Towards developing new strategies to reduce the adverse side-effects of nonsteroidal anti-inflammatory drugs.
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 (EP(3)) pathway, whereas the analgesic action is mediated predominantly by a reduced input to the EP(1) 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 EP(2) or EP(4) agonists that do not block the antipyretic or analgesic actions of NSAIDs that are mediated by reduced activation of EP(1) or EP(3) receptors. Moreover, EP(2) receptor-deficient mice had salt-sensitive hypertension and EP(4) receptor blockade moderated salt and water excretion and both EP(2) and EP(4) agonists had renoprotective effects. This suggests that strategies to maintain activation of EP(2) and EP(4) receptors during NSAID administration may not only reduce adverse effects but might confer additional benefits. In conclusion, enhancing EP(2) and EP(4) 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.
Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. nk37@kid.med.osaka-u.ac.jp
Noritaka
N
Kawada
Toshiki
T
Moriyama
Harumi
H
Kitamura
Ryohei
R
Yamamoto
Yoshiyuki
Y
Furumatsu
Isao
I
Matsui
Yoshitsugu
Y
Takabatake
Yasuyuki
Y
Nagasawa
Enyu
E
Imai
Christopher S
CS
Wilcox
Hiromi
H
Rakugi
Yoshitaka
Y
Isaka
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D058633:Antipyretics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005334:Fever / Q000188:drug therapy; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D009318:Natriuresis / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D018078:Receptors, Prostaglandin E / Q000187:drug effects*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists / Q000187:drug effects / Q000502:physiology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000187:drug effects / Q000502:physiology
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D058633:Antipyretics; D052246:Cyclooxygenase 2 Inhibitors; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype