoscopic evaluation

We prospectively evaluated the effects of celecoxib (CEL) on the gastrointestinal (GI) tract of rheumatoid arthritis (RA) patients with endoscopically identified GI mucosal injury after therapeutic switching from the long-term use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Upper GI endoscopy was performed on RA patients who had been treated with NSAIDs for ≥3 months. GI mucosal injury was evaluated according to the modified LANZA score. Patients with mucosal injury without ulcers were switched from NSAIDs to CEL, while those with ulcers were switched to CEL with famotidine after ulcer healing. At week 16 of treatment, GI mucosal injury was endoscopically revaluated. An efficacy analysis was performed before therapeutic switching and at 8 and 16 weeks post-switching. Endoscopic analysis revealed GI mucosal injury, including six ulcers, in 45 of the 82 patients (54.9%). Sixteen weeks after switching to CEL, LANZA scores were significantly improved [2.1 ± 0.8 (pre-switching) vs. 1.6 ± 1.3, P = 0.0073] in patients with LANZA scores of 1, 2, or 3 (n = 35). The Disease Activity Score using 28 joint counts (DAS28) [erythrocyte sedimentation rate item score (ESR4) (P = 0.0257) and C-reactive protein item score (CRP4) (P = 0.0031)] was also significantly improved by week 16. Based on these results, we conclude that preexisting NSAID-induced upper GI injury is improved following therapeutic switching to CEL without any reduction in analgesic efficacy.

Prospective Cohort Study of Gastrointestinal Complications and Vascular Diseases in Patients Taking Aspirin: Rationale and Design of the MAGIC Study

Although aspirin has been widely prescribed for the prevention of cardiovascular events, its risk of gastrointestinal complications is of great concern. Despite expectations for such, few data are available on the prevalence or incidence of gastrointestinal complications in aspirin users in Japan. The Management of Aspirin-induced GastroIntestinal Complications (MAGIC) is the first attempt at collaboration among cardiologists, neurologists, and gastroenterologists to obtain such findings. We aim to share all about the MAGIC study. The MAGIC is a prospective cohort study involving patients taking low-dose aspirin (81 mg to 325 mg per day) for longer than 1 month. Participants are recruited from multiple disease categories, including those with coronary artery disease, cerebrovascular disease, atrial fibrillation, and other cardiovascular conditions requiring antithrombotic therapy. Its duration of follow-up is 1 year. At baseline and 1 year follow-up, all participants will undergo endoscopic examination. The primary outcome is upper gastrointestinal complications, classified as erosions, ulcers, and bleeding. Secondary outcomes include LANZA score, non-fatal cardiovascular events, any bleeding, cancer, and death. 1,533 participants were entered in the MAGIC cohort. By underlying disease, about 45% of them had coronary artery diseases, followed by cerebrovascular diseases (35%), atrial fibrillation (10%) and other cardiovascular diseases (10%). The MAGIC study will yield important findings with regard to the prevalence and incidence of gastrointestinal complications and related risk factors for low-dose aspirin users. It may also report that use of anti-secretory agents such as proton pump inhibitors reduces the risk of such complications.

Preventive Effects of Lansoprazole and Famotidine on Gastric Mucosal Injury Induced by Low-Dose Aspirin inHelicobacter pylori-Negative Healthy Volunteers

The preventive effects of lansoprazole and famotidine on low-dose aspirin-induced gastric mucosal injury in relation to gastric acidity were compared in healthy Japanese volunteers. Fifteen Helicobacter pylori-negative volunteers with different CYP2C19 genotypes were randomly administered aspirin 100 mg, aspirin plus famotidine 20 mg twice daily, or aspirin plus lansoprazole 15 mg once daily for 7 days each in a crossover fashion. Gastroscopy for the evaluation of mucosal injury based on modified Lanza score (MLS) and 24-hour intragastric pH monitoring were performed on day 7 of each regimen. Aspirin induced gastric mucosal injury (median MLS = 3). Lansoprazole significantly decreased MLS to 0, which was significantly lower than that by famotidine (MLS = 1) (P < .05). Medians of pH 3 holding time and mean 24-hour pH values with the lansoprazole regimen were significantly higher than those with famotidine (P < .05). No significant differences in MLS were observed among the different CYP2C19 genotype groups in any of the treatment regimens. In this 7-day study, lansoprazole appeared to be more protective than famotidine against low-dose aspirin-induced mucosal injury but a larger well-controlled study is necessary to establish a definitive clinical benefit.

Tu1588 Comparison of Narrow Band Imaging With High Resolution White Light Endoscopy for the Assessment of Non Steroidal Anti-Inflammatory Drug Induced Gastroduodenal Injury

The diagnosis of NSAID induced gastro-duodenal injury is often associated with difficulties in determination of the degree of injury. The Lanza score and its many modifications are commonly used in clinical trials, but are considered subjective and susceptible to errors in interpretation. The aim of this study was to determine the inter-observer variability in assessing NSAID induced gastro-duodenal injury among endoscopists with and without experience in narrow band imaging (NBI) using both high resolution white light endoscopy (HR-WLE) and NBI. Corresponding NBI and HR-WLE images were taken during endoscopy from healthy volunteers taking different NSAID preparations. Six blinded endoscopists (3 experts in NBI imaging) counted the number of ulcers, erosions and hemorrhagic lesions to derive a 5 point modified Lanza scale and evaluated image quality on a 10 point visual analogue score (VAS). Overall agreement and kappa value with bias corrected 95% confidence intervals using bootstrapping techniques were calculated to assess inter-observer reliability. The inter-observer agreement (κ) with HR-WLE among all 6 endoscopists was 0.62 (95% CI 0.52-0.72), which improved significantly with NBI to 0.76(95% CI 0.69-0.84, p=0.02). The inter-observer agreement among expert endoscopists with HR-WLE was “substantial” (κ=0.75, 95% CI 0.63-0.87) and improved with NBI to “almost perfect agreement (κ= 0.87, 95% CI 0.78-0.95, p=0.06) which almost reached statistical significance. The inter-observer agreement among non-expert endoscopists with HR-WLE was “moderate” (κ=0.54, 95% CI 0.42-0.67) and significantly improved with NBI to “substantial” (κ=0.72, 95% CI 0.60-0.82, p=0.02). Non-expert endoscopists found significantly higher number of mucosal hemorrhages on NBI images (p=0.03). VAS scores for NBI images were higher than HR-WLE for experts while the opposite was true for non-experts. VAS scores for NBI images were however consistently higher than HR-WLE when the paired images were presented side by side. Inter-observer reliability between both expert and non-expert endoscopists for assessment of NSAID induced injury is better with NBI than HR-WLE images. NBI imaging improves the visualization of mucosal hemorrhages especially in non-expert endoscopists.

Comparison of narrow band imaging with high resolution white light endoscopy for the assessment of non-steroidal anti-inflammatory drug induced gastroduodenal injury

IntroductionThe diagnosis of NSAID induced gastroduodenal injury is often associated with difficulties in determination of the degree of injury. The Lanza score and its many modifications are commonly used in...

Gastric acid secretion level modulates the association between Helicobacter pylori infection and low-dose aspirin-induced gastropathy

The relative contribution of gastric acid secretion and Helicobacter pylori infection to low-dose aspirin-induced gastropathy remains to be clarified. This is partly because the capability of the infection to modify gastric acid secretion complicates the interaction. The aim of this study was to estimate the association of aspirin-induced mucosal injury, as well as H. pylori infection, with gastric acid output. A total of 186 male outpatients, comprising 60 aspirin takers, on 100 mg of enteric-coated aspirin daily and 126 non-aspirin takers were prospectively enrolled in this study. Gastrin-stimulated acid output was estimated by the endoscopic gastrin test. The grade of gastric mucosal injury was assessed endoscopically according to the modified Lanza score. Multiple logistic regression analyses were used to adjust for potential confounders. The gastric acid secretion level, with an odds ratio (OR) (95% confidence interval [CI]) of 10.5 (3.0-36.9) and aspirin administration, with an OR (95% CI) of 7.4 (3.0-18.3) were independently associated with gastric mucosal injury, and the co-existence of both factors greatly elevated the risk of mucosal injury, with an OR (95% CI) of 77.0 (13.5-440.0). H. pylori infection, itself, did not show any significant effect on the aspirin-induced mucosal injury after adjusting for gastric acid secretion. This study has demonstrated that aspirin-induced gastropathy is directly associated with gastric acid secretion. In addition, it also suggested that the gastric acid secretion level modulates the association between H. pylori infection and aspirin-induced gastropathy.

