Effect Of High-dose Aspirin Research Articles

Abstract 1133: Risk effect of primary prevention strategy with aspirin on lung cancer incidence depends on high-level use, bodyweight and age: A U.S. adults evidence

Abstract Chemoprevention of cancer with aspirin is of particular interest as a primary prevention strategy, which was still in controversial. Using 101,462 individual participants' data from a U.S. adult's cohort, Cox regression model was used to detect the aspirin dosage effect on lung cancer risk. We calculated the effects of irregular use, low-dose use, and high-dose use of aspirin on lung cancer risk in population stratified by bodyweight and age. High-dose use of aspirin raised up 28% risk of lung cancer compared to no use (HR = 1.28, 95%CI = [1.14-1.45], P = 3.37×10-5). Meanwhile, the risk effect of high-dose aspirin significantly decreased with bodyweight increasing, indicating an antagonistic interaction (HRinteraction = 0.96, 95%CI = [0.94-0.99], P = 1.26×10-2). Furthermore, for these participants prone to lung cancer with bodyweight less than 80 kg, high-dose aspirin usage showed an elevated risk if their age less than 76 (HRage≤76 = 1.47, 95%CI = [1.25-1.73], P = 3.81×10-6), but did not exhibit risk effect in elders (HRage>76 = 1.13, 95%CI = [0.46-2.69], P = 0.80). The three-way interaction among dose of aspirin, bodyweight and age indicated that these vulnerable people (age ≤76 years and bodyweight <80 kg) with high lung cancer risk should be cautious to use high-dose aspirin for lung cancer chemoprevention. Citation Format: Xuesi Dong. Risk effect of primary prevention strategy with aspirin on lung cancer incidence depends on high-level use, bodyweight and age: A U.S. adults evidence [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1133.

Aspirin may inhibit angiogenesis and induce autophagy by inhibiting mTOR signaling pathway in murine hepatocarcinoma and sarcoma models.

Aspirin is known to have inhibitory effects on growth development in various types of tumor. In previous studies, it was observed to inhibit angiogenesis by downregulating the expression of vascular endothelial growth factor-A (VEGF-A). In the present study, murine H22 hepatocarcinoma and S180 sarcoma models were used to ascertain whether aspirin could inhibit angiogenesis and promote autophagy in tumors. Tumor-bearing mice were randomly divided into four groups with 10 mice per group: i) no treatment; ii) low-dose aspirin (100 mg/kg); iii) high-dose aspirin (400 mg/kg); iv) everolimus group (4 mg/kg). The effects of high-dose aspirin were validated through preliminary experiments. The drug treatment was administered every day for 14 days. The tumor size was measured every other day and then the tumor growth curve was plotted, and the tumor inhibitory rates were calculated. The expression levels of phosphorylated mammalian target of rapamycin (p-mTOR), hypoxia-inducible factor-1α (HIF-1α), VEGF-A, UNC-51-like kinase-1 (ULK1) and microtubule-associated protein 1 light chain 3A (LC3A) were detected by immunohistochemistry and western blot analysis, respectively. We observed that tumor growth delay was achieved in both H22 hepatocarcinoma and S180 sarcoma models following treatment with aspirin. The tumor growth inhibition rates induced by low and high-dose aspirin and everolimus were 19.6, 33.6 and 53.7% (P<0.05) in H22 hepatocarcinoma, and 25.7, 40.6 and 48.7% (P<0.05) in S180 sarcoma. The immunohistochemistry and western blot analysis data from the models revealed that the expression of p-mTOR, HIF-1α and VEGF-A was decreased, while the expression of ULK1 and LC3A was increased following treatment with aspirin and everolimus. The changes were more apparent in the high-dose aspirin and everolimus groups (P<0.01). The inhibitory action of aspirin and everolimus on tumor angiogenesis may be through inhibiting the expression of p-mTOR, HIF-1α and VEGF-A. Alternatively, aspirin may induce autophagy by inhibiting the mTOR signaling target and then increasing ULK1 and LC3A.

ROLE OF HIGH DOSE ASPIRIN IN MODULATING HYPERLIPIDEMIA AND HYPERGLYCEMIA

This study was designed to evaluate the antidiabetic and antihyperlipidemic effects of high dose aspirin in rabbits. Healthy rabbits were made diabetic by injecting 150mg/kg body weight of Alloxan, in normal saline solution. intravenously in the marginal ear vein for seven days. The rabbits with serum glucose levels greater than 200mg/dl were considered as diabetic and used in this study. High dose aspirin (120mg/kg) p.o. showed maximum decrease in serum triglyceride level (42.07%), serum total cholesterol level (19.36%), and serum LDL level (6.18%). Glibenclamide showed decrease in fasting blood glucose level 56.31% as compared to high dose aspirin (23.91%). In the light of these results, it is suggested that such study should be carried out in human beings to make use of agents having S inhibitory activity of kappa Kinase Beta (IKKs) pathway, which will provide a novel approach for treatment of diabetes- associated hyperlipidaemia.

Effect of High-Dose Aspirin on Helicobacter pylori Eradication

We conducted a pilot study aimed at comparing the efficacy of the standard OAC (omeprazole-amoxicillin-clarithromycin) regimen with a combination of the OAC regimen and aspirin (OACA). Follow-up endoscopic findings showed that the previous ulcers were completely healed in all subjects. The eradication rates (per protocol) were 80.3% (49/61) in the OAC group and 86.7% (52/60) in the OACA group. The eradication rate was not significantly different between the two groups. The most common adverse event was a bad taste, and the overall adverse events were similar in the two groups. The combination of the OAC regimen and aspirin was not significantly superior to the standard OAC regimen, but it was well tolerated in a group of patients with peptic ulcer disease. Its potential for clinical use to augment the efficacy of H. pylori eradication may warrant further investigation.

Aspirin reduces experimental cerebral blood flow in vivo

Aspirin therapy for stroke prophylaxis in low risk patients has paradoxically demonstrated an increased risk of ischemic stroke in several studies. Moreover, the MAST-ltaly trial reported a near doubling of mortality with the addition of aspirin to thrombolytics while experimentally, we have noted that aspirin antagonizes t-PA-mediated clot lysis. The mechanisms responsible for these observations is unclear. Of interest, few studies have examined the effect of aspirin on cerebral blood flow (CBF). The objective of this study was to examine the acute effect of high dose aspirin on CBF in a rabbit model. Mean arterial pressure, arterial blood gases, and core and brain temperature were controlled throughout the protocol. CBF, measured by the technique of hydrogen clearance using Platinum-lridium flow probes, was measured before and 20 min following aspirin administration (20 mg kg-1 i.v.) in a cohort of 50 rabbits and compared to rabbits receiving vehicle (n=79j. Following aspirin therapy, CBF (cc/100 g^1 min^1) was reduced from 80.8±27.4 to 65.1 ±31.7 (mean±SD), a reduction to 80.4± 21.3% of baseline (p < 0.00001, t-test), whereas CBF in the control group remained unchanged (81.0±25.4 vs. 77.5±24.0, mean±SD). Thus aspirin acutely reduced CBF by approximately 20% in a rabbit model, perhaps related to inhibitory effects on prostacyclin and/or nitric oxide. This result may help explain the possible increase in ischemic stroke seen in low risk patients on aspirin therapy. A reduction in CBF by aspirin may also assist in understanding the antagonism of t-PA-mediated clot lysis by aspirin seen in our rabbit model of thromboembolic stroke, particularly since all agents which share the ability to reverse this antagonism (nitric oxide donors, beta blockers, hydralazine, prostacyclin) also increase CBF by approximately 20%. Future strategies for ‘antiplatelet’ therapy may benefit from using agents which do not adversely affect CBF. [Neurol Res 1999;: 488-490]

Bleeding times and the antithrombotic effects of high-dose aspirin, hirudin and heparins in the rat.

