Another Perk of Painkillers? Decreased Hormone Levels May Reduce Cancer Risk

Science Daily (Mar. 23, 2010) — Postmenopausal women who regularly use aspirin and other analgesics (known as painkillers) have lower estrogen levels, which could contribute to a decreased risk of breast or ovarian cancer.

“We observed some significant inverse associations between concentrations of several estrogens and the use of aspirin, aspirin plus non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), and all analgesics combined,” said Margaret A. Gates, Sc.D., research fellow at the Channing Laboratory at Brigham and Women’s Hospital and Harvard Medical School.

“Our results suggest that among postmenopausal women, regular users of aspirin and other analgesics may have lower estrogen levels than non-users,” Gates added.

These study results are published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Gates and colleagues examined the association between use of aspirin, NSAIDs and acetaminophen and concentrations of estrogens and androgens among 740 postmenopausal women who participated in the Nurses’ Health Study.

Frequency of all analgesic use was inversely associated with estradiol, free estradiol, estrone sulfate and the ratio of estradiol to testosterone.

Average estradiol levels were 10.5 percent lower among women who regularly used aspirin or non-aspirin NSAIDs. Similarly, free estradiol levels were 10.6 percent lower and estrone sulfate levels were 11.1 percent lower among regular users of aspirin or other NSAIDs. Among regular users of any analgesic (aspirin, NSAIDs or acetaminophen), levels of these hormones were 15.2 percent, 12.9 percent and 12.6 percent lower, respectively, according to Gates.

Michael J. Thun, M.D., M.S., vice president emeritus of epidemiology and surveillance research at the American Cancer Society, said the question of whether regular use of aspirin and other NSAIDs is causally related to reduced breast cancer risk is important, but still unresolved.

Thun believes these study results do not confirm whether aspirin-like drugs caused the reduction in circulating estradiol. However, the results do provide evidence that aspirin and other NSAIDs might reduce circulating levels of estradiol by about 10 percent, according to Thun, who is an editorial board member of Cancer Epidemiology, Biomarkers & Prevention, and was not associated with this study.

“Hopefully these findings will motivate a trial to determine whether the association between aspirin use and hormone levels is causal,” he said. “Until then, we have a possible mechanism for a potentially important, but as yet unproven chemopreventive benefit.”

Gates agreed and said that additional research, like a randomized trial of NSAID use and hormone levels, is needed to confirm these results and to determine whether the decrease in hormone levels translates to a reduced risk of breast or ovarian cancer. If an inverse association between analgesic use and risk of breast or ovarian cancer is confirmed, then this research may have important public health implications.

“Although the overall risks and benefits would need to be weighed, analgesics could be implemented as a chemopreventive and may decrease the risk of several cancers,” she said.

American Association for Cancer Research (2010, March 23). Another perk of painkillers?

Aspirin reduces IL-6 plasma levels:

http://www.ncbi.nlm.nih.gov/pubmed/17881186?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Aspirin, but not propranolol, attenuates the acute stress-induced increase in circulating levels of interleukin-6: a randomized, double-blind, placebo-controlled study.

 von Känel R, Kudielka BM, Metzenthin P, Helfricht S, Preckel D, Haeberli A, Stutz M, Fischer JE.

Department of General Internal Medicine, University Hospital Bern, CH-3010 Bern, Switzerland. roland.vonkaenel@insel.ch

Psychosocial stress might increase the risk of atherothrombotic events by setting off an elevation in circulating levels of the proinflammatory cytokine interleukin (IL)-6. We investigated the effect of aspirin and propranolol on the responsiveness of plasma IL-6 levels to acute psychosocial stress. For 5 days, 64 healthy subjects were randomized, double-blind, to daily oral aspirin 100mg plus long-acting propranolol 80 mg, aspirin 100mg plus placebo, long-acting propranolol 80 mg plus placebo, or placebo plus placebo. Thereafter, all subjects underwent the 13-min Trier Social Stress Test, which combines a preparation phase, a job interview, and a mental arithmetic task. Plasma IL-6 levels were measured in blood samples collected immediately pre- and post-stress, and 45 min and 105 min thereafter. The change in IL-6 from pre-stress to 105 min post-stress differed between subjects with aspirin medication and those without (p =0.033; eta p2=0.059). IL-6 levels increased less from pre-stress to 105 min post-stress (p <0.027) and were lower (p =0.010) at 105 min post-stress in subjects with aspirin than in subjects without aspirin. The significance of these results was maintained when controlling for gender, age, waist-to-hip ratio, mean arterial blood pressure, and smoking status. Medication with propranolol was not significantly associated with the stress-induced change in IL-6 levels. Also, aspirin and propranolol did not significantly interact in determining the IL-6 stress response. Aspirin but not propranolol attenuated the stress-induced increase in plasma IL-6 levels. This suggests one mechanism by which aspirin treatment might reduce the risk of atherothrombotic events triggered by acute mental stress.

Aspirin lowers pro-inflammatory cytokines in children:

http://www.ncbi.nlm.nih.gov/pubmed/17699316?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Pro- and anti-inflammatory cytokines in chronic pediatric dialysis patients: effect of aspirin.

Goldstein SL, Leung JC, Silverstein DM.

Department of Pediatrics, Renal Section, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, USA.

Dialysis provides effective and safe treatment of ESRD in children, but patients who are maintained on chronic dialysis are at risk for cardiovascular disease. One major risk factor for cardiovascular disease in adult patients with ESRD is chronic inflammation. The effect of anti-inflammatory therapy with aspirin on serum cytokine concentration was studied in seven children who were receiving hemodialysis (HD) and seven who were receiving continuous cycling peritoneal dialysis (CCPD or PD). Dialysis vintage was 4.3 +/- 4.6 yr; single-pool Kt/V was 1.46 +/- 1.4, mean equilibrated Kt/V was 1.27 +/- 0.16, and PD weekly Kt/V was 2.45 +/- 0.30. Baseline proinflammatory cytokine IL-1beta, IL-6, IL-8, and TNF-alpha serum concentrations were significantly elevated, whereas serum anti-inflammatory cytokine IL-4 and IL-10 concentrations were normal. The patterns of cytokine elevation were similar for patients who were receiving HD versus PD. IL-4 and IL-6 concentrations demonstrated strong positive correlation with dialysis vintage (IL-4, P < 0.03; IL-6, P < 0.0001). Pre-aspirin serum cytokine concentrations did not vary with single-pool Kt/V or equilibrated Kt/V for HD patients or with weekly Kt/V for PD patients. Serum IL-8 and TNF-alpha concentrations were significantly reduced by aspirin treatment at 4 mo (P = 0.04 and P = 0.007, respectively). Serum IL-6 concentration decreased with aspirin treatment but not significantly (P = 0.1). Serum IL-1beta concentration remained unchanged, and IL-4 and IL-10 concentrations remained stable throughout aspirin treatment. The effect of aspirin treatment on serum cytokine concentrations was similar for HD and PD patients. In HD patients, IL-6, IL-8, and TNF-alpha remained suppressed 1 mo after discontinuation of aspirin. It is concluded that proinflammatory cytokines are elevated in pediatric HD and PD patients without counterbalance from anti-inflammatory cytokines, and aspirin therapy attenuates inflammation.

Aspirin decreases pro-inflammatory cytokines in people with Vitiligo:

http://www.ncbi.nlm.nih.gov/pubmed/15951873?ordinalpos=17&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Decreased proinflammatory cytokine production by peripheral blood mononuclear cells from vitiligo patients following aspirin treatment.

Zailaie MZ.

The Vitiligo Unit, King Abdul-Aziz University Medical Center, PO Box 80170, Jeddah 21589, Kingdom of Saudi Arabia. mzailaie@kaau.edu.sa

OBJECTIVE: Limited studies have shown that treatment of cells with aspirin modulates their cytokine production. Consequently, the aim of the present study is to investigate the pattern of important proinflammatory cytokines production by stimulated peripheral blood mononuclear cells (PBMC) from patients with active vitiligo following long-term treatment with low-dose oral aspirin. METHODS: The study was conducted at the Vitiligo Unit, King Abdul-Aziz University Medical Center, Jeddah, Kingdom of Saudi Arabia between March and October 2003. Thirty-two patients (18 females and 14 males) with non-segmental vitiligo were divided into 2 equal groups, one group received a daily single dose of oral aspirin (300 mg) and the other group received placebo for a period of 12 weeks. The concentrations of interleukin (IL)-1beta, IL-6, IL-8 and tumor necrosis factor-alpha (TNF-alpha) were determined in the supernatant of isolated cultured PMBC after being stimulated with bacterial lipopolysaccharide (LPS), before the start of aspirin treatment and at end of treatment period. Cytokine levels were measured using the quantitative sandwich enzyme-linked immunosorbent assay (ELISA) technique, utilizing commercially available kits. RESULTS: The proinflammatory cytokine production by the PBMC of patients with active vitiligo was significantly increased compared to normal controls. Thus, the relative percentage increase in the production of IL-1beta, IL-6, IL-8 and TNF-alpha was: 39.4%, 110.5% (p<0.05), 91.5% (p<0.01), and 37% (p<0.05). At the end of treatment, proinflammatory cytokine production in the aspirin-treated group of active vitiligo patients was significantly decreased compared to the placebo group. Thus, the relative percentage decrease in the production of IL-1beta IL-6, IL-8 and TNF-alpha was: 42.5%, 45.2% (p<0.05), 30.8% (p<0.01), and 50.6% (p<0.05). The vitiligo activity was arrested in all aspirin-treated patients, while 2 patients demonstrated significant repigmentation. CONCLUSION: Chronic administration of low-dose oral aspirin can down-regulate the PBMC proinflammatory cytokine production in active vitiligo with concomitant arrest of disease activity.

http://www.ncbi.nlm.nih.gov/pubmed/18349287?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

Nonsteroidal anti-inflammatory drug use and serum total estradiol in postmenopausal women.

Hudson AG, Gierach GL, Modugno F, Simpson J, Wilson JW, Evans RW, Vogel VG, Weissfeld JL.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. alg33@pitt.edu

Laboratory and epidemiologic evidence suggest that nonsteroidal anti-inflammatory drug (NSAID) use may be inversely related to the risk of breast cancer; however, the mechanism by which NSAIDs may protect against the development of this disease is uncertain. The objective of this observational study was to assess the relationship between current NSAID use and endogenous estradiol levels, an established breast cancer risk factor. To evaluate this aim, we conducted a cross-sectional investigation among 260 postmenopausal women who were not recently exposed to exogenous hormones. Information on current NSAID use (aspirin, cyclooxygenase-2 inhibitors, and other NSAIDs combined) was collected using a questionnaire at the time of blood draw. Estradiol was quantified in serum by radioimmunoassay. General linear models were used to evaluate the association between NSAID use and serum total estradiol. The age-adjusted and body mass index-adjusted geometric mean serum estradiol concentration among NSAID users (n = 124) was significantly lower than nonusers of NSAIDs (n = 136; 17.8 versus 21.3 pmol/L; P = 0.03). Further adjustment for additional potential confounding factors did not substantially alter estimates (17.7 versus 21.2 pmol/L; P = 0.03). To our knowledge, this report is the first to examine the relationship between NSAID use and serum estradiol in postmenopausal women. These cross-sectional findings suggest that NSAID use may be associated with lower circulating estradiol levels, potentially representing one mechanism through which NSAIDs exert protective effects on breast cancer.

J Pharm Pharmacol. 2009 Nov;61(11):1505-10.

Efficacy of different doses of aspirin in decreasing blood levels of inflammatory markers in patients with cardiovascular metabolic syndrome.

Gao XR, Adhikari CM, Peng LY, Guo XG, Zhai YS, He XY, Zhang LY, Lin J, Zuo ZY.

Department of Cardiology, First Affiliated Hospital, Zhong-Shan University, Guangzhou, China. xiurengao@yahoo.com.

