Anti-inflammatory Agents and Cholesterol Metabolism

The recruitment status of this study is unknown because the information has not been verified recently.
Verified June 2012 by Winthrop University Hospital.
Recruitment status was  Recruiting
Sponsor:
Information provided by (Responsible Party):
Allison B. Reiss, MD, Winthrop University Hospital
ClinicalTrials.gov Identifier:
NCT01279395
First received: January 14, 2011
Last updated: June 14, 2012
Last verified: June 2012
  Purpose

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.


Condition
Osteoarthritis

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Impact of Anti-inflammatory Agents on Cholesterol Metabolism and Atherogenic Potency of Patient Plasma

Resource links provided by NLM:


Further study details as provided by Winthrop University Hospital:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 60
Study Start Date: November 2010
Estimated Study Completion Date: March 2013
Estimated Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
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.

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.

  Eligibility

Ages Eligible for Study:   40 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

Patients age 40-70 who fulfill the ACR criteria for a diagnosis of primary osteoarthritis are considered

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01279395

Contacts
Contact: Allison B Reiss, MD 516-663-3455 areiss@winthrop.org

Locations
United States, New York
Winthrop University Hospital Recruiting
Mineola, New York, United States, 11501
Contact: Allison B Reiss, MD    516-663-3455    AReiss@winthrop.org   
Contact: Betsy Pinnick, LPN    516-663-9582    BPinnick@winthrop.org   
Sponsors and Collaborators
Winthrop University Hospital
Investigators
Principal Investigator: Allison B Reiss, MD Winthrop University Hospital
  More Information

Publications:
Responsible Party: Allison B. Reiss, MD, Associate Professor of Medicine, Winthrop University Hospital
ClinicalTrials.gov Identifier: NCT01279395     History of Changes
Other Study ID Numbers: 151973-1
Study First Received: January 14, 2011
Last Updated: June 14, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Winthrop University Hospital:
atherosclerosis
cholesterol
cyclooxygenase
gene expression
lipid metabolism

Additional relevant MeSH terms:
Osteoarthritis
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 28, 2014