Inhibitory Influence of Panax notoginseng Saponins on Aspirin Hydrolysis in Human Intestinal Caco-2 Cells.

Herb-drug interactions are important safety concerns in clinical practice. The interactions occur firstly in the intestinal absorption for orally administered drugs. Aspirin and Panax notoginseng saponins (PNS)-based drugs are often combined in China to prevent larger-artery atherosclerosis. Here, we aimed to characterize the aspirin transport across Caco-2 cell monolayers, a model of the intestinal absorption, and further to evaluate the influence of PNS on aspirin hydrolysis and the relating mechanisms. Transcellular transport of aspirin and the influence of PNS were explored using Caco-2 cell monolayers. The protein expression of human carboxylesterase 1 (hCE1) and hCE2 in Caco-2 cells after PNS treatment was analyzed by ELISA, and the mRNA level were determined by qRT-PCR. In the study, Caco-2 cells showed high level of hydrolase activity, and most aspirin was hydrolyzed inside the cells during the transport process. Interestingly, PNS were demonstrated to inhibit the esterase activities responsible for aspirin hydrolysis in Caco-2 cells. PNS could also decrease the protein expression of hCE1 and hCE2, whereas exhibited minor effect on the mRNA expression. These results indicated that oral administration of PNS-based drugs might inhibit the hydrolysis of aspirin during intestinal absorption thus promoting its bioavailability.

Influence of omeprazole and famotidine on the antiplatelet effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes: a prospective, randomized, multicenter study.

BACKGROUND: It remains unclear whether concomitant use of omeprazole attenuates platelet function as compared with that of famotidine in patients with acute coronary syndromes (ACS) who receive clopidogrel. METHODS AND RESULTS: In this prospective study, 130 ACS patients treated with aspirin and clopidogrel who underwent stent implantation were randomly assigned to receive a Japanese standard dose of omeprazole 10mg daily or famotidine 20mg daily for at least 4 weeks. Between 14 and 28 days after enrollment, there was no significant difference in the platelet reactivity index (PRI) measured with vasodilator-stimulated phosphoprotein phosphorylation assay between the omeprazole group (n=65) and famotidine group (n=65) (55±17% vs. 51±19%; P=0.26). The cumulative rate of adverse cardiovascular events at 12 months was similar in the groups (13% vs. 17%; P=0.81). The PRI was similar (54.9±17.9% vs. 54.0±17.8%; P=0.83) in the omeprazole group (n=33) and the famotidine group (n=39) among patients with ST-elevation myocardial infarction (STEMI). However, there was a trend toward a higher PRI (55.2±15.9% vs. 46.4±19.4%; P=0.06) in the omeprazole group (n=32) as compared with the famotidine group (n=26) among patients without persistent ST-segment elevation ACS. CONCLUSIONS: As compared with famotidine, concomitant use of low-dose omeprazole does not significantly attenuate the antiplatelet effects of clopidogrel in patients with ACS, especially in those with STEMI.

Parameters of microcirculation in paired formations after single aspirin administration: laser Doppler flowmetry data.

Laser Doppler flowmetry showed that aspirin can induce blood flow reduction and transitory manifold increase or decrease in vascular tone in rat skin and kidneys. The dynamics is more illustrative when parameters of individual animals are evaluated and depends on the areas of blood flow recording. Deaths and reduction of narcotic sleep duration were noted in concomitant use of nembutal and aspirin.

Controversies and future perspectives of antiplatelet therapy in secondary stroke prevention.

Antiplatelet agents are a cornerstone in the treatment of acute arterial thrombotic events and in the prevention of thrombus formation. However, existing antiplatelet agents (mainly aspirin, the combination of aspirin and dipyridamole and clopidogrel) reduce the risk of vascular events only by about one quarter compared with placebo. As a consequence, more efficacious antiplatelet therapies with a reduced bleeding risk are needed. We give an overview of several new antiplatelet agents that are currently investigated in secondary stroke prevention: adenosine 5'-diphosphonate receptor antagonists, cilostazol, sarpogrelate, terutroban and SCH 530348. There are unique features in secondary stroke prevention that have to be taken into account: ischaemic stroke is a heterogeneous disease caused by multiple aetiologies and the blood-brain barrier is disturbed after stroke which may result in a higher intracerebral bleeding risk. Several small randomized trials indicated that the combination of aspirin and clopidogrel might be superior to antiplatelet monotherapy in the acute and early post-ischaemic phase. There is an ongoing debate about antiplatelet resistance. Decreasing response to aspirin is correlated independently with an increased risk of cardiovascular events. However, there is still no evidence from randomized trials linking aspirin resistance and recurrent ischaemic events. Similarly, randomized trials have not demonstrated a clinical significantly decreased antiplatelet effect by the concomitant use of clopidogrel and proton pump inhibitors. Nevertheless, a routine use of this drug combination is not recommended.

Identifying and assessing benefit-risk in primary care--a family physician's perspective.

For the family physician, NSAIDs, both traditional and cyclo-oxygenase-2 inhibitors, are a valuable contribution to managing arthritis and other rheumatological conditions in primary care. Yet, many of the patients seen by the family doctor have complex comorbidities and polypharmacy issues. This review looks at the main considerations for primary-care physicians while choosing an anti-inflammatory treatment for a hypothetical patient case study. In addition to looking at the evidence for gastrointestinal and cardiovascular risk, the concomitant use of aspirin with an NSAID is also examined. New evidence for interaction between selective serotonin re-uptake inhibitors is reviewed and the interaction between angiotensin-converting enzyme inhibitors and NSAIDs is considered. Making careful judgements based on individual needs, medical history and comorbidities is recommended based on the evidence reviewed.

In vitro effects of ethanol with aspirin on rat brain synaptosomes: the potential protective role of betaine.

Physicians recommend aspirin for prevention of heart attacks and stroke in people above the age of 40 years. In some cases, alcohol consumption accompanies aspirin intake. In this study, the in vitro effects of different doses of ethanol (50, 100, and 200 mM) and 100 microg/mL of aspirin and the possible protective role of betaine (0.5 and 1 mM) were investigated on rat cerebral synaptosomes. Synaptosomally enriched fractions, derived from Sprague Dawley rat brains, were incubated with ethanol and aspirin so as to measure sialic acid (SA), nitric oxide levels, and adenosine deaminase (ADA) activities, which are known to be the markers of alcohol damage. When combined with aspirin, ethanol increased SA levels compared with the control group at all doses, resulting in loss of SA residue from synaptosomal membrane. Betaine (0.5 mM) decreased SA levels with respect to the ethanol (200 mM) plus aspirin group (p < .05), thereby preventing SA loss. Moreover, betaine reversed the destructive effects of ethanol by elevating reduced nitric oxide levels. Aspirin, when combined with all doses of ethanol, increased ADA activity, which is crucial for purine metabolism. ADA activities were also elevated in betaine-administered groups. We propose that betaine is an effective compound in protecting the rat brain synaptosomes against ethanol and aspirin together.

Aspirin induces apoptosis through the blockade of IL-6-STAT3 signaling pathway in human glioblastoma A172 cells.

Aspirin has been reported to induce apoptosis in various cancer cell lines. However, the apoptotic effects of aspirin on human brain tumor cells are not well understood. Here, we have assessed the effect of aspirin on human gliobalstoma cell line A172 and found that aspirin induced the apoptosis of A172 cells, as determined by TUNEL assay, FACS analysis, and Hoechst staining. The underlying mechanism of this effect consists of reduction in the level of phosphorylated STAT3 (Tyr705), a transcription factor required for survival of A172 cells. Moreover, the expression of STAT3 target genes such as Cyclin D1, XIAP, and Bcl-2 that are essential for cell growth and survival was apparently attenuated after aspirin treatment. We also showed that the expression and secretion of interleukin-6 (IL-6), leading to STAT3 phosphorylation, was inhibited by aspirin. When administered exogenous IL-6 to aspirin-treated A172 cells, the phosphorylation of STAT3 and cellular apoptosis were restrained compared to aspirin only-treated cells. Taken together, our results indicate that aspirin causes apoptosis via down-regulation of IL-6-dependent STAT3 signaling, suggesting that aspirin could be therapeutically useful for a potential anti-glioblastoma therapeutic approach.

Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis.

