Gastro-duodenal mucosal changes associated with low-dose aspirin therapy: a prospective, endoscopic study.

OBJECTIVES: The association of low-dose aspirin use and gastro-intestinal bleeding is well described. However, the gastroduodenal mucosal changes associated with low-dose aspirin therapy have not been properly evaluated. We undertook a prospective, endoscopic study to evaluate gastro-duodenal mucosal lesions produced by low-dose aspirin. METHODS: Forty-seven patients with non-hemorrhagic cerebral infarct or transient ischemic attacks and normal upper gastrointestinal endoscopy were randomized to receive either enteric-coated (n=25) or plain (n=22) aspirin (150 mg/day). Follow-up endoscopy was done at 2, 4 and 8 weeks; gastro-duodenal mucosal lesions, if present, were scored. Forty-seven patients with hemorrhagic infarct who were not treated with aspirin served as controls. RESULTS: Twenty eight (60%) of 47 patients receiving aspirin had mucosal lesions; stomach alone was the most frequent site (32%), followed by both stomach and duodenum (23%). Frequency of mucosal changes in the stomach at 8 weeks (19%) was significantly lower (p<0.05) than those at 2 weeks (53%) and 4 weeks (55%). Coated (56%) and plain (63.6%) aspirin induced mucosal lesions with similar frequency. CONCLUSION: Administration of low-dose aspirin, either plain or enteric-coated, induces endoscopic gastro-duodenal mucosal lesions in a large majority of patients. The frequency of damage decreased after 8 weeks of therapy.     

Salicylsalicylic acid causes less gastroduodenal mucosal damage than enteric-coated aspirin

The gastroduodenal mucosal damage caused by aspirin and nonsteroidal antiinflammatory drugs is a common clinical problem. We compared two medications designed to diminish mucosal damage: enteric-coated aspirin and salicylsalicylic acid (salsalate). Ten healthy volunteers were randomized to receive either 1.5 g salsalate twice a day or 650 mg enteric-coated aspirin four times a day for six days and were then crossed over to the other drug after a one-week medication-free period. Endoscopic inspection of gastroduodenal mucosa was performed at entry and again after six days of drug therapy for each medicine. Mean serum salicylate concentrations taken before the morning drug dose were 11.2 mg/dl for enteric-coated aspirin and 18.1 mg/dl for salsalate. Only one of 10 subjects receiving salsalate developed mild (grade 1) mucosal damage while six of 10 receiving enteric-coated aspirin developed moderate to severe damage (grade 2-3) (P = 0.01). Symptoms were mild in both groups. We conclude that salsalate causes less gastroduodenal mucosal damage than enteric-coated aspirin.     

A Double-Blind, Placebo-Controlled, 6-Day Evaluation of Two Doses of Misoprostol in Gastroduodenal Mucosal Protection against Damage from Aspirin and Effect on Bowel Habits

Ninety-one normal, healthy volunteers participated in a single-center, double-blind, placebo-controlled, randomized, parallel group study: 1) to compare the prostaglandin E1 analog, misoprostol, given at a dose of 200 micrograms bid, with the recommended dose of 200 micrograms qid in protecting the gastroduodenal mucosa against injury due to anti-inflammatory doses of aspirin (3900 mg/day); and 2) to determine whether the reduced dose was associated with a lesser incidence of gastrointestinal (GI) side effects, particularly diarrhea. All subjects received 975 mg of aspirin qid with meals and at bedtime. They were concurrently administered either misoprostol 200 micrograms qid, misoprostol 200 micrograms bid and placebo bid, or placebo qid. All subjects were endoscopically normal at the onset of the study and were re-endoscoped on the morning of the 7th day of therapy, 2 h after the morning dose of medications. Gastric and duodenal mucosa were assessed separately on a 0-7 scale which gave a greater weight to erosions than to hemorrhages. GI symptoms, especially bowel habits, were assessed by means of diary cards. Subjects in both misoprostol groups had significantly less gastric and duodenal mucosal injury than subjects who received placebo (p less than 0.007 for each pairwise comparison). There was no statistically significant difference between the two misoprostol groups (p less than 0.093). Subjects in the misoprostol 200 micrograms qid group had significantly more loose and watery bowel movements than the subjects in the misoprostol 200 micrograms bid group (p less than 0.013), whereas there were no significant differences in bowel habits between the misoprostol 200 micrograms bid and placebo groups (p less than 0.122). More subjects in the misoprostol 200 micrograms qid group reported abdominal pain, loose stools, watery stools, flatulence, dyspepsia, and nausea than in the misoprostol 200 micrograms bid and placebo groups. In conclusion, the adverse events in the misoprostol 200 micrograms bid group were not significantly different from those in the placebo group, and were significantly better than in the misoprostol 200 micrograms qid group. The lower dose retained mucosal protective activity that was statistically indistinguishable from that of misoprostol 200 micrograms qid.     

