Aspirin-induced Changes Research Articles

Aspirin's effect on kinetic parameters of cells contributes to its role in reducing incidence of advanced colorectal adenomas, shown by a multiscale computational study.

Aspirin intake has been shown to lead to significant protection against colorectal cancer, for example with an up to twofold reduction in colorectal adenoma incidence rates at higher doses. The mechanisms contributing to protection are not yet fully understood. While aspirin is an anti-inflammatory drug and can thus influence the tumor microenvironment, in vitro and in vivo experiments have recently shown that aspirin can also have a direct effect on cellular kinetics and fitness. It reduces the rate of tumor cell division and increases the rate of cell death. The question arises whether such changes in cellular fitness are sufficient to significantly contribute to the epidemiologically observed protection. To investigate this, we constructed a class of mathematical models of in vivo evolution of advanced adenomas, parameterized it with available estimates, and calculated population level incidence. Fitting the predictions to age incidence data revealed that only a model that included colonic crypt competition can account for the observed age-incidence curve. This model was then used to predict modified incidence patterns if cellular kinetics were altered as a result of aspirin treatment. We found that changes in cellular fitness that were within the experimentally observed ranges could reduce advanced adenoma incidence by a sufficient amount to account for age incidence data in aspirin-treated patient cohorts. While the mechanisms that contribute to the protective effect of aspirin are likely complex and multi-factorial, our study demonstrates that direct aspirin-induced changes of tumor cell fitness can significantly contribute to epidemiologically observed reduced incidence patterns.

Hemodynamic modeling of long-term aspirin effects on blood oxygenated level dependent responses at 7 Tesla in patients at cardiovascular risk.

Aspirin is considered a potential confound for functional magnetic resonance imaging (fMRI) studies. This is because aspirin affects the synthesis of prostaglandin, a vasoactive mediator centrally involved in neurovascular coupling, a process underlying blood oxygenated level dependent (BOLD) responses. Aspirin-induced changes in BOLD signal are a potential confound for fMRI studies of at-risk individuals or patients (e.g. with cardiovascular conditions or stroke) who receive low-dose aspirin prophylactically and are compared to healthy controls without aspirin. To examine the severity of this potential confound, we combined high field (7 Tesla) MRI during a simple hand movement task with a biophysically informed hemodynamic model. We compared elderly individuals receiving aspirin for primary or secondary prophylactic purposes versus age-matched volunteers without aspirin medication, testing for putative differences in BOLD responses. Specifically, we fitted hemodynamic models to BOLD responses from 14 regions activated by the task and examined whether model parameter estimates were significantly altered by aspirin. While our analyses indicate that hemodynamics differed across regions, consistent with the known regional variability of BOLD responses, we neither found a significant main effect of aspirin (i.e., an average effect across brain regions) nor an expected drug×region interaction. While our sample size is not sufficiently large to rule out small-to-medium global effects of aspirin, we had adequate statistical power for detecting the expected interaction. Altogether, our analysis suggests that patients with cardiovascular risk receiving low-dose aspirin for primary or secondary prophylactic purposes do not show strongly altered BOLD signals when compared to healthy controls without aspirin.

Unique Effect of Aspirin Therapy on Biomarkers in Aspirin-exacerbated Respiratory Disease. A Prospective Trial.

