Statin therapy and thromboxane generation in patients with coronary artery disease treated with high-dose aspirin

SummaryAspirin and statin therapy are mainstay treatments in patients with coronary artery disease (CAD). The relation between statin therapy, in vivo thromboxane (Tx) generation; a marker of inflammation, and blood thrombogenicity has never been explored. Urinary 11-dehydro (dh) TxB2 was determined in patients with suspected CAD on 325 mg daily aspirin therapy prior to undergoing cardiac catheterisation (n=281). Thrombogenicity was estimated by thrombelastographic measurement of thrombin-induced platelet-fibrin clot strength (TIP-FCS) and lipids/lipoproteins were determined by vertical density gradient ultracentrifugation/ELISA. The influence of statin therapy and dose was analysed by the atorvastatin equivalent dose (5–10 mg, 20–40 mg, or 80 mg daily). Statin therapy (n=186) was associated with a dose-dependent reduction in urinary 11-dh TxB2 (p=0.046) that was independent of LDL and apo B100 levels but was strongly related to TIP-FCS (p=0.006). By multivariate analysis, no statin therapy (n=95) and female gender were independently associated with high urinary 11-dh TxB2 [OR=2.95 (0.1.57–5.50, p=0.0007); OR=2.25 (1.24–4.05, p=0.007)], respectively. In aspirin-treated patients, statin therapy was independently and inversely associated with inflammation in a dose-dependent manner. Elevated 11-dh TxB2 was associated with a prothrombotic state indicated by high TIP-FCS. Our data suggest that measurement of urinary 11-dTxB2 may be a useful method to optimise statin dosing in order to reduce thrombotic risk.

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A Study of Effects of Addition of Coenzyme Q 10 to High Dose Statins in Patients of Coronary Artery Disease with Special Reference to Oxidative Balance

Indian Journal of Cardiovascular Disease in Women WINCARS ◽

10.1055/s-0038-1656452 ◽

2017 ◽

Vol 02 (01) ◽

pp. 006-013

Author(s):

Malleswara Dangeti ◽

Siva Katkam ◽

Raghu Galla ◽

Ravi Kiran ◽

Indrani Garre

Keyword(s):

Oxidative Stress ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Statin Therapy ◽

Coenzyme Q10 ◽

Coenzyme Q ◽

High Dose ◽

Plasma Glutathione ◽

Artery Disease ◽

Plasma Malondialdehyde

AbstractBackground: Oxidative stress is one of the most potent inductors of endothelial dysfunction and is involved at all stages of atherosclerotic plaque evolution. Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. Statins also possess direct free radical scavenging activity. However, the prooxidant effect of statins has also been reported as statins block the mevalonate pathway and the synthesis coenzyme Q10. This Additional Coenzyme Q10 depletion by statins in patients with coronary artery disease (CAD) may be a critical issue as it may reduce absolute benefits of statins.Objectives: The purpose of this study was to investigate the effects of high dose statins on plasma Malondialdehyde (MDA) levels and plasma glutathione levels in CAD patients who underwent recent PCI and to study whether addition of coenzyme Q10 (100 mg/d) has any additional effect on plasma Malondialdehyde (MDA) levels and plasma glutathione levels in patients already receiving high dose statin therapy.Methods: Twenty-one consecutive patients who underwent percutaneous transluminal coronary angioplasty (PTCA) in Department of Cardiology at our institute were studied. The cases (n = 21) were given high dose statins for first 1 week and then coenzyme Q10 (100 md /day) is added for next 1 week. Plasma Malondialdehyde(MDA) levels and plasma glutathione levels were analyzed at the time of admission before giving statins and at the end of 1 week of statin therapy and again after 1 week of Co-Q therapy.Results: Our results indicate that a relation exists between high plasma Malondialdehyde (MDA) levels and low plasma glutathione levels with coronary artery disease. High dose statins decrease MDA levels and increase plasma glutathione levels, even though they decrease coenzyme q levels in the body. It was also shown that addition of Coenzyme Q10 at 100 mg/d enhances plasma glutathione levels and decreases plasma MDA level still further in patients who have CAD, already receiving high dose statin therapy.Conclusions: Addition of Coenzyme Q10 at 100 mg/d has an additive effect with high dose statins in decreasing oxidative stress. Particularly in light of the excellent tolerance and affordability of this natural physiological compound, supplemental Coenzyme Q10 may emerge as an attractive option in future, and merits evaluation in additional large studies.

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Incremental Benefit and Cost-Effectiveness of High-Dose Statin Therapy in High-Risk Patients With Coronary Artery Disease

Circulation ◽

10.1161/circulationaha.106.667683 ◽

2007 ◽

Vol 115 (18) ◽

pp. 2398-2409 ◽

Cited By ~ 52

Author(s):

Paul S. Chan ◽

Brahmajee K. Nallamothu ◽

Hitinder S. Gurm ◽

Rodney A. Hayward ◽

Sandeep Vijan

Keyword(s):

Coronary Artery Disease ◽

Cost Effectiveness ◽

Coronary Artery ◽

High Risk ◽

Statin Therapy ◽

High Dose ◽

Incremental Benefit ◽

High Risk Patients ◽

Risk Patients ◽

Artery Disease

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Incremental Benefit and Cost-Effectiveness of High-Dose Statin Therapy in High-Risk Patients With Coronary Artery Disease

Circulation ◽

10.1161/circulationaha.106.677683 ◽

2007 ◽

Author(s):

P. S. Chan ◽

B. K. Nallamothu ◽

H. S. Gurm ◽

R. A. Hayward ◽

S. Vijan

Keyword(s):

