Myocardial Infarction Clinical Trial
Official title:
A Randomized, Double-Blind, Crossover Study to Evaluate the Mechanism of Action of Acetaminophen
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.
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.
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