Rationale: Daily high-dose aspirin therapy benefits many patients with aspirin-exacerbated respiratory disease but provides no benefit for aspirin-tolerant patients with asthma. Type 2 inflammation characterizes aspirin-exacerbated respiratory disease.Objectives: To determine whether high-dose aspirin therapy changes biomarkers of type 2 inflammation in aspirin-exacerbated respiratory disease.Methods: Forty-two subjects with aspirin-exacerbated respiratory disease underwent an aspirin desensitization and were placed on high-dose aspirin (1,300 mg daily). Fifteen aspirin-tolerant subjects with asthma were also placed on high-dose aspirin. Biologic specimens and clinical parameters were collected at baseline and after 8 weeks on aspirin. Urinary eicosanoids, plasma tryptase and cytokine levels, platelet-leukocyte aggregates, and granulocyte transcripts were assessed.Measurements and Main Results: Eight weeks of high-dose aspirin decreased nasal symptoms and urinary prostaglandin E metabolite (P < 0.05) and increased urinary leukotriene E4 (P < 0.01) levels in subjects with aspirin-exacerbated respiratory disease, but not in those with aspirin-tolerant asthma. Urinary prostaglandin D2 and thromboxane metabolites decreased in both groups. Only in subjects with aspirin-exacerbated respiratory disease, exhaled nitric oxide (P < 0.05), plasma tryptase (P < 0.01), and blood eosinophil (P < 0.01) and basophil (P < 0.01) counts increased and plasma tryptase correlated with eosinophil counts (Pearson r = 0.514; P < 0.01) on aspirin. After correction for eosinophil counts, aspirin-induced changes in blood granulocyte transcripts did not differ between groups. Aspirin had no effect on platelet-leukocyte aggregates, platelet activation markers, or plasma cytokines in either group.Conclusions: High-dose aspirin therapy for 8 weeks paradoxically increases markers of type 2 inflammation in subjects with aspirin-exacerbated respiratory disease, despite reducing nasal symptoms. This effect of aspirin is unique to aspirin-exacerbated respiratory disease and not observed in subjects with aspirin-tolerant asthma.

Aspirin restores ABT-737-mediated apoptosis in human renal carcinoma cells

Aspirin is a novel chemopreventive agent against malignancy. However, outcomes of aspirin monotherapy of renal cell carcinoma (RCC) are inconsistent across studies. ABT-737, an BH3 mimetic inhibitor, is also a promising antitumor drug. Cancer cells including those from RCC, that have high levels of Mcl-1, are refractory to ABT-737-induced apoptosis. We here investigated how aspirin treatment modulates the ABT-737-induced apoptosis. Using the in vitro model of human 786-O cells, we showed that aspirin had sensitized cells to ABT-737 induced apoptosis. Such aspirin-induced changes of ABT-737 resistance was accompanied by a host of biochemical events like protein phosphatase 2A (PP2A) activation, AKT dephosphorylation, Mcl-1/FLICE inhibiting protein (FLIP)/XIAP downregulation, and Bax mitochondrial redistribution. The PP2A inhibitor, okadaic acid, was able to reverse the apirin-induced apoptotic changes. Apart from the aspirin treatment, Mcl-1 silencing also rendered cells vulnerable to ABT-737 induced apoptosis. Since PP2A, Akt, and Mcl-1 play critical roles in RCC malignancy and treatment resistance, our present study showed that aspirin, an alternative adjuvant agent, had recalled ABT-737 sensitivity in the RCC cells through processes involving the PP2A/Akt/Mcl-1 axis.

Ascorbic Acid may Exacerbate Aspirin-Induced Increase in Intestinal Permeability.

Ascorbic acid in combination with aspirin has been used to prevent aspirin-induced oxidative GI damage. We aimed to determine whether ascorbic acid reduces or prevents aspirin-induced changes in intestinal permeability over a 6-hr period using saccharidic probes mannitol and lactulose. The effects of administration of 600mg aspirin alone, 500mg ascorbic acid alone and simultaneous dosage of both agents were compared in a cross-over study in 28 healthy female volunteers. These effects were also compared with that of a placebo. The ability of ascorbic acid to mitigate the effects of aspirin when administered either half an hour before or after dosage with aspirin was also assessed in 19 healthy female volunteers. The excretion of lactulose over the 6-hr period was augmented after consumption of either aspirin or ascorbic acid compared with that after consumption of placebo. Dosage with ascorbic acid alone augmented the excretion of lactulose more than did aspirin alone. Simultaneous dosage with both agents augmented the excretion of lactulose in an additive manner. The timing of dosage with ascorbic acid in relation to that with aspirin had no significant effect on the excretion of the two sugars. These findings indicate that ascorbic acid does not prevent aspirin-induced increase in gut permeability rather that both agents augment it to a similar extent. The additive effect on simultaneous dosage with both agents in augmenting the absorption of lactulose suggests that each influences paracellular permeability by different pathways.