Coronary Artery Disease ◽

Cost Effectiveness ◽

Coronary Artery ◽

High Risk ◽

Statin Therapy ◽

High Dose ◽

Incremental Benefit ◽

High Risk Patients ◽

Risk Patients ◽

Artery Disease

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High-Dose α-Tocopherol Therapy Does Not Affect HDL Subfractions in Patients with Coronary Artery Disease on Statin Therapy

Clinical Chemistry ◽

10.1373/clinchem.2006.078865 ◽

2007 ◽

Vol 53 (3) ◽

pp. 525-528 ◽

Cited By ~ 10

Author(s):

Uma Singh ◽

James Otvos ◽

Amitava Dasgupta ◽

James A de Lemos ◽

Sridevi Devaraj ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Statin Therapy ◽

Hdl Cholesterol ◽

Apolipoprotein A1 ◽

Controlled Study ◽

Resonance Spectroscopy ◽

High Dose ◽

Hdl Subfractions ◽

Artery Disease

Abstract Background: Subfractions of HDL, particularly large HDL (HDL2), are inversely correlated with the severity of coronary artery disease (CAD). α-Tocopherol (AT) is the main lipid-soluble antioxidant in plasma. Results of a previous small study (n = 44) suggested that either a combination of an antioxidant cocktail [800 IU/day 2R,4′R,8′R-(RRR)-AT plus 1 g vitamin C, 25 mg β-carotene, and 100 μg selenium] or individual antioxidant vitamins combined with simvastatin–niacin (S-N) therapy attenuated the protective increase in HDL2 seen with S-N alone. Few data are available on the effect of AT therapy alone on HDL subfractions, which we addressed in this study. Methods: In a prospective placebo-controlled study, we randomized 127 patients with stable CAD to receive high-dose RRR-AT (1200 IU/day for 2 years) or placebo. HDL subfractions (small, medium, and large HDL particles) were analyzed by nuclear magnetic resonance spectroscopy. Results: AT concentrations significantly increased in the AT arm but not with placebo. No differences were noted between AT and placebo groups in concentrations of total cholesterol, triglyceride, LDL-cholesterol, or HDL-cholesterol. AT therapy did not affect total, small, medium, or large HDL particles compared with baseline or placebo. Furthermore, serum apolipoprotein A1 concentrations did not change after 2 years AT therapy as compared with baseline. Conclusions: High-dose AT therapy administered for a 2-year period does not negatively affect either HDL subfractions or apolipoprotein A1 in patients with CAD on statin therapy. Thus the negative interaction previously proposed between antioxidant cocktail and statin therapy cannot be attributed to AT.

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Incremental Benefit and Cost-Effectiveness of High-Dose Statin Therapy in High-Risk Patients With Coronary Artery Disease

Yearbook of Endocrinology ◽

10.1016/s0084-3741(08)79119-4 ◽

2008 ◽

Vol 2008 ◽

pp. 76-77

Author(s):

W.J. Howard

Keyword(s):

Coronary Artery Disease ◽

Cost Effectiveness ◽

Coronary Artery ◽

High Risk ◽

Statin Therapy ◽

High Dose ◽

Incremental Benefit ◽

High Risk Patients ◽

Risk Patients ◽

Artery Disease

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Niacin improves lipid profile but not endothelial function in patients with coronary artery disease on high dose statin therapy

Atherosclerosis ◽

10.1016/j.atherosclerosis.2012.10.067 ◽

2013 ◽

Vol 226 (2) ◽

pp. 453-458 ◽

Cited By ~ 12

Author(s):

Andrew C. Philpott ◽

Jaroslav Hubacek ◽

Yichun C. Sun ◽

Darlene Hillard ◽

Todd J. Anderson

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Endothelial Function ◽

Lipid Profile ◽

Statin Therapy ◽

High Dose ◽

Artery Disease

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High Dose Alpha Tocopherol therapy does not affect subfractions of High Density Lipoproteins in patients with Coronary Artery Disease on Statin therapy

The FASEB Journal ◽

10.1096/fasebj.20.4.a132-b ◽

2006 ◽

Vol 20 (4) ◽

Author(s):

Uma Singh ◽

J Otvos ◽

B Huet ◽

J Delemos ◽

S Devaraj ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Statin Therapy ◽

High Density ◽

Alpha Tocopherol ◽

High Density Lipoproteins ◽

High Dose ◽

Artery Disease

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High-Dose Statin Therapy in Patients With Stable Coronary Artery Disease

Circulation ◽

10.1161/circulationaha.112.000712 ◽

2013 ◽

Vol 127 (25) ◽

pp. 2485-2493 ◽

Cited By ~ 29

Author(s):

Johannes A.N. Dorresteijn ◽

S. Matthijs Boekholdt ◽

Yolanda van der Graaf ◽

John J.P. Kastelein ◽

John C. LaRosa ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Statin Therapy ◽

Stable Coronary Artery Disease ◽

High Dose ◽

Artery Disease

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Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽

10.3390/pharmaceutics13030386 ◽

2021 ◽

Vol 13 (3) ◽

pp. 386

Author(s):

Tung-Hu Tsai ◽

Yu-Jen Chen ◽

Li-Ying Wang ◽

Chen-Hsi Hsieh

Keyword(s):

Stereotactic Body Radiation Therapy ◽

In Vivo Studies ◽

Control Group ◽

High Dose ◽

Dependent Manner ◽

Hep G2 ◽

Time Curve ◽

Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

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