Aspirin and Blood Glucose and Insulin Resistance

Background: Diabetes mellitus (DM) is a disorder in which blood sugar levels are abnormally high because either absolute or relative insulin deficiency. Treatment of diabetes involves diet, exercise, education and for most people, drugs. Oral antidiabetic drugs and/or insulin doses may be affected by co-administration of many drugs including aspirin. Dose adjustments may be necessary. The pain killer effect of aspirin is best known for its effects on the two cyclooxygenase enzymes (COX1 & COX2), but, recently, aspirin could specifically inhibit the protein I-kappa-β-kinase beta (IKK-beta). This kinase is used for its role in the cascade of signals that activate the nuclear factor kappa-b (NF-kappa-B) family of cellular genes which regulate inflammatory and immune responses. Now, it turns out that IKK-beta also works in another pathway to contribute to insulin resistance by interfering with insulin signaling. Objective: In view of the recent rodent data demonstrating a potentially important role of IKKβ in mediating insulin resistance and the ability of salicylates to inhibit IKKβ activity, we decided to examine the role of different doses of aspirin (low, moderate and high) in experimentally induced diabetic rats. Materials and Methods: DM in rats were induced by administration of nicotinamide (NAD), 15 min prior to the single dose of streptozotocin STZ i.p. Ninety male albino rats were used in this study. They were divided into 6 main groups. The first was served as control which receives no medications. The second group was diabetic induced rats as mentioned above. The third group was controlled by insulin after induction of D.M. Groups from the fourth to the six consist of 20 diabetic induced rats and further subdivided into rats taking either aspirin alone in different doses (low, moderate or high) or aspirin and insulin. At the end of the protocol, fasting blood sugar level (FBS), glycosylated hemoglobin (HBA1c%), total serum proteins, C-peptide, lipid profile and C-reactive proteins were measured. Results: Different doses of aspirin showed that moderate and to a greater extent high dose aspirin administration to diabetic rats have greater impact on fasting blood glucose levels whether treated with insulin or not. Again, HBA1c% in diabetic rats treated with insulin and receiving HDA was lower than diabetic rats treated with insulin only or even taking LDA in addition. On the contrary, different doses of aspirin (LDA, MDA&HDA) administration to diabetic rats have no any influence on HBA1c% as compared to normal non-diabetic rats. TGs in diabetic rats receiving MDA alone was elevated as compared to normal non-diabetic rats. Again, moderate and HDA in diabetic rats not taking insulin had high TGs level as compared to diabetic rats treated with insulin only. Conclusion: The study concluded that the inflammatory pathways hold a substantial part in insulin resistance in type 2 DM. The influence of salicylate compounds on insulin sensitivity is multifactorial especially in high doses, and involves both beneficial and deleterious effects depending on the species and experimental model studied.

Aspirin responsive platelet thrombophilia in essential thrombocythemia and polycythemia vera

Essential thrombocythemia(ET) and polycythemia vera(PV) frequently present with erythromelalgia and acrocyanotic complications, migraine-like microvascular cerebral and ocular transient ischemic attacks(MIAs) and/or acute coronary disease. The spectrum of MIAs in ET range from poorly localized symptoms of transient unsteadiness, dysarthria and scintillating scotoma to focal symptoms of transient monocular blindness, transient mono- or hemiparesis or both. The attacks all have a sudden onset, occur sequentially rather than simultaneously, last for a few seconds to several minutes and are usually associated with a dull, pulsatile or migraine-like headache. Increased hematocrit and blood viscosity in PV patients aggravate the microvascular ischemic syndrome of thrombocythemia to major arterial and venous thrombotic complications. Phlebotomy to correct hematocrit to normal in PV significantly reduces major arterial and venous thrombotic complications, but fails to prevent the platelet-mediated erythromelalgia and MIAs. Complete long-term relief of the erythromelalgic microvascular disturbances, MIAs and major thrombosis in ET and PV patients can be obtained with low dose aspirin and platelet reduction to normal, but not with anticoagulation. Skin punch biopsies from the erythromelalgic area show fibromuscular intimal proliferation of arterioles complicated by occlusive plateletrich thrombi leading to acrocyanotic ischemia. Symptomatic ET patients with erythromelalgic microvascular disturbances have shortened platelet survival, increased platelet activation markers β-thromboglobulin(β-TG), platelet factor 4(PF4) and thrombomoduline(TM), increased urinary thromboxane B2(TXB2) excretion, and no activation of the coagulation markers thrombin fragments F1+2 and fibrin degradation products. Inhibition of platelet cyclooxygenase(COX1) by aspirin is followed by the disappearance and no recurrence of microvascular disturbances, increase in platelet number, correction of the shortened platelet survival times to normal, and reduction of increased plasma levels of β-TG, PF4, TM and urinary TXB2 excretion to normal. These results indicate that platelet-mediated fibromuscular intimal proliferation and platelet-rich thrombi in the peripheral, cerebral and coronary end-arterial microvasculature are responsible for the erythromelalgic ischemic complica-tions, MIAs and splanchnic vein thrombosis. Baseline platelet P-selectin levels and arachidonic acid induced COX1 mediated platelet activation showed a highly significant increase of platelet P-selectin expression(not seen in ADP and collagen stimulated platelets), which was significantly higher in JAK2V617 F mutated compared to JAK2 wild type ET.

Stress Degradation Behavior of a Polypill and Development of Stability Indicating UHPLC Method for the Simultaneous Estimation of Aspirin, Atorvastatin, Ramipril and Metoprolol Succinate

A novel, sensitive and precise UHPLC method has been developed and validated for the simultaneous determination of the all the active components of a Polypill viz Zycad, i.e., Aspirin (ASP) Atorvastatin (ATV), Ramipril (RMP) and Metoprolol (MTP) in Zycad tablet dosage form in the presence of degradation products. Forced degradation of individual as well as combination of all the drug substances components of Polypill was conducted in accordance with ICH guidelines. Acidic, basic, neutral, and oxidative hydrolysis, thermal stress, and photolytic degradation were used to assess the stability-indicating power of the method. Use of 100 × 2.1 mm, 1.7 μm stationary phases with simple mobile phase combination buffer consisting of 0.1% Perchloric acid (adjusted to pH 2.5) and Acetonitrile, delivered in a gradient mode and quantitation was carried out using ultraviolet detection at 215 nm with a flow rate of 0.6 mL?min–1. The method was optimized using samples generated by forced degradation studies. The method was validated for linearity, accuracy (recovery), precision, Specificity and robustness. The method was linear in the range of 37.5 to 150.0 μg?mL–1 for ASP, 5.0 to 20.0 μg?mL–1 for ATV and 2.5 to 10.0 μg?mL–1 for RMP and 25.0 to 100.0 μg?mL–1 for MTP.

Quantitative Application to a Polypill by the Development of Stability Indicating LC Method for the Simultaneous Estimation of Aspirin, Atorvastatin, Atenolol and Losartan Potassium

Polypill is a fixed-dose combination (FDC) containing three or more drugs in a single pill with the intention of reducing the number of tablets or capsules that need to be taken. Developing a single analytical method for the estimation of individual drugs in a Polypill is very challenging, due to the formation of drug-drug and drug-excipients interaction impurities. Here an attempt was made to develop a new, sensitive, single stability-indicating HPLC method for the simultaneous quantitative determination of Aspirin (ASP) Atorvastatin (ATV), Atenolol (ATL) and Losartan potassium (LST) in a polypill form in the presence of degradation products. Efficient chromatographic separation was achieved on a C18 stationary phase with simple mobile phase combination of buffer and Acetonitrile. Buffer consists of 0.1% Orthophosphoric acid (pH 2.9), delivered in a gradient mode and quantitation was carried out using ultraviolet detection at 230 nm with a flow rate of 1.0 mL/min. The retention times of Atenolol, Aspirin, Losartan potassium, and Atorvastatin were 3.3, 7.6, 10.7 and 12.9 min respectively. The combination drug product are exposed to thermal, acid/base hydrolytic, humidity and oxidative stress conditions, and the stressed samples were analyzed by proposed method. The method was validated with respect to linearity;the method was linear in the range of 37.5 to 150.0 μg/mL for ASP, 5.0 to 20.0 μg/mL for ATV and 25.0 to 100.0 μg/mL for ATL and LST. Acceptable precision and accuracy were obtained for concentrations over the standard curve ranges. The validated method was successfully applied to the analysis of Starpill tablets constituting all the four drugs;the percentage recoveries obtained were 99.60% for ASP, 99.30% for ATV, 99.41% for ATL and 99.62% for LST.

The effects of EPA + DHA and aspirin on inflammatory cytokines and angiogenesis factors

Objective: In a recent study, we showed that the combination of aspirin plus the ω3 fatty acids eicosapen-taenoic acid (EPA) and docosahexaenoic acid (DHA) synergistically inhibited platelet function. As aspirin, EPA, and DHA have demonstrated anti-inflammatory properties, we hypothesized that the ingestion of EPA and DHA, with and without aspirin, would reduce plasma levels of inflammatory cytokines and angiogenesis factors more than aspirin alone and before aspirin was ingested. Methods: Using multiplex technology, we investigated the effects of aspirin (single-dose 650 mg on day 1), EPA + DHA (3.4 g/d for days 2 - 29), and aspirin with EPA + DHA (day 30) on plasma levels of inflammatory cytokines and angiogenesis factors in healthy adults. Results: Aspirin alone had no effect on any factor versus baseline, but EPA + DHA, with and without aspirin, significantly reduced concentrations of 8 of 9 factors. Although EPA + DHA plus aspirin reduced concentrations of a subset of the factors compared to baseline, neither aspirin alone nor the combination significantly reduced the level of any analyte more robustly than EPA + DHA alone. Conclusions: These data suggest that EPA + DHA has more pronounced down-regulatory effects on inflammation and angiogenesis than aspirin. The implications of these findings for the use of combined therapy for cardiovascular disease remain to be clarified.

Gastroduodenal ulcer bleeding in elderly patients on low dose aspirin therapy

AIM To determine the clinical characteristics of elderly patients of hemorrhagic gastroduodenal ulcer on low-dose aspirin(LDA)therapy.METHODS A total of 1105 patients with hemorrhagic gastroduodenal ulcer treated in our hospital between January 2000 and March 2016 were grouped by age and drugs used,and these groups were compared in several factors.These groups were compared in terms of length of hospital stay,presence/absence of hemoglobin(Hb)decrease,presence/absence of blood transfusion,Forrest Ⅰ,percentage of Helicobacter pylori infection,presence/absence of underlying disease,and percentage of severe cases.RESULTS The percentage of blood transfusion(62.6%vs 47.7%,P<0.001),Hb decrease(53.8% vs 40.8%,P<0.001),and the length of hospital stay(23.5 d vs 16.7 d,P<0.001)were significantly greater in those on drug therapy.The percentage of blood transfusion(65.3%vs 47.8%,P<0.001),Hb decrease(54.2%vs 42.1%,P<0.001),and length of hospital stay(23.3 d vs 17.5 d,P<0.001)were significantly greater in the elderly.In comparison with the LDA monotherapy group,the percentage of severe cases was significantly higher in the LDA combination therapy group when elderly patients were concerned(16.1%vs34.0%,P=0.030).Meanwhile,among those on LDA monotherapy,there was no significant difference between elderly and non-elderly(16.1%vs 16.0%,P=0.985).CONCLUSION A combination of LDA with antithrombotic drugs or nonsteroidal anti-inflammatory drugs(NSAIDs)contributes to aggravation.And advanced age is not an aggravating factor when LDA monotherapy is used.