Differences in platelet microRNA profiles after aspirin use are associated with differences in whole blood aggregation and might identify aspirin resistance

Background: MicroRNAs have been established as markers for cardiovascular disease in many studies. However, most of the patients included in these studies were treated with aspirin for secondary prevention reasons. It is known, that there are individual differences in the response of platelets to aspirin. Whether the response of platelets to aspirin shows differences in miRNA expression is not know. We therefore, studied the influence of aspirin on microRNA expression levels, in isolated platelets of healthy volunteers. Additionally we analyzed, whether the in vitro response of platelets to indometacine, a surrogate for aspirin, in ADP-mediated whole blood aggregation was related to differences in miRNA profiles. Methods and results: We measured relative expression levels of platelet microRNAs using microarrays before and after two weeks of aspirin use (100 mg, once daily) in 15 healthy individuals (age 45-65 years). Based on aspirin-induced changes in microRNA profile, two subgroups could be distinguished: a group of individuals (n=9) with similar and a group with different (n=6) miRNA profiles before and after aspirin use. Additionally, we performed in vitro whole blood aggregation studies to determine whether the observed difference in microRNA profile before and after aspirin use, could be linked to platelet function. Whole blood from the same individuals, in the absence of aspirin, was tested using Multiplate® aggregometry and was incubated with indometacine to mimic aspirin use. The subjects with a similar microRNA profile had significantly reduced ADP-mediated aggregation as compared to the group in which the microRNA profile was different before and after medication. Conclusion: Differences in platelet microRNA profiles after aspirin use are related to differences in ADP-mediated indometacine-treated whole blood aggregation. This could imply that differences in miRNA profiles might identify individuals with aspirin resistance.

LC–MS/MS for the simultaneous analysis of arachidonic acid and 32 related metabolites in human plasma: Basal plasma concentrations and aspirin-induced changes of eicosanoids

Eicosanoids play an important role in various biological responses and can be used as biomarkers for specific diseases. Therefore, we developed a highly selective, sensitive, and robust liquid chromatography–tandem mass spectrometric method to measure arachidonic acid and its 32 metabolites in human plasma. Sample preparation involved solid phase extraction, which efficiently removed sources of interference present in human plasma. Chromatographic separation was performed using a Luna C8-column with 0.5mM ammonium formate buffer and acetonitrile as the mobile phase under gradient conditions. Detection was performed using tandem mass spectrometry equipped with an electrospray ionization interface in negative ion mode. The matrix did not affect the reproducibility and reliability of the assay. All analytes showed good linearity over the investigated concentration range (r>0.997). The validated lower limit of quantitation for the analytes ranged from 10 to 400pg/mL. Intra- and inter-day precision (RDS%) over the concentration ranges for all eicosanoids were within 16.8%, and accuracy ranged between 88.1 and 108.2%. This assay was suitable for the determination of basal plasma levels of eicosanoids and the evaluation of effect of aspirin on eicosanoid plasma levels in healthy subjects.

Effect of lapachol, a naphthaquinone isolated from Tectona grandis, on experimental peptic ulcer and gastric secretion

Lapachol, a naphthaquinone isolated from the roots of Tectona grandis given at a dose of 5 mg kg-1 p.o. twice daily for 3 days was found to have an anti-ulcerogenic effect on subsequently induced experimental gastric and duodenal ulcers in rats and guinea-pigs. Its action appears to be associated with an effect on the protein content of gastric juice, and it reversed aspirin-induced changes in peptic activity, protein and sialic acid.