OBJECTIVES: Inflammation and platelet aggregation and activation are key processes in the initiation of a cardiovascular event. Patients with metabolic syndrome have a high risk of cardiovascular events. This study determined whether small and medium doses of aspirin have anti-inflammation and antiplatelet aggregation effects in patients with metabolic syndrome. METHODS: One hundred and twenty-one consecutive patients with metabolic syndrome were randomized into three groups, receiving 100 mg/day of aspirin, 300 mg/day of aspirin or a placebo, respectively, for 2 weeks. The blood levels of thromboxane B2 (TXB2), a stable product of the platelet aggregation mediator TXA2, 6-keto-prostaglandin F1-alpha (6-keto-PGF1-alpha), a stable product of the endogenous cyclooxygenase metabolite prostaglandin I2, and inflammatory mediators including high-sensitivity C-reactive protein (hs-CRP), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), were determined by ELISA and radioimmunoassay. KEY FINDINGS: The blood levels of hs-CRP, TNF-alpha, IL-6 and TXB2 were significantly decreased after 2 weeks of treatment with 300 mg/day of aspirin. Patients who received 100 mg/day of aspirin had decreased blood levels of hs-CRP and TXB2. The blood level of IL-6 in the 300 mg/day aspirin group was significantly lower than that in the other two groups after 2 weeks of therapy. Aspirin at either dose did not affect the blood level of 6-keto-PGF1-alpha. CONCLUSIONS: Aspirin at all doses suppresses the blood levels of inflammatory markers and the platelet aggregation mediator TXA2 in Chinese patients with metabolic syndrome. Since the suppression induced by 300 mg/day of aspirin was greater than that induced by 100 mg/day of aspirin, these data suggest that 300 mg/day of aspirin may be beneficial in decreasing the risk of cardiovascular events in Chinese patients with metabolic syndrome.

Time-dependent effects of low-dose aspirin on plasma renin activity, aldosterone, cortisol, and catecholamines.

Snoep JD, Hovens MM, Pasha SM, Frölich M, Pijl H, Tamsma JT, Huisman MV.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. J.D.Snoep@lumc.nl

Studies have shown that aspirin may decrease blood pressure when given at bedtime but not when administered on awakening. However, until now, a biologically plausible mechanism of this striking phenomenon was not revealed. We investigated the effect of 100 mg of aspirin administered at bedtime compared with administration on awakening on plasma renin activity and aldosterone levels over 24 hours and excretion of cortisol and catecholamines in 24-hour urine samples. A randomized, placebo-controlled, double-blind, crossover trial was performed in 16 grade 1 hypertensive subjects. During 2 periods of 2 weeks separated by a 4-week washout period, participants used aspirin both at morning and at night, which was blinded with placebo. After both periods, subjects were admitted for 24 hours to measure the aforementioned parameters. Aspirin intake at bedtime compared with on awakening reduced average (24-hour) plasma renin activity by 0.08 microg/L per hour (95% CI: 0.03 to 0.13 microg/L per hour; P=0.003) without affecting aldosterone levels (95% CI: -0.01 to 0.01 nmol/L; P=0.93). Cortisol excretion in 24-hour urine was 52 nmol/24 hours (95% CI: 5 to 99 nmol/24 hours; P=0.05) lower, and dopamine and norepinephrine excretions were 0.25 micromol/24 hours (95% CI: 0.01 to 0.48 micromol/24 hours; P=0.04) and 0.22 micromol/24 hours (95% CI: -0.03 to 0.46 micromol/24 hours; P=0.02) lower in patients treated with bedtime aspirin. In conclusion, aspirin taken at bedtime compared with on awakening significantly diminished 24-hour plasma renin activity and excretion of cortisol, dopamine, and norepinephrine in 24-hour urine. Decreased activity of these pressor systems forms a biologically plausible explanation for the finding that aspirin at night may reduce blood pressure, whereas aspirin at morning does not.

Do non-steroidal anti-inflammatory drugs influence the steroid hormone milieu in male athletes?

Di Luigi L, Rossi C, Sgrò P, Fierro V, Romanelli F, Baldari C, Guidetti L.

Unit of Endocrinology, Department of Health Sciences, University of Rome “IUSM”, Rome, Italy.

Prostaglandins modulate the hypothalamus-pituitary-adrenal and -gonadal axis pathways. We explored the effects of a single course of treatment with acetylsalicylic acid (ASA), an inhibitor of prostaglandin synthesis, on the steroid milieu in athletes. Morning plasma cortisol (F), dehydroepiandrosterone sulphate, free-testosterone, testosterone (T) and their ratios were evaluated before and after the administration of either ASA or placebo in twelve male athletes, when affected by minor musculoskeletal trauma and, as control, after a five/six week wash-out in healthy conditions respectively. One tablet of ASA (800 mg), or placebo, was administered two times daily for 10 days during treatment. All the volunteers suspended exercise training during treatment. The results revealed that compared to placebo, plasma F was significantly lower after ASA treatment (p = 0.023). Furthermore, the comparison of hormone’s absolute and percentage of variations (Delta and Delta%) between ASA and placebo treatment showed significant differences respectively for DeltaF (p = 0.045), for DeltaT (p = 0.047), for DeltaT/F (p = 0.042), for DeltaF% (p = 0.04) and for DeltaT% (p = 0.049). Our data suggest that in comparison to placebo, a short-term ASA treatment is able to influence the plasma steroid milieu in athletes. Due to the observed variability of the individual hormonal patterns, further research is required to substantiate these findings.

[The effect of different dosage of aspirin on inflammatory biomarkers and prognosis in acute coronary syndrome.]

[Article in Chinese]

Ren WL, Song LF, Liang YQ, Li RJ, Yin ZN, Xu YY, Hu DY.

Cardiac Center, People Hospital, Beijing 100044, China. Email: dayi.hu@medmail.com.cn.

Abstract

OBJECTIVE: To observe and assess the effect of different dosages of aspirin on inflammatory biomarkers, hemorheology (platelet aggregation rate) and clinical prognosis in patients with acute coronary syndrome (ACS).

METHODS: ACS patients were randomly assigned to receive different dosages of aspirin treatment orally. Patients in group A, B and C took 100 mg, 500 mg and 1000 mg of aspirin per day respectively. They were treated and followed-up for 1 year. High-sensitivity C-reactive protein (hsCRP), IL-6, tumor necrosis TNFalpha and platelet aggregation rate were examined and major adverse cardiac events (MACE) were recorded.

RESULTS: A total of 312 patients with ACS were enrolled in the study. The baseline characteristics of the three groups were not different with respect to age, gender, cardiovascular risk profile, level of inflammatory biomarkers and concomitant treatment before and after randomization. The levels of baseline serum hsCRP, IL-6 and TNFalpha were higher in subjects of the study as compared with normal reference value (P < 0.05, < 0.05, < 0.01) and they decreased significantly after therapy with 3 different doses of aspirin (detected at 30 days, 6 months and 12 months, P < 0.001), but there were no significant differences among the three groups (P > 0.05). Rehospitalization, MACE and the change of platelet aggregation ratio were not significantly different among the three groups. The incidence of gastrointestinal complaints was significantly higher in groups B and C than in group A (P < 0.05).

CONCLUSIONS: The levels of serum inflammatory biomarker increase in patients with ACS. Aspirin therapy may decrease the level of inflammatory markers significantly, but increasing the dosage of aspirin from 100 mg to 1000 mg daily does not decrease the level of inflammatory markers and the clinical MACEs further. However, the incidence of gastrointestinal complaints increase significantly with the increase of aspirin dosage.

Med Sci Sports Exerc. 2001 Dec;33(12):2029-35.

Acetylsalicylic acid inhibits the pituitary response to exercise-related stress in humans.

Di Luigi L, Guidetti L, Romanelli F, Baldari C, Conte D.

Endocrinology Unit, Laboratory of Endocrine Research, University Institute of Motor Sciences (IUSM), Piazza Lauro de Bosis, 15, 00194 Rome, Italy. iusm.endocrinol@iusm.it

Abstract

PURPOSE: Prostaglandins (PGs) modulate the activity of the hypothalamus-pituitary axis, and pituitary hormones are largely involved in the physiological responses to exercise. The purpose of this study was to analyze the effects of acetylsalicylic acid (ASA), an inhibitor of PGs synthesis, in the pituitary responses to physical stress in humans.

METHODS: Adrenocorticotropin (ACTH), beta-endorphin, cortisol, growth hormone (GH), and prolactin (PRL) responses to exercise were evaluated after administration of either placebo or ASA. Blood samples for hormone evaluations before (-30, -15, and 0 pre) and after (0 post, +15, +30, +45, +60, and +90 min) a 30-min treadmill exercise (75% of .VO(2max)) were taken from 12 male athletes during two exercise trials. One tablet of ASA (800 mg), or placebo, was administered two times daily for 3 d before and on the morning of each exercise-test.

RESULTS: The results clearly show that, compared with placebo, ASA ingestion significantly blunted the increased serum ACTH, beta-endorphin, cortisol, and GH levels before exercise (anticipatory response) and was associated with reduced cortisol concentrations after exercise. Furthermore, although no differences in the GH response to exercise were shown, a significantly reduced total PRL response to stress condition was observed after ASA.

