Tissue selectivity and variability of effects of acetaminophen on arachidonic acid metabolism

Tolman, E.L.; Fuller, Barbara L.; Marinan, Barbara; Capetola, Robert J.; Levinson, Susan L; Rosenthale, Marvin E.

doi:10.1016/0262-1746(83)90025-2

Cited by 39 publications

(7 citation statements)

References 12 publications

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“…Paracetamol was virtually inactive on guinea-pig lung and spleen enzymes, but it was as potent as aspirin on an enzyme prepared from brain tissue (Flower & Vane 1972). Another group (Tolman et al 1983) has since repeated this finding but it has not been investigated further. My feeling is that there may be an isoenzyme system for cyclooxygenase and that paracetamol has a selective action on the brain component.…”

Section: Discussionmentioning

confidence: 85%

The Evolution of Non-Steroidal Anti-Inflammatory Drugs and their Mechanisms of Action

Vane

1987

Drugs

123

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The pro-inflammatory effects of prostaglandins have been clearly demonstrated with the use of various animal models of inflammation. Furthermore, the anti-inflammatory effects and some of the side effects of aspirin and other non-steroidal anti-inflammatory agents have been shown to depend on their ability to inhibit cyclo-oxygenase. These drugs, therefore, reduce the synthesis of prostaglandins, prostacyclin and thromboxane. They do not affect leukotriene production and there is no firm evidence to suggest that they alleviate inflammation through any other mechanism. In contrast, the corticosteroids facilitate the release of lipocortin which, through inhibition of phospholipase A, reduces arachidonic acid release. These drugs possess potent anti-inflammatory properties and attempts have been made to develop non-steroidal drugs, such as BW755C, that display similar anti-inflammatory activity through inhibition of the 2 main pathways of the arachidonic acid cascade.Administration of low dose aspirin 40 mg/day selectively inhibits production ofthromboxane A, without affecting prostacyclin. This may be because, firstly, about 60% of an administered dose of aspirin is deacylated to salicylate during first-pass metabolism and, secondly, platelets cannot regenerate cyclo-oxygenase. Thus, absorbed aspirin irreversibly affects platelet thromboxane production in the pre-systemic circulation, but the systemic plasma aspirin concentration is likely to be too low to affect prostacyclin synthesis. Studies in experimental inflammation have shown that after the administration of aspirin, the concentration of salicylate in inflammatory exudate is considerably higher than that of aspirin. In addition, a comparison of prostaglandin synthesis inhibitory potencies shows that the concentration of salicylate, but not of aspirin, at the inflammatory site is high enough to substantially inhibit prostaglandin synthesis.

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Section: Discussionmentioning

confidence: 85%

The Evolution of Non-Steroidal Anti-Inflammatory Drugs and their Mechanisms of Action

Vane

1987

Drugs

123

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“…Paracetamol possess potent analgesic and antipyretic properties, with very weak anti-inflammatory activity [27] and in vitro is a weak inhibitor of prostaglandin biosynthesis in peripheral tissues [28,29]. At therapeutic antinociceptive concentrations paracetamol is not a cyclooxygenase inhibitor [30].…”

Section: Discussionmentioning

confidence: 99%

Adrenergic mechanisms in antinociceptive effects of non steroidal anti-inflammatory drugs in acute thermal nociception in mice

Pinardi¹,

Sierralta²,

Miranda³

2002

Inflamm. res.

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NSAIDs induced antinociception in an acute thermal pain model without inflammation. The mechanism of antinociception induced by ketoprofen, diclofenac and piroxicam involves an activation of alpha2-adrenoceptors at spinal and supraspinal levels, while paracetamol-induced antinociception is probably due mainly to central activation of the descending noradrenergic inhibitory system by alpha1-adrenoceptors.

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“…Acetaminophen (ACET) may also selectively inhibit brain prostaglandin synthetase [2,3] . However, their mechanisms of action on the central nervous system are not fully defi ned.…”

Section: Introductionmentioning

confidence: 99%

Effect of Aspirin and Acetaminophen on Proinflammatory Cytokine-Induced Pain Behavior in Mice

Kwon¹,

Shim²,

Seo³

et al. 2005

Pharmacology

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Aspirin (ASA) is a widely used oral analgesic which acts as an inhibitor of cyclooxygenase. Acetaminophen (ACET) is also an effective analgesic and may selectively inhibit brain prostaglandin synthetase. Various proinflammatory cytokines injected into the central nervous system show pain behavior. In the present study, the effects of orally administered ASA and ACET on pain behaviors induced by various proinflammatory cytokines were examined. At a dose of 100 mg/kg, ASA or ACET did not affect the pain behavior induced by TNF-α (100 pg), IL-1β (100 pg) or IFN-γ (100 pg) administered intrathecally. However, at doses of 200 and 300 mg/kg, ASA or ACET significantly and dose-dependently attenuated pain behavior induced by TNF-α, IL-1β or IFN-γ administered intrathecally. Our results suggest that orally administered ASA and ACET produce antinociception by inhibiting the nociceptive action of TNF-α, IL-1β or IFN-γ administered intrathecally.

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Tissue selectivity and variability of effects of acetaminophen on arachidonic acid metabolism

Cited by 39 publications

References 12 publications

The Evolution of Non-Steroidal Anti-Inflammatory Drugs and their Mechanisms of Action

The Evolution of Non-Steroidal Anti-Inflammatory Drugs and their Mechanisms of Action

Adrenergic mechanisms in antinociceptive effects of non steroidal anti-inflammatory drugs in acute thermal nociception in mice

Effect of Aspirin and Acetaminophen on Proinflammatory Cytokine-Induced Pain Behavior in Mice

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