Use of Selective Serotonin Reuptake Inhibitors and Upper Gastrointestinal Disease

Selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants in the world. Recent studies, however, have raised the concern that SSRIs increase the risk of gastrointestinal dysfunction. Therefore, we conducted a case-control study on gastrointestinal symptoms and endoscopic findings in patients who were taking SSRIs in Japan. Forty-one patients who were taking SSRIs (SSRI-treated group) and 82 age- and sex-matched patients who were not taking antidepressants (control group) were selected from the population of patients who underwent endoscopic examination from January 1, 2005 to March 31, 2010 in our institution, and their subjective symptoms and endoscopic findings were analyzed. Patients who were taking proton pump inhibitors (PPIs) and/or histamine H(2)-receptor antagonists (H2RAs) were excluded from this study. The chief complaints at the endoscopic examination were classified into the following 4 categories: reflux symptoms, dysmotility symptoms, ulcer-like symptoms, and no upper abdominal symptoms. No significant difference was found in the complaint rate of each category between the SSRI-treated and the control groups. No significant differences were found between the groups in endoscopic findings, the LANZA score and the rate of chief complaints in patient classes stratified by the endoscopic finding. It was not evident that SSRIs induced mucosal damage of the upper gastrointestinal tract. And, it is considered that SSRIs do not increase the risk of upper gastrointestinal symptoms in patients treated with SSRIs for 1 month or longer. The present study suggests that SSRI medication does not have a bad influence on gastrointestinal symptoms and gastrointestinal organic diseases.

Clinical trial: endoscopic evaluation of naproxen etemesil, a naproxen prodrug, vs. naproxen – a proof‐of‐concept, randomized, double‐blind, active‐comparator study

Nonsteroidal anti-inflammatory drugs are associated with upper gastrointestinal mucosal injury. Naproxen etemesil is a lipophilic, non-acidic, inactive prodrug of naproxen that is hydrolysed to pharmacologically active naproxen once absorbed. We hypothesized that with lesser topical exposure to naproxen from the prodrug, there would be reduced gastroduodenal mucosal injury compared with naproxen. To compare the degree of endoscopic mucosal damage of naproxen etemesil vs. naproxen. This multicentre, randomized, double-blind, double-dummy trial compared oral naproxen etemesil 1200 mg twice daily (n = 61) with naproxen 500 mg twice daily (n = 59) for 7.5 days in 120 healthy subjects (45-70 years; mean 51 years; 58% female) with baseline total modified gastroduodenal Lanza score ≤ 2 (no erosions/ulcers) on endoscopy. The primary endpoint was mean total modified gastroduodenal Lanza score on day 7. A secondary endpoint was incidence of gastric ulcers. The day 7 mean total modified gastroduodenal Lanza score was 2.8 ± 1.7 for naproxen etemesil vs. 3.5 ± 2.0 for naproxen (P = 0.03), and significantly fewer naproxen etemesil-treated subjects (3.3%) developed gastric ulcers compared with naproxen-treated subjects (15.8%) (P = 0.02). In this first proof-of-concept study, naproxen etemesil was associated with significantly lower gastroduodenal mucosal injury compared with naproxen after 7 days of exposure ( NCT00750243).

Association between adherence to evidence-based guidelines for the prescription of non-steroidal anti-inflammatory drugs and the incidence of gastric mucosal lesions in Japanese patients

Recently, guidelines for the treatment and prevention of ulcers induced by non-steroidal anti-inflammatory drugs (NSAIDs) were established. This study investigated the association between the current adherence to the guidelines and the incidence of gastric mucosal lesions caused by NSAIDs. This study included 254 NSAIDs users (128 regular and 126 on-demand users) who had undergone upper gastrointestinal endoscopy. The patients were characterized as high risk based on the following: age 65 years or older, history of peptic ulcers, concurrent use of corticosteroids or anticoagulants, and high-dose NSAIDs use. Adherence was defined as the prescription of NSAIDs with proton pump inhibitors, prostaglandin analogues, or high-dose histamine 2 receptor antagonists in high-risk NSAIDs user. The severity of gastric mucosal lesions was evaluated using the modified LANZA score (MLS). Seventy-nine (61.7%) of the regular NSAIDs users and 65 (51.6%) of the on-demand NSAIDs users met our definition of high-risk patients. Adherence in the regular NSAIDs users and on-demand NSAIDs users was 25 (31.7%) and 16 (24.6%), respectively. The incidence of gastric mucosal lesions (MLS ≧ 1) was significantly higher in the nonadherence group than in the adherence group for both regular NSAIDs users (59.3 vs. 28.0%, P = 0.01) and on-demand NSAIDs users (63.3 vs. 25.0%, P = 0.01). Gastric ulcers in the regular NSAIDs users were more frequently observed in the nonadherence group than in the adherence group (29.6 vs. 4.0%, P < 0.01). Nonadherence was associated with a high prevalence of NSAIDs-induced gastric mucosal lesions.