BACKGROUND: Anti-inflammatory analgesics, including ibuprofen and naproxen, are known to interfere with the antiplatelet effect of aspirin, presumably as a result of a drug-drug interaction at the level of platelet cyclooxygenase-1 (COX-1). OBJECTIVE: We studied whether dipyrone, which has recently been reported to inhibit COX isoforms by a mechanism different from conventional non-steroidal anti-inflammatory drugs (NSAIDs), also interferes with the antiplatelet effect of aspirin. METHODS: Arachidonic acid- and collagen-induced aggregation, as well as thromboxane formation, were measured in human platelet-rich plasma. Platelet P-selectin expression was determined by flow cytometry and cell-free COX enzyme activity was quantified by luminol-enhanced luminescence of human platelet microsomes. In addition, computerized docking was performed based on the crystal structure of COX-1. RESULTS: 4-Methylaminoantipyrine (MAA), the active metabolite of dipyrone, largely attenuated or even completely abolished the inhibition of arachidonic acid-induced platelet aggregation, thromboxane formation and P-selectin expression by aspirin. Similar results were obtained for other pyrazolinones, as well as for the conventional NSAIDs ibuprofen and naproxen. Moreover, MAA attenuated the effect of aspirin on COX activity of platelet microsomes, suggesting a competition with aspirin at the COX-1 enzyme. This was confirmed by docking studies, which revealed that MAA forms a strong hydrogen bond with serine 530 within the COX-1, thereby preventing enzyme acetylation by aspirin. CONCLUSION: This study demonstrates for the first time that dipyrone and other pyrazolinones have a high potential to attenuate or prevent the antiplatelet effect of aspirin. This should be considered if pyrazolinone analgesics are administered to patients with cardiovascular disease requiring antiplatelet aspirin therapy.

Salicylate-aspirin interaction in the rat. Evidence that salicylate accumulating during aspirin administration may protect vascular prostacyclin from aspirin-induced inhibition.

Aspirin inhibits cyclooxygenase, thus preventing thromboxane A2 production in blood platelets and prostacyclin in vascular cells. Aspirin is rapidly hydrolyzed to salicylate in the circulation. The objectives of this study were (a) to evaluate whether administration of salicylate, though ineffective by itself, prevents the inhibitory effect of aspirin on platelet and/or vascular cyclooxygenase activity; (b) to verify whether salicylate accumulating in blood after aspirin administration interferes with the pharmacological activity of further doses of aspirin. Pretreatment of rats with sodium salicylate (25-100 mg/kg i.p.) resulted in dose-related prevention of the effect of a subsequent dose of aspirin (2.5-10 mg/kg i.v.) on both platelet and vascular cells. Sodium salicylate appeared to amplify the greater response of platelets to aspirin compared with vessel wall. Pretreatment of rats with repeated high doses of aspirin (200 mg/kg) resulted after 24 h in blood salicylate levels (150-200 microgram/ml) that significantly prevented the inhibitory effect of a subsequent dose of aspirin on newly synthesized vascular prostacyclin. Blood salicylate levels obtained after 36 or 48 h (less than 50 microgram/ml) were too low to blunt aspirin's effect. The interference with aspirin of its major endogenous metabolite should be borne in mind when interpreting results obtained with high dose aspirin or during repeated administration of this drug.

Gastroprotective effect of cardamom, Elettaria cardamomum Maton. fruits in rats.

Cardamom, the fruits of Elettaria cardamomum Maton. (Zingiberaceae) commonly known as "Heel khurd" is used in Unani system of medicine to treat gastrointestinal disorders. A crude methanolic extract (TM), essential oil (EO), petroleum ether soluble (PS) and insoluble (PI) fractions of methanolic extract, were studied in rats at doses of 100-500, 12.5-50, 12.5-150 and 450 mg/kg, respectively for their ability to inhibit the gastric lesions induced by aspirin, ethanol and pylorous ligature. In addition their effects on wall mucus and gastric acid output were recorded. All fractions (TM, EO, PS, PI) significantly inhibited gastric lesions induced by ethanol and aspirin but not those induced by pylorus ligation. TM proved to be active reducing lesions by about 70% in the EtOH-induced ulcer model at 500 mg/kg. The PS fraction reduced the lesions by 50% at 50 and 100mg/kg (no dose response was observed) with similar effect than the PI fraction at 450 mg/kg. In the aspirin-induced gastric ulcer, the best gastroprotective effect was found in the PS fraction, which inhibited lesions by nearly 100% at 12.5mg/kg. In our experimental conditions, the PS extract at doses >or=12.5mg/kg proved to be more active than ranitidine at 50mg/kg.

