Clinical trial NCT00646906
Conditions: Myocardial Infarction Arthritis
Keywords: acetaminophen low dose aspirin cyclooxygenase prostaglandin drug interaction platelet inhibition urinary prostaglandin metabolites oxidant stress smoking
Sponsor: University of Pennsylvania
Start date: 2004-06-02; Completion date: 2012-01-24
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

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 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.

The third aim, will compare the degree of COX inhibition by acetaminophen with that of a thoroughly characterized nonselective COX inhibitor, ibuprofen.

Arms: arm 1: 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. arm 2: 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. arm 3: 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. arm 4: 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.
Interventions: intervention 1: Aspirin First intervention 2: Aspirin Last intervention 3: Acetaminophen 1000 mg/d intervention 4: Acetaminophen 4000 mg/d intervention 5: Ibuprofen 800 mg/d
Intervention descriptions: intervention 1: Crossover period Aspirin First: Subjects will receive 81 mg aspirin at approximately 8 am followed by acetaminophen at approximately 10 am. intervention 2: Crossover period Aspirin Last: Subjects will receive acetaminophen at approximately 8 am followed by 81 mg aspirin at approximately 10 am. intervention 3: Subjects will receive a daily oral dose of 1000 mg acetaminophen for six days each administered at 8 AM. intervention 4: 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. intervention 5: 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.

Protocol documents: