Anti-inflammatory Agents and Cholesterol Metabolism
Maneno muhimu
Kikemikali
Maelezo
Drugs that inhibit cyclooxygenase (COX) are frequently administered to relieve pain and inflammation, but have been associated with cardiovascular (CV) toxicity and an elevated risk of acute myocardial infarction. We have demonstrated that drugs that inhibit the COX-2 isoform act to interfere with cellular cholesterol movement by suppressing expression of proteins that facilitate efflux of cholesterol as well as by enhancing expression of scavenger receptors that mediate cholesterol uptake. We further showed that in cultured THP-1 human macrophages, COX-2 inhibition with drugs (celecoxib, NS398) or by COX-2 RNA silencing leads to foam cell transformation, a critical component of atherogenesis. Thus, COX-2 inhibitors act in a pro-atherogenic fashion on a series of genes which we have named the "Cholesterol Metabolic Signature." Alterations in this signature may contribute to heightened risk of development of atherosclerotic CV disease associated with prolonged use of this drug class. COX enzyme activity supports cholesterol homeostasis through catalysis of prostaglandin (PG) production, and we have shown in vitro that specific subsets of these PGs (PGD2 or PGE2) are sufficient to maintain balance. The aims of this project is: In an observational study of persons with pharmacologic COX-2 selective inhibition (celecoxib) or COX-1/2 inhibition (naproxen, diclofenac), document treatment effects on the Cholesterol Metabolic Signature in isolated subject mononuclear cells and in naïve THP-1 monocytes/macrophages exposed to subject plasma. This will allow detection of variations in degree of pro-atherogenic response of the Cholesterol Metabolic Signature to COX inhibition within human patients that may be associated with a higher likelihood of developing CV sequelae. Understanding the nature of the association between COX inhibition and cholesterol metabolism, and the extent to which they may promote atherosclerotic CV disease, is of critical importance in developing analgesic and anti-inflammatory medications with a more favorable risk profile. The knowledge gained may also improve clinical decision-making by identifying subsets of patients most vulnerable to adverse CV effects of COX inhibition.
Tarehe
Imethibitishwa Mwisho: | 07/31/2019 |
Iliyowasilishwa Kwanza: | 01/13/2011 |
Uandikishaji uliokadiriwa Uliwasilishwa: | 01/13/2011 |
Iliyotumwa Kwanza: | 01/18/2011 |
Sasisho la Mwisho Liliwasilishwa: | 08/12/2019 |
Sasisho la Mwisho Lilichapishwa: | 08/15/2019 |
Tarehe halisi ya kuanza kwa masomo: | 10/31/2010 |
Tarehe ya Kukamilisha Msingi iliyokadiriwa: | 01/17/2018 |
Tarehe ya Kukamilisha Utafiti: | 01/17/2018 |
Hali au ugonjwa
Awamu
Vikundi vya Arm
Mkono | Uingiliaji / matibabu |
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naproxen Patients age 40-70 who fulfill the American College of Rheumatology (ACR) criteria for a diagnosis of primary osteoarthritis are considered eligible. This group has been prescribed naproxen (1000 mg/day) for a minimum of two weeks. | |
diclofenac Patients age 40-70 who fulfill the ACR criteria for a diagnosis of primary osteoarthritis. The group consists of patients who have been prescribed diclofenac (150 mg/day)for a minimum of two weeks. | |
celecoxib Patients age 40-70 who fulfill the ACR criteria for a diagnosis of primary osteoarthritis are considered eligible. This group has been prescribed celecoxib (200 mg/day) for a minimum of two weeks. |
Vigezo vya Kustahiki
Zama zinazostahiki Kujifunza | 40 Years Kwa 40 Years |
Jinsia Inastahiki Kujifunza | All |
Njia ya sampuli | Probability Sample |
Hupokea Wajitolea wa Afya | Ndio |
Vigezo | Inclusion Criteria: - Age 40-70, osteoarthritis, male or female Exclusion Criteria: - other known autoimmune or inflammatory rheumatic conditions, renal disease, current or recent (>1 month) corticosteroid or statin treatment, contraindications to medication (i.e. those taking oral anticoagulants, e.g. warfarin), those pregnant or trying to become pregnant or breastfeeding. Participants will not have consumed any medications containing aspirin or other NSAIDs for at least 2 weeks before the trial. |
Matokeo
Hatua za Matokeo ya Msingi
1. Difference in expression of the cholesterol-metabolizing enzyme cytochrome P450 cholesterol 27-hydroxylase in peripheral blood mononuclear cells (PBMC) before and after treatment with naprosyn, celecoxib or diclofenac. [2 weeks]
Hatua za Matokeo ya Sekondari
1. Difference in expression of cholesterol 27-hydroxylase in naive THP-1 human macrophages incubated in plasma from patients obtained before and after treatment with naprosyn, diclofenac or celecoxib. [2 weeks]