ACEA (arachidonyl-2-chloroethylamide), the selective cannabinoid CB1 receptor agonist, protects against aspirin-induced gastric ulceration.

The effect of a selective cannabinoid CB1 receptor agonist, ACEA (arachidonyl-2-chloroethylamide) in an aspirin-induced ulcer model was studied in rats. ACEA (1.25-5 mg/kg i.p.) significantly reduced gastric ulcer formation to 24, 21 and 0.6% respectively. These results confirm the cytoprotective effect of CB1 receptor agonists and suggest that the endocannabinoid system might be the target for a novel class of anti-ulcer drugs.

PGHS-2 inhibitors, NS-398 and DuP-697, attenuate the inhibition of PGHS-1 by aspirin and indomethacin without altering its activity.

Since the discovery of the inducible form of prostaglandin (PG) H synthase (PGHS), PGHS-2, considerable effort has been made to design selective inhibitors of this isozyme. N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (NS-398) and 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonyl) thiophene (DuP-697) have been shown to interact reversibly with PGHS-1, while irreversibly inhibiting PGHS-2 in a time-dependent manner. In the present study we have tested the effects of DuP-697 and NS-398 on the activity of PGHS-1 and further explored the interactions between these agents and the inhibition of PGHS-1 by aspirin, indomethacin and ibuprofen. Three independent experimental systems, namely bovine aortic endothelial cells (BAEC), human fibroblasts and ram seminal vesicle microsomes were used to investigate the effects of DuP-697 and NS-398 on PGHS-1. The results show that DuP-697 and NS-398, at concentrations ranges which do not inhibit PGHS-1 activity, significantly attenuated the inhibition of PGHS-1 that was caused by aspirin and indomethacin. The same concentrations of DuP-697 and NS-398 did not affect the inhibition of PGHS-1 that was induced by the competitive reversible inhibitors ibuprofen and naproxen. Similar effects of DuP-697 and NS-393 were obtained with ram seminal vesicle microsomes. These results suggest that PGHS-2 inhibitors DuP-697 and NS-398 possibly interact with PGHS-1 at a site different from the enzyme's catalytic site, thus causing attenuation of PGHS-1 inhibition by aspirin and indomethacin without altering PGHS-1 basal activity or the ibuprofen-induced inhibition.

Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal antiinflammatory drugs.

BACKGROUND: There is clear evidence from numerous randomized trials and their meta-analyses that aspirin reduces risks of first myocardial infarction (MI). Recent data also suggest that other nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with this benefit of aspirin. METHODS AND RESULTS: We performed subgroup analysis from a 5-year randomized, double-blind, placebo-controlled trial of 325 mg aspirin on alternate days among 22 071 apparently healthy US male physicians with prospective observational data on use of NSAIDs. A total of 378 MIs were confirmed, 139 in the aspirin group and 239 in the placebo group. Aspirin conferred a statistical extreme (P<0.00001) 44% reduction in risk of first MI. Among participants randomized to aspirin, use of NSAIDs on 1 to 59 d/y was not associated with MI (multivariable adjusted relative risk [RR], 1.21; 95% confidence interval [CI], 0.78 to 1.87), whereas the use of NSAIDs on > or =60 d/y was associated with MI (RR, 2.86; 95% CI, 1.25 to 6.56) compared with no use of NSAIDs. In the placebo group, the RRs for MI across the same categories of NSAID use were 1.14 (95% CI, 0.81 to 1.60) and 0.21 (95% CI, 0.03 to 1.48). CONCLUSIONS: These data suggest that regular but not intermittent use of NSAIDs inhibits the clinical benefits of aspirin. Chance, bias, and confounding remain plausible alternative explanations, despite the prospective design and adjustment for covariates. Nonetheless, we believe the most plausible interpretation of the data to be that regular but not intermittent use of NSAIDs inhibits the clinical benefit of aspirin on first MI.