Lafutidine prevents low‐dose aspirin and loxoprofen induced gastric injury: A randomized, double‐blinded, placebo controlled study

The concomitant use of non-steroidal anti-inflammatory drugs is a risk factor for low-dose aspirin (LDA)-associated upper gastrointestinal toxicity. Lafutidine is an H2-receptor antagonist with gastroprotective activity, produced by acting on capsaicin-sensitive afferent neurons. To evaluate the preventive effect of lafutidine on gastric damage caused by LDA alone and by the combination of both LDA and loxoprofen, we conducted a clinical study using healthy volunteers. A randomized, double-blinded, placebo-controlled, crossover study was carried out. Sixteen healthy volunteers without Helicobacter pylori infection were randomly assigned to two groups. Both groups received 81 mg of aspirin once daily for 14 days (on days 1 to 14) and 60 mg of loxoprofen three times daily for the last 7 days (on days 8 to 14). Placebo or 10 mg of lafutidine was administered twice daily for 14 days in each group. After a 2-week washout period, placebo and lafutidine were crossed over. Endoscopic findings of gastric mucosal damage were evaluated according to the modified Lanza score. The mean modified Lanza score was 2.19 ± 1.06 (SD) for aspirin plus placebo as compared with 0.50 ± 0.77 for aspirin plus lafutidine (P < 0.001), and 3.00 ± 1.56 for aspirin plus loxoprofen and placebo as compared with 1.25 ± 1.37 for aspirin plus loxoprofen and lafutidine (P < 0.01). The addition of loxoprofen to LDA increases gastric mucosal damage. Standard-dose lafutidine significantly prevents gastric mucosal damage induced by LDA alone or LDA plus loxoprofen in H. pylori-negative volunteers. Larger controlled studies are needed to strengthen these findings.

T1144 Aggravation by Clopidogrel, the Antiplatelet Drug, of Antral Ulcers Induced by NSAIDs in Rats

Background/Aims: Recent studies have revealed that interindividual differences in metabolic disposition of non-steroidal anti-inflammatory drugs (NSAIDs) are associated with risk of NSAID-induced gastrointestinal mucosal injury. Individuals with poor metabolizer alleles of either or both CYP2C8 (such as CYP2C8*3) or CYP2C9 (such as CYP2C9*2 or CYP2C9*3), whichmetabolize NSAIDs, show increased risk of developing acute or chronic gastrointestinal injury on using NSAIDs. However, precise estimation of the metabolic profile of NSAIDs in an individual by combination of single nucleotide polymorphisms is difficult due to the variety of enzymes involved in NSAID metabolism. Given that 13CO2 is known to be produced on the metabolization of 13C-labeled naproxen ([13C]-naproxen), we examined whether or not the [13C]-naproxen breath test can be used to predict naproxen-induced gastric mucosal injury. Methods: Fifteen H. pylori-negative healthy volunteers (CYP2C9*1/ *1, n=13; CYP2C9*1/*3, n=2) ingested 300 mg of [13C]-naproxen, after which breath samples were collected over a period of 48 hours. Changes from baseline in carbon isotope ratios (13CO2/12CO2) in carbon dioxide were measured and expressed as a delta-overbaseline (DOB) ratio (‰), and plasma PGE2 and TXB2 were also measured at the same time. Gastric mucosal injury based on the modified Lanza score (MLS) was evaluated before and after twice daily dosing of naproxen 300 mg for 2 days. Results: At baseline, the median MLS was 0 (range: 0-1). After twice daily dosing with naproxen 300 mg for 2 days, however, MLS ranged from 1 to 5. Subjects were classified into one of three groups based on MLS level: patients with MLS of 1 or 2 were designated as mild (n = 5), MLS 3 as moderate (n = 7), and MLS 4 or 5 as severe (n =3). The AUC0-120min of DOB was 6.55 ± 0.31 h*‰ for the mild group, 5.45 ± 0.45) h*‰ for the moderate group, and 4.04 ± 0.97) h*‰ for the severe group; the AUC0-120min of DOB in the mild group was significantly higher than that in the severe group (P < 0.05). Overall, CYP2C9*1/*3 participants showed MLSs which fell in the severe group and had lower AUC0-120min of DOB values and lower rates of PGE2 and TXB2 than CYP2C9*1/*1 participants. Conclusion: [13C]-naproxen breath test results were significantly correlated with naproxen-induced mucosal injury, suggesting the usefulness of this test as a predictive determinant of naproxen-induced gastric mucosal injury.