Gastrointestinal Blood Loss with Low Dose (325 mg) Plain and Enteric-Coated Aspirin Administration

Objectives : The purpose of this study was to assess gastrointestinal blood loss with low dose (325 mg) plain and enteric-coated aspirin. Methods : A total of 47 healthy volunteers participated in randomized, controlled acute and chronic trials. Seventeen participated in a repeated measures acute trial, and 30 participated in an independent sample chronic trial. Gastrointestinal blood loss was determined by obtaining 72-hour stool collections and quantitating Chromium-51 labeled erythrocytes Results : Acute phase trials: gastrointestinal blood loss during base line was 0.47 (±0.11) mL/day, 0.96 (±0.12) mL/day with enteric-coated aspirin ( p < 0.0006), and 1.82 (±0.35) mL/day with plain aspirin ( p < 0.0001 vs . base line, p = 0.0476 vs . enteric-coated aspirin). Chronic phase trials: gastrointestinal blood loss was 1.12 (±0.31) mL/day with enteric-coated aspirin ( p = 0.0024 vs . control) and 2.60 (±0.68) with plain aspirin ( p < 0.0001 vs. control, p = 0.0364 vs . enteric-coated aspirin). Conclusions : During acute and chronic ingestion, plain aspirin at a dose of 325 mg/day significantly increased gastrointestinal blood loss when compared to control or enteric-coated aspirin values, although enteric-coated aspirin values were also significantly increased compared to control. Gastric adaptation does not decrease blood loss with low dose aspirin consumption.     

含加替沙星的四联方案补救治疗幽门螺杆菌的临床观察

[目的]分析含加替沙星的四联疗法补救初次根除治疗幽门螺杆菌(H.pylori,Hp)失败的有效性和安全性.[方法]将133例Hp感染初次根除失败患者随机分为治疗组71例,对照组62例.治疗组给予加替沙星、呋喃唑酮、果胶铋、兰索拉唑治疗,对照组给予甲硝唑、呋喃唑酮、果胶铋、兰索拉唑治疗,疗程均为10 d.停药4周后复查Hp,分析Hp的根除率及不良反应发生率.[结果]治疗组、对照组Hp根除率分别为91.18％、81.67％ (P＜0.05).不良反应发生率治疗组为13.23％,对照组为21.67％,2组间差异有统计学意义(P＜0.05).[结论]含加替沙星的四联方案是治疗Hp初次根除失败后的一种安全、有效的补救治疗方案.     

Randomized,double-blind,pilot study of geranylgeranylacetone versus placebo in patients taking low-dose enteric-coated aspirin. Low-dose aspirin-induced small bowel damage

Abstract

Objective. Low-dose enteric-coated aspirin is increasingly being used for prevention of cardiovascular disease. The aim of this study was to evaluate whether geranylgeranylacetone (GGA) could prevent aspirin-induced small bowel injury. Material and methods. This was a prospective, randomized, double-blind, pilot study of GGA versus placebo in subjects taking low-dose enteric-coated aspirin. Young healthy volunteers were enrolled and each received 100 mg of enteric-coated aspirin per day plus either GGA (150 mg/day) or matching placebo for 7 days. Video capsule endoscopy of the small bowel and the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire were performed before and after the administration of aspirin. Results. Twenty volunteers were evaluated. There was no significant difference in the number of lesions in any category between those receiving or not receiving GGA. Large erosions or ulcers were observed in 12 (60%; 95% confidence interval 36%– 80%) aspirin users. Mucosal breaks were most frequently found in the latter half of the proximal small bowel. Conclusions. Short-term administration of low-dose enteric-coated aspirin was associated with visible small bowel damage in the majority of users. We could not prove that aspirin-induced small bowel mucosal injury was prevented by GGA.     