Aspirin resistance in young men with Type 2 diabetes

Objective: Aspirin resistance (AR) or poor response to aspirin is said to be high among subjects with diabetes and more so in patients with poor glycemic control. The aim of our study was to evaluate the prevalence of AR among subjects with diabetes with moderate glycemic control and its association with inflammatory markers and cytokines. Design: This is a single-center open-label prospective clinical study. Methods: The study included 142 young male veterans (mean age of 49years) with Type 2 diabetes, with HbA1C of 7.7 ± 1.1. Urinary 11-dehydro-thromboxane beta-2 (11DhTx2) concentrations measured by immunoassay are the primary outcome measures. Results: Urinary 11DhTxB2 levels ≥ 1500 pg/mg of creatinine is considered as AR. Approximately 53% of subjects had AR. There are no significant differences in the clinical parameters, such as age, history of hypertension or BMI, waist to hip ratio;as well as biochemical parameters, such as HbA1C, lipid parameters or serum creatinine, between subjects with or without AR. Levels of 11DhTxB2 /cre correlated with history of CAD, abdominal fat content and IL-6 levels (p < 0.01) as well as abdominal fat content and IL-6 levels;duration of diabetes and history of CAD. Conclusions: Aspirin resistance is common in subjects with diabetes even with moderate control. Additional measures to improve aspirin response should be considered. Further studies with larger groups are needed to clarify the AR with various associated risk factors.

Aspirin plus Pseudoephedrine (Aspirin Complex) for the Treatment of Symptoms of Upper Respiratory Tract Infection

Upper respiratory tract infections or common colds are a multi-symptom disease which is usually symptomatically treated with fixed dose multi-active ingredient medicinal products which are commonly used as non-prescription and over the counter. However, the active ingredients combined require a particular and clinically sound justification. Analgesics and decongestant can be combined to treat simultaneously the prominent symptoms cold-related pain (e.g. headache, muscle aches and pains), fever, inflammationand nasal/sinus congestion. This overview provides a summary of the evidence supporting the combination of acetylsalicylic acid (aspirin) and pseudoephedrine available in the common cold product Aspirin? Complex.

Feasibility of gastric endoscopic submucosal dissection with continuous low-dose aspirin for patients receiving dual antiplatelet therapy

BACKGROUND Endoscopic submucosal dissection(ESD) for gastric neoplasms during continuous low-dose aspirin(LDA) administration is generally acceptable according to recent guidelines. This retrospective study aimed to investigate the effect of continuous LDA on the postoperative bleeding after gastric ESD in patients receiving dual antiplatelet therapy(DAPT).AIM To investigate the feasibility of gastric ESD with continuous LDA in patients with DAPT.METHODS A total of 597 patients with gastric neoplasms treated with ESD between January2010 and June 2017 were enrolled. The patients were categorized according to type of antiplatelet therapy(APT).RESULTS The postoperative bleeding rate was 6.9%(41/597) in all patients. Patients were divided into the following two groups: no APT(n = 443) and APT(n = 154). APT included single-LDA(n = 95) and DAPT(LDA plus clopidogrel, n = 59)subgroups. In the single-LDA and DAPT subgroups, 56 and 39 patients were received continuous LDA, respectively. The bleeding rate with continuous singleLDA(10.7%) was similar to that with discontinuous single-LDA(10.3%)(P >0.99). Although the bleeding rate with continuous LDA in patients receiving DAPT(23.1%) was higher than that with discontinuous LDA in patients receiving DAPT(5.0%), no significant difference was observed(P = 0.141).CONCLUSION The bleeding rate with continuous LDA in patients receiving DAPT was not statistically different from that with discontinuous LDA in patients receiving DAPT. Therefore, continuous LDA administration may be acceptable for ESD in patients receiving DAPT, although patients should be carefully monitored for possible bleeding.

A case of a patient positive for anti-cardiolipin antibodies with recurrent fetal wastage and cerebral infarction who was successfully treated with Sairei-to, low dose aspirin, and heparin

We report a successful case of a pregnant female positive for anti-cardiolipin antibodies who experienced two abnormal pregnancies with postpartum cerebral hemispheric infarctions. A 38-year-old female diagnosed as being positive for anti-cardiolipin antibodies was referred to our hospital due to her strong desire to have a baby. The administration of Japanese herbal medicine, Sairei-to, as immunosuppressive therapy, and low dose aspirin, as anti-coagulation therapy, were initiated prior to the patient’s pregnancy. Five months after beginning the treatment, the patient conceived spontaneously. At 34 weeks of gestation, emergency cesarean section was performed due to increasing genital bleeding resulting from coincidental placenta previa and the patient delivered an appropriate-for-date female infant (1970 g). Treatment with Japanese herbal medicine (Sairei-to) and low-dose aspirin is considered to be an effective treatment option for patients positive for anti-phospholipid antibodies with past histories of abnormal pregnancies.

Clinical features of gastroduodenal injury associated with long-term low-dose aspirin therapy

Low-dose aspirin(LDA) is clinically used for the prevention of cardiovascular and cerebrovascular events with the advent of an aging society.On the other hand,a very low dose of aspirin(10 mg daily) decreases the gastric mucosal prostaglandin levels and causes significant gastric mucosal damage.The incidence of LDAinduced gastrointestinal mucosal injury and bleeding has increased.It has been noticed that the incidence of LDA-induced gastrointestinal hemorrhage has increased more than that of non-aspirin non-steroidal anti-inflammatory drug(NSAID)-induced lesions.The pathogenesis related to inhibition of cyclooxygenase(COX)-1 includes reduced mucosal flow,reduced mucus and bicarbonate secretion,and impaired platelet aggregation.The pathogenesis related to inhibition of COX-2 involves reduced angiogenesis and increased leukocyte adherence.The pathogenic mechanisms related to direct epithelial damage are acid back diffusion and impaired platelet aggregation.The factors associated with an increased risk of upper gastrointestinal(GI) complications in subjects taking LDA are aspirin dose,history of ulcer or upper GI bleeding,age > 70 years,concomitant use of non-aspirin NSAIDs including COX-2-selective NSAIDs,and Helicobacter pylori(H.pylori) infection.Moreover,no significant differences have been found between ulcer and non-ulcer groups in the frequency and severity of symptoms such as nausea,acid regurgitation,heartburn,and bloating.It has been shown that the ratios of ulcers located in the body,fundus and cardia are significantly higher in bleeding patients than the ratio of gastroduodenal ulcers in patients taking LDA.Proton pump inhibitors reduce the risk of developing gastric and duodenal ulcers.In contrast to NSAIDinduced gastrointestinal ulcers,a well-tolerated histamine H2-receptor antagonist is reportedly effective in prevention of LDA-induced gastrointestinal ulcers.The eradication of H.pylori is equivalent to treatment with omeprazole in preventing recurrent bleeding.Continuous aspirin therapy for patients with gastrointestinal bleeding may increase the risk of recurrent bleeding but potentially reduces the mortality rates,as stopping aspirin therapy is associated with higher mortality rates.It is very important to prevent LDA-induced gastroduodenal ulcer complications including bleeding,and every effort should be exercised to prevent the bleeding complications.

Anaphylaxis and Undiagnosed Aspirin Exacerbated Respiratory Disease in the Ambulatory Surgery Center: A Case Report

Severe bronchospasm and anaphylaxis are unanticipated emergencies that may occur in the ambulatory surgery setting. I present a case in which an asthmatic male with nasal congestion has anaphylaxis after induction, with severe bronchospasm as the primary manifestation. During the course of hospitalization, he was exposed to aspirin and a second episode of severe bronchospasm occurred. He was diagnosed with both anaphylaxis to an anesthetic medication and Aspirin Exacerbated Respiratory Disease, or Samter’s Triad.