T1140 Usefulness of the [13C]-Naproxen Breath Test in Predicting Naproxen-Induced Gastric Mucosal Injury

Background/Aims: Recent studies have revealed that interindividual differences in metabolic disposition of non-steroidal anti-inflammatory drugs (NSAIDs) are associated with risk of NSAID-induced gastrointestinal mucosal injury. Individuals with poor metabolizer alleles of either or both CYP2C8 (such as CYP2C8*3) or CYP2C9 (such as CYP2C9*2 or CYP2C9*3), whichmetabolize NSAIDs, show increased risk of developing acute or chronic gastrointestinal injury on using NSAIDs. However, precise estimation of the metabolic profile of NSAIDs in an individual by combination of single nucleotide polymorphisms is difficult due to the variety of enzymes involved in NSAID metabolism. Given that 13CO2 is known to be produced on the metabolization of 13C-labeled naproxen ([13C]-naproxen), we examined whether or not the [13C]-naproxen breath test can be used to predict naproxen-induced gastric mucosal injury. Methods: Fifteen H. pylori-negative healthy volunteers (CYP2C9*1/ *1, n=13; CYP2C9*1/*3, n=2) ingested 300 mg of [13C]-naproxen, after which breath samples were collected over a period of 48 hours. Changes from baseline in carbon isotope ratios (13CO2/12CO2) in carbon dioxide were measured and expressed as a delta-overbaseline (DOB) ratio (‰), and plasma PGE2 and TXB2 were also measured at the same time. Gastric mucosal injury based on the modified Lanza score (MLS) was evaluated before and after twice daily dosing of naproxen 300 mg for 2 days. Results: At baseline, the median MLS was 0 (range: 0-1). After twice daily dosing with naproxen 300 mg for 2 days, however, MLS ranged from 1 to 5. Subjects were classified into one of three groups based on MLS level: patients with MLS of 1 or 2 were designated as mild (n = 5), MLS 3 as moderate (n = 7), and MLS 4 or 5 as severe (n =3). The AUC0-120min of DOB was 6.55 ± 0.31 h*‰ for the mild group, 5.45 ± 0.45) h*‰ for the moderate group, and 4.04 ± 0.97) h*‰ for the severe group; the AUC0-120min of DOB in the mild group was significantly higher than that in the severe group (P < 0.05). Overall, CYP2C9*1/*3 participants showed MLSs which fell in the severe group and had lower AUC0-120min of DOB values and lower rates of PGE2 and TXB2 than CYP2C9*1/*1 participants. Conclusion: [13C]-naproxen breath test results were significantly correlated with naproxen-induced mucosal injury, suggesting the usefulness of this test as a predictive determinant of naproxen-induced gastric mucosal injury.

T1141 Preventive Effect of Lansoprazole and Famotidine on Gastric Mucosal Injury Induced by Low-Dose Aspirin in H. pylori-Negative Healthy Volunteers

Background/Aims: Recent studies have revealed that interindividual differences in metabolic disposition of non-steroidal anti-inflammatory drugs (NSAIDs) are associated with risk of NSAID-induced gastrointestinal mucosal injury. Individuals with poor metabolizer alleles of either or both CYP2C8 (such as CYP2C8*3) or CYP2C9 (such as CYP2C9*2 or CYP2C9*3), whichmetabolize NSAIDs, show increased risk of developing acute or chronic gastrointestinal injury on using NSAIDs. However, precise estimation of the metabolic profile of NSAIDs in an individual by combination of single nucleotide polymorphisms is difficult due to the variety of enzymes involved in NSAID metabolism. Given that 13CO2 is known to be produced on the metabolization of 13C-labeled naproxen ([13C]-naproxen), we examined whether or not the [13C]-naproxen breath test can be used to predict naproxen-induced gastric mucosal injury. Methods: Fifteen H. pylori-negative healthy volunteers (CYP2C9*1/ *1, n=13; CYP2C9*1/*3, n=2) ingested 300 mg of [13C]-naproxen, after which breath samples were collected over a period of 48 hours. Changes from baseline in carbon isotope ratios (13CO2/12CO2) in carbon dioxide were measured and expressed as a delta-overbaseline (DOB) ratio (‰), and plasma PGE2 and TXB2 were also measured at the same time. Gastric mucosal injury based on the modified Lanza score (MLS) was evaluated before and after twice daily dosing of naproxen 300 mg for 2 days. Results: At baseline, the median MLS was 0 (range: 0-1). After twice daily dosing with naproxen 300 mg for 2 days, however, MLS ranged from 1 to 5. Subjects were classified into one of three groups based on MLS level: patients with MLS of 1 or 2 were designated as mild (n = 5), MLS 3 as moderate (n = 7), and MLS 4 or 5 as severe (n =3). The AUC0-120min of DOB was 6.55 ± 0.31 h*‰ for the mild group, 5.45 ± 0.45) h*‰ for the moderate group, and 4.04 ± 0.97) h*‰ for the severe group; the AUC0-120min of DOB in the mild group was significantly higher than that in the severe group (P < 0.05). Overall, CYP2C9*1/*3 participants showed MLSs which fell in the severe group and had lower AUC0-120min of DOB values and lower rates of PGE2 and TXB2 than CYP2C9*1/*1 participants. Conclusion: [13C]-naproxen breath test results were significantly correlated with naproxen-induced mucosal injury, suggesting the usefulness of this test as a predictive determinant of naproxen-induced gastric mucosal injury.