Frequency of gastroduodenal lesions in asymptomatic patients on chronic aspirin or nonsteroidal antiinflammatory drug therapy

Endoscopy in 49 patients without upper gastrointestinal symptoms and who were receiving chronic aspirin or nonsteroidal antiinflammatory drug therapy showed the frequency of gastric and duodenal mucosal lesions to be 76 and 27%, respectively. Fifteen (31%) had gastric ulcers, 31 (63%) had gastric erosions, and 10 (20%) had gastric mucosal hemorrhages. Gastric mucosal lesions were noted in 9 (90%) patients taking plain aspirin, in 25 (74%) receiving nonsteroidal antiinflammatory agents, and in 3 (60%) patients taking enteric-coated aspirin. Duodenal lesions were noted in 30 and 26% of patients taking plain aspirin and nonsteroidal antiinflammatory drugs, respectively. Patients taking enteric-coated aspirin had less severe duodenal injury than patients receiving ibuprofen or indomethacin, but the difference was not statistically significant. Endoscopy in 20 normal subjects not taking aspirin or nonsteroidal antiinflammatory drugs showed no gastroduodenal ulcers, erosions, or hemorrhage. Patients chronically taking antiarthritic drugs, including enteric-coated aspirin, have a high frequency of asymptomatic gastroduodenal lesions.     

Persistence of gastric ulcers caused by plain aspirin or nonsteroidal antiinflammatory agents in patients treated with a combination of cimetidine,antacids, and enteric-coated aspirin

Twenty-three patients chronically ingesting plain aspirin or nonsteroidal antiinflammatory drugs, who had endoscopically proven solitary or multiple gastric ulcers, were treated for eight weeks with cimetidine and antacids. Plain aspirin and nonsteroidal antiinflammatory drugs were discontinued in all patients. Seven patients received enteric-coated aspirin throughout the treatment phase and continuously for the entire study period (2.5–12 months). The remainder of patients (N=16) did not receive enteric-coated aspirin. An endoscopy was performed to assess ulcer healing. None of seven patients receiving enteric-coated aspirin had complete healing of their ulcer(s) while 15 of 16 patients not receiving enteric-coated aspirin demonstrated complete healing of their ulcer(s) (P<0.001). An eight-week course of cimetidine and antacids is ineffective in completely healing gastric ulcers caused by plain aspirin or nonsteroidal antiinflammatory drugs while enteric-coated aspirin is continued.The results of this study have been presented in part at the annual meeting of American Gastroenterological Association in Chicago, Illinois, in May 1987.     

Effect of alternate-day regular and enteric-coated aspirin on platelet aggregation, bleeding time, and thromboxane A2 levels in bleeding-time blood

The effectiveness of low-dose aspirin for primary prevention of cardiovascular mortality is being assessed among the nearly 22,000 United States physicians currently participating in the Physicians' Health Study. Because of occasional reports of gastric irritation among study participants, two enteric-coated aspirin preparations were tested as possible alternatives to regular compressed aspirin for platelet inhibition. Thirty-three volunteers were assigned randomly to one of four treatment groups: regular aspirin (325 mg), placebo, and two enteric-coated aspirin preparations (325 mg). Pills were administered every other day, duplicating the regimen used in the Physicians' Health Study. Bleeding times, platelet aggregation, and thromboxane A2 levels produced by aggregating platelets in vitro, as well as in collected bleeding-time blood, were determined. Measurements were taken before and after a single dose as well as after seven alternate-day doses. Regular and enteric-coated aspirin preparations were equally efficacious in prolonging the bleeding time, inhibiting platelet aggregation, and suppressing thromboxane A2 production. There was virtually complete suppression of thromboxane A2 production (over 99 percent), by platelets in vitro and in collected bleeding-time blood. The levels were still profoundly reduced (89 percent) 48 hours after the last dose. Enteric-coated aspirin may provide an alternative to regular aspirin in a low-dose regimen designed to inhibit platelet activity.     

