6-ketoprostaglandin-f1-alpha and 6-methoxy-2-naphthylacetic-acid

6MNA, the active metabolite of the non-acidic anti-inflammatory drug nabumetone, was investigated using intravenous administration for effects on (a) carrageenan paw oedema and gastric irritancy compared to either oral nabumetone or both oral and intravenous indomethacin when given acutely and (b) gastrointestinal irritancy when given in repeat dosing studies. An oral dose of nabumetone or intravenous 6MNA produced effective anti-inflammatory activity together with significant inhibition of paw exudate PGE2. An anti-inflammatory oral dose of nabumetone or intravenous 6MNA produced minimal effects on gastric 6-keto-PGF1 alpha production, with an absence of gastric damage, in contrast to indomethacin. In repeat dose studies, 6MNA failed to induce gastrointestinal damage even at doses where general toxicity was evident. These results show that in the rat 6MNA, the active metabolite of nabumetone, is an effective anti-inflammatory drug but, even in very high intravenous doses, does not have the propensity to induce gastrointestinal damage.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Butanones; Carrageenan; Dinoprostone; Gastric Mucosa; Indomethacin; Inflammation; Injections, Intravenous; Nabumetone; Naphthaleneacetic Acids; Rats; Rats, Wistar

Nabumetone is a novel non-steroidal anti-inflammatory drug (NSAID) which although a weak cyclooxygenase inhibitor is converted by the liver to metabolites which are more potent inhibitors of cyclooxygenase. Nabumetone may thus avoid the occurrence of gastric erosion while maintaining its efficacy as an anti-inflammatory drug. We compared the effects of nabumetone and 6-methoxy-2-naphthylacetic acid (6MNA; the principal metabolite of nabumetone) with naproxen and indomethacin on in vitro synthesis of the gastroprotective prostaglandins I2 and E2 by human gastric mucosa. To study the effects of 6MNA on peripheral target tissues the effects of the above NSAIDs on human platelet aggregation and thromboxane A2 synthesis were also studied. Prostanoid synthesis by the human gastric mucosa was inhibited by indomethacin, naproxen and 6MNA (in this order of potency) whereas nabumetone was completely without effect. Platelet aggregation and thromboxane A2 synthesis were similarly inhibited by the NSAIDS (viz. indomethacin greater than naproxen greater than 6MNA greater than nabumetone). These results support the view that nabumetone does not inhibit gastroprotective prostanoid synthesis, whereas its active metabolite 6MNA is an effective inhibitor of prostanoid synthesis in target tissues.

Topics: 6-Ketoprostaglandin F1 alpha; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Butanones; Culture Techniques; Dinoprostone; Epoprostenol; Gastric Mucosa; Humans; Indomethacin; Nabumetone; Naphthaleneacetic Acids; Naproxen; Platelet Aggregation; Thromboxane A2; Thromboxane B2