Role of melatonin in mucosal gastroprotection against aspirin‐induced gastric lesions in humans

Melatonin and its precursor, l-tryptophan, have been shown to exert gastroprotective effects in animals, but their influence on the gastric damage by aspirin (ASA) in humans has been sparingly investigated. In this study, we designed to determine the effects of melatonin and l-tryptophan on ASA-induced gastric mucosal damage, gastric microbleeding, mucosal generation of prostaglandin E(2), and plasma melatonin, and gastrin levels. Three groups of healthy male volunteers (n = 30) with intact gastric mucosa received daily for 11 days either ASA alone or that combined with melatonin or tryptophan. Gastric blood loss and mucosal damage were evaluated at 3rd, 7th, and 11th days of ASA administration by endoscopy using Lanza score. ASA alone caused a marked rise of gastric damage and gastric blood loss, mainly at day 3rd and 7th, but they were significantly reduced at 11th day. Pretreatment with melatonin or tryptophan remarkably reduced ASA induced gastric lesions and microbleeding. Gastric mucosal generation of PGE(2) was suppressed by about 90% in all subjects treated with ASA alone without or with addition of melatonin or tryptophan. Plasma melatonin was markedly increased after treatment with melatonin or tryptophan plus ASA, but it was also raised significantly after application of ASA alone. Plasma gastrin levels were raised in subjects given melatonin or tryptophan plus ASA, but not in those with ASA alone. We conclude that melatonin and its precursor tryptophan given orally significantly reduce gastric lesions induced by ASA possibly due to (a) direct gastroprotective action of exogenous melatonin or that generated from tryptophan and (b) gastrin released from the gastric mucosa by melatonin or tryptophan.

Role of Helicobacter pylori Infection in Gastroduodenal Damage in Patients Starting NSAID Therapy: 4 Months Follow-Up Study

We aimed to determine differences in gastroduodenal damage related to the presence of Helicobacter pylori (Hp) in patients starting long-term NSAID therapy. Seventy-one candidates for chronic NSAIDs therapy (33 Hp negative and 38 Hp positive) entered the study and underwent upper GI endoscopy before, and 8 and 16 weeks after, continuous NSAID therapy. Lanza score increased in both Hp positive and negative patients in the course of NSAID therapy (P < 0.001), being significantly higher in Hp positive than Hp negative (4.31 ± 1.33 vs 3.15 ± 1.95, P < 0.05) after 16 weeks of follow-up. In gastric mucosa, no significant difference in mean Lanza score was observed between the two groups. Duodenal ulcer was diagnosed in 18 (36.8%) Hp positive and 1 (3%) Hp negative patient (P < 0.05). Hp is more closely related to duodenal than gastric mucosal injury in NSAID users. Risk for duodenal ulcer in Hp-infected individual increases after 4 months of NSAID therapy.

Low-Dose Aspirin-Induced Gastroduodenal Mucosal Injury in Japanese Patients with Arteriosclerotic Disease

We aimed to elucidate the risk factors and preventive factors associated with chronic low-dose aspirin (L-ASA)-induced gastroduodenal mucosal injury in Japanese patients with arteriosclerotic disease. This retrospective observational study included 400 L-ASA users who underwent upper gastrointestinal endoscopy. We investigated patients' clinical characteristics, including age, peptic ulcer history, concomitant drugs [i.e. gastric agents, antiplatelet drugs, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids], abdominal symptoms, endoscopic findings, and interruption of L-ASA before endoscopy. The severity of gastroduodenal mucosal lesions was evaluated using the modified LANZA score (MLS). Of 400 patients, 249 (62%) and 41 (10%) had gastroduodenal mucosal lesions (MLS ≥1) and gastroduodenal ulcers, respectively. Peptic ulcer history, abdominal symptoms, proton pump inhibitor (PPI), histamine type 2-receptor antagonists (H2RA), and the cessation of L-ASA before endoscopy were significantly associated with L-ASA-induced gastroduodenal ulcers; the odds ratio (OR) (confidence interval (CI)) was 5.49 (1.82-16.55), 4.56 (1.93-10.75), 0.12 (0.03-0.42), 0.13 (0.04-0.40) and 0.11 (0.04-0.29), respectively. Moreover, patients having two or more of five factors [i.e. advanced age (≥75), anticoagulants, antiplatelet drugs, NSAIDs and corticosteroids] had a significantly higher prevalence of L-ASA-induced gastroduodenal ulcers [OR (CI): 2.39 (1.002-5.69)]. Peptic ulcer history, abdominal symptoms and the summation of risk factors increased the risk for L-ASA-induced gastroduodenal ulcers. H2RAs and PPIs were effective for the prevention of L-ASA-induced gastroduodenal ulcers. The cessation of L-ASA before endoscopy might lead to the underestimation of L-ASA-induced gastroduodenal injury.

