Inhibition of prostaglandin biosynthesis by etodolac. I. Selective activities in arthritis

Abstract

Etodolac is the first anti-inflammatory drug belonging to the tetrahydropyranoindole class. In contrast to several other common anti-inflammatory drugs, etodolac exhibited an unusually high potency as an inhibitor of established adjuvant arthritis relative to its activity against carrageenan paw edema in the rat. This phenomenon led us to investigate whether the ability of NSAIDs to inhibit prostaglandin biosynthesis differed between cultures of macrophages, which are present in inflammatory exudates, and cultures of synoviocytes and chondrocytes, which contribute to inflammation of the articulating joint. Although other anti-inflammatory drugs were found to be equally active in all three cell types, etodolac was found to be much more effective on the cells of the joint than on the macrophage. This differential activity may be responsible for the striking efficacy of etodolac as an anti-arthritic drug.

Etodolac: Efficacy in osteoarthritis and effects on chondrocyte function

“…Etodolac has been shown to inhibit PGE 2 biosynthesis by macrophages, but is even more effective in inhibiting PGE 2 biosynthesis by chondrocytes and synoviocytes [12]. That etodolac is effective as a treatment for OA is demonstrated in the controlled double-blind data reviewed here: etodolac is clearly more efficacious than placebo and is comparable to aspirin, diclofenac, piroxicam, and naproxen [5][6][7][8].…”

“…Etodolac readily penetrates synovial fluid [18], and is a potent inhibitor of prostaglandin synthesis [12], but does not inhibit production of IL-1. Therefore, one might expect increased cartilage damage during treatment with etodolac.…”

Prostaglandins in inflammatory bone pathology: Mechanism and therapeutic benefit of etodolac

“…Bone resorption was somewhat attenuated even at the lower drug concentrations tested, possibly reflecting a PGE/-dependent contribution to the total response which accounts for IL-1 stimulation of bone resorption. The concentration dependence of etodolac inhibition of PGE 2 accumulation in calvarial cultures is in accord with the concentrations required to inhibit PGE~ biosynthesis in other connective tissue cells, such as synoviocytes and chondrocytes [14]. Other cyclooxygenase inhibitors have demonstrated the ability to inhibit bone resorption in vitro [23].…”

“…Bones were incubated for an additional 72 h, then bones and culture medium were assessed for 4SCa content. The PGE 2 content of some cultures was determined with an ELISA [14].…”

A optimized process for the synthesis of a key starting material for etodolac, a non steroidal anti- inflammatory drug.

“…Its therapeutic effects are due to its ability to inhibit prostaglandin synthesis. It is indicated for relief of signs and symptoms of rheumatoid arthritis and osteoarthritis 7 . A recent clinical trial demonstrated that etodolac was effective in improving rear limb function in dogs with chronic osteoarthritis secondary to hip dysplasia 8 .…”