Mechanisms of Action of Acetaminophen

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania
ClinicalTrials.gov Identifier:
NCT00646906
First received: March 26, 2008
Last updated: May 14, 2013
Last verified: December 2011
  Purpose

This research study investigates whether the ability of aspirin to reduce the risk of heart attacks may be diminished by the administration of acetaminophen. Patients who have heart disease are often prescribed aspirin because of its unique ability to permanently prevent platelets from aggregating and forming a blood clot. Such blood clots cause heart attacks when they form in a blood vessel that supplies the heart with oxygen rich blood. Some of these same patients also take acetaminophen everyday for relief from arthritis pain. Higher doses of acetaminophen may also have the ability to prevent the platelets from clotting, however only temporarily. Therefore, this study evaluates whether the timing of the administration of acetaminophen (before or after aspirin) interferes with the permanent blood clotting effects of aspirin.

The primary hypothesis is that acetaminophen given two hours before aspirin will antagonize the effects of aspirin, while reversing the order of administration will not.


Condition Intervention Phase
Myocardial Infarction
Arthritis
Drug: Aspirin first
Drug: Aspirin last
Drug: Acetaminophen
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Crossover Study to Evaluate the Mechanism of Action of Acetaminophen

Resource links provided by NLM:


Further study details as provided by University of Pennsylvania:

Primary Outcome Measures:
  • Serum thromboxane B2 concentration [ Time Frame: 7 days ] [ Designated as safety issue: No ]
  • Arachidonic acid induced platelet aggregation [ Time Frame: 7 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Urinary 11-dehydro thromboxane B2 concentration [ Time Frame: 7 days ] [ Designated as safety issue: No ]
  • Urinary 2,3 doner-6 keto PGF1α concentration [ Time Frame: 7 days ] [ Designated as safety issue: No ]
  • Urinary 8,12-iso-iPF2α-VI concentration [ Time Frame: 7 days ] [ Designated as safety issue: No ]

Enrollment: 12
Study Start Date: May 2004
Study Completion Date: February 2012
Primary Completion Date: January 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Acetaminophen 1000mg
All subjects in this arm (smokers (n=8) and non-smokers (n=8) will receive 81 mg aspirin at approximately 8 am followed by 1000 mg acetaminophen at approximately 10 am during one treatment phase (see "Aspirin first" intervention). During the other treatment phase, beginning after a 2 week washout, the order will be reversed and the subjects will receive 1000 mg acetaminophen at 8 am followed by 81 mg aspirin at 10 am (see "Aspirin last" intervention). The occurrence of the two study phases (interventions) will be randomized by order. Smokers and non-smokers will be matched for age and gender.
Drug: Aspirin first
Subjects will receive 81 mg aspirin at approximately 8 am followed by 1000 or 2000 mg acetaminophen at approximately 10 am during this intervention phase.
Drug: Aspirin last
Subjects will receive 1000 or 2000 mg acetaminophen at approximately 8am followed by 81 mg aspirin at approximately 10 am during this intervention phase.
Experimental: Acetaminophen 2000mg
All subjects in this arm (smokers (n=8) and non-smoking volunteers (n=8)) will receive 81 mg aspirin at approximately 8 am followed by 2000 mg acetaminophen at approximately 10 am during one treatment phase (see "Aspirin first" intervention). During the other treatment phase, beginning after a 2 week washout, the order will be reversed and the subjects will receive 2000 mg acetaminophen at 8 am followed by 81 mg aspirin at 10 am (see "Aspirin last" intervention). The occurrence of the two study phases (interventions) will be randomized by order. Smokers and non-smokers will be matched for age and gender.
Drug: Aspirin first
Subjects will receive 81 mg aspirin at approximately 8 am followed by 1000 or 2000 mg acetaminophen at approximately 10 am during this intervention phase.
Drug: Aspirin last
Subjects will receive 1000 or 2000 mg acetaminophen at approximately 8am followed by 81 mg aspirin at approximately 10 am during this intervention phase.
Experimental: Acetaminophen 325 mg
In Part B of this protocol, non-smokers (N=8), we propose to establish the measurement of the acetylation of COX-1 in human platelets. Just like in Part A of this study, healthy, non-smoking male and female volunteers will be administered a single tablet of plain 325mg aspirin. Blood will be drawn and spot urine samples collected at 2 hrs, 4 hrs, 8 hrs, 24 hrs, 48 hrs (2 days), 96 hrs (4 days), 168 hrs (7 days), 240 hrs (10 days) after the Platelet COX-1 acetylation will be measured at various time points following drug administration to determine the kinetics of COX acetylation. Platelet and COX enzyme function assays will be performed at the same time to allow correlation of the enzyme acetylation kinetics with biological function.
Drug: Acetaminophen
The data will be handled the same as Part A.
Other Name: aspirin

Detailed Description:

Acetaminophen has antipyretic and moderate analgesic properties, but largely lacks anti-inflammatory activity. While its mechanism of action is not entirely understood, it is probably both an isoform nonspecific and partial cyclooxygenase (COX) inhibitor in humans at doses commonly taken for mild pain and pyrexia, such as 1000 mg. Although no inhibition of platelet aggregation is observed at this dosage, platelet thromboxane formation by COX is depressed by roughly 40%. Epidemiological studies suggest that at higher doses, 2000 mg and above, acetaminophen exhibits a gastrointestinal adverse effect profile indistinguishable from traditional, nonspecific NSAIDs. Thus, it is possible that maximal COX inhibition is achieved at higher doses. Interestingly, complete COX inhibition by non-selective COX inhibitors has the potential to antagonize the irreversible platelet inhibition induced by aspirin. In contrast to reversible inhibitors, aspirin acts by acetylation of a serine residue in the substrate binding channel of COX. For example, ibuprofen, a reversible and non-selective COX inhibitor, is thought to prevent aspirin from gaining access to this target site. This study investigates, whether COX inhibition by acetaminophen is dose dependent in humans and whether acetaminophen interacts with the irreversible COX inhibition by low dose aspirin. It addresses the dose-related effect of acetaminophen on COX activity and assesses potential pharmacological interactions with low dose aspirin in normal healthy volunteers. The primary hypothesis is that administrating acetaminophen before aspirin would antagonize the irreversible effects of aspirin, as assessed by the measurement of serum thromboxane B2 and platelet aggregation 24 hrs after the administration of the first study drug on day 6 of combination therapy.

The second aim will determine the effects of acetaminophen on oxidant stress and cyclooxygenase activity in patients who smoke. While the structural interaction of acetaminophen with COX is unknown, it may inactivate the enzyme by a molecular mechanism different from other NSAIDs. Thus, acetaminophen, which is a good reducing agent, might act to reduce COX from its active, oxidized form. When uninhibited, the peroxidase component of this bifunctional enzyme oxidizes its catalytic center to generate a tyrosyl radical that is required for its activity. Indeed, some reducing agents have the capacity to prevent COX activation in vitro. If reduction were the basis for COX inhibition by acetaminophen in vivo, it would be expected to be less pronounced under conditions of high peroxide tone, as occurs in inflammation. Indeed, acetaminophen, which is a phenol derivative, may act as a free radical scavenging antioxidant like other phenolic compounds, such as vitamin E and has been shown to alleviate oxidative damage in model systems. This study explores the potential antioxidant effect of acetaminophen in smokers. Such individuals represent a human model of oxidant stress. Novel approaches to the quantitative assessment of free radical induced damage to lipids are applied, which are elevated in smokers. Additionally, it is determined whether COX inhibition by acetaminophen is conditioned by oxidant tone in vivo.

Part B:

To develop and validate of a method to measure platelet COX-1 acetylation by aspirin.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age between 18 - 55
  • Subjects recruited for the "non-smoker group" must be in good health as based on medical history, physical examination, vital signs, and laboratory tests.
  • Subjects recruited for the "smokers group" will be chronic smokers of at least 4 years duration, but no longer than 20 years duration, who smoke 11-20 cigarettes per day. Smokers must be otherwise healthy as described above.
  • Female subjects of child bearing potential must be using a medically acceptable method of contraception (oral contraception, depo-provera injection, IUD, condom with spermicide, diaphragm, cervical cap, progestin implant, abstinence, tubal ligation, oophorectomy, TAH) throughout the entire study period. All female subjects must consent to a urine pregnancy test at screening and just prior to the start of each treatment phase of the study, which must be negative at all time points.
  • Subjects must be within 30% of their ideal body weight.

Exclusion Criteria:

  • Female subjects who are pregnant or nursing a child.
  • Subjects, who have received an experimental drug, used an experimental medical device within 30 days prior to screening, or who gave a blood donation of ≥ one pint within 8 weeks prior to screening.
  • Subjects with any coagulation, bleeding or blood disorders.
  • Subjects who are sensitive or allergic to acetaminophen and/or aspirin, as well as any of their components.
  • Subjects with documented history of any gastrointestinal disorders, including bleeding ulcers.
  • Subjects with any evidence of cancer.
  • Subjects with a history of heart disease, including myocardial infarction, angina, coronary artery disease, any evidence of coronary artery stenosis, arrhythmias, heart failure, having had a CABG or significant irregularities in the EKG.
  • Subjects with history of peripheral artery disease (claudication, bypass surgery or stent placement in extremity.)
  • Subjects with a history of stroke or transitory ischemic attacks (TIA).
  • Subjects with renal, hepatic, respiratory, endocrine, metabolic, hematopoietic or neurological disorder.
  • Subjects with a history of liver disease or abnormal LFTs (>2x upper limit normal).
  • Subjects with any abnormal laboratory value or physical finding that according to the investigator may interfere with interpretation of the study results, be indicative of an underlying disease state, or compromise the safety of a potential subject.
  • Subjects who have had a history of drug or alcohol abuse within the last 6 months.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00646906

Locations
United States, Pennsylvania
Hospital of The University of PA
Phila., Pennsylvania, United States
Sponsors and Collaborators
University of Pennsylvania
Investigators
Principal Investigator: Garret A. FitzGerald, MD University of Pennsylvania, Institute for Translationals Medicine and Therapeutics
Principal Investigator: Susanne Fries, MD University of Pennsylvania, Institute for Translationals Medicine and Therapeutics
Principal Investigator: Tilo Grosser, MD University of Pennsylvania, Institute for Translationals Medicine and Therapeutics
  More Information

Additional Information:
No publications provided

Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT00646906     History of Changes
Other Study ID Numbers: 708270, 0898
Study First Received: March 26, 2008
Last Updated: May 14, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Pennsylvania:
acetaminophen
low dose aspirin
cyclooxygenase
prostaglandin
drug interaction
platelet inhibition
urinary prostaglandin metabolites
oxidant stress
smoking

Additional relevant MeSH terms:
Infarction
Myocardial Infarction
Cardiovascular Diseases
Heart Diseases
Ischemia
Myocardial Ischemia
Necrosis
Pathologic Processes
Vascular Diseases
Acetaminophen
Aspirin
Analgesics
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antipyretics
Antirheumatic Agents
Cardiovascular Agents
Central Nervous System Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Fibrin Modulating Agents
Fibrinolytic Agents
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Platelet Aggregation Inhibitors
Sensory System Agents

ClinicalTrials.gov processed this record on October 21, 2014