Incidence of Gastroduodenal Ulcers is Significantly Reduced When Analgesic Doses of Aspirin are Administered as PA65020, A Novel Combination of Enteric-Coated Aspirin (EC-ASA) and Immediate-Release (IR) Omeprazole

Purpose: To evaluate the gastroduodenal effects (via endoscopy) and safety profile of PA65020 vs. EC-ASA at analgesic doses. Methods: In a single-center, Phase 1, randomized, double-blind study, PA65020 (n=20) or EC-ASA 650 mg (n=20) was administered in the clinic twice daily for 28 days to healthy volunteers (≥50 yrs) with normal baseline endoscopy (Lanza score 0). Each dose of PA65020 was administered as one tablet of PA32520 [a fixed-dose combination tablet of EC-ASA 325 mg and IR omeprazole 20 mg] + one tablet of EC-ASA 325 mg. EC-ASA 650 mg was administered as 2 × EC-ASA 325 mg tablets. The total daily ASA dose was 1300 mg. Outcome evaluations included the occurrence of endoscopically proven gastric and/or duodenal lesions meeting Grade 3 or Grade 4 Lanza scores on Day 28 (primary endpoint), incidence of gastroduodenal ulcers (GU/DU), as well as assessments of dyspepsia-associated abdominal pain by mSODA (modified severity of dyspepsia assessment score, range 2-47), heartburn, and adverse events. Results: A total of 40 subjects (mean age 59.7 years) were treated. At Day 28, the incidence of Grade 3 or 4 Lanza scores was significantly less for the PA65020 group (3 [15%]) than for the EC-ASA 650 mg group (17 [85%]), P<0.001. The incidence of GU/DU on Day 28 was also significantly lower with PA65020 vs. EC-ASA 650 mg (0% vs. 40%, P=0.003). At Day 28, the mean change from baseline in mSODA was 0 for PA65020 and 0.7 for EC-ASA 650 mg. More PA65020 subjects were heartburn-free (90%) throughout the study compared with subjects in the EC-ASA 650 mg group (75%). The most commonly reported adverse events were GI-related, primarily dyspepsia (2 subjects in each treatment group) and stomach discomfort (3 subjects in the EC-ASA 650 mg group vs. 0 subjects in the PA65020 group). Conclusion: Analgesic doses of over-the-counter ASA produced significant mucosal damage in most subjects following 1 month of treatment. PA65020 is associated with a significantly decreased risk of GU/DU, and may provide an important option for at-risk patients who require analgesic doses of ASA. Disclosure: Drs. Fort and Plachetka - Employees and Stockholders: Pozen, Inc. Drs. Orlemans and Unal - Employees: Pozen, Inc.Table

Relationship Between Low-Dose Aspirin-Induced Gastric Mucosal Injury and Intragastric pH in Healthy Volunteers

Gastric acid plays an important role in the pathogenesis of gastric mucosal lesions. We investigated whether aspirin-induced gastric mucosal injury might have any association with the intragastric pH. Fifteen healthy, Helicobacter pylori-negative volunteers randomly underwent the four different 7-day regimens: (1) aspirin 100 mg, (2) rabeprazole 10 mg, (3) aspirin 100 mg + rabeprazole 10 mg, and (4) aspirin 100 mg + rabeprazole 40 mg. Gastric mucosal injury based on the modified Lanza score (MLS), 24-h intragastric pH, and histopathology of gastric mucosa were evaluated prior to the start and on day 7 of each regimen. The median MLSs were 0 in the baseline and the rabeprazole 10 mg regimen. The median MLS in the aspirin regimen was 3, while those in both aspirin + rabeprazole 10 mg and aspirin + rabeprazole 40 mg regimens were 0. Rabeprazole significantly prevented the gastric mucosal injury by aspirin (P = 0.001 for rabeprazole 10 mg and P = 0.005 for rabeprazole 40 mg). The MLSs were negatively correlated with the 24-h intragastric pH (P = -0.711, < 0.001), whereas aspirin had no effect on the intragastric pH. Aspirin expanded the mean diameter of the microvessels of the gastric mucosa, which, in turn, was negatively correlated with the intragastric pH. Aspirin might induce gastric mucosal injury by affecting the mucosal microvessels in an acid-dependent manner. Sustained maintenance of the intragastric pH at an elevated value is necessary to prevent gastric mucosal damage induced by aspirin.

T1069 Effect of Low-Dose Administration of Lansoprazole On the Gastric Mucosal Lesions Induced By Low-Dose Aspirin in Relation to Intragastric pH in Healthy Volunteers with Different CYP2C19 Genotypes

Backgrounds and Aims: Given the major role gastric acid plays in the development of aspirininduced gastric mucosal lesions, proton pump inhibitors (PPIs) are now employed as firstline therapy in treating aspirin-related gastrointestinal disorders. Low-dose PPIs are also expected to have a similar preventive effect on aspirin-induced gastric injury. PPIs are metabolized by CYP2C19 in the liver, and their therapeutic effects are influenced by CYP2C19 genotype status. However, the effect of low-dose PPI on aspirin-induced gastric mucosal injury in relation to gastric acidity in humans has not been examined. Here, we investigated the relationship between intragastric pH and aspirin-induced gastric mucosal lesions with regard to CYP2C19 genotype status in healthy subjects receiving aspirin with and without a low-dose administration of lansoprazole. Methods: Fifteen Helicobacter pylori-negative subjects with different CYP2C19 genotype statuses (5 RMs, 5 intermediate metabolizers [IMs], and 5 poor metabolizers [PMs]) were each administered a series of three 7-day regimens of 15 mg of lansoprazole alone, 100 mg of aspirin alone, and both 15 mg of lansoprazole and 100 mg aspirin, with the order randomized among individuals. A washout period of 2 weeks or more was provided between regimens. Gastric mucosal injury was endoscopically evaluated on day 7 of each dosing period based on the modified Lanza score (MLS). 24-hour intragastric pH monitoring was started after endoscopy. Results: Median values (range) of MLS were 0 (0-1) in controls, 0 (0-1) in subjects receiving 15 mg of lansoprazole alone, 3 (0-5) in subjects receiving aspirin alone, and 0 (0-1) in subjects receiving both aspirin and 15 mg of lansoprazole. Lansoprazole increased the intragastric pH and significantly prevented aspirin-induced gastric mucosal injury (p = 0.0009 for aspirin and lansoprazole 15 mg). MLSs were negatively correlated with 24-hour intragastric pH (r = -0.740, P < 0.0001), whereas aspirin had no effect on intragastric pH. With regard to treatment with aspirin and lansoprazole 15 mg, although median values of MLS did not differ among the three genotype groups, median values of intragastric pH during treatment with this regimen were higher in PMs than in RMs and IMs (P = 0.009 for RMs, P = 0.028 for IMs). Conclusion: We observed a significant relationship between 24-hour intragastric pH and grade of aspirin-induced gastric mucosal lesions. Further, the acid inhibition attained on administration of 15 mg of lansoprazole appeared sufficient to prevent aspirin-induced gastric mucosal damage, irrespective of CYP2C19 genotype status.

Usefulness of anti-ulcer drugs for the prevention and treatment of peptic ulcers induced by low doses of aspirin

To investigate the usefulness of anti-ulcer drugs for the prevention and treatment of low-dose aspirin-induced peptic ulcer. Upper gastrointestinal endoscopy was performed in 68 patients receiving daily low-dose aspirin (81 or 100 mg/day). The endoscopic findings were classified according to the Lanza score, and the scores were compared between groups categorized according to the concomitant use of anti-ulcer drugs and the types of drugs used. In another study, 31 hemorrhagic peptic ulcer patients who had been receiving low-dose aspirin were enrolled. The patients were randomly classified into the proton pump inhibitor (PPI)-treated group and the H2 receptor antagonist (H2RA)-treated group. The administration of low-dose aspirin was continued concomitantly, and endoscopic examinations were performed 8 wk later. The Lanza scores (mean +/- SD) of the gastro-mucosal lesions were 1.0 +/- 1.9 and 1.9 +/- 2.3 in 8 and 16 patients receiving prevention therapy with a PPI and an H2RA, respectively. Both scores were significantly smaller than the scores in 34 patients who were not receiving prevention therapy (4.7 +/- 1.0) and in 10 patients receiving cytoprotective anti-ulcer drugs (4.3 +/- 1.6). In the prospective study, 18 and 13 patients received a PPI and an H2RA, respectively. Endoscopic examinations revealed that the tissue in the region of the gastro-mucosal lesions had reverted to normal in all patients in the PPI-treated group and in 12 patients (92%) in the H2RA-treated group; no significant differences were observed between the groups. H2RA therapy was effective for both the prevention and treatment of low-dose aspirin-induced peptic ulcer, similar to the effects of PPIs, while cytoprotective anti-ulcer drugs were ineffective in preventing ulceration.