Bleeding can occur unexpectedly during antithrombotic therapy. Impaired haemostasis is commonly measured by the bleeding time. We measured it by 3 methods in controls and in anticoagulated animals and related it to their antithrombotic status. In 42 control rats template, tail-tip transection and needle occlusion bleeding times correlated poorly (r = 0.05-0.34). The template method had the best range (mean 126.97 +/- SEM secs) and consistency. In 10 control animals it correlated mildly (r = 0.55) with venous thrombus in the same animal. Thrombus was measured by its weight deposited on platinum wires (2 cm long, 0.4 mm diameter) set in vein and in artery for 1 h. In respective groups of 10 rats, a decrease of mean thrombogenesis was obtained using aspirin, heparin and low molecular weight heparin in 2 dosages and hirudin in 1 dosage. The drugs reduced mean venous thrombus by 13-86 per cent of the mean control thrombus, and prolonged the mean template bleeding time by 29-199 per cent. The ranking of the drugs according to their increase of template bleeding time was virtually the same as the ranking given by their reduction of thrombus weight (Spearman rank coefficient 0.81, sig 0.007). The transection test produced a similar ranking and similar correlation with thrombus (0.71, sig 0.049). Low molecular weight heparin induced the greatest thrombus reduction (39 per cent) for least prolongation of bleeding time (24 per cent). Arterial thrombus was more variable. The bleeding times and thrombus weight were measured in each animal of 2 groups given aspirin, the template method correlating mildly with venous thrombus reduction (r = 0.23, 0.58 respectively), the transection method with arterial (0.74, 0.45) and the occlusion test poorly with either (0.13, 0.22). Bleeding time lengthens with increasing antithrombotic effect of drugs, but not in direct proportion, nor similarly with each drug.

Adverse effects of high dose aspirin on platelet adhesion to experimental autogenous vein grafts

Prostacyclin (PGI2) production and platelet adhesion were studied in veins grafted into the arterial system of rabbits. Animal groups consisted of: no treatment; low dose aspirin (ASA) (0.5 mg . kg-1 X 24 h-1) plus dipyridamole (2 mg . kg-1 X 6 h-1); high dose ASA (40 mg . kg-1 X 24 h-1) plus dipyridamole (2 mg . kg-1 X 6 h-1); dipyridamole (2 mg . kg-1 X 6 h-1) alone. Results showed that vein grafts from animals treated with high dose ASA plus dipyridamole produced significantly less PGI2 than the other three groups (p less than 0.05 compared with the dipyridamole group; p less than 0.01 compared with the other two groups). In addition, there was significantly greater platelet deposition on the vein grafts from this high dose ASA group as compared to the low dose ASA group (p less than 0.05). By contrast, animals treated with dipyridamole alone had significantly less platelet deposition compared to both the control and high dose ASA groups (p less than 0.05). High dose ASA given to prevent thrombotic occlusion following coronary artery bypass grafting may, by reducing PGI2, result in enhanced platelet deposition. This in turn is likely to increase intimal hyperplasia as has been demonstrated previously with high dose ASA. Clinical studies, which have shown the early anti-thrombotic benefits of high dose ASA plus dipyridamole, have not measured graft intimal thickness. Since this process is an important cause of graft narrowing, ASA, in high dose, may adversely affect long-term graft survival.

Effect of high dose aspirin on coronary hemodynamics during pacing-induced myocardial ischemia