A comparison of the effects of bid and qid dosing on compliance with inhaled flunisolide.

Noncompliance with inhaled steroids is a well-recognized problem in asthma therapy. We compared compliance with bid and qid regimens of inhaled flunisolide in 16 asthmatic subjects. Patients were instructed to take four inhalations bid for T1 to establish baseline compliance. During T2, half (group A) continued this dosing regimen, while the other half (group B) switched to two inhalations qid. Group A compliance did not significantly change from T1 to T2. The percentage of days with less than eight inhalations (underuse) for group B, however, increased from 20.2 +/- 40.3 in T1 (bid dosing) to 57.1 +/- 49.6 in T2 (qid dosing) (p less than 0.001). Concomitantly, the number of daily inhalations decreased from 7.9 +/- 2.5 to 6.8 +/- 3.1 (p less than 0.01). Reduced compliance with qid dosing was due in large part to an increase in frequency of six inhalations per day, resulting from tid use. Compliance with inhaled flunisolide, therefore, was worse with qid than bid dosing.     

Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target

Essential thrombocythemia (ET) is characterized by enhanced platelet generation and thrombotic complications. Once-daily low-dose aspirin incompletely inhibits platelet thromboxane A(2) (TXA(2)) in the majority of ET patients. In the present study, we investigated the determinants of aspirin-insensitive platelet TXA(2) biosynthesis and whether it could be further suppressed by changing the aspirin dose, formulation, or dosing interval. In 41 aspirin-treated ET patients, the immature platelet count predicted serum TXB(2) independently of platelet count, age, JAK-2 V617F mutation, or cytoreduction (β = 3.53, P = .001). Twenty-one aspirin-treated patients with serum TXB(2) ≥ 4 ng/mL at 24 hours after dosing were randomized to the following 7-day regimens in a crossover design: enteric-coated aspirin 100 mg twice daily, enteric-coated aspirin 200 mg once daily, or plain aspirin 100 mg once daily. A twice-daily regimen caused a further 88% median (IQR, 78%-92%, P < .001) TXB(2) reduction and normalized the functional platelet response to aspirin, as assessed by urinary 11-dehydro-TXB(2) excretion and the VerifyNow Aspirin assay. Doubling the aspirin dose reduced serum TXB(2) only partially by 39% median (IQR, 29%-54%, P < .05). We conclude that the abnormal megakaryopoiesis characterizing ET accounts for a shorter-lasting antiplatelet effect of low-dose aspirin through faster renewal of platelet cyclooxygenase-1, and impaired platelet inhibition can be rescued by modulating the aspirin dosing interval rather than the dose.     

Activity of Procanbid Procainamide Twice-Daily Formulation, to Suppress Ventricular Premature Depolarizations

Procainamide is a class IA antiarrhythmic drug indicated for the treatment of life-threatening or symptomatic ventricular arrhythmias. The current sustained-release formulation requires 6-hour dosing (qid). To improve patient compliance, a new sustained-release formulation for twice-daily (bid) administration has been developed (Procanbid, Parke-Davis). This study assesses the pharmacologic equivalence of the bid and qid formulations in the suppression of symptomatic ventricular premature depolarizations (VPDs). Fourteen centers enrolled a total of 99 patients with frequent symptomatic VPDs (average 20 VPDs/hr) who previously responded to and tolerated the procainamide qid formulation. During the first week of the double-blind phase, patients were randomized to either placebo or procainamide dosages of 1000, 2000, or 4000 mg/d (bid or qid formulations). In the second week, the patients were crossed over to the alternate formulation. Seventy-seven patients qualified for the primary activity analysis. The bid and qid formulations showed comparable effectiveness in the suppression of mean VPDs with a linear dose-response relationship. The VPD suppression was not attenuated towards the end of the dosing interval for either formulation. Sixty-eight of these patients entered an optional 1-year extension to receive the bid formulation. Thirty-seven (54%) patients had adverse effects. Of those, 15 (22%) had side effects considered treatment related. Most of the adverse events occurred during the first 6 weeks of treatment. Only a few patients (8%) withdrew as a consequence of treatment with the bid formulation. The overall safety profile of the bid formulation was similar to other formulations, and the procainamide bid formulation has a low proarrhythmic rate (`3%). In conclusion, the effectiveness of the twice-daily formulation of procainamide in the suppression of VPDs is comparable to the currently available qid formulation.     

