Mechanisms of Action of Acetaminophen

NCT00646906 | Completed Results

• 1 other identifier: 708270
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Myocardial Infarction; Arthritis

Keywords

acetaminophen; low dose aspirin; cyclooxygenase; prostaglandin; drug interaction; platelet inhibition; urinary prostaglandin metabolites; oxidant stress; smoking

Outcome Measures

Primary Outcomes (1)

• Percent Change in Serum Thromboxane B2

  Thromboxan B2 is a stable metabolite of thromboxane A2. Thromboxane B2 formation during clotting of whole blood (37 degrees Celsius, 1 hour) is reflective of the capacity of platelets to form thromboxane A2. Serum Thromboxane B2 was measured by radio-immuno assay. The quantity of interest was percent change from start (8:00 am on day 1) to finish (8:00 am on last day) of each crossover period in serum thromboxane B2. This was calculated as: 100%\*(value at start of period minus value at end of period)/value at start of period.

  7 days (Phase 1a and 1b), 4 days (Phase 2)

Secondary Outcomes (1)

• Percent Change in Arachidonic Acid Induced Platelet Aggregation

  7 days (only Phase 1a)

Study Arms (4)

Phase 1a: Acetaminophen 1000mg / aspirin

EXPERIMENTAL

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 crossover period (see "Crossover period: Aspirin first" intervention). During the other crossover period, 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 "Crossover Period: Aspirin last" intervention). The occurrence of the two crossover periods will be randomized by order. Smokers and non-smokers will be matched for age and gender.

Drug: Aspirin First; Drug: Aspirin Last

Phase 1a: Acetaminophen 2000mg / aspirin

EXPERIMENTAL

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 crossover period (see "Crossover Period: Aspirin first" intervention). During the other crossover period, 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 "Crossover Period: Aspirin last" intervention). The occurrence of the two crossover periods will be randomized by order. Smokers and non-smokers will be matched for age and gender.

Drug: Aspirin First; Drug: Aspirin Last

Phase 1b: Acetaminophen 1000 mg alone

EXPERIMENTAL

Eight male and non-pregnant female subjects who are healthy and non-smoking will be recruited. They will receive a daily oral dose of 1000 mg acetaminophen for six days each administered at 8 AM (see "Acetaminophen 1000 mg/d" intervention). Study assessments will be performed on day 1 and on day 6. This is not a crossover design. Just one treatment period.

Drug: Acetaminophen 1000 mg/d

Phase 2: Acetaminophen vs. Ibuprofen

EXPERIMENTAL

Eight male and non-pregnant female subjects who are healthy and non-smoking will be recruited. In one period of this crossover study acetaminophen (1000 mg p.o.) will be administered orally at 8 AM, 2 PM, 8 PM and 2 AM for 3 days (see "Crossover Period: Acetaminophen 4000 mg/d" intervention). The last dose will be administered on day four at 8 AM In the other crossover period, after a washout period of at least 14 days, the subjects will receive ibuprofen (200 mg) orally at at 8 AM, 2 PM, 8 PM and 2 AM for 3 days (see "Crossover Period: Ibuprofen 800 mg/d" intervention). The last dose will be administered on day four at 8 AM Study assessments will be performed on day 1 and day 4 of each crossover period. The occurrence of the two crossover periods will be randomized by order.

Drug: Acetaminophen 4000 mg/d; Drug: Ibuprofen 800 mg/d

Interventions

Aspirin First DRUG

Crossover period Aspirin First: Subjects will receive 81 mg aspirin at approximately 8 am followed by acetaminophen at approximately 10 am.

Phase 1a: Acetaminophen 1000mg / aspirin; Phase 1a: Acetaminophen 2000mg / aspirin

Aspirin Last DRUG

Crossover period Aspirin Last: Subjects will receive acetaminophen at approximately 8 am followed by 81 mg aspirin at approximately 10 am.

Phase 1a: Acetaminophen 1000mg / aspirin; Phase 1a: Acetaminophen 2000mg / aspirin

Acetaminophen 1000 mg/d DRUG

Subjects will receive a daily oral dose of 1000 mg acetaminophen for six days each administered at 8 AM.

Phase 1b: Acetaminophen 1000 mg alone

Acetaminophen 4000 mg/d DRUG

Crossover period Acetaminophen 4000 mg/d: Acetaminophen (1000 mg p.o.) orally at 8 AM, 2 PM, 8 PM and 2 AM for 3 days. The last dose will be administered on day four at 8 AM.

Phase 2: Acetaminophen vs. Ibuprofen

Ibuprofen 800 mg/d DRUG

Crossover period Ibuprofen 800 mg/d: Ibuprofen (200 mg) orally at at 8 AM, 2 PM, 8 PM and 2 AM for 3 days. The last dose will be administered on day four at 8 AM.

Phase 2: Acetaminophen vs. Ibuprofen

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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, intrauterine device, 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.

You may not qualify if:

• 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 coronary intervention 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.
• Subjects with renal, hepatic, respiratory, endocrine, metabolic, hematopoietic or neurological disorder.
• Subjects with a history of liver disease or abnormal liver function tests (\>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.

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (1)

Hospital of The University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Links

• Institute for Translational Medicine and Therapeutics, University of Pennsylvania

MeSH Terms

Conditions

Myocardial Infarction; Arthritis; Smoking

Interventions

Acetaminophen; Ibuprofen

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis; Joint Diseases; Musculoskeletal Diseases; Behavior

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Phenylpropionates; Acids, Carbocyclic; Carboxylic Acids

Results Point of Contact

• Title: Tilo Grosser, MD
• Organization: University of Pennsylvania

tilo@pennmedicine.upenn.edu

215-573-7600

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 26, 2008
• First Posted: March 31, 2008
• Study Start: June 2, 2004
• Primary Completion: January 24, 2012
• Study Completion: January 24, 2012
• Last Updated: February 12, 2026
• Results First Posted: December 3, 2019

Record last verified: 2026-01

Locations

US (1)