In vivo assessment of intratumoral aspirin injection to treat hepatic tumors

AIM: To study the antineoplastic efficacy of 10% aspirin intralesional injection on VX2 hepatic tumors in a rabbit model. METHODS: Thirty-two male rabbits (age: 6-9 wk; body weight: 1700-2500 g) were inoculated with VX2 hepatic tumor cells (104 cells/rabbit) via supraumbilical median laparotomy. On day 4 post-implantation, when the tumors were about 1 cm in diameter, the rabbits were randomly divided into the following groups (n = 8 each group) to assess early (24 h) and late (7 d) antineoplastic effects of intratumoral injection of 10% bicarbonate aspirin solution (experimental groups) in comparison to intratumoral injection of physiological saline solution (control groups): group 1, 24 h control; group 2, 24 h experimental; group 3, 7 d control; group 4, 7 d experimental. The serum biochemistry profile (measurements of glycemia, alkaline phosphatase, gamma-glutamyl transferase, aspartateaminotransferase, and alanine aminotransferase) and body weight measurements were obtained for all animals at the following time points: D0, before tumor implant; D4, day of treatment; D5, day of sacrifice for groups 1 and 2; D11, day of sacrifice for groups 3 and 4. Gross assessments of the abdominal and thoracic cavities were carried out upon sacrifice. The resected liver tissues, including hepatic tumors, were qualitatively (general morphology, signs of necrosis) and quantitatively (tumor area) assessed by histopathological analysis. RESULTS: Gross examination showed no alterations, besides the left hepatic lobe tumors, had occurred in the thoracic and abdominal cavities of any animal at any time point evaluated. However, the features of the tumor foci were distinctive between the groups. Compared to the control groups, which showed normal unabated tumor progression, the aspirin-treated groups showed imprecise but limited tumor boundaries and a general red-white coloration (indicating hemorrhaging) at 24 h post-treatment, and development of yellow-white areas of a cicatricial aspect at 7 d after treatment. At all time points evaluated, all except one biochemical parameters tested within the reference range (P > 0.05); a significant increase was detected in the alkaline phosphatase level of the control group 3 on D11 (P < 0.05). At 24 h post-treatment, the aspirintreated groups showed extensive coagulation necrosis accompanied by a remarkable absence of viable tumor foci; at 7 d after treatment, the tumors had completely disappeared in these animals and fibrous necrotic nod- ules had developed. In contrast, throughout the study course, the tumors of the control groups remained unchanged, showing tumor nodules without necrosis at the time point corresponding to 24 h post-treatment and increased amounts of tumor nodules at the time point corresponding to 7 d post-treatment. Quantitative analysis of the remaining tumor area revealed that the aspirin-treated groups had significantly smaller tumor foci at 24 h post-treatment (8.5% ± 0.7%) andat 7 d after treatment (11.0% ± 4.2%), compared to those in the control groups (24 h: 98.5% ± 1.5% and 7 d: 94.0% ± 2.7%; both,P < 0.005). CONCLUSION: Intralesional injection of a 10% aspirin solution causes destruction of VX2 hepatic tumors in rabbits without evidence of relapse at 7 d after treat- ment administration.

Clinical importance of aspirin and clopidogrel resistance

Aspirin and clopidogrel are important components of medical therapy for patients with acute coronary syndromes, for those who received coronary artery stents and in the secondary prevention of ischaemic stroke. Despite their use, a significant number of patients experience recurrent adverse ischaemic events. Interindividual variability of platelet aggregation in response to these antiplatelet agents may be an explanation for some of these recurrent events, and small trials have linked "aspirin and/or clopidogrel resistance", as measured by platelet function tests, to adverse events. We systematically reviewed all available evidence on the prevalence of aspirin/clopidogrel resistance, their possible risk factors and their association with clinical outcomes. We also identified articles showing possible treatments. After analyzing the data on different laboratory methods, we found that aspirin/clopidogrel resistance seems to be associated with poor clinical outcomes and there is currently no standardized or widely accepted definition of clopidogrel resistance. Therefore, we conclude that specific treatment recommendations are not established for patients who exhibit high platelet reactivity during aspirin/clopidogrel therapy or who have poor platelet inhibition by clopidogrel.

Impairment of aspirin antiplatelet effects by non-opioid analgesic medication

Aspirin is the mainstay in prophylaxis of cardiovascular diseases. Impaired aspirin antiplatelet effects are associated with enhanced incidence of cardiovascular events. Comedication with non-opioid analgesic drugs has been described to interfere with aspirin,resulting in impaired aspirin antiplatelet effects. Additionally,nonopioid analgesic medication has been shown to enhance the risk of cardiovascular events and death. Pain is very frequent and many patients rely on analgesic drugs to control pain. Therefore effective analgesic options without increased risk of cardiovascular events are desirable. This review focuses on commonly used nonopioid analgesics,interactions with aspirin medication and impact on cardiovascular risk.

Clinical use of low-dose aspirin for elders and sensitive subjects

The use of low-dose aspirin(LDA)has been a common preventive measure to reduce the risk of cardiovascular events.This is attributed to aspirin’s ability to inhibit platelet activation.On the other hand,the use of LDA in human subjects has been associated with the development of gastrointestinal injuries like ulcer and bleeding,especially for those sensitive subjects such as elder human subjects.This opinion review will summarize the recent clinical reports regarding the use of LDA and the development of gastrointestinal conditions in China.Based on these reports,it seems that the use of LDA is commonly associated with gastrointestinal injuries,and stopping its use leads to recovery in elderly subjects.Therefore,we would like to suggest that gastroduodenal health and conditions should be seriously taken into consideration when LDA is recommended to the elderly,or other alternative means to reduce the risk of cardiovascular events such as nutritional interventions should be suggested.

Does aspirin or non-aspirin non-steroidal anti-inflammatory drug use prevent colorectal cancer in inflammatory bowel disease?

AIM: To determine whether aspirin or non-aspirin nonsteroidal anti-inflammatory drugs(NA-NSAIDs) prevent colorectal cancer(CRC) in patients with inflammatory bowel disease(IBD).METHODS: We performed a systematic review and meta-analysis. We searched for articles reporting the risk of CRC in patients with IBD related to aspirin or NANSAID use. Pooled odds ratios(OR) and 95%CIs were determined using a random-effects model. Publication bias was assessed using Funnel plots and Egger's test. Heterogeneity was assessed using Cochran's Q and the I2 statistic.RESULTS: Eight studies involving 14917 patients and 3 studies involving 1282 patients provided data on the risk of CRC in patients with IBD taking NA-NSAIDs and aspirin respectively. The pooled OR of developing CRC after exposure to NA-NSAIDs in patients with IBD was 0.80(95%CI: 0.39-1.21) and after exposure to aspirin it was 0.66(95%CI: 0.06-1.39). There was significant heterogeneity(I2 > 50%) between the studies. There was no change in the effect estimates on subgroup a na ly s e s o f t he po pulat io n s t udie d o r w he t he r adjustment or matching was performed.CONCLUSION: There is a lack of high quality evidence on this important clinical topic. From the available evidence NA-NSAID or aspirin use does not appear to be chemopreventative for CRC in patients with IBD.

The rationale for pre-race aspirin to protect susceptible runners from sudden cardiac death during marathons: Deconstructing the Pheidippides conundrum

