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Salicylate (12.1 mg/min)

Oral

Figure 2.38 Temperature and heat elimination responses to intravenous sodium salicylate in a febrile patient. Oral and ear temperatures (°C) and finger heat elimination (cal/min) are shown during an intravenous infusion of saline (0-30 min), an intravenous bolus injection of 2 g, and subsequent intravenous infusion of sodium salicylate at 12.1 mg/min (30-80 min). Plasma salicylate concentrations at 20 and 42 min after start of salicylate infusion were 215 mg/ml and 229 mg/ ml, respectively. Note the increased heat production that parallels the fall in body temperature, suggesting uncoupling of oxidative phosphorylation (Section 2.2.3) (modified after [383]).

Figure 2.38 Temperature and heat elimination responses to intravenous sodium salicylate in a febrile patient. Oral and ear temperatures (°C) and finger heat elimination (cal/min) are shown during an intravenous infusion of saline (0-30 min), an intravenous bolus injection of 2 g, and subsequent intravenous infusion of sodium salicylate at 12.1 mg/min (30-80 min). Plasma salicylate concentrations at 20 and 42 min after start of salicylate infusion were 215 mg/ml and 229 mg/ ml, respectively. Note the increased heat production that parallels the fall in body temperature, suggesting uncoupling of oxidative phosphorylation (Section 2.2.3) (modified after [383]).

A recently discovered additional mechanism of the antipyretic aspirin action might be the inhibition of "primary" pyrogen generation by inhibition of viral replication. This has been shown for influ-

References

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Summary

Aspirin inhibits COX-2-dependent prostaglandin (PGE2) formation in vitro whereas salicylic acid is considerably less potent. In vivo, both compounds are about equipotent inhibitors ofinflammation, fever, and (inflammatory) pain. Inhibition of prostaglandin biosynthesis is a central component of the anti-inflammatory, antipyretic, and analgesic actions of aspirin but independently does not sufficiently explain all of the multiple biological activities. Therefore, NSAIDs that were designed to solely inhibit prostaglandin synthesis via modulation of COX-enzyme activity do not share the full spectrum ofbiological activities with salicylates.

The anti-inflammatory action of aspirin involves interactions with other mediator systems, allowing for the accumulation and activation of white cells and cytokine production. This might also include generation of 15-(R)-HETE via acety-lation of COX-2 and subsequent generation of aspirin-triggered lipoxin, an anti-inflammatory mediator that stimulates resolution of inflammation. Further actions include transcriptional effects on regulation ofgene expression, including inhibition of inflammatory cytokines and other mediators of inflammatory or immune responses, including COX-2.

The analgesic effect ofaspirin involves peripheral and central sites of actions and also additional mediator systems. Both of them probably involve prostaglandins that are generated in both injured tissues and neuronal cells by an upregulated COX-2. Peripheral analgesic actions of aspirin include inhibition of prostaglandin release at a site of injury with subsequent reduced sensitiza-tion of nociceptive nerve terminals. Central effects involve changes in serotoninergic neurotransmission and interactions with antinocicep-tive hypothalamic neurons. There might be a relationship to the analgesic effects mediated via the endocannabioid system. In clinical conditions, different sites of action might be involved, dependent on the kind of injury and kind and intensity ofthe noxious stimulus. The functional consequences are hyperalgesia and allodynia that are both antagonized by aspirin.

The antipyretic action ofaspirin is due to inhibition of PGE2 formation in the central nervous system. In addition, aspirin and salicylate not only interfere with endogenous pyrogens and their induction of COX-2 expression and activity but will also reduce fever by peripheral anti-inflammatory effects. Whether aspirin in man directly interacts with viral replication, a possible additional explanation for an antipyretic action, remains to be determined.

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