Nitric oxide-releasing aspirin derivative, NCX 4016, promotes reparative angiogenesis and prevents apoptosis and oxidative stress in a mouse model of peripheral ischemia.

BACKGROUND: Recently, nitric oxide (NO) donors have been developed that mimic the physiological intracellular release of NO. We evaluated whether one of these new compounds, consisting of aspirin coupled to an NO-releasing moiety (NCX 4016), would protect limbs from supervening arterial occlusion. METHODS AND RESULTS: Mice were assigned to receive regular chow or chow containing NCX 4016 or aspirin (both at 300 mumol/kg body weight, daily) throughout the 3-week experimental period. One week after randomization, they underwent surgical excision of the left femoral artery. Limb blood flow recovery (laser Doppler flowmetry) was accelerated by NCX 4016 as compared with aspirin or vehicle (P<0.05). In controls, histological analysis revealed a 35% increase in the capillary density of ischemic muscles compared with contralateral ones, indicative of spontaneous angiogenesis. Neovascularization was enhanced by NCX 4016 (91%; P<0.05 versus vehicle), but not by aspirin (51%; P=NS versus vehicle). Furthermore, NCX 4016 reduced endothelial cell (EC) apoptosis (4.3+/-1.0 versus 8.7+/-2.0 in aspirin and 12.6+/-3.3 ECs/1000 cap in vehicle; P<0.05 for either comparison) as well as caspase-3 mRNA levels in ischemic muscles ([caspase-3/GAPDH]*100 = 0.09+/-0.04 versus 2.30+/-0.44 in aspirin and 2.30+/-0.32 in vehicle; P<0.01 for either comparison). Nitrite levels and the ratio of reduced to oxidized glutathione were selectively increased in ischemic muscles by NCX 4016. Vascular endothelial growth factor-A expression was reduced by aspirin, with this effect being blunted by NCX 4016. CONCLUSIONS: Pretreatment with the new oral NO-releasing aspirin derivative stimulates reparative angiogenesis and prevents apoptosis and oxidative stress, thereby alleviating the consequences of supervening arterial occlusion.

Persistent gastric-protective effect of antacid evaluated by measurement of transmucosal gastric potential difference.

The aim of this study was to determine the effect of 1 week of antacid dosing on the aspirin-induced potential differences (PDs) across the gastric mucosa. The study design was double blind and randomized with crossover. Ten healthy subjects received aluminum hydroxide gel, 8 gm t.i.d., or placebo for 1 week. They then received 1 gm aspirin after an overnight fast and the PD across the mucosa was measured. Baseline potentials were the same before both treatment periods. Antacids reduced the aspirin-induced PDs. The mean (+/- SD) maximal PD was 27.4 +/- 1.7 mV with placebo vs. 10.7 +/- 2.2 mV with antacids (p less than 0.001). Recovery time was 65.5 +/- 5.2 minutes with placebo vs. 29.0 +/- 6.7 minutes with antacids (p less than 0.001). These results suggest the effect is due to a longer-term cytoprotective property of antacids rather than to acid-neutralizing activity.

Protection against aspirin-induced gastric lesions by lansoprazole: simultaneous evaluation of functional and morphologic responses.

The protective effect of lansoprazole, a new proton pump inhibitor, against aspirin-induced gastric lesions was studied in a double-blind crossover trial with a simultaneous measure of the functional capacities of the mucosal barrier (by a recording of the gastric potential difference) and of the morphologic changes in the mucosa (by gastric endoscopy). After 1 week of treatment with lansoprazole (30 mg per day) or placebo, each healthy volunteer received 1 gm aspirin by mouth. Recording of the gastric potential difference lasted for 3 hours and was followed by gastric endoscopy. Morphologic lesions induced by aspirin were effectively prevented by lansoprazole: Lanza score was 0.67 +/- 0.98 (mean +/- SD) versus 2.25 +/- 1.1 with placebo (p < 0.005, ANOVA). Conversely, the decrease in the gastric potential difference was similar. The inhibition of acid secretion induced by lansoprazole was therefore sufficient to prevent aspirin-induced mucosal lesions without reinforcing the defense capacities of the mucosa. This simple pharmacologic model makes it possible to simultaneously evaluate the functional and morphologic effects of aspirin intake on the gastric mucosa.