Objectives: While endurance exercise such as training for marathons is cardioprotective, cardiac arrests and sudden death occur in previously healthy runners during races predominantly in middle-aged males due to atherosclerotic heart disease. Recent evidence related to this problem is reviewed herein including epidemiologic studies and findings related to acute cardiac risk in asymptomatic middle-aged male runners during races. Method: Literature review related to the above. Findings: The risks of cardiac arrest and sudden death were 1 in 57,002 and 1 in 171,005 respectively in runners with a mean age of 49.7 years among 1,710,052 participants in marathons in the United States since 1980. Atherosclerotic heart disease was the cause of death in over 90% of cases in two retrospective studies and a greater than two-fold increase in cardiac arrests was observed in middle-aged men in the latter half of a 10-year prospective registry beginning in the year 2000. Asymptomatic middle-aged male runners showed elevated biomarkers of inflammation such as interleukin-6, C-reactive protein together with procoagulant effects including in vivo platelet activation, indicating susceptibility to atherothrombosis. Conclusions: Antithrombotic prophylaxis is evidence-based by validated clinical paradigms to prevent cardiac arrest and sudden death in susceptibile marathon runners at high risk for atherothrombosis during races.

Rectal ulcers and massive bleeding after hemorrhoidal band ligation while on aspirin

Endoscopic hemorrhoidal band ligation is a well-established nonoperative method for treatment of bleeding internal hemorrhoids(grade 1 to 3). It is a safe and effective technique with a high success rate. Complications with this procedure are uncommon. Although rectal ulceration due to band ligation is a rare complication, it can cause life-threatening hemorrhage especially when patients are on medications which impair hemostasis like aspirin or non steroidal antiinflammatory drugs. We present 2 cases of massive lower gastro-intestinal bleeding in patients who had a band ligation procedure performed 2 wk prior to the presentation and were on aspirin at home. Both the patients were hemodynamically unstable requiring resuscitation. They required platelet and blood transfusions and were found to have rectal ulcers on colonoscopy done subsequently. The rectal ulcers corresponded to the site of band ligation. The use of aspirin by these patients would have caused defects in the hemostasis and may have predisposed them to massive bleeding in the presence of rectal ulcers occurring after the band ligation procedure. Managing aspirin before and after the ligation may be difficult especially since adequate guidelines are unavailable. Stopping aspirin in all the cases might not be safe and the decision should be individualized.

Aspirin cures erythromelalgia and cerebrovascular disturbances in JAK2-thrombocythemia through plateletcycloxygenase inhibition

Hypersensitive(sticky) platelets in JAK2-mutated essential thrombocythemia(ET) and polycythemia vera(PV) with thrombocythemia spontaneously activate at high shear in arterioles, secrete their inflammatory prostaglandin endoperoxides and induce plateletmediated arteriolar fibromuscular intimal proliferation. Constitutively activated JAK2 mutated hypersensitive(sticky) platelets spontaneously aggregate at high shear in the endarteriolar circulation as the cause of aspirin responsive erythromelalgia and platelet arterial thrombophilia in JAK2-mutated thrombocythemia patients. Increased production of prostglandin endoperoxides E2 and thromboxane A2 released by activated sticky platelets in arterioles account for redness warmth and swelling of erythromelalgia and platelet derived growth factor can readily explain the arteriolar fibromuscular intimal proliferation. Von Willebrand factor(VWF) platelet rich occlusive thrombi in arterioles are the underlying pathobiology of erythromelalgic acrocyanosis, migraine-like transient cerebral attacks(MIAs), acute coronary syndromes and abdominal microvscular ischemic events. Irreversible platelet cyco-oxygenase inhibition by aspirin cures the erythromelalgia, MIAs and microvascular events, corrects shortened platelet survival to normal, and returns increased plasma levels of betaTG, platelet factor 4, thrombomoduline and urinary thromboxane B2 excretion to normal in symptomatic JAK2-thrombocythemia patients. In vivo activation of sticky platelets and VWF-platelet aggregates account for endothelial cell activation to secrete thrombomoduline and sVCAM followed by occlusion of arterioles by VWF-rich platelet thrombi in patients with erythromelalgic thrombotic thrombocythemia(ETT) in ET and PV patients. ETT is complicated by spontaneous hemorrhagic thrombocythemia(HT) or paradoxical ETT/HT due to acquired von Willebrand disease type 2A at platelet counts above 1000 × 10~9/L and disappears by cytoreduction of platelets to normal(< 400 × 10~9/L).