Aspirin, salicylate and prostaglandins

Smith, M. J. H.; Ford‐Hutchinson, A. W.; Walker, John R.; Slack, Joan

doi:10.1007/bf01968116

Cited by 17 publications

(6 citation statements)

References 17 publications

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“…We have also confirmed that high concentrations of salicylate, lasting for several hours, are found in inflammatory exudates after oral administration of aspirin (20).…”

Section: Discussionsupporting

confidence: 79%

Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Higgs¹,

Salmon²,

Henderson³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

202

109

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Among the nonsteroid antiinflammatory drugs there is generally a close correlation between the potency of their inhibition of arachidonate cyclooxygenase, and thus prostaglandin production, and their antiinflammatory activity.One anomaly in this generalization is that whereas aspirin and salicylate are equipotent as antiinflammatory agents, salicylate is less active than aspirin in inhibiting prostaglandin production in vitro. Using rats, we have now measured the concentrations of aspirin and salicylate in plasma and in inflammatory exudates after their oral administration and determined their effects on thromboxane B2 production in clotting blood and prostaglandin (PG) E2 concentrations in the exudates. We have also investigated the effects of both drugs, at concentrations achieved in the exudates, on PGE2 production by nonproliferative explants of acutely inflamed tissues. Aspirin is rapidly metabolized, resulting in peak concentrations of salicylate in the plasma and exudate that exceeded peak concentrations of aspirin by 30-to 50-fold. Furthermore, concentrations of aspirin rapidly declined, whereas high concentrations of salicylate persisted in the plasma and in the exudate for up to 6 hr after a single administration of aspirin. Both drugs reduced PGE2 concentrations in inflammatory exudates by 50-70%, but aspirin was considerably more potent than salicylate in inhibiting thromboxane B2 production in clotting blood. The concentration of salicylate found in inflammatory exudates 6 hr after the administration of aspirin was sufficient to reduce PGE2 production in explants by more than 50%. We conclude that the antiinflammatory action of both drugs depends on the inhibition of PGE2 synthesis by salicylate.The discovery that aspirin, indomethacin, and salicylate inhibit the synthesis of prostaglandins (1-3) provided the first comprehensive explanation of the mechanism of action of these drugs. Subsequent studies have shown that the broad group of nonsteroid antiinflammatory drugs inhibits arachidonate cyclooxygenase, the enzyme that converts arachidonic acid to prostaglandin endoperoxides (for review see ref. 4). However, anomalies exist in the potencies of these drugs with respect to their antiinflammatory activities and to their ability to inhibit cyclooxygenase; of particular interest has been the disparity between the potency of aspirin and salicylate in inhibiting cyclooxygenase. Aspirin and salicylate are equipotent as antiinflammatory agents, but aspirin is some 20 times more potent than salicylate in inhibiting an enzyme preparation from guinea pig lung in vitro (1). Furthermore, it has been reported that oral administration of aspirin (10 mg/kg) inhibited thromboxane (TX) production by rat platelets but 20 times this dose of salicylate had no effect (5). These findings led to speculation that the antiinflammatory activity of these drugs was not related to inhibition of prostaglandin (PG) synthesis (5, 6).We have now (i) measured the concentrations of aspirin and salicylate in plasma and inflam...

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“…We have also confirmed that high concentrations of salicylate, lasting for several hours, are found in inflammatory exudates after oral administration of aspirin (20).…”

Section: Discussionsupporting

confidence: 79%

Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Higgs¹,

Salmon²,

Henderson³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

202

109

View full text Add to dashboard Cite

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“…Furthermore, these oxymetabolites can regulate the production of inflammatory cytokines which may profoundly affect the course of inflammation. The problem in explaining the apparent equipotency of aspirin and sodium salicylate in vivo, despite their quite different activities as cyclooxygenase inhibitors in vitro, was extensively discussed in the 1970's [l, [38][39][40]. That active metabolites of salicylate might account for this discrepancy was indeed proposed: gentisate was considered but apparently rejected, based on its inactivity in the carrageenan paw oedema assay [38].…”

Section: Cytokine Actionmentioning

confidence: 98%

Is aspirin a prodrug for antioxidant and cytokine-modulating oxymetabolites

et al. 1993

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Aspirin and salicylate are transformed by stimulated human polymorphonuclear leucocytes (PMN), likely to be found at inflammatory sites, into both 2,3- and 2,5-dihydroxybenzoates (DHB). These DHB inhibit both the production of hydrogen peroxide by stimulated human PMN and prostaglandin (PG) E2 by activated rat macrophages. In contrast, DHB stimulated production of interleukin (IL)-1 and tumour necrosis factor (TNF) but inhibited IL-6 production by rat macrophages. These effects were probably a consequence of PGE2 inhibition. Gentisate (2,5-DHB) and homogentisate (a tyrosine metabolite) inhibited the lymphoproliferative action of IL-1. Some related phenols, e.g. 5-aminosalicylate, inhibited H2O2 production but had little effect on PGE2 production. These findings suggest that the local synthesis of DHB may contribute to the overall anti-inflammatory activity of salicylate, which (unlike aspirin) has little direct effect on PG production.

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“…It would therefore appear that the pharmacological properties of salicylate from pharmaceutical or dietary sources have relevance to human health and disease. Evidence extending over several decades demonstrates that salicylate exerts a number of effects on prostaglandin pathways [42]. More recent evidence suggests that these effects appear to be dependent, at least in part, on the intra-cellular oxidative conditions [43].…”

Section: Hypotheses That Salicylate Might Protect Against Childhood Cmentioning

confidence: 99%

Might salicylate exert benefits against childhood cancer?

Morgan¹,

Johnsen²

2010

ecancer

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Childhood cancers are a broad range of diseases. Research on the chemopreventive potential of non-steroidal anti-inflammatory drugs, such as aspirin (acetylsalicylate) has yet to be fully directed towards childhood cancers. A prima facie hypothesis on salicylate and childhood cancer would therefore be based on several factors. Firstly, salicylate inhibits the production of inflammatory prostaglandins, which have been shown to stimulate the growth of cancer cells. Secondly, salicylate inhibits the growth of cancer cells in pre-clinical models. Thirdly, salicylate is a natural component of fruits and vegetables so it is consumed within the diet. Further research, of which some possibilities are identified, is recommended.

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Aspirin, salicylate and prostaglandins

Cited by 17 publications

References 17 publications

Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Is aspirin a prodrug for antioxidant and cytokine-modulating oxymetabolites

Might salicylate exert benefits against childhood cancer?

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