Simultaneous Determination of Tetramethylpyrazine and Aspirin in a New Compound Formulation by Liquid Chromatography

Aim To establish a reversed-phase liquid chromatographic (LC) method forsimultaneous determination of tetramethylpyrazine (TMP) and aspirin in a new compound formulation.Methods Chromatographic separation of the two drugs was achieved on a Diamonsil C_(18) column, usinga binary mixture of methanol-1.5% acetic acid (35:65, V/V, pH = 3.1) as mobile phase at a flow rateof 1.0 mL·min^(-1). Results Separation was completed in less than 12 min. Benzoic acid was used asthe internal standard. Recoveries at levels corresponding to 80 % to 120 % of the label claim ofthe formulation ranged from 99.6 to 100.3 % for aspirin and from 99.9 to 101.3% for TMP. The linearrange was 12.6 - 150.9 μg·mL^(-1)(r= 0.9997, n = 5) for aspirin and 25.0- 300.0 μg·mL^(-1) (r =0.9999, n = 5) for TMP. Conclusion The method developed can be used for the simultaneousdetermination of TMP and aspirin in pharmaceutical preparations.

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

AIM： To investigate the usefulness of anti-ulcer drugs for the prevention and treatment of low-dose aspirin-induced peptic ulcer.METHODS： Upper gastrointestinal endoscopy was performed in 68 patients receiving daily low-dose aspirin （81 or 100 rag/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.RESULTS： 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.CONCLUSION： 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.

Attenuation of gastric mucosal inflammation induced by aspirin through activation of A_(2A) adenosine receptor in rats

AIM： To determine whether a specific adenosine A2A receptor agonist （ATL-146e） can ameliorate aspirin-induced gastric mucosal lesions in rats, and reduce neutrophil accumulation and production of pro-inflammatory cytokines. METHODS： Gastric lesions were produced by oral gavage of aspirin （200 mg/kg） and HCI （0.15 mol/L, 8.0 mL/kg）. 4-{3-[6-Amino-9-（5-ethylcarbamoyl-3,4- dihydroxy-tetrahydro-furan-2-yl）-9H-purin-2-yl]-prop-2- ynyl}-cyclohexanecarboxylic acid methyl ester （ATL-146e, 2.5-5μg/kg, IP） was injected 30 min before the administration of aspirin. Tissue myeloperoxidase （MPO） concentration in gastric mucosa was measured as an index of neutrophil infiltration. Gastric mucosal concentrations of tumor necrosis factor-α （TNF-α） and interleukin-1β （IL-1β） were determined by ELISA. Also, we examined the effect of ATL-146e on tissue prostaglandin E2 （PGE2） production and gastric secretion. RESULTS： Intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. The total length of gastric erosions （ulcer index） in control rats was 29.8±7.75 mm and was reduced to 3.8±1.42 mm alter pretreatment with 5.0 g/kg ATL-146e （P〈 0.01）. The gastric contents of MPO and pro-inflammatory cytokines were all increased after the administration of aspirin and reduced to nearly normal levels by ATL-146e. Gastric mucosal PGE2 concentration was not affected by intraperitoneal injection of ATL-146e. CONCLUSION： The specific adenosine A2A receptor agonist, ATL-146e, has potent anti-ulcer effects presumably mediated by its anti-inflammatory properties.

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension

AIM: To study the mechanism involved in the potentially beneficial effect of ultra low dose aspirin (ULDA) in prehepatic portal hypertension, rats were pretreated with selective COX 1 or 2 inhibitors (SC-560 or NS-398 respectively), and subsequently injected with ULDA or placebo. METHODS: Portal hypertension was induced by portal vein ligation. Platelet activity was investigated with an in-vivo model of laser induced thrombus production in mesenteric circulation and induced hemorrhagic time (IHT). Platelet aggregation induced by ADP and dosing of prostanoid products 6-keto-PGF1α, TXB2, PGE2 and LTB4 were also performed. RESULTS: The portal hypertensive group receiving a placebo showed a decreased in vivo platelet activity with prolonged IHT, an effect that was normalized by ULDA. SC-560 induced a mild antithrombotic effect in the normal rats, and an unmodified effect of ULDA. NS-398 had a mild prothrombotic action in portal hypertensive rats, similar to ULDA, but inhibited a further effect when ULDA was added. An increased 6-keto-PGF1α was observed in portal hypertensive group that was normalised after ULDA administration. TXA2 level after ULDA, remained unchanged. CONCLUSION: These results suggest that the effect of ULDA on platelet activity in portal hypertensive rats, could act through a COX 2 pathway more than the COX 1, predominant for aspirin at higher doses.