CONCLUSION: ASA influences ACTH, beta-endorphin, cortisol, GH, and PRL responses to exercise-related stress in humans (preexercise activation/exercise-linked response). Even though it is not possible to exclude direct action for ASA, our data indirectly confirm a role of PGs in these responses. We have to further evaluate the nature of the preexercise endocrine activation and, because of the large use of anti-inflammatory drugs in athletes, whether the interaction between ASA and hormones might positively or negatively influence health status, performance, and/or recovery.

Neuroprotective effects of aspirin in patients with acute cerebral infarction

This article is not included in your organization’s subscription. However, you may be able to access this article under your organization’s agreement with Elsevier.

José Castillo ,  , a, Rogelio Leiraa, María Ángeles Morob, Ignacio Lizasoainb, Joaquín Serenac and Antoni Dávalosc

a Department of Neurology, Hospital Clínico Universitario de Santiago de Compostela, c/ Travesía da Choupana, s/n 15706, Santiago de Compostela, Spain

b Department of Pharmacology, School of Medicine, Universidad Complutense Madrid, Madrid, Spain

c Department of Neurology, Hospital Universitari Doctor Josep Trueta, Girona, Spain

Received 8 October 2002;

revised 28 November 2002;

accepted 19 December 2002. ;

Available online 12 February 2003.

Abstract

Aspirin may reduce ischemic brain injury. The aim of this study was to explore the effect of aspirin on glutamate release after acute stroke. We studied 238 patients with a first episode of hemispheric ischemic stroke of less than 24 h duration. Early neurological deterioration was diagnosed when the Canadian Stroke Scale dropped 1 or more points between admission and 48 h. Glutamate was determined on cerebrospinal fluid (CSF) samples obtained at admission. Sixty-three patients were undergoing treatment with 75–500 mg/day of aspirin at the time of stroke onset. CSF glutamate concentrations were higher in the group of patients not taking aspirin (8.9±5.2 vs. 4.9±3.1 μM/l, P<0.0001). Aspirin treatment at stroke onset had a 97% risk reduction of early neurological deterioration, and this effect remained unchanged after a further adjustment for glutamate concentrations. These findings suggest that low doses of aspirin may be useful in the management of patients with cerebral ischemia, not only for its antithrombotic properties, but also by direct neuroprotective effects.

Author Keywords: Cerebrospinal fluid; Glutamate; Neuroprotection; Stroke

Synergistic inhibition of cyclooxygenase-2 expression by vitamin E and aspirin

This article is not included in your organization’s subscription. However, you may be able to access this article under your organization’s agreement with Elsevier.

Aida Abate*, Guang Yang, Phyllis A. Dennery†, Stefanie Oberle* and Henning Schröder

* Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Halle (Saale), Germany

† Stanford University School of Medicine, Department of Pediatrics, Stanford, CA, USA

Received 8 March 2000;

revised 27 July 2000;

accepted 24 August 2000.

Available online 27 November 2000.

Abstract

The use of aspirin in rheumatoid arthritis is limited since inhibition of the pro-inflammatory enzyme cyclooxygenase-2 occurs only at higher aspirin doses that are often associated with side effects such as gastric toxicity. Using a macrophage cell line (J774.1A), the present study explores possible synergistic effects of aspirin and vitamin E on the expression and activity of cyclooxygenase-2. Lipopolysaccharide-induced prostaglandin E2 formation was significantly reduced by aspirin (1–100 μM) or vitamin E (100–300 μM). When combined with vitamin E, aspirin-dependent inhibition of prostaglandin E2 formation was increased from 59% to 95% of control. Likewise, lipopolysaccharide-induced cyclooxygenase-2 protein and mRNA expression were virtually abolished by the combined treatment of aspirin and vitamin E, whereas the two agents alone were only modestly effective. Vitamin C did not mimic the actions of vitamin E under these conditions, suggesting that redox-independent mechanisms underlie the action of vitamin E. In agreement with this, vitamin E and aspirin were without effect on lipopolysaccharide-induced translocation of the redox-sensitive transcription factor NF-κ B. Our results show that co-administration of vitamin E renders cyclooxygenase-2 more sensitive to inhibition by aspirin by as yet unknown mechanisms. Thus, anti-inflammatory therapy might be successful with lower aspirin doses when combined with vitamin E, thereby possibly avoiding the side effects of the usually required high dose aspirin treatment.

Clin Biochem. 2010 Feb;43(3):287-90. Epub 2009 Nov 3.

Effects of acetylsalicylic acid on serum paraoxonase activity, Ox-LDL, coenzyme Q10 and other oxidative stress markers in healthy volunteers.

Kurban S, Mehmetoglu I.

University of Selcuk, Meram Faculty of Medicine, Department of Biochemistry, Konya, Turkey. svlkrbn@yahoo.com

Abstract

OBJECTIVES: The aim of the study was to examine the effects of acetylsalicylic acid (ASA) on oxidative stress in healthy volunteers.

DESIGN AND METHODS: 30 volunteers of which 17 received ASA as 100 mg/day (Group I) and 13 received ASA as 150 mg/day (Group II) for 2 months. Serum paraoxonase 1 (PON1), arylesterase, total antioxidant status (TAS), total oxidant status (TOS), oxidized LDL (Ox-LDL) and coenzyme Q(10) (CoQ(10)) levels were measured before and 1 and 2 months after treatment.

RESULTS: There was no significant differences between the measured parameters of the groups. However, TOS and Ox-LDL levels of group II were significantly reduced after 2 months of treatment (p<0.05).

CONCLUSIONS: Significantly inhibition of LDL oxidation and significantly reduction in TOS levels of group II after 2 months of ASA treatment shows that ASA treatment may contribute to the prevention of atherosclerosis, a beneficial effect which is dose and time dependent.

http://www.jacn.org/cgi/content/abstract/27/4/505

Evidence for Anti-Inflammatory Effects of Combined Administration of Vitamin E and C in Older Persons with Impaired Fasting Glucose: Impact on Insulin Action

Maria Rosaria Rizzo, Angela Marie Abbatecola, Michelangela Barbieri, Maria Teresa Vietri, Michele Cioffi, Rodolfo Grella, AnnaMaria Molinari, Rosalyn Forsey, Jonathan Powell and Giuseppe Paolisso

Department of Geriatric and Metabolic Diseases (M.R.R., A.M.A., M.B., R.G., G.P.)

Department of General Pathology (M.T.V., M.C., A.M.M.), II University of Naples, ITALY

Unilever Corporate Research, Colworth Park, Sharnbrook, Beds, ENGLAND (R.F., J.P.)

Address reprint requests to: Giuseppe Paolisso, MD, Second University of Naples, Italy, Department of Geriatric Medicine and Metabolic Diseases, VI Divisione di Medicina Interna, Piazza Miraglia 2, I-80138 Napoli, ITALY. E-mail: giuseppe.paolisso@unina2.it

Objective: Vitamin E and C given separately improve insulin sensitivity due to an inhibitory effect on oxidative stress and inflammation, however their combined effect on glucose control and inflammation is unknown. To investigate combined effect of Vitamin E and C in elderly with Impaired Fasting Glucose (IFG) on insulin action and substrate oxidation.

Design: Controlled-trial administration of Vitamin E (1000 mg/day) and Vitamin C (1000 UI/day) for four weeks. Hyperinsulinemic euglycemic glucose clamp was performed before and following supplementation.

Setting: Out-patient clinic.

Participants: Thirteen older men with IFG.

Main Outcome Parameters: Variations in whole body glucose disposal (WBGD), anti-oxidant, and inflammatory cytokines plasma levels.

Results: An increase in plasma Vitamin E (8.3 + 0.8 vs. 64.9 + 2.1 µmol/l; p < 0.001] and C (35.9 + 5.4 vs. 79.4 + 7.4 µmol/l; p < 0.001) was found. Vitamin administration reduced insulin, glucose, lipid, TNF- and [8-]isoprostane levels. Increase in plasma vitamin E levels correlated with decline in both plasma [8-]isoprostane levels (r = –0.58; p = 0.048) and TNF- levels (r = – 0.62; p = 0.025), while no correlations were found for Vitamin C. Whole body glucose disposal (WBGD) (22.7 + 0.6 vs. 30.4 + 0.8 mmol x kg-1 x min-1; p = 0.001) and non-oxidative glucose metabolism rose after supplementation. Rise in plasma levels of Vitamin C and E correlated with WBGD. Multivariate linear regression models showed independent associations among the change in Vitamin E and the decline in TNF- and [8-]isoprostane levels.

