Anti-inflammatory Agents and Cholesterol Metabolism

• ClinicalTrials.gov Identifier: NCT01279395
• Recruitment Status: Terminated
• First Posted: January 19, 2011
• Last Update Posted: August 16, 2019
• Sponsor: Winthrop University Hospital
• Information provided by (Responsible Party): Allison B. Reiss, MD, Winthrop University Hospital

Tracking Information

• First Submitted Date: January 14, 2011
• First Posted Date: January 19, 2011
• Last Update Posted Date: August 16, 2019
• Study Start Date: November 2010
• Actual Primary Completion Date: January 18, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 14, 2011)

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. [ Time Frame: 2 weeks ]

PBMC are isolated directly from patient blood by Ficoll hypaque gradient centrifugation. Total RNA is obtained (TriZol) from PBMC. 27-hydroxylase message is quantitated by quantitative real-time polymerase chain reaction (QRT-PCR) using specific primers.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: January 14, 2011)

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. [ Time Frame: 2 weeks ]

Comparison of abundance of the cholesterol-metabolizing enzyme cytochrome P450 cholesterol 27-hydroxylase in the THP-1 human monocyte/macrophage cell line incubated in plasma taken from the same patient before and after treatment with naprosyn, celecoxib or diclofenac. 27-hydroxylase message is quantitated by QRT-PCR and protein by immunoblot.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Anti-inflammatory Agents and Cholesterol Metabolism
• Official Title: Impact of Anti-inflammatory Agents on Cholesterol Metabolism and Atherogenic Potency of Patient Plasma
• Brief Summary: We hypothesize that administration of anti-inflammatory medications such as celecoxib, naprosyn and diclofenac will cause changes in the blood plasma and white blood cells of patients such that they will be less able to efficiently process cholesterol.
• Detailed Description: 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.
• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Probability Sample
• Study Population: Patients age 40-70 who fulfill the ACR criteria for a diagnosis of primary osteoarthritis are considered
• Condition: Osteoarthritis
• Intervention: Not Provided

Study Groups/Cohorts

• 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.

Publications *

• Anwar K, Voloshyna I, Littlefield MJ, Carsons SE, Wirkowski PA, Jaber NL, Sohn A, Eapen S, Reiss AB. COX-2 inhibition and inhibition of cytosolic phospholipase A2 increase CD36 expression and foam cell formation in THP-1 cells. Lipids. 2011 Feb;46(2):131-42. doi: 10.1007/s11745-010-3502-4. Epub 2010 Dec 22.
• Reiss AB, Anwar F, Chan ES, Anwar K. Disruption of cholesterol efflux by coxib medications and inflammatory processes: link to increased cardiovascular risk. J Investig Med. 2009 Aug;57(6):695-702. doi: 10.2310/JIM.0b013e31819ec3c7.
• Chan ES, Zhang H, Fernandez P, Edelman SD, Pillinger MH, Ragolia L, Palaia T, Carsons S, Reiss AB. Effect of cyclooxygenase inhibition on cholesterol efflux proteins and atheromatous foam cell transformation in THP-1 human macrophages: a possible mechanism for increased cardiovascular risk. Arthritis Res Ther. 2007;9(1):R4. doi: 10.1186/ar2109.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 13, 2019): 3
• Original Estimated Enrollment (submitted: January 14, 2011): 60
• Actual Study Completion Date: January 18, 2018
• Actual Primary Completion Date: January 18, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01279395
• Other Study ID Numbers: 151973-1
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Allison B. Reiss, MD, Winthrop University Hospital
• Original Responsible Party: Allison B. Reiss, M.D., Winthrop University Hospital
• Current Study Sponsor: Winthrop University Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Allison B Reiss, MD; Winthrop University Hospital

• PRS Account: Winthrop University Hospital
• Verification Date: August 2019