Anti-apoptotic effects of aspirin following cerebral ischemia-reperfusion injury in rats

BACKGROUND： The pharmacological effects of aspirin on apoptosis are complex. The underlying mechanisms have not been properly defined. OBJECTIVE： To observe the effect of different doses of aspirin on brain cell apoptosis following focal cerebral iscbemia-reperfusion injury （CIRI） in rats. DESING, TIME AND SETTING： A randomized, controlled, animal experiment, performed at the School of Medicine and Pharmaceutics, Jiangnan University between June and October 2006. MATERIALS： Twenty-six male, adult, Sprague Dawley rats （grade Ⅱ）, weighing 240-290 g, were obtained from Shanghai Experimental Animal Center, Chinese Academy of Sciences. Aspirin was provided by Sigma （USA）. METHODS： The rats were randomly divided into four groups： sham-operation （SO）, CIRI ＋ vehicle, CIRI ＋ aspirin （6 mg/kg）, and CIRI ＋ aspirin （60 mg/kg）. Rats in the lesion groups were intragastrically administrated saline, aspirin （6 mg/kg）, or aspirin （60 mg/kg）, respectively. MAIN OUTCOME MEASURES： The number of pyramidal neurons with normal appearance in the cerebral cortex at 24 mm from the midline; apoptotic cell death as measured by TUNEL; Bcl-2 and Bax protein localization was determined by immunohistochemistry; malondialdehyde （MDA） and super oxidation （SOD） content were determined by biochemistry method; adenosine triphosphate （ATP） content measured by capillary electrophoresis. RESULTS： Following CIRI, the following parameters were altered compared with sham-operated animals： the number of neurons with normal appearance was significantly reduced in the cerebral cortex; the number of apoptotic cells increased; Bax protein expression was enhanced; and the ratio between Bcl-2 and Bax decreased. In addition, MDA content increased significantly, whereas ATP content decreased （P 〈 0.01）. Aspirin ameliorated the loss of healthy pyramidal neurons. Both 6 and 60 mg/kg aspirin increased the ratio between Bcl-2 and Bax, with no significant difference between the treatment groups. In addition, 60 mg/kg aspirin decreased MDA content and increased ATP levels. However, 6 mg/kg aspirin did not have the same effect. CONCLUSION： Aspirin reduced the number of apoptotic cells following CIRI. These results suggest that the neuroprotective mechanism of aspirin could be related to elevated Bcl-2 protein levels or decreased Bax protein expression. The increase in the ratio of Bcl-2 to Bax appears to be a common anti-apoptotic mechanism of aspirin.

A rare case of hypokalemia-induced rhabdomyolysis

A 68-year-old male was complained of chest pain for two years and fatigue for one week. He was admitted to other hospitals two years ago because of severe chest pain. A diagnosis of acute non-ST segment elevation myocardial infarction （NSTEMI） was made. But the coronary angiography was refused by himself. After effective conservative treatment, he got better and discharged. A regular administration of aspirin, metoprolol and simvastatin was taken. No recurrent sympotoms occurred. However, he felt fatigue and palpitation after 30-m walking one week ago without predisposing factors.

Aspirin-induced small bowel injuries and the preventive effect of rebamipide

AIM:To evaluate the influence of taking low-dose aspirin for 4 wk on small intestinal complications and to examine the preventive effect of rebamipide.METHODS:This study was conducted as a single-center,randomized,double-blind,cross-over,placebo-controlled study.Eleven healthy male subjects were enrolled.Each subject underwent video capsule endos-copy after 1 and 4 wk of taking aspirin and omepra-zole,along with either rebamipide or placebo therapy.The primary endpoint was to evaluate small bowel damage in healthy subjects before and after taking low-dose aspirin for 4 wk.RESULTS:The number of subjects with mucosal breaks(defined as multiple erosions and/or ulcers)were 1 at 1 wk and 1 at 4 wk on the jejunum,and 6 at 1 wk(P = 0.0061)and 7 at 4 wk on the ileum(P =0.0019).Rebamipide significantly prevented mucosal breaks on the ileum compared with the placebo group(P = 0.0173 at 1 wk and P = 0.0266 at 4 wk).CONCLUSION:Longer-term,low-dose aspirin adminis-tration induced damage in the small bowel.Rebamipide prevented this damage,and may be a candidate drug for treating aspirin-induced small bowel complications.

