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Sponsor study identifier
interventional
10
1 country
1
Study Start
January 17, 2018
Actual (reported)Primary Completion
July 9, 2018
Actual (reported)Study Completion
September 30, 2018
Actual (reported)Glucocorticoids (GCs) are a class of endogenous steroid hormones produced by the adrenal glands and controlled by the hypothalamic-pituitary-adrenal axis (HPA). One of the mechanisms of their action is achieved through ligand-receptor attachment to a class of cytosolic steroid hormone receptors termed Glucocorticoid Receptors (GRs). The formed ligand-receptor complex is a transcription factor involved in gene activation of anti-inflammatory products or repression of pro-inflammatory products \[1\]. Synthetic forms of GCs are a group of anti-inflammatory and immunosuppressive medications (e.g. Prednisone) that are widely used in clinical practice to treat inflammatory diseases (e.g. Rheumatoid Arthritis, Vasculitis, Asthma). The effectiveness of this class of drugs is limited by numerous adverse effects that include, but not limited to, insulin resistance, glucose intolerance, dyslipidemia, and hypertension, all of which are well known risk factors for cardiovascular diseases (CVD) \[2,3\]. Furthermore, recent research suggest that inflammation has a key role in development of CVD and can predict prognosis \[4\]. Inflammatory cells have an important role in the development of atherosclerotic lesion in the arteries. Blood monocyte-derived macrophages are involved in this process, and they infiltrate the lesion where they take up various forms of lipids (cholesterol - rich LDL, and oxidized LDL) as well as triglycerides - rich VLDL), followed by the formation of lipid-laden foam cells, the hallmark of early atherogenesis. Inflammatory cells and molecules as well as proteolytic enzymes secreted from inflammatory cells in the atherosclerotic lesion, have a central role in destabilizing the plaque (vulnerable plaque) leading to its rupture, which, in turn, induces thrombosis, and initiating acute coronary events \[4,5\]. Based on our understanding of the involvement of inflammation in the early development of atherosclerotic lesion, and our experience with the anti-inflammatory effects of synthetic GCs, a hypothesis emerged suggesting this class of drugs as a way to inhibit early atherosclerotic plaque formation, and to attenuate CVDs \[6\]. Research results in this field are surprising because while glucocorticoids treatment in humans increase the risk of CVDs \[6,7,8,9\], animal models shows the opposite, atheroprotection was shown in rabbits \[10,11,12\] and mice \[13,14,15\]. This paradox may be explained partially by the fact that clinical studies in this field are mainly conducted in patients with predisposing factors to develop CVD, either because of pre-existing traditional risk factors like Diabetes and Hyperlipidemia, or because of the pre-existing medical condition they are being treated for with GCs (e.g. Rheumatoid Arthritis). Mechanism based research to study the effects of GCs on atherogenesis, without confounding factors, is lacking. Only few studies were performed on GCs in healthy subjects but none of them explored their effects on foam cell formation \[16,17\]. Our study thus aims to further our understanding of the role of specific glucocorticoid, prednisone, in the process of atherogenesis. In order to achieve that we plan to study the following: 1. The effects of five days of treatment with prednisone on serum lipid concentration and oxidative stress. 2. an Ex-vivo study is planned where the serum of healthy human subjects treated with Prednisone, will be introduced to J774A.1 murine macrophage-like cell line, a well-studied macrophage foam cell formation model.
Registry-reported information. Elapsed time and enrollment totals alone do not measure study progress or recruitment pace.
September 30, 2018
Actual (reported)Click on a node to explore related trials.
Dates and qualifiers reported by the registry. Estimated dates do not confirm that a milestone has occurred.
December 5, 2017
Actual (reported)December 11, 2017
Actual (reported)January 17, 2018
Actual (reported)July 9, 2018
Actual (reported)September 30, 2018
Actual (reported)Serum atherogenicity
Macrophage lipids (triglycerides and cholesterol) content (μg/mg cell protein) following incubation with serum derived from the subjects.
3 months
Each participant will be randomly assigned to one of two treatment groups, low dose of Prednisone 20mg/d (n=10) and high dose of Prednisone 40 mg/d (n=10). During the experimental periods, the subjects will take either one or two 20mg tablet of Prednisone, according to their assigned group. Subjects will be instructed to take the tablets at home in the mornings after a meal each day for 5 consecutive days. At the baseline visit, a medical history will be documented and a physical examination will be performed. Subjects will be asked to come to the research unit on days 1,2,5 after a 14h fasting where two blood samples (5ml each) will be taken, immediately centrifuged, one for biochemical analysis (Lipid profile, Liver function tests, Glucose, Electrolytes and Renal function tests) and the second will be aliquoted, and stored at -20°C until later analyses.
Each participant will be randomly assigned to one of two treatment groups, low dose of Prednisone 20mg/d (n=10) and high dose of Prednisone 40 mg/d (n=10). During the experimental periods, the subjects will take either one or two 20mg tablet of Prednisone, according to their assigned group. Subjects will be instructed to take the tablets at home in the mornings after a meal each day for 5 consecutive days. At the baseline visit, a medical history will be documented and a physical examination will be performed. Subjects will be asked to come to the research unit on days 1,2,5 after a 14h fasting where two blood samples (5ml each) will be taken, immediately centrifuged, one for biochemical analysis (Lipid profile, Liver function tests, Glucose, Electrolytes and Renal function tests) and the second will be aliquoted, and stored at -20°C until later analyses.
Each participant will be randomly assigned to one of two treatment groups, low dose of Prednisone 20mg/d (n=10) and high dose of Prednisone 40 mg/d (n=10). During the experimental periods, the subjects will take either one or two 20mg tablet of Prednisone, according to their assigned group. Subjects will be instructed to take the tablets at home in the mornings after a meal each day for 5 consecutive days. At the baseline visit, a medical history will be documented and a physical examination will be performed. Subjects will be asked to come to the research unit on days 1,2,5 after a 14h fasting where two blood samples (5ml each) will be taken, immediately centrifuged, one for biochemical analysis (Lipid profile, Liver function tests, Glucose, Electrolytes and Renal function tests) and the second will be aliquoted, and stored at -20°C until later analyses.
Rambam Health Care Campus
Haifa, 31096, Israel
Cohen DM, Steger DJ. Nuclear Receptor Function through Genomics: Lessons from the Glucocorticoid Receptor. Trends Endocrinol Metab. 2017 Jul;28(7):531-540. doi: 10.1016/j.tem.2017.04.001. Epub 2017 May 8.
Stahn C, Buttgereit F. Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol. 2008 Oct;4(10):525-33. doi: 10.1038/ncprheum0898. Epub 2008 Sep 2.
Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002 Oct;96(1):23-43. doi: 10.1016/s0163-7258(02)00297-8.
Tony Hayek, MD
Rambam Health Care Campus
10 participants (actual enrollment reported by the registry).
First Submitted
December 5, 2017
First Posted
December 11, 2017
Study Start
January 17, 2018
Actual (reported)Each participant will be randomly assigned to one of two treatment groups, low dose of Prednisone 20mg/d (n=10) and high dose of Prednisone 40 mg/d (n=10). During the experimental periods, the subjects will take either one or two 20mg tablet of Prednisone, according to their assigned group. Subjects will be instructed to take the tablets at home in the mornings after a meal each day for 5 consecutive days. At the baseline visit, a medical history will be documented and a physical examination will be performed. Subjects will be asked to come to the research unit on days 1,2,5 after a 14h fasting where two blood samples (5ml each) will be taken, immediately centrifuged, one for biochemical analysis (Lipid profile, Liver function tests, Glucose, Electrolytes and Renal function tests) and the second will be aliquoted, and stored at -20°C until later analyses.
Contact the study team to confirm eligibility.
Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005 Apr 21;352(16):1685-95. doi: 10.1056/NEJMra043430. No abstract available.
Dickhout JG, Basseri S, Austin RC. Macrophage function and its impact on atherosclerotic lesion composition, progression, and stability: the good, the bad, and the ugly. Arterioscler Thromb Vasc Biol. 2008 Aug;28(8):1413-5. doi: 10.1161/ATVBAHA.108.169144. No abstract available.
Walker BR. Glucocorticoids and cardiovascular disease. Eur J Endocrinol. 2007 Nov;157(5):545-59. doi: 10.1530/EJE-07-0455.
del Rincon I, O'Leary DH, Haas RW, Escalante A. Effect of glucocorticoids on the arteries in rheumatoid arthritis. Arthritis Rheum. 2004 Dec;50(12):3813-22. doi: 10.1002/art.20661.
del Rincon I, Battafarano DF, Restrepo JF, Erikson JM, Escalante A. Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis. Arthritis Rheumatol. 2014 Feb;66(2):264-72. doi: 10.1002/art.38210.
Ajeganova S, Svensson B, Hafstrom I; BARFOT Study Group. Low-dose prednisolone treatment of early rheumatoid arthritis and late cardiovascular outcome and survival: 10-year follow-up of a 2-year randomised trial. BMJ Open. 2014 Apr 7;4(4):e004259. doi: 10.1136/bmjopen-2013-004259.
Cavallero C, Di Tondo U, Mingazzini PL, Nicosia R, Pericoli MN, Sarti P, Spagnoli LG, Villaschi S. Cell proliferation in the atherosclerotic plaques of cholesterol-fed rabbits. Part 3. Histological and radioautographic observations on glucocorticoids-treated rabbits. Atherosclerosis. 1976 Nov-Dec;25(2-3):145-52. doi: 10.1016/0021-9150(76)90020-4.
Makheja AN, Bloom S, Muesing R, Simon T, Bailey JM. Anti-inflammatory drugs in experimental atherosclerosis. 7. Spontaneous atherosclerosis in WHHL rabbits and inhibition by cortisone acetate. Atherosclerosis. 1989 Apr;76(2-3):155-61. doi: 10.1016/0021-9150(89)90099-3.
Asai K, Funaki C, Hayashi T, Yamada K, Naito M, Kuzuya M, Yoshida F, Yoshimine N, Kuzuya F. Dexamethasone-induced suppression of aortic atherosclerosis in cholesterol-fed rabbits. Possible mechanisms. Arterioscler Thromb. 1993 Jun;13(6):892-9. doi: 10.1161/01.atv.13.6.892.
Auvinen HE, Wang Y, Princen H, Romijn JA, Havekes LM, Smit JW, Meijer OC, Biermasz NR, Rensen PC, Pereira AM. Both transient and continuous corticosterone excess inhibit atherosclerotic plaque formation in APOE*3-leiden.CETP mice. PLoS One. 2013 May 22;8(5):e63882. doi: 10.1371/journal.pone.0063882. Print 2013.
Out C, Dikkers A, Laskewitz A, Boverhof R, van der Ley C, Kema IP, Wolters H, Havinga R, Verkade HJ, Kuipers F, Tietge UJ, Groen AK. Prednisolone increases enterohepatic cycling of bile acids by induction of Asbt and promotes reverse cholesterol transport. J Hepatol. 2014 Aug;61(2):351-7. doi: 10.1016/j.jhep.2014.03.025. Epub 2014 Mar 26.
Tauchi Y, Zushida L, Chono S, Sato J, Ito K, Morimoto K. Effect of dexamethasone palmitate-low density lipoprotein complex on cholesterol ester accumulation in aorta of atherogenic model mice. Biol Pharm Bull. 2001 Aug;24(8):925-9. doi: 10.1248/bpb.24.925.
Fleishaker DL, Mukherjee A, Whaley FS, Daniel S, Zeiher BG. Safety and pharmacodynamic dose response of short-term prednisone in healthy adult subjects: a dose ranging, randomized, placebo-controlled, crossover study. BMC Musculoskelet Disord. 2016 Jul 16;17:293. doi: 10.1186/s12891-016-1135-3.
Kauh EA, Mixson LA, Shankar S, McCarthy J, Maridakis V, Morrow L, Heinemann L, Ruddy MK, Herman GA, Kelley DE, Hompesch M. Short-term metabolic effects of prednisone administration in healthy subjects. Diabetes Obes Metab. 2011 Nov;13(11):1001-7. doi: 10.1111/j.1463-1326.2011.01432.x.
Nikitina NA, Sobenin IA, Myasoedova VA, Korennaya VV, Mel'nichenko AA, Khalilov EM, Orekhov AN. Antiatherogenic effect of grape flavonoids in an ex vivo model. Bull Exp Biol Med. 2006 Jun;141(6):712-5. doi: 10.1007/s10517-006-0260-7. English, Russian.
Hamoud S, Hayek T, Volkova N, Attias J, Moscoviz D, Rosenblat M, Aviram M. Pomegranate extract (POMx) decreases the atherogenicity of serum and of human monocyte-derived macrophages (HMDM) in simvastatin-treated hypercholesterolemic patients: a double-blinded, placebo-controlled, randomized, prospective pilot study. Atherosclerosis. 2014 Jan;232(1):204-10. doi: 10.1016/j.atherosclerosis.2013.11.037. Epub 2013 Nov 19.
Primary Completion
July 9, 2018
Actual (reported)Study Completion
September 30, 2018
Actual (reported)Last Updated
February 21, 2019
Record last verified: 2019-02
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