Antiinflammatory drug — valdecoxib/parecoxib
Non-steroidal antiinflammatory drugs, such as aspirin, are effective analgesic, but can lead to substantial gastrointestinal side-effects, notably ulcers. The numerous NSAIDs developed had different activity profiles, but all are still gastrotoxic.
NSAIDs work by inhibiting the formation of prostaglandins, synthesis of which is controlled by the enzyme cyclooxygenase (COX), and the discovery that this enzyme exists in two forms has led to the development of novel NSAIDs. COX-2 is the form that has the inflammatory effects, whereas COX-1 is believed to be implicated in the gastrotoxic side-effects. Traditional NSAIDs affect both forms, hence their side-effect profiles. The recent development of selective COX-2 inhibitors like Pharmacia's celecoxib and rofecoxib from Merck & Co have been found to be effective for inflammatory conditions.
Acute pain is frequently treated by infusion and NSAIDs, notably ketorolac, have been used for this indication, as their side-effect profile is different to the opiates. However, the gastrotoxicity is still a problem, and other side-effects such as kidney and liver dysfunction and increased post-operative bleeding are problematic. But, like most NSAIDs, the marketed COX-2 inhibitors are only sparingly soluble in water. So the development of a COX-2 inhibitor that can be formulated parenterally would be extremely advantageous.
A selective COX-2 inhibitor that can be formulated in this way is being developed at Pharmacia. Researchers have made the sulphonamide-based compound valdecoxib, and its prodrug parecoxib sodium (pictured)1. The latter is rapidly converted to the former, and has been shown to have potent activity as both an antiinflammatory and analgesic. Parecoxib can be formulated parenterally.
In a randomised, double-blind placebo-controlled one week study, 94 healthy elderly patients were dosed intravenously with a formulation of parecoxib, ketorolac or a placebo. The total incidence of gastric or gastroduodenal ulcers in those receiving ketorolac was 39%, compared to those given parecoxib sodium or placebo where the incidence was 0%.2 It was found to be substantially more effective than morphine sulphate or placebo.3
Valdecoxib is now in Phase III clinical trials as an oral treatment for pain and arthritis, and parecoxib sodium has been submitted for regulatory approval.