Protective effects of electroacupuncture on acetylsalicylic acid-induced acute gastritis in rats

AIM: To investigate the protective effects of electroacupuncture (EA) pretreatment on acetylsalicylic acid (ASA)-induced ulceration in rats. METHODS: We randomly divided 72 rats into three groups including control (administered with distilled water), ASA group (administered 100 mg/kg ASA) and EA group (administered EA + 100 mg/kg ASA). Each rat was fasted for 18 to 24 h before experimentation, and lesion scores, gastric acidity, cyclooxygenase (COX)-1 and -2 mRNA levels, and total nitric oxide (NO) concentration were measured. RESULTS: The lesion scores of the EA group were significantly lower than those of the ASA group. Gastric acidity of the ASA and EA groups was reduced compared to the control group. COX-1 and -2 mRNA levels were significantly increased in the EA group as compared to the control and ASA groups, and NO levels were also significantly increased in the EA group as compared to the ASA group. CONCLUSION: These results suggest that EA-mediated protection against ASA-induced ulceration in rats may occur via gastric defense components.

Impact of triple antithrombotic therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention in real-world practice

Objective The optimal antithrombotic regimen for patients on oral anticoagulation （OAC） after acute coronary syndrome （ACS） and percutaneous coronary intervention （PCI） remains debated. This study sought to evaluate the efficacy and safety of OAC plus clopidogrel with or without aspirin in a real-world setting. Methods We retrospectively analyzed data from an international, multi-center registry be- tween 2003 and 2014 （n = 15,401）. Patients with ACS and receiving OAC after PCI were screened. The composite primary endpoint was 1-year all-cause death, re-infarction, or severe bleeding. Results The final analysis enrolled 642 patients including 62 patients （9.7%） with OAC and clopidogrel （dual therapy）, and 580 patients （90.3%） with the combination of aspirin, OAC and clopidogrel （triple therapy）. Pa- tients on triple therapy were more often female and were more likely to have comorbidities. There was no significant difference regarding the primary end point between dual therapy with triple therapy patients [17.74% vs. 17.24%; unadjusted hazard ratio （HR）： 1.035; 95% confi- dence interval （CI）： 0.556-1.929; adjusted HR： 1.026; 95% CI： 0.544-1.937]. However, the re-infarction rate was significantly higher in dual therapy than triple therapy patients （14.52% vs. 5.34%; unadjusted HR： 2.807; 95% CI： 1.329-5.928; adjusted HR： 2.333; 95% CI： 1.078-5.047）. In addition, there was no difference between two regimes in all-cause death and severe bleeding. Conclusions In real-life patients with ACS following PCI and with an indication of OAC, triple therapy was not associated with an increased rate of adverse out- comes compared to dual therapy. Moreover, it decreased risk of re-infarction and did not increase risk of severe bleeding.

Poor awareness of preventing aspirin-induced gastrointestinal injury with combined protective medications