Effect of vitamin E supplementation on prostaglandin concentrations in aspirin-induced acute gastric injury in aged rats.

Nonsteroidal antiinflammatory drugs (NSAIDs), such as aspirin, frequently cause gastric mucosal injury in the elderly. Impairment of prostaglandin synthesis is a crucial step by which aspirin attenuates mucosal defense capacity. Vitamin E has been shown to decrease prostanoid concentrations, which implies an ulceropermissive effect of vitamin E. To assess the effect of vitamin E on aspirin-induced gastric injury and mucosal prostanoid concentrations, 20 male rats aged 20 mo were divided into two groups and fed diets containing either 30 (physiologic requirement) or 500 mg all-rac-alpha-tocopheryl acetate/kg. After 6 wk, all rats received two intragastric doses of aspirin (1.4 mumol/kg body wt). A third group of six animals fed the high-vitamin E diet received a vehicle solution without aspirin. Mucosal samples for vitamin E and prostaglandin E2, 6-keto-prostaglandin F1 alpha, and thromboxane A2 measurements were collected. The prevalence and degree of mucosal lesions were not significantly different among all groups. Rats fed the high-vitamin E diet had significantly higher mucosal vitamin E concentrations than rats fed the low-vitamin E diet. Mucosal concentrations of all three prostanoids were 95% lower in aspirin-treated rats than in controls (P = 0.0001 in all instances). The high-vitamin E diet group had significantly lower mucosal 6-keto-prostaglandin F1 alpha concentrations (P = 0.02) than the low-vitamin E diet group, indicating decreased prostacyclin formation, whereas concentrations of prostaglandin E2 and thromboxane A2 were similar in the aspirin-treated groups. Aspirin markedly reduced mucosal prostanoid concentrations in rats, without apparent effects on gastric injury, whereas vitamin E supplementation significantly reduced mucosal 6-keto-prostaglandin F(1 alpha) concentrations. Nevertheless, vitamin E supplementation did not result in more gastric injury in aspirin-treated rats than in controls.

Differential effects of itanoxone--a new hypolipidemic and hypouricemic drug--on platelet and vascular prostaglandin generation in rats.

Itanoxone ((chloro-2'-diphenyl)-4-oxo-4 methylene 2-butyric acid), a newly developed, hypolipidemic and hypouricemic compound with moderate anti-inflammatory activity, showed a short-lived, dose-dependent (20--200 mg/kg, orally), apparently competitive inhibition of platelet malondialdehyde (MDA), stimulated by either thrombin or arachidonic acid. Repeated doses did not result in any cumulative effect. At doses which completely blocked MDA production, itanoxone also inhibited thrombin-stimulated thromboxane B2 production in platelets but had no measurable effect on vascular prostacyclin generation. Pretreatment with itanoxone partially prevented the inhibitory effect of aspirin on both platelet and vascular prostaglandin synthesis. This suggests that itanoxone--like aspirin--acts at the level of cyclo-oxygenase but with greater selectivity on the platelet enzyme. This pharmacological activity is of great theoretical interest for the potential use of this compound as an antithrombic drug.

Role of H2-receptor blockers in the prevention of gastric injury resulting from nonsteroidal anti-inflammatory agents.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can produce injury to the gastric and duodenal mucosa. The histamine (H2)-receptor blocker cimetidine was studied to determine whether protection of the gastric mucosa of normal volunteers could be provided against a single dose of aspirin, 1,300 mg. Gastric mucosal injury was assessed with gastroscopy performed two hours after aspirin intake. Three liquid cimetidine doses were administered over 24 hours prior to the aspirin dose, the last dose one hour before the aspirin. The 200-mg and 400-mg doses of cimetidine protected a sufficient number of subjects to warrant further study. In the second study, these two doses were further examined to determine whether three doses were necessary and whether the final dose could be coadministered with the aspirin instead of one hour before. Concomitant administration of a single dose of cimetidine with aspirin was found to protect the gastric mucosa from aspirin damage as effectively as the other cimetidine regimens employed. A final, double-blind comparison of cimetidine, 200 mg, with placebo administered with the aspirin, 1,300 mg, confirmed that cimetidine protected the gastric mucosa from the hemorrhagic effects of aspirin.