Nonsteroidal anti-inflammatory drugs, acetaminophen, cyclooxygenase 2, and fever.Nonsteroidal anti-inflammatory drugs acetaminophen cyclooxygenase 2 and fever the contents of www. The Xyclooxygenase envisages the development of a common methodology for the preparation, storage, dissemination and evaluation of scientific literature in electronic format. As the project develops, new journal titles are being added in the library collection. The objective of the site is to implement an electronic virtual library, lean xtreme during cycle full access to a collection of serial titles, a collection of issues from individual serial titles, as well as to the full text of articles. The access to both serial titles and articles is available via indexes and search forms.
Nonsteroidal anti-inflammatory drug - Wikipedia
Humans have been using nonsteroid antiinflammatory drugs NSAIDs in various forms for more than 3, years 1. They are still our favorite medicines. Estimates vary, but it appears, for instance, that each year we consume around 40, metric tons of aspirin, equating to about billion aspirin tablets mg is a standard size.
However, despite this long history and large volume of use, we still have an incomplete understanding of how the NSAIDs achieve their actions. Most recently, molecular biology, together with pharmacology, has brought the greatest steps forward in knowledge.
After 3, years, the first real progress in our understanding of the mechanism of the NSAIDs came 30 years ago. After 3, years, the first real progress in our understanding of the mechanism of action of the NSAIDs came 30 years ago, when it was revealed that these chemically varied drugs all reduced the formation of prostaglandins.
This ability was associated with inhibition of COX, which converts arachidonic acid to the prostaglandin precursor prostaglandin PG H 2 3.
Understanding that the NSAIDs inhibited prostanoid formation led to an appreciation of the mechanisms underlying the effects of these drugs. At sites of inflammation, the local production of prostanoids such as PGE 2 can sensitize pain nerve endings and increase blood flow, promoting feelings of pain and driving tissue swelling and redness 1 , 5.
Similarly, prostanoids such as PGI 2 and PGE 2 were found to be protective to the stomach and so inhibition of their formation provided an explanation for the gastrointestinal toxicity associated with prolonged and high-dose use of NSAIDs 1 , 5 , 6. The inhibition of COX in platelets provided an explanation for the ability of aspirin to reduce blood clotting 7. But still there were a number of questions that remained unanswered through the s and s.
For instance, why, when used at similar antiinflammatory doses, were the NSAIDs differently toxic to the gastrointestinal tract 5 , 8?
Also, how did acetaminophen fit into this scheme? Did it act by inhibiting COX? Intriguingly, test tube experiments showed that acetaminophen might selectively target the COX present in the brain 9. Could this explain why it was analgesic and antipyretic but not antiinflammatory? COX-2 was rapidly up-regulated at inflammatory sites and appeared responsible for the formation of proinflammatory prostanoids.
COX-1, meanwhile, appeared to shoulder the responsibility for the production of physiologically relevant prostanoids such as those in the stomach and platelets 1 , 5. These drugs would, it was hoped, be antiinflammatories as good as the traditional NSAIDs but have much reduced toxic side effects, particularly on the gastrointestinal tract 1 , 5. Even though in inflammatory models COX-2 inhibitors were as active as traditional NSAIDs, worked similarly in both human and animal models of pain, and reduced fever in a similar way to the NSAIDs 1 , 5 , 16 , there were still some confusing issues.
For example, the widespread use of the newer generation of COXselective compounds demonstrated that COX-2 also had physiological roles, being involved, for instance, in the maintenance of fluid balance by the kidney Dan Simmon's group suggest this is because of the presence of a variant of COX-1, which they have named COX-3, that is especially sensitive to acetaminophen and related compounds 2.
If this enzyme were particularly expressed in the brain, could it explain both the characteristics of acetaminophen and Flower and Vane's findings from 30 years ago 9? It is difficult to produce an unequivocal reply, but let us try to approach an answer by drawing on what we know about acetaminophen and the roles of COX-1 and To begin with, let us consider fever, because pyresis is a more simply modeled process than analgesia.
Interestingly, and at odds with Chandrasekharan et al. Finally, the sites of COX-3 expression do not appear to accord well with those sites associated with fever, and we might expect to see the protein present within the hypothalamus 25 rather than the cerebral cortex.
All these considerations appear to argue against the COX-3 of Chandrasekharan et al. However, the results from Chandrasekharan et al. Pain is a more difficult process to unravel. As outlined above, prostanoids produced at sites of inflammation can sensitize nerve endings and so promote the localized feelings of pain associated with inflammatory events and tissue injury These prostanoids can be produced by COX-2 induced by the local inflammatory processes.
How then does acetaminophen bring about its analgesic effects, because it is not a peripheral antiinflammatory? With the discovery of COX-2, new efforts have been made to comprehend the roles of prostanoids within the central nervous system CNS. It appears that COX-2 is constitutively expressed in the CNS and also rapidly up-regulated to reinforce pain perception 27 , Could acetaminophen act on this CNS enzyme?
COXselective inhibitors appear to produce analgesic responses at least as good as traditional NSAIDs in inflammatory, dental, or postoperative pain 29 — But maybe acetaminophen targets an additional enzyme. Furthermore, Dan Simmon's group has previously proposed the existence of an isoform of COX-2 that is particularly sensitive to acetaminophen 33 , From the above, it seems that the most significant implication of the study of Chandrasekharan et al.
If we express variants of COX-1 and -2, could different drugs inhibit different variants to different extents? For example, much recent attention has been paid to the ability of COXselective inhibitors to reduce circulating PGI 2 levels and to the hypothesis that this could be linked to an increase in thrombotic risk Or could varied products from just two distinct genes provide a family of COX proteins with overlapping contributions to prostanoid production throughout the body?
We know that both COX-1 and -2 have constitutive roles in the kidney. All this has yet to be understood, but as we continue to push toward an understanding, it is important to note that Chandrasekharan et al. In terms of our 3,year quest to understand the mechanism of action of the NSAIDs, Dan Simmon's group has provided another significant step forward.
Two distinct genes for COX-1 and -2 may give rise to a number of constitutive and inducible COX proteins with overlapping functions. We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail.
We do not capture any email address. Skip to main content. Filling in the gaps toward a COX continuum? Warner and Jane A. PNAS October 15, Figure 1 A COX continuum? See companion article on page Samuelsson B Biosci Rep 3: Patrono C Am J Med Botting R J Physiol Pharmacol Thank you for your interest in spreading the word on PNAS.
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