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Towards developing new strategies to reduce the adverse side-effects of nonsteroidal anti-inflammatory drugs

Journal

CLINICAL AND EXPERIMENTAL NEPHROLOGY
Volume 16, Issue 1, Pages 25-29

Publisher

SPRINGER
DOI: 10.1007/s10157-011-0492-3

Keywords

COX-1; COX-2; PGE(2); EP; Antipyretic; Analgesic

Funding

  1. JSPS-KAKENHI [20590973]
  2. AHA [0465440U]
  3. NIDDK [DK-036079, DK-049870]
  4. NHLBI from National Institutes of Health [HL-68686]
  5. Grants-in-Aid for Scientific Research [20590973] Funding Source: KAKEN

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The antipyretic and analgesic actions of nonsteroidal anti-inflammatory drugs (NSAIDs) are caused by the inhibition of prostaglandin E-2 (PGE(2)), thromboxane A(2) and prostacyclin (PGI(2)) production. Accumulating evidence suggests that the inhibition of PGE(2) production can cause adverse side-effects of NSAIDs on fluid and blood pressure regulation, such as hypertension and edema formation. Since both cyclooxygenase (COX)-1 and COX-2 isoforms contribute to the production of PGE(2), selective COX-2 inhibitors are not free of these adverse side-effects although they may be less severe. Four subtypes of PGE(2) receptors have been identified. The antipyretic action of blunted PGE(2) production is mediated predominantly by a reduced input to the prostaglandin E receptor 3 (EP3) pathway, whereas the analgesic action is mediated predominantly by a reduced input to the EP1 pathway and perhaps by contributions from the other EP receptors. Accordingly, some of the adverse side-effects might be moderated by combined use of NSAIDs with selective EP2 or EP4 agonists that do not block the antipyretic or analgesic actions of NSAIDs that are mediated by reduced activation of EP1 or EP3 receptors. Moreover, EP2 receptor-deficient mice had salt-sensitive hypertension and EP4 receptor blockade moderated salt and water excretion and both EP2 and EP4 agonists had renoprotective effects. This suggests that strategies to maintain activation of EP2 and EP4 receptors during NSAID administration may not only reduce adverse effects but might confer additional benefits. In conclusion, enhancing EP2 and EP4 receptor activity by administration of selective agonists during the administration of NSAIDs has the potential to permit treating fever, inflammation and pain but with marginal adverse effects on fluid or blood pressure regulation.

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