Comparison of enteric-coated aspirin and uncoated aspirin effect on bleeding time

Aspirin therapy is an essential part of the drug regimen for patients with acute myocardial infarction (MI), unstable angina, or after coronary angioplasty and coronary stenting. Recognizing this importance, this study sought to compare the bleeding time in two groups of 10 normal volunteers 4 hr after ingestion of either an enteric-coated aspirin or an uncoated aspirin, assuming that a difference between the two groups could be clinically significant. Defining ≤ 8 min as normal, 80% of the uncoated group developed abnormal bleeding times, compared to 10% of the enteric-coated group (P < 0.01). The study demonstrates a significant difference between the two types of aspirin preparations on bleeding times in normal individuals. This strongly suggests that some enteric-coated aspirin preparations may not be as effective as uncoated aspirin in acutely decreasing platelet aggregation. Therefore, uncoated aspirin is recommended in the setting of acute MI, unstable angina, or after percutaneous transluminal coronary angioplasty. Cathet. Cardiovasc. Diagn. 45:396–399, 1998. © 1998 Wiley-Liss, Inc.     

Superior antiplatelet action of alternate day pulsed dosing versus split dose administration of aspirin

To explore the effect of timing on the antiplatelet action of aspirin, a constant mean amount of 40 mg aspirin/day was administered either as a split regimen of 20 mg twice daily, a single dose of 40 mg or a doubled dose of 80 mg every other day for 1 week each and compared to a current standard low dose regimen of 324 mg/day. Bleeding time, serum thromboxane, collagen-stimulated platelet aggregation and associated thromboxane formation and excretion of thromboxane and prostacyclin metabolites were measured both at peak and trough action of the drug. The inhibitory effects on platelet aggregation and associated thromboxane formation were significantly less marked with the split dose regimen, intermediate with the single dose of 40 mg aspirin/day and best with the alternate day doubled dose, but still inferior to the effects of 324 mg/day. Thromboxane excretion was suppressed by greater than 80% with all regimens. Prostacyclin metabolite excretion was similar for all 40 mg/day regimens with about 40% suppression at trough and 60% at peak drug action, respectively. Suppression was more pronounced after 324 mg/day. For best platelet inactivation at comparable sparing of prostacyclin formation, low doses of aspirin should be administered in pulsed rather than split regimens.     

Rapidity and duration of platelet suppression by enteric-coated aspirin in healthy young men.

The recent demonstration of aspirin's ability to prevent and reduce the severity of myocardial infarction has led to a marked increase in its use and to a need for information regarding the time-course of onset and offset of its antiplatelet effect. A study of healthy men was conducted to determine (1) the rapidity of onset of inhibition of platelet aggregation in response to adenosine diphosphate, and thromboxane A2 production after chewed enteric-coated aspirin (325 mg, n = 10); and (2) the duration of platelet inhibition after cessation of enteric-coated aspirin (325 mg) every other day for 14 days (n = 10). When chewed, enteric-coated aspirin greatly inhibited platelet aggregation response to adenosine diphosphate and thromboxane A2 production within 15 minutes. Complete recovery of platelet aggregation occurred in half of the subjects by day 3, and in 80% of the subjects by day 4; the platelet response was not affected by exercise. This study demonstrates a rapid onset of aspirin's antiplatelet effect and provides information relevant for optimal timing of initiation of aspirin for acute conditions such as myocardial infarction and unstable angina, and cessation of aspirin before surgery.     

