Prostanoids formation

Antipyretic analgesics represent p-ami-nophenol or pyrazolone derivatives with clinically useful analgesic and antipyretic efficacy. Their mechanism of action is not completely understood but thought to be mediated via inhibition of prostanoid formation by variants of COX enzymes. Acetaminophen (paracetamol), phenazone, and dipyrone belong in this group. 

The reduced activity of the n-6 fatty acid biosynthetic pathway in the diabetic nerve could decrease the availability of AA for prostanoid formation and this could have deleterious consequences on the nerve vasculature, with resultant adverse effects on nerve function. The depletion of AA could be exacerbated by a heightened level of reactive oxygen species (ROS), which react readily with the double bonds of polyunsaturated... 

ICgo used since relative potency of NSAID varies with concentration and NSAIDs are used therapeutically at doses that produce more than 50 % reduction of prostanoid formation... 

This chapter presents the main biosynthetic pathways for prostanoid formation, mechanisms of prostanoid action via specific receptors and, finally, the biological and pharmacological roles of individual prostaglandins, prostacyclins and thromboxanes. 

Although PLAj activity is the first step for prostanoid biosynthesis and can limit their availability, it is not the rate-limiting step in prostanoid formation. However, direct inhibition of PLA could potentially block the production of all eicosanoids, making it a desirable target for pharmacological intervention (Yedgar et al., 2000). 

Patrono, C, Patrignani, P and Garcia Rodriguez, LA (2001) Cyclooxygenase-selective inhibition of prostanoid formation transducing biochemical selectivity into clinical readouts. J Clin Invest, 108, 7-13. 

Serhan, CN and OUw, E (2001) Unorthodox routes to prostanoid formation new twists in cyclooxygenase-initiated pathways. J Clin Invest, 107, 1481-1489. 

Finally a few remarks should be made about essential fatty acid (EFA) deficiency (section 5.2.2). Linoleic acid is the precursor of the eicosanoids, leukotrienes, prostaglandins, thromboxanes and related compounds (section 3.4). Until recently it was thought that the classic skin symptoms resulting from a deficiency were due to a lack of eicosanoids. However, the specific role of n-6 acids (such as linoleate) as opposed to n-3 acids (such as a-linolenate) in membrane fluidity and their function cannot explain their essentiality. For example, aspirin ingestion which effectively prevents prostanoid formation does not result in the appearance of EFA-deficiency symptoms. It is also generally accepted that at least some cell lines in culture do not have an EFA requirement - thus suggesting that EFAs are not essential for the formation and function of cellular membranes in general. 

Cyclooxygenases. Figure 1 Pathways for the formation of prostanoids from arachidonic acid. Arachidonic acid is converted by cyclooxygenase to endoperoxides, which are acted upon by various synthesases to form the prostanoids. Prostacyclin and thromboxane are relatively unstable and break down rapidly to form the inactive metabolites 6-oxo-PGF1a and thromboxane B2, respectively. 

FIGURE 25.3 The formation of linear hydroperoxides and cyclic prostanoids during peroxidation of unsaturated acids with bisallylic positions. 

Certain polyunsaturated fatty acids are essential in the human diet (see Box 21-B). One of these, arachidonic acid (which may be formed from dietary linoleic acid), serves as a precursor for the formation of the hormones known as prostaglandins and a series of related prostanoids. Lipids of animal origin also... 

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