The Effect of Prednisone on Atherogenesis as Studied in the Macrophage Foam Cell Formation Model System.

Diabetes Clinical Trial

Official title:

The Effect of Prednisone on Atherogenesis as Studied in the Macrophage Foam Cell Formation Model System.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03367663
• Other study ID #: 0254-17-RMB
• Status: Completed
• Phase: Early Phase 1
• Start date: January 17, 2018
• Est. completion date: September 30, 2018

Study information

• Verified date: February 2019
• Source: Rambam Health Care Campus
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: September 30, 2018
• Est. primary completion date: July 9, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

• Male subjects between the ages of 18-50 years of age, with a body mass index within the range of 18 to 27 kg/m2, with no previous medical history of illnesses or drug allergy and with no current medical treatments.

Exclusion Criteria:

• Students or hospital employees under the direct supervision of the PI or lead researcher. Any previous history of acute or chronic illnesses including but not limited to Cardiovascular, Pulmonary, Gastrointestinal, Renal, Endocrinal, Cancer, Diabetes or Pre-Diabetes (HbA1c > 5.5%), Hypertension, Dyslipidemia, Smoking, or who had taken glucocorticoids within the previous 3 months before the study.

Related Conditions & MeSH terms

• Atherosclerosis
• Diabetes
• Dyslipidemias

Intervention

Drug:
• Prednisone 20 Mg
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.
• Prednisone 40 Mg
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.

Locations

Country	Name	City	State
Israel	Rambam Health Care Campus	Haifa

Sponsors (1)

Lead Sponsor	Collaborator
Prof. Tony hayek MD

Country where clinical trial is conducted

Israel, 

References & Publications (19)

Ajeganova S, Svensson B, Hafström 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

del Rincón 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. — View Citation

del Rincón 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. Erratum in: Arthritis Rheum. 2005 Feb;52(2):678. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005 Apr 21;352(16):1685-95. Review. — View Citation

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. — View Citation

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. — View Citation

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. English, Russian. — View Citation

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. — View Citation

Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002 Oct;96(1):23-43. Review. — View Citation

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. Review. — View Citation

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. — View Citation

Walker BR. Glucocorticoids and cardiovascular disease. Eur J Endocrinol. 2007 Nov;157(5):545-59. Review. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serum atherogenicity	Macrophage lipids (triglycerides and cholesterol) content (µg/mg cell protein) following incubation with serum derived from the subjects.	3 months