AIM:To investigate prescribing pattern in low-dose aspirin users and physician awareness of preventing aspirin-induced gastrointestinal(GI) injury with combined protective medications.METHODS:A retrospective drug utilization study was conducted in the 2nd Affiliated Hospital,School of Medicine,Zhejiang University.The hospital has 2300 beds and 2.5 million outpatient visits annually.Data mining was performed on all aspirin prescriptions for outpatients and emergency patients admitted in 2011.Concomitant use of proton-pump inhibitors(PPIs),histamine 2-receptor antagonists(H2RA) and mucoprotective drugs(MPs) were analyzed.A defined daily dose(DDD) methodology was applied to each MP.A further investigation was performed in aspirin users on combination use of GI injurious medicines [non-steoid anti-inflammatory drugs(NSAIDs),corticosteroids and clopidogrel and warfarin] or intestinal protective drugs(misoprostol,rebamipide,teprenone and gefarnate).Data of major bleeding episodes were derived from medical records and adverse drug reaction monitoring records.The annual incidence of major GI bleeding due to low-dose aspirin was estimated for outpatients.RESULTS:Prescriptions for aspirin users receiving PPIs,H2RA and MPs(n = 1039) accounted for only 3.46% of total aspirin prescriptions(n = 30 015).The ratios of coadministration of aspirin/PPI,aspirin/H2RA,aspirin/MP and aspirin/PPI/MP to the total aspirin prescriptions were 2.82%,0.12%,0.40% and 0.12%,respectively.No statistically significant difference was observed in age between patients not receiving any GI protective medications and patients receiving PPIs,H2RA or MPs.The combined medication of aspirin and PPI was used more frequently than that of aspirin and MPs(2.82% vs 0.40%,P < 0.05) and aspirin/H2RA(2.82% vs 0.12%,P < 0.05).The values of DDDs of MPs in descending order were as follows:gefarnate,hydrotalcite > teprenone > sucralfate oral suspension > L-glutamine and sodium gualenate granules > rebamipide > sucralfate chewable tablets.The ratio of MP plus aspirin prescriptions to the total MP prescriptions was as follows:rebamipide(0.47%),teprenone(0.91%),L-glutamine and sodium gualenate granules(0.92%),gefarnate(0.31%),hydrotalcite(1.00%) and sucralfate oral suspension(0.13%).Percentages of prescriptions containing aspirin and intestinal protective drugs among the total aspirin prescriptions were:rebamipide(0.010%),PPI/rebamipide(0.027%),teprenone(0.11%),PPI/teprenone(0.037%),gefarnate(0.017%),and PPI/gefarnate(0.013%).No prescriptions were found containing coadministration of aspirin and other NSAIDs.Among the 3196 prescriptions containing aspirin/clopidogrel,3088(96.6%) prescriptions did not contain any GI protective medicines.Of the 389 prescriptions containing aspirin/corticosteroids,236(60.7%) contained no GI protective medicines.None of the prescriptions using aspirin/warfarin(n = 22) contained GI protective medicines.Thirty-five patients were admitted to this hospital in 2011 because of acute hemorrhage of upper digestive tract induced by low-dose aspirin.The annual incidence rates of major GI bleeding were estimated at 0.25% for outpatients taking aspirin and 0.5% for outpatients taking aspirin/warfarin,respectively.CONCLUSION:The prescribing pattern of low-dose aspirin revealed a poor awareness of preventing GI injury with combined protective medications.Actions should be taken to address this issue.

Synthesis of activated carbon from spent tea leaves for aspirin removal

Adsorption capacity of activated carbon prepared from spent tea leaves （STL-AC） for the removal of aspirin from aqueous solution was investigated in this study. Preliminary studies have shown that treatment with phosphoric acid （H3PO4） increased removal efficiency of STL-AC. Characterizations on STL-AC revealed excellent textural properties （1200 m2.g-1, 51% mesoporosity）, as well as distinctive surface chemistry （1.08 mmol.g-1 and 0.54 mmol.g-1 for acidic and basic oxygenated groups, pHpzc = 2.02）. Maximum removal efficiency of aspirin observed was 94.28% after 60 rain when the initial concentration was 100 mg.L-1, 0.5 g of adsorbent used, pH 3 and at a temperature of 30 ℃. The adsorption data were well fitted to the Freundlich isotherm model and obeyed the pseudo-second order kinetics model. The adsorption of aspirin onto STL-AC was exothermic in nature （△H = - 13.808 kJ.mol-1） and had a negative entropy change, △S （-41.444 J.mol-1）. A negative Gibbs free energy, △G was obtained indicating feasibility and spontaneity of the adsorption process. The adsorp- tion capacity of △C-STL （178.57 mg.g-1） is considerably high compared to most adsorbents synthesized from various sources, due to the well-defined textural properties coupled with surface chemistry of STL-AC which fa- vors aspirin adsorption. The results demonstrate the potential of STL-AC as aspirin adsorbent.