The effects of aspirin on coronary hemodynamics and transcardiac concentrations of thromboxane B2 (the stable metabolite of thromboxane A2) were determined at rest and during pacing-induced myocardial ischemia in 11 patients with coronary disease. Control coronary sinus pacing increased both arterial thromboxane B2 (331 +/- 70 to 623 +/- 132 pg/ml, p less than 0.02) and coronary sinus thromboxane B2 (184 +/- 3 to 403 +/- 156 pg/ml, p less than 0.05), but positive transmyocardial gradients developed in only three patients. After 650 mg of oral aspirin, more than 90% inhibition of in vitro thromboxane B2 production was demonstrated and circulating thromboxane B2 was undetectable at rest and during pacing in all patients. Despite these changes in thromboxane B2 concentrations, coronary blood flow was unchanged by aspirin at rest (107 +/- 14 versus 112 +/- 13 ml/min, p = NS) and during pacing (189 +/- 29 versus 181 +/- 25 ml/min, p = NS). Myocardial lactate extraction was also unchanged at rest (24 +/- 7 versus 19 +/- 5%, p = NS) and during pacing (5 +/- 6 versus 9 +/- 5%, p = NS). No change occurred in the anginal threshold. Thus, aspirin does not have the vasoconstrictive properties that have been reported with another cyclo-oxygenase inhibitor, indomethacin. These findings also suggest that thromboxane A2 production does not play a major role in the pathogenesis of stress-induced ischemia. Nonetheless, intracoronary thromboxane A2 production in some patients may potentiate platelet activation and coronary thrombosis. Such patients may benefit from long-term aspirin therapy and can be treated with aspirin without risk of adverse coronary hemodynamic effects.

Aspirin inhibits platelet function independent of the acetylation of ciclo-oxygenase

Aspirin inhibits platelet function and prevents thrombosis in some clinical situations. This antithrombotic effect is attributed to the irreversible inhibition of platelet thromboxane A 2 synthesis, an effect which is achieved by a low dose of aspirin. There is some evidence that higher doses of aspirin may have additional antithrombotic effects. To test this possibilitv, we measured the effect of high and low dose aspirin on hemostasis in vivo and platelet function ex vivo in the rabbit. Both carotid arteries were isolated. One was replaced with a 2 cm piece of polyethylene tubing and the other was left intact. The prosthetic and intact vessels were then punctured with a needle and the time take for bleeding from each to cease was measured. Aspirin (3 and 100mg/kg given 1 or 20 hours beforehand) had no effect on the bleeding from the intact vessel, but prolonged the bleeding time in the prosthetic vessel in a dose-related manner. Washed platelets obtained from the 100 mg/kg-treated rabbits were less responsive to collagen and thrombin than platelets obtained from the 3mg/kg-treated rabbits which in turn, were less responsive than control platelets. This additional effect of aspirin on platelet function was not due to the further inhibition of platelet thromboxane A 2 release nor to further inhibition of the platelet release phenomenon. It is suggested that the enhanced effect of high dose aspirin on haemostasis from the arterial prosthesis is related to the second platelet inhibiting effect of aspirin.

Thrombogenic Effect of High-Dose Aspirin in Rabbits

Aspirin is a promising antithrombogenic agent. It inhibits the generation of thromboxane A(2) by acetylating platelet cyclo-oxygenase. Aspirin also inhibits vessel wall production of PGI(2) which is an inhibitor of platelet aggregation, and therefore is potentially thrombotic. To investigate these two opposing effects we studied the effects of aspirin upon fibrin accretion onto experimentally induced venous thrombi in rabbits and on the PGI(2)-like activity of vessel wall using the thrombin-induced [(14)C]serotonin release assay. A 200-mg/kg dose of aspirin significantly augmented thrombus size when compared to (a) sodium salicylate administered in equal doses, (b) aspirin in a 10-mg/kg dose or (c) controls (P < 0.001). A 200-mg/kg dose of aspirin totally inhibited vessel wall PGI(2)-like activity whereas aspirin in a 10-mg/kg dose produced less inhibition, and 200 mg/kg sodium salicylate had no effect. Local instillation of tranylcypromine, an inhibitor of PGI(2) formation, also significantly augmented thrombus size compared to saline-treated controls and totally inhibited the production of PGI(2)-like activity. The thrombogenic effect of high dose aspirin was lost if an interval of 2.5 h or longer elapsed between vessel damage and drug administration, indicating that in contrast to the platelet, the effect of aspirin on vessel wall prostaglandin synthesis is relatively short-lived. It is concluded that aspirin, in doses higher than those used clinically, can augment experimental thrombosis, presumably by inhibiting the synthesis of vessel wall PGI(2).