![]() 6 However, ACT was subsequently found to inhibit COX in the brain. 6 Initially, due to ACT’s weak anti‐inflammatory and antiplatelet action it was not thought to inhibit COX. 6 More precisely, NSAIDs exert their action on the cyclooxygenase (COX) enzyme. Despite their use since the late 1800s, the mechanism of action of NSAIDs was not elucidated until 1971. 5 ACT has similar functions (i.e., analgesic/antipyretic) to non‐steroidal anti‐inflammatory drug (NSAIDs). 4 Thereafter, ACT use increased markedly, currently used by 60 million people per week in the United States. 2 In 1949 it was established that the therapeutic efficacy of phenacetin was due to its metabolite ACT, 3 with phenacetin use subsequently discontinued in the United Kingdom (1980) and United States (1983). 1 Erroneously, phenacetin was preferred to ACT at this time due to a perceived greater safety profile however, it was found to have a role in analgesic nephropathy. Robust research designs are required in humans to objectively confirm these hypotheses.Īcetaminophen (ACT also known as paracetamol) is an effective and safe analgesic/antipyretic drug, used as early as 1893. Thus, we suggest with specificity to human in vivo physiology that ACT: (i) does not act on a third COX isoform (ii) is not selective in its COX inhibition and (iii) inhibition of COX isoforms are determined by subtle and nuanced physiological variations. ACT is an effective antipyretic (COX2 preference for PG synthesis) and can reduce afebrile core temperature (likely COX1 preference for PG synthesis). In vivo ACT efficacy is reliant on intact cells and low peroxide tone while the arachidonic acid concentration state can dictate the COX isoform preferred for PG synthesis. COX isoform inhibition by ACT may depend on subtle in vivo physiological variations specific to ACT. However, this is markedly lower than other available selective COX2 inhibitors (up to 433‐fold) and tempered by proof of potent COX1 inhibition within intact cells when peroxide tone is low. ACT may selectively inhibit COX2, with evidence of a 4.4‐fold greater COX2 inhibition than COX1. Yet a physiologically functional COX3 isoform has not been sequenced in humans, refuting these claims. A COX1 splice variant (often termed COX3) is purported by some as the elusive target of ACT’s mechanism of action. COX variants have been sequenced among various mammalian species including humans. Two COX isoforms (COX1/2) share 60% sequence structure, yet their functions vary. ACT’s analgesic and antipyretic actions are attributed to cyclooxygenase (COX) inhibition preventing prostaglandin (PG) synthesis. The precise mechanistic action of acetaminophen (ACT paracetamol) remains debated.
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