Dipyrone is a common antipyretic drug and the most popular non-opioid analgesic in many countries. In spite of its long and widespread use, molecular details of its fate in the body are not fully known. We administered dipyrone orally to mice. Two unknown metabolites were found, viz. the arachidonoyl amides of the known major dipyrone metabolites, 4-methylaminoantipyrine (2) and 4-aminoantipyrine (3). They were identified by ESI-LC-MS/MS after extraction from the CNS, and comparison with reference substances prepared synthetically. The arachidonoyl amides were positively tested for cannabis receptor binding (CB1 and CB2) and cyclooxygenase inhibition (COX-1 and COX-2 in tissues and as isolated enzymes), suggesting that the endogenous cannabinoid system may play a role in the effects of dipyrone against pain.

In patients with HPS/aBS, excessive PGE2 synthesis and hyperreninemia is dependent on COX-2 activity. This observation proves the stimulatory role of COX-2 on renin-secretion in salt-depletion in humans. Clinical long-term efficacy and potential side effects of rofecoxib need to be evaluated in a larger cohort of HPS/aBS-patients.

Peroxisome proliferator-activated receptor (PPARs) modulate target gene expression in response to unsaturated fatty acid ligands, such as arachidonic acid (AA). Here, we report that the AA metabolite 15-hydroxyeicosatetraenoic acid (15-HETE) activates the ligand-dependent activation domain (AF2) of PPAR␤/␦ in vivo, competes with synthetic agonists in a PPAR␤/␦ ligand binding assay in vitro, and triggers the interaction of PPAR␤/␦ with coactivator peptides. These agonistic effects were also seen with PPAR␣ and PPAR␥, but to a significantly weaker extent. We further show that 15-HETE strongly induces the expression of the bona fide PPAR target

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