Conclusions: Combined administration of Vitamin E and C lowered inflammation and improved insulin action through a rise in non-oxidative glucose metabolism.

Blood. 2001 Mar 15;97(6):1742-9.

Selective inhibition of interleukin-4 gene expression in human T cells by aspirin.

Cianferoni A, Schroeder JT, Kim J, Schmidt JW, Lichtenstein LM, Georas SN, Casolaro V.

Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD, USA.

Abstract

Previous studies indicated that aspirin (acetylsalicylic acid [ASA]) can have profound immunomodulatory effects by regulating cytokine gene expression in several types of cells. This study is the first in which concentrations of ASA in the therapeutic range were found to significantly reduce interleukin (IL)-4 secretion and RNA expression in freshly isolated and mitogen-primed human CD4+ T cells. In contrast, ASA did not affect IL-13, interferon-gamma, and IL-2 expression. ASA inhibited IL-4, but not IL-2, promoter-driven chloramphenicol acetyltransferase expression in transiently transfected Jurkat T cells. The structurally unrelated nonsteroidal anti-inflammatory drugs indomethacin and flurbiprofen did not affect cytokine gene expression in T cells, whereas the weak cyclo-oxygenase inhibitor salicylic acid was at least as effective as ASA in inhibiting IL-4 expression and promoter activity. The inhibitory effect of ASA on IL-4 transcription was not mediated by decreased nuclear expression of the known salicylate target nuclear factor (NF)-kappaB and was accompanied by reduced binding of an inducible factor to an IL-4 promoter region upstream of, but not overlapping, the NF of activated T cells- and NF-kappaB-binding P1 element. It is concluded that anti-inflammatory salicylates, by means of a previously unrecognized mechanism of action, can influence the nature of adaptive immune responses by selectively inhibiting the expression of IL-4, a critical effector of these responses, in CD4+ T cells.

Inhibition of histamine release by sodium salicylate and other compounds

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1510554/

Metab Brain Dis. 2004 Jun;19(1-2):71-7.

Aspirin curtails the acetaminophen-induced rise in brain norepinephrine levels.

Maharaj H, Maharaj DS, Saravanan KS, Mohanakumar KP, Daya S.

Source

Division of Pharmacology, Department of Pharmacy, Rhodes University, Grahamstown, South Africa.

Abstract

We previously showed that acetaminophen administration to rats increases forebrain serotonin levels as a result of the inhibition of liver tryptophan-2,3-dioxygenase (TDO). In this study we determined whether aspirin alone and in combination with acetaminophen could further influence brain serotonin as well as norepinephrine levels and if so whether the status of the liver TDO activity would be altered. The results show that acetaminophen alone increases brain serotonin as well as norepinephrine levels with a concomitant inhibition of liver TDO activity. In contrast, aspirin did not alter the levels of these monoamines but increased serotonin turnover in the brain while acetaminophen decreased the turnover. When combined with acetaminophen, aspirin overrides the reduced serotonin turnover induced by acetaminophen. This report demonstrates the potential of these agents to alter neurotransmitter levels in the brain.

Exp Gerontol. 2011 Feb-Mar;46(2-3):108-11. Epub 2010 Sep 17.

Growth hormone, insulin and aging: the benefits of endocrine defects.

Bartke A.

Source

Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL 62794-9628, USA. abartke@siumed.edu

Abstract

Longevity of mice can be increased by spontaneous or experimentally induced mutations that interfere with the biosynthesis or actions of growth hormone (GH), insulin-like growth factor 1 (IGF-1), or insulin in the adipose tissue. The effects of GH resistance and deficiency of GH (along with thyrotropin and prolactin) on aging and lifespan are the most pronounced and best established of these mutations. Potential mechanisms linking these endocrine deficits with delayed aging and extended longevity include increased stress resistance, alterations in insulin and mammalian target of rapamycin (mTOR) signaling and metabolic adjustments. Physiological relationships deduced from the extreme phenotypes of long-lived mouse mutants appear to apply broadly, encompassing genetically normal (“wild-type”) mice and other mammalian species. The role of GH in the control of human aging continues to be hotly debated, but recent data indicate that reduced somatotropic signaling provides protection from cancer and other age-related diseases and may promote old age survival.

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