Effects of aspirin and an aspirin-acetaminophen combination on the gastric mucosa in normal subjects. A double-blind endoscopic study

Coadministration or preadministration of acetaminophen with aspirin affords partial protection against aspirin-induced gastric mucosal injury in animals. Recently, it was reported that preadministration of acetaminophen in humans yielded similar protection. That study used pylorus occlusion, intravenous atropine, and exogenous acid, and thus may not have mimicked the usual clinical situation. We studied a clinical regimen, in 7 normal volunteers. We coadministered acetaminophen (1.95 or 2.6 g/day) and aspirin (in a 1:1 ratio) and used gastroscopy to evaluate if there was gastric mucosal protection. Aspirin alone was used as a positive control. We found the expected significant increase in mucosal damage associated with increasing aspirin dose (p less than 0.05) comparing the lowest and highest aspirin doses (1.95 g vs. 3.9 g) after 7 days of continuous therapy. There was no difference in the degree of mucosal injury when receiving the same dose of aspirin (p = 0.38) whether or not acetaminophen was administered in a dose equal to that of aspirin. Thus, in a more normal clinical situation, we were unable to confirm the findings from the pylorus-occluded model, i.e., we failed to identify either a beneficial effect, or a trend, for protection from gross mucosal damage by the coadministration of acetaminophen and aspirin in equal dosages.     

稳心颗粒对不稳定型心绞痛患者心率变异性的影响

目的观察稳心颗粒对不稳定型心绞痛(UAP)患者心率变异性(HRV)的影响。方法将86例UAP患者随机分为两组,稳心颗粒组及对照组各43例,两组均接受单硝酸异山梨酯缓释片、阿司匹林肠溶片、硫酸氢氯吡格雷片及辛伐他汀片等常规治疗。稳心颗粒组加服稳心颗粒9g,3次/d,共治疗4周,治疗前后行三导联24h动态心电图检查,观察两组患者HRV的时域指标全部正常窦性心搏间期的标准差(SDNN)、窦性心搏间期平均标准差(SDANN)、全程每5minR-R间期标准差的平均值(SDNN Index)、全程相邻R-R间期之差的均方根(rMSSD)、全部R-R间期中相邻R-R间期之差大于50ms心搏数所占比重(PNN50)。结果两组患者治疗后各项HRV指标均明显增高,差异有统计学意义(P<0.05);而稳心颗粒组较对照组升高更显著,差异有统计学意义(P<0.05)。结论UAP患者应用稳心颗粒治疗可改善HRV,对预防心源性猝死及恶性心律失常的发生有积极的作用。     

Enteric-coated aspirin in rheumatoid arthritis

Sixty patients with active rheumatoid arthritis (mean ESR = 51 mm/h) were treated for six months with D-penicillamine (15 patients), sodium aurothiomalate (15 patients), hydroxychloroquine (15 patients) or enteric-coated aspirin (15 patients). The three groups receiving specific anti-rheumatoid therapy were also allowed enteric-coated aspirin in the dose of their choice as the only 'back-up' drug; the group treated with aspirin alone was encouraged to take the maximum tolerated dose. The mean duration of treatment tolerated by patients receiving aspirin alone was 12.3 weeks. Only four patients completed a 24-week treatment period and n improvement was seen in acute-phase reactants. Those patients receiving an anti-rheumatoid drug showed serial improvements in ESR as the dose of aspirin required fell. Plasma salicylate concentrations correlated well with aspirin dosage. Even as an enteric-coated formulation, aspirin alone is not the treatment of choice for active rheumatoid disease.     

ENTERIC-COATED ASPIRIN IN RHEUMATOID ARTHRITIS

Sixty patients with active rheumatoid arthritis (mean ESR =51 mm/h) were treated for six months with D-penicillamine (15patients), sodium aurothiomalate (15 patients), hydroxychloroquine(15 patients) or enteric-coated aspirin (15 patients). The threegroups receiving specific anti-rheumatoid therapy were alsoallowed enteric-coated aspirin in the dose of their choice asthe only "back-up" drug; the group treated with aspirin alonewas encouraged to take the maximum tolerated dose. The mean duration of treatment tolerated by patients receivingaspirin alone was 12.3 weeks. Only four patients completed a24-week treatment period and no improvement was seen in acute-phasereactants. Those patients receiving an anti-rheumatoid drugshowed serial improvement in ESR as the dose of aspirin requiredfell. Plasma salicylate concentrations correlated well withaspirin dosage. Even as an enteric-coated formulation, aspirin alone is notthe treatment of choice for active rheumatoid disease.