Paracetamol is used worldwide for its analgesic and antipyretic actions. It has a spectrum of action similar to that of NSAIDs and resembles particularly the COX-2 selective inhibitors. Paracetamol is, on average, a weaker analgesic than NSAIDs or COX-2 selective inhibitors but is often preferred because of its better tolerance. Despite the similarities to NSAIDs, the mode of action of paracetamol has been uncertain, but it is now generally accepted that it inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes. This results in inhibition of phenoxyl radical formation from a critical tyrosine residue essential for the cyclooxygenase activity of COX-1 and COX-2 and prostaglandin (PG) synthesis. Paracetamol shows selectivity for inhibition of the synthesis of PGs and related factors when low levels of arachidonic acid and peroxides are available but conversely, it has little activity at substantial levels of arachidonic acid and peroxides. The result is that paracetamol does not suppress the severe inflammation of rheumatoid arthritis and acute gout but does inhibit the lesser inflammation resulting from extraction of teeth and is also active in a variety of inflammatory tests in experimental animals. Paracetamol often appears to have COX-2 selectivity. The apparent COX-2 selectivity of action of paracetamol is shown by its poor anti-platelet activity and good gastrointestinal tolerance. Unlike both non-selective NSAIDs and selective COX-2 inhibitors, paracetamol inhibits other peroxidase enzymes including myeloperoxidase. Inhibition of myeloperoxidase involves paracetamol oxidation and concomitant decreased formation of halogenating oxidants (e.g. hypochlorous acid, hypobromous acid) that may be associated with multiple inflammatory pathologies including atherosclerosis and rheumatic diseases. Paracetamol may, therefore, slow the development of these diseases. Paracetamol, NSAIDs and selective COX-2 inhibitors all have central and peripheral effects. As is the case with the NSAIDs, including the selective COX-2 inhibitors, the analgesic effects of paracetamol are reduced by inhibitors of many endogenous neurotransmitter systems including serotonergic, opioid and cannabinoid systems. There is considerable debate about the hepatotoxicity of therapeutic doses of paracetamol. Much of the toxicity may result from overuse of combinations of paracetamol with opioids which are widely used, particularly in USA.

Paracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of prostaglandins (PGs). However, the in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 (COX-2) inhibitors. Paracetamol also decreases PG concentrations in vivo, but, unlike the selective COX-2 inhibitors, paracetamol does not suppress the inflammation of rheumatoid arthritis. It does, however, decrease swelling after oral surgery in humans and suppresses inflammation in rats and mice. Paracetamol is a weak inhibitor of PG synthesis of COX-1 and COX-2 in broken cell systems, but, by contrast, therapeutic concentrations of paracetamol inhibit PG synthesis in intact cells in vitro when the levels of the substrate arachidonic acid are low (less than about 5 mumol/L). When the levels of arachidonic acid are low, PGs are synthesized largely by COX-2 in cells that contain both COX-1 and COX-2. Thus, the apparent selectivity of paracetamol may be due to inhibition of COX-2-dependent pathways that are proceeding at low rates. This hypothesis is consistent with the similar pharmacological effects of paracetamol and the selective COX-2 inhibitors. COX-3, a splice variant of COX-1, has been suggested to be the site of action of paracetamol, but genomic and kinetic analysis indicates that this selective interaction is unlikely to be clinically relevant. There is considerable evidence that the analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but its primary site of action may still be inhibition of PG synthesis. The action of paracetamol at a molecular level is unclear but could be related to the production of reactive metabolites by the peroxidase function of COX-2, which could deplete glutathione, a cofactor of enzymes such as PGE synthase.

Different types of consent are used to obtain human biospecimens for future research. This variation has resulted in confusion regarding what research is permitted, inadvertent constraints on future research, and research proceeding without consent. The NIH Clinical Center’s Department of Bioethics held a workshop to consider the ethical acceptability of addressing these concerns by using broad consent for future research on stored biospecimens. Multiple bioethics scholars, who have written on these issues, discussed the reasons for consent, the range of consent strategies, gaps in our understanding, and concluded with a proposal for broad initial consent coupled with oversight and, when feasible, ongoing provision of information to donors. The manuscript describes areas of agreement as well as areas that need more research and dialogue. Given recent proposed changes to the Common Rule, and new guidance regarding storing and sharing data and samples, this is an important and timely topic.

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