Obesity in aspirin‐tolerant and aspirin‐intolerant asthmatics

Obesity is an important factor in the development of asthma. Aspirin hypersensitivity affects 5-10% of asthmatics. The association between obesity and aspirin hypersensitivity in asthma is unclear. This study evaluated the association of BMI and asthma in patients with aspirin-tolerant asthma (ATA) and aspirin-intolerant asthma (AIA). Aspirin provocation tests were performed in 667 asthmatic patients and changes in FEV(1) were used to categorize patients as ATA or AIA. The BMI of asthmatics was graded using the percentile BMI of 406 normal controls. Aspirin-induced changes in FEV(1)% ranged from 15% to 68%. Compared with the controls, the ATA group had a higher BMI (24.5 +/- 0.1 vs 23.8 +/- 0.2 kg/m(2), P = 0.001). The AIA group had a lower BMI. The aspirin-induced percentage fall in FEV(1) was inversely correlated with BMI in asthmatic patients (r = -0.094, P = 0.016). BMI was correlated with age and PC20, but not with FEV(1) in asthmatic patients. In a logistic regression adjusted for age, gender, and smoking status, FEV(1) and PC20 were associated with AIA with odds ratios of 0.986 and 0.586, respectively. BMI was associated with AIA with an odds ratio of 0.916. Aspirin intolerance in asthmatics explains the lesser association with obesity. Obesity is not a risk factor in the development of asthma in patients with AIA.

Thromboelastography as a measure of coagulation in high risk pregnant patients receiving low dose aspirin

SummaryLow dose aspirin is being used with increasing frequency in certain high risk pregnancies, potentially increasing the risk of haemorrhage. The thromboelas-tograph and bleeding time were performed before and 4 weeks after daily low dose aspirin (75 mg) in 11 high risk pregnant patients. Measured thromboelastograph parameters were unaltered after aspirin although bleeding time was prolonged. Although the thromboelastograph appeared not to detect aspirin-induced changes in platelet function, it measures all phases of coagulation and the unaltered values suggest a functioning coagulation system.

THROMBELASTOGRAPHY AFTER ASPIRIN INGESTION IN PREGNANT AND NON-PREGNANT SUBJECTS

The thrombelastograph (TEG) and bleeding time were performed before and 6 h after a single oral dose of aspirin 600 mg in a group of eight healthy volunteers and 12 pregnant patients. Measured TEG variables (r, k, r+k times and maximum amplitude) were unaltered after aspirin although there was a significant prolongation of the bleeding time in both groups. Although the TEG appeared not to detect aspirin-induced changes in platelet function, the TEG measures all phases of coagulation and the unaltered TEG after aspirin suggested a functioning coagulation system.

Aspirin-induced changes in gastric function: Role of endogenous prostaglandins and mucosal damage

The relative roles of prostaglandins and mucosal injury in aspirin-induced changes in gastric function were evaluated. Conscious rhesus monkeys received a subcutaneous injection of sodium bicarbonate or aspirin (25, 50, 100, or 150 mg/kg) and sodium bicarbonate or 150 mg/kg aspirin subcutaneously plus oral sucralfate (25 mg/kg twice a day). Gastric emptying and fluid and H+ outputs were determined during a fasting period and after an 80-ml water load using a 99mTc-diethyIenetriaminepentaacetic acid dilution technique. At the end of each study, the monkeys were gastroscoped to assess mucosal damage, which was ranked blindly on a scale of 0 to 5. Biopsy samples were taken from antrum and fundus for determination of prostaglandins and histological evaluation. All doses of aspirin significantly suppressed prostaglandins in both the antrum and fundus. In contrast, the aspirin-induced increase in gastric mucosal injury was dose dependent. Aspirin also produced a dose-dependent decrease in gastric emptying that was significantly correlated with erosions scores. When aspirin-induced lesions were prevented by sucralfate, the inhibition of gastric emptying was blocked during the fasting period and was attenuated following the water load. Acid secretion was also decreased significantly by aspirin. This action was not modified by sucralfate protection, suggesting that aspirin has a direct inhibitory effect on parietal cell secretion. These data show that mucosal damage contributes significantly to the aspirin-induced changes in gastric function. Moreover, prostaglandins may play a role in the control of gastric emptying, especially during early phase of the response to a water load.

The Antigastrolesive Activity of Rioprostil, a 16-Methyl Prostaglandin-E! Analogue in Healthy Volunteers

The antigastrolesive activity of rioprostil, an orally effective synthetic 16-methyl analogue of prostaglandin-E1, with potent antisecretory and antigastrolesive properties in animals, is evaluated in a series of studies involving 166 healthy male volunteers. Three double-blind, randomized, parallel, placebo-controlled studies are conducted independently at three study centres. In two studies the protective effect of rioprostil against endoscopically-demonstrated mucosal changes caused by concurrent administration of aspirin is examined. The third study evaluates the inhibitory effect of rioprostil on faecal blood loss produced by co-administration of aspirin. Oral doses of rioprostil give significant dose-dependent protection against aspirin-induced mucosal changes. The total mucosal scores at day 3 and day 11 are significantly lower in each of the rioprostil + aspirin groups compared with the aspirin treated group. The total mucosal scores generally decrease with increasing rioprostil dose. Daily faecal blood loss is significantly lower in each of the groups of subjects treated with rioprostil + aspirin, compared with those treated with aspirin + placebo. This study shows that rioprostil provides significant protection against mucosal damage caused by high doses of concomitantly administered aspirin.

Does aspirin damage canine gastric mucosa by reducing its surface hydrophobicity?

Intraluminally administered aspirin disrupts the gastric mucosal barrier in a pH-dependent manner and may do so by compromising the hydrophobic or nonwettable lining to the stomach. We examined the pH dependence and time-course of aspirin's effects on barrier integrity by measuring the aspirin-induced changes in surface wettability, potential difference (PD), and electrical resistance (R) of canine gastric mucosa mounted in Ussing chambers. Luminal surface hydrophobicity, as determined by contact angle (CA) measurements, and PD were reduced by acidic aspirin solutions but were not reduced by acidic solutions without aspirin (pH 2.6) or by aspirin solutions that were neutral or only mildly acidic (pH greater than 4.0). Significant reductions in CA were correlated well with the proportion of aspirin in its lipid-soluble undissociated form (r = 0.93, P less than 0.001). Acidified-aspirin solutions significantly reduced CA and PD after a 2.5-min incubation period. Significant reductions in R occurred 25 min after exposure to acidified aspirin. Morphological damage to the gastric epithelium was not apparent after a 5-min exposure to acidified aspirin but was conspicuous 30 min after aspirin treatment. Aspirin-induced reductions in CA were highly associated with decreases in mucosal PD in both the pH and time-dependent studies (r = 0.93 and r = 0.99, respectively, P less than 0.001). These data support the hypothesis that the undissociated form of aspirin compromises the protective nonwettable lining of the stomach and in doing so, disrupts the gastric mucosal barrier.

Influence of clonidine and a new related imidazoline derivative (tizanidine) on rat gastric mucosa.

The effects of a novel imidazoline derivative (tizanidine) on experimental ulcers and glycoproteins in the gastric mucosa and juice of rats were examined and compared with that of clonidine. Tizanidine and clonidine inhibited indomethacin ulcer and aspirin ulcers. Tizanidine, however, did not influence stress ulcer while clonidine showed an inhibitory effect. Although tizanidine and clonidine did not increase glycoproteins in the gastric mucosa, they prevented aspirin-induced changes of glycoproteins in the gastric mucosa and juice, as well as aspirin-induced gastric ulcers. The results suggest that, as with clonidine, tizanidine inhibits drug-induced gastric ulcers and that tizanidine-mediated gastric mucosal protection may prevent gastric ulcers induced by anti-inflammatory agents.

Effects of intracerebroventricular bombesin on gastric ulcers and gastric glycoproteins in rats.

Effects of intracerebroventricular injection of bombesin on gastric mucosal glycoproteins and acid secretion were studied to clarify its action mechanism for experimental ulcers in rats. Bombesin (10 micrograms) prevented stress ulcers and indomethacin ulcers. Aspirin (300 mg/kg p.o.) reduced the high molecular weight glycoproteins extracted from the gastric mucosa, and increased the degraded glycoproteins extracted from gastric juice in pylorus-ligated rats. Bombesin inhibited the aspirin-induced changes of the glycoproteins. Bombesin also inhibited basal gastric acid secretion. These results support the hypothesis that bombesin may affect the central nervous system's control of both gastric defensive and aggressive factors, which contributes to its antiulcerogenic action.

Aspirin-induced hearing loss as a model of sensorineural hearing loss

Performance in forward-masking, temporal-integration, and gap-detection tasks was measured in five normal-hearing subjects before and during a five-day period of aspirin use. The drug regimen was 3.9 g per day, taken in four equal doses at 6-h intervals. In the subjects showing substantial temporary hearing loss induced by the aspirin, (1) forward masking declined at about a normal rate as the masker-to-signal interval was increased, (2) the temporal-integration functions were flatter than normal, and (3) detection of a temporal gap was worse than normal at low sound-pressure levels (SPLs) but was essentially normal at levels above about 60 dB SPL. These aspirin-induced changes in performance are similar to the differences observed between normal listeners and listeners with mild sensorineural hearing loss. Thus, temporary, aspirin-induced hearing loss offers promise as a model condition for sensorineural hearing loss. The advantages offered by this model include all those typically attributed to within-subjects experimental designs, as well as the ability to manipulate the amount of hearing loss. Its primary disadvantages are that the hearing loss is not asymmetrically distributed toward the high-frequency region, as it typically is with sensorineural deafness, and there are large individual differences in the amount of temporary hearing loss induced by fixed doses of aspirin.

Effect of geranylgeranylacetone on aspirin-induced changes in gastric glycoproteins.

The effects of aspirin and treatment with geranylgeranylacetone (GGA), an antiulcer drug, on the content of gastric glycoproteins were investigated in pylorus-ligated rats. In normal rats, the amount of gastric glycoproteins in the mucous layer was about 1.5 times higher than that in the gastric mucosa, indicating that the glycoproteins were distributed in the mucous layer as a highly concentrated state. Aspirin (100 mg/kg, p.o.) decreased the content of gastric glycoproteins both in the mucous layer and in the gastric mucosa. The amount of the macromolecular fraction in the gastric juice, which corresponded to the gastric glycoproteins on the basis of molecular size, was not affected by aspirin. GGA (300 mg/kg, i.d.) could prevent the decreases of the total amount of gastric glycoproteins in the mucous layer plus gastric mucosa. These results indicated that the glycoproteins coating the surface of the gastric mucosa may play a role as a defensive mechanism and that GGA exerted an antiulcer effect on aspirin-induced mucosal damage through preventing the decreases in gastric glycoproteins.

Aspirin-induced depression of glomerular filtration rate in normal humans: role of sodium balance.

The renal clearance of endogenous creatinine, inulin and para-aminohippurate was measured in 10 healthy human volunteers taking aspirin during severe dietary sodium restriction (10 meq/d) to clarify the clinical significance and pathophysiology of aspirin-induced changes in renal function. Sodium restriction alone had no effect on renal clearances but did increase plasma renin activity and urinary prostaglandin E excretion. The addition of aspirin decreased the urinary clearance of prostaglandin E but not plasma renin activity, and caused a significant fall in both endogenous creatinine (from 92.3 +/- 4.1 SE ml/min . 1.73 m2 body surface area to 80.8 +/- 4.4 mL/min . 1.73 m2, p = 0.02) and inulin (from 95.3 +/- 7.0 mL/min . 1.73 m2 to 80.9 +/- 7.0 mL/min . 1.73 m2, p less than 0.001). The fall in inulin clearance was directly related to the salicylate level. The clearance of para-aminohippurate showed only a slight, statistically insignificant decline with aspirin. The results of this study suggest that aspirin-induced depression of glomerular filtration rate may be independent of total renal plasma flow. Aspirin should be used cautiously, with careful attention to dosage, in sodium-restricted patients whose glomerular filtration rate may, in part, be under the homeostatic control of renal prostaglandins.