Aspirin increases susceptibility of Helicobacter pylori to metronidazole by augmenting endocellular concentrations of antimicrobials

AIM： To investigate the increasing the susceptibility pylon） to metronidazole. mechanisms of aspirin of Helicobacter pylori （H METHODS： Hpylori reference strain 26695 and two metronidazole-resistant isolates of H pylori were included in this study. Strains were incubated in Brucella broth with or without aspirin （1 mmol/L）. The rdxA gene of Hpylori was amplified by PCR and sequenced. The permeability of Hpylori to antimicrobials was determined by analyzing the endocellular radioactivity of the cells after incubated with [7-^3H]-tetracycline. The outer membrane proteins （OMPs） of Hpylori 26695 were depurated and analyzed by SDS-PAGE. The expression of 5 porins （hopA, hopB, hopC, hopD and hopE） and the putative RND efflux system （hefABC） of H pylori were analyzed using real-time quantitative PCR. RESULTS： The mutations in rdxA gene did not change in metronidazole resistant isolates treated with aspirin. The radioactivity of H pylori increased when treated with aspirin, indicating that aspirin improved the permeability of the outer membrane of H pylori. However, the expression of two OMP bands between 55 kDa and 72 kDa altered in the presence of aspirin.The expression of the mRNA of hopA, hopB, hopC, hopD, hopE and herA, hefB, hefC of H pylori did not change when treated with aspirin. CONCLUSION： Although aspirin increases the susceptibility of H pylori to metronidazole, it has no effect on the mutations of rdxA gene of Hpylori. Aspirin increases endocellular concentrations of antimicrobials probably by altering the OMP expression.

Establishing a predictive model for aspirin resistance in elderly Chinese patients with chronic cardiovascular disease

Background Resistance to anti-platelet therapy is detrimental to patients. Our aim was to establish a predictive model for aspirin resistance to identify high-risk patients and to propose appropriate intervention. Methods Elderly patients （n = 1130） with stable chronic coronary heart disease who were taking aspirin （75 mg） for 〉 2 months were included. Details of their basic characteristics, laboratory test results, and medications were collected. Logistic regression analysis was performed to establish a predictive model for aspirin resistance. Risk score was finally established according to coefficient B and type of variables in logistic regression. The Hosmer-Lemeshow （HL） test and receiver operating characteristic curves were performed to respectively test the calibration and discrimination of the model. Results Seven risk factors were included in our risk score. They were serum creatinine （〉 110 μmol/L, score of 1）; fasting blood glucose （〉 7.0 mmol/L, score of 1）; hyperlipidemia （score of 1）; number of coronary arteries （2 branches, score of 2; 〉 3 branches, score of 4）; body mass index （20-25 kg/m2, score of 2; 〉 25 kg/m2, score of 4）; percutaneous coronary intervention （score of 2）; and smoking （score of 3）. The HL test showed P ≥ 0.05 and area under the receiver operating characteristic curve ≥ 0.70. Conclusions We explored and quantified the risk factors for aspirin resistance. Our predictive model showed good calibration and discriminative power and therefore a good foundation for the further study of patients undergoing anti-platelet therapy.

High prevalence of aspirin resistance in elderly patients with cardiovascular disease and metabolic syndrome

Background Metabolic syndrome is known to be a prothrombotic state. We undertook this study to examine a hypothesis that aspirin resistance may be associated with metabolic syndrome, and to assess other potential determinants of aspirin resistance in patients with cardiovascular disease （CVD）. Methods A total of 469 elderly patients with CVD were recruited. One hundred and seventy-two patients with metabolic syndrome and 297 without metabolic syndrome （control group） received daily aspirin therapy （〉 75 mg） over one month. Platelet aggregation was measured by light transmission aggregometry （LTA）. Aspirin resistance was defined as 〉 20% arachidonic acid （AA）- and 〉 70% adenosine diphosphate （ADP）-induced aggregation according to LTA. Aspirin semi-responders were defined as meeting one （but not both） of these criteria. Results By LTA, 38 of 469 （8.1%） patients were aspirin resistant. The prevalence of aspirin resistance was higher in the metabolic syndrome group compared with the control group [11.6 % vs. 6.6%, odds ratio （OR） = 2.039; 95% confidence interval （CI）： 1.047-3.973]. In the multivariate logistic regression analysis, metabolic syndrome （OR = 4.951, 95% CI： 1.440-17.019, P = 0.011） was a significant risk factor for aspirin resistance. Conclusions A significant number of patients with CVD and metabolic syndrome are resistant to aspirin therapy. This might further increase the risk of cardiovascular morbidity and mortality in these patients.

Evaluation of small bowel blood flow in healthy subjects receiving low-dose aspirin

AIM:To investigate the relationship between low-dose aspirin-induced small bowel mucosal damage and blood flow,and the effect of rebamipide. METHODS:Ten healthy volunteers were enrolled in this study.The subjects were divided into two groups:a placebo group given low-dose aspirin plus placebo and a rebamipide group given low-dose aspirin plus rebamipide for a period of 14 d.Capsule endoscopy and contrast-enhanced ultrasonography were performed before and after administration of drugs.Areas under the curves and peak value of time-intensity curve were calculated. RESULTS:Absolute differences in areas under the curves were-1102.5(95%CI:-1980.3 to-224.7,P=0.0194) in the placebo group and-152.7(95%CI:-1604.2 to 641.6,P=0.8172) in the rebamipide group. Peak values of time intensity curves were-148.0(95% CI:-269.4 to-26.2,P=0.0225) in the placebo group and 28.3(95%CI:-269.0 to 325.6,P=0.8343) in the rebamipide group.Capsule endoscopy showed mucosal breaks only in the placebo group. CONCLUSION:Short-term administration of low-dose aspirin is associated with small bowel injuries and blood flow.

Incidence and predictors of upper gastrointestinal bleeding in patients receiving low-dose aspirin for secondary prevention of cardiovascular events in patients with coronary artery disease

AIM： The use of low-dose aspirin to prevent cardiovascular disease events is well established. However, the incidence and predictors of upper gastrointestinal bleeding （UGIB） with its use are unknown. We studied prospectively the incidence and outcome of peptic ulceration in low-dose aspirin users. METHODS： A total of 991 patients with coronary artery disease （CAD） on low-dose aspirin were prospectively followed-up for two years for the occurrence and clinical features of first hospitalized episode of UGIB. RESULTS： UGIB had a bimodal presentation with 45% occurring within four months of aspirin initiation and had an overall prevalence of 1.5% per year. There was no UGIB-related death. Hypertension （OR = 4.6, 95%CI 1.5 - 14.7, P = 0.009）, history of peptic ulceration （OR = 3.1, 95%CI 1.1 - 9.0, P = 0.039）, tertiary education （OR = 3.08, 95%CI 1.1 - 9.0, P = 0.039） and higher lean body mass （P = 0.016） were independent factors associated with UGIB. Use of nitrate did not reduce UGIB. CONCLUSION： The incidence of UGIB in patients with CAD on long-term low-dose aspirin is low, but is accompanied with significant morbidity. With prolonged use of aspirin, UGIB continues to be a problem for those with risk factors and especially in patients with a history of peptic ulcers, in which UGIB tends to occur early after aspirin therapy.

Nitric oxide-releasing aspirin but not conventional aspirin improves healing of experimental colitis

AIM:To determine the effect of non-selective cyclooxygenase (COX) inhibitors,selective COX-2 inhibitors and nitric oxide (NO)-releasing aspirin in the healing of ulcerative colitis.METHODS:Rats with 2,4,6 trinitrobenzenesulfonic acid (TNBS)-induced colitis received intragastric (ig) treatment with vehicle,aspirin (ASA) (a nonselective COX inhibitor),celecoxib (a selective COX-2 inhibitor) or NO-releasing ASA for a period of ten days.The area of colonic lesions,colonic blood flow (CBF),myeloperoxidase (MPO) activity and expression of proinflammatory markers COX-2,inducible form of nitric oxide synthase (iNOS),IL-1β and tumor necrosis factor (TNF)-α were assessed.The effects of glyceryl trinitrate (GTN),a NO donor,and 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide,onopotassium salt (carboxy-PTIO),a NO scavenger,administered without and with ASA or NO-ASA,and the involvement of capsaicin-sensitive afferent nerves in the mechanism of healing the experimental colitis was also determined.RESULTS:Rats with colitis developed macroscopic and microscopic colonic lesions accompanied by a significant decrease in the CBF,a significant rise in colonic weight,MPO activity and plasma IL-1β and TNF-α levels.These effects were aggravated by ASA and 5-(4-chlorophenyl)-1-(4-methoxyphenyl)3-(trifluoromethyl)-1H-pyrazole (SC-560),but not celecoxib and counteracted by concurrent treatment with a synthetic prostaglandin E 2 (PGE 2) analog.Treatment with NO-ASA dose-dependently accelerated colonic healing followed by a rise in plasma NO x content and CBF,suppression of MPO and downregulation of COX-2,iNOS,IL-1β and TNF-α mRNAs.Treatment with GTN,the NO donor,significantly inhibited the ASA-induced colonic lesions and increased CBF,while carboxy-PTIO or capsaicin-denervation counteracted the NO-ASAinduced improvement of colonic healing and the accompanying increase in the CBF.These effects were restored by co-treatment with calcitonin gene related peptide (CGRP) and NO-ASA in capsaicin-denervated animals.CONCLUSION:NO-releasing ASA,in contrast to ASA,COX-1 inhibitors,and SC-560,accelerated the healing of colitis via a mechanism involving NO mediated improvement of microcirculation and activation of sensory nerves releasing CGRP.

Esophageal mucosal lesion with low-dose aspirin and prasugrel mimics malignancy: A case report

Dual antiplatelet therapy consisting of low-dose aspirin (LDA) and other antiplatelet medications is recommended in patients with coronary heart disease, but it may increase the risk of esophageal lesion and bleeding. We describe a case of esophageal mucosal lesion that was difficult to distinguish from malignancy in a patient with a history of ingesting LDA and prasugrel after implantation of a drug-eluting stent. Multiple auxiliary examinations were performed to make a definite diagnosis. The patient recovered completely after concomitant acid-suppressive therapy. Based on these findings, we strongly argue for the evaluation of the risk of gastrointestinal mucosal injury and hemorrhage if LDA therapy is required, and we stress the paramount importance of using drug combinations in individual patients.

AKT1 and AKT2 Promote Malignant Transformation in Human Brain Glioma LN229 Cells

OBJECTIVE To confirm the role played by AKT1 and AKT2 in the β- catenin/Tcf-4 signaling pathway in promoting malignant transfor- mation of glioma cells. METHODS LN229 cells were divided into five groups： a control group, acetone （ACE）group, acetylsalicylic acid （ASA; aspirin） group, ASA＋AKT1 plasmid group and ASA＋AKT2 plasmid group. Western blot and PCR were used to detect the expression of AKT1 and AKT2 after dealing with ASA and transferring AKTI/2 genes into LN229 cells. Cell proliferation was determined by flow cytometry, cell invasion was evaluated by transwell assay and cell apoptosis was detected with annexin V staining. The molecules regulating proliferation and invasion were examined by western blot analysis. RESULTS Aspirin down-regulates AKT1 and AKT2 expression by modulating β-cateninfrcf-4 activity. AKT1 and AKT2 can enhance cell proliferation and invasion by up-regulating the expression of cyclin-D and matrix metalloprotein-9 （MMP-9） in LN229 glioma cells. CONCLUSION AKT1 and AKT2 play an important role in the β- catenin/Tcf-4 signaling pathway promoting malignant transformation; AKT1 is more effective than AKT2. AKT1 and AKT2 may be potential targets for brain glioma therapy and an effective way to prevent metastasis of gliomas.

Dual versus single antiplatelet therapy for patients with long-term oral anticoagulation undergoing coronary intervention： a systematic review and meta-analysis

Objective The main aim of this meta-analysis is to compare the efficacy and safety of dual versus single antiplatelet therapy for pa- tients taking oral anticoagulation （OAC） after coronary intervention. Background The optimal regimen remains controversial for patients taking OAC after coronary intervention. Methods PubMed, Embase and Cochrane Central Register of Controlled Trials were searched for eligible studies including data of triple therapy （TT） versus OAC plus single antiplatelet therapy for patients requiring OAC after coronary intervention. The primary outcome was major adverse cardiac and cerebrovascular event （MACCE）. The safety outcome was major bleeding. Results Fourteen studies with 32,825 patients were included. Among prospective studies, patients with TT had a trend toward a higher risk of major bleeding [odds ratios （OR）： 1.56, 95% confidence interval （CI）： 0.98-2.49, P = 0.06] and a markedly higher risk of all-cause death （OR; 2.11, 95% CI： 1.10-4.06 P = 0.02） compared with OAC plus clopidogrel. Meanwhile, TT was associated with decreased risks of MACCE （OR： 0.63, 95% CI： 051-0.77 P 〈 0.0001）, all-cause death （OR： 0.45, 95% CI： 0.20-0.97, P = 0.04）, and stroke/transient ischemic attack （TIA）/peripheral embolism （PE） （OR= 0.29, 95% CI： 0.09~3.96, P = 0.04） compared with OAC plus aspirin. Conclusions For pa- tients requiring OAC after coronary intervention, OAC plus clopidogrel may bring more clinical net benefit than TT, whereas OAC plus aspirin should be the last choice. More large-size randomized control trials are needed to confirm these findings.