The Effect of Prednisone on Atherogenesis as Studied in the Macrophage Foam Cell Formation Model System.
Condition: Atherosclerosis; Dyslipidemias; Diabetes
MeSH terms: Atherosclerosis; Dyslipidemias
Study type: Interventional
Phase: Early Phase 1

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.
    


Intervention name(s): Prednisone 20 Mg; Prednisone 40 Mg
Intervention type(s): Drug; Drug
Intervention description(s): 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.
Intervention MeSH terms: Prednisone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science