NSAID therapy is really a complex topic, and is associated with a wide range of cautions and adverse effects, as is well known. Aspirin was really the first drug that was used as an NSAID, over a century ago. Of course, we know all these years later if aspirin came on the market now, it surely would be a prescription drug because it has such a profound effect on bleeding and it causes irreversible problems with platelets. Today, with COX-2 specific or relatively COX-2 specific drugs, it is no secret to anybody who really knows the pharmacology that you can’t trick the body. If you’re going to specifically block COX-2 and not COX-1 to avoid the toxicities such as the COX-1 blockade, you’re going to pay for that in some other way. The payment is a negative feedback loop that’s going to cause clotting, so that the risk for clotting is much higher with COX-2 specific drugs like celecoxib, Vioxx or rofecoxib which is no longer available. That’s problematic and that has led us to look to develop newer drugs for the future.
One of the problems we have with drugs that don’t selectively block COX-2, these drugs affect the cyclooxygenase-1 and certain protective prostaglandins in the stomach. The result of that is vasoconstriction and possible bleeding in the gut. A new alternative, Naproxcinod, was a formulation that combined naproxen with a nitric acid molecule and so, when the molecule split in the gut, it would release nitric oxide and will cause vasodilation in the vessels in the stomach. It had a protective mechanism but unfortunately, when we looked at how patients did on it, there was not really any superiority over this drug compared to other drugs. So it never made it to market.
Another example of what we probably will see in the future are drugs that affect hydrogen sulfide binds. We know again that the oxygenation changes and vasodilation and vasoconstriction changes with these NSAIDs and hydrogen sulfide is diminished in rodents and other animals that take anti-inflammatories. If we can enhance hydrogen sulfide in the gut that’s combined with these NSAIDs, we can provide a protective mechanism. There’s a lot of research going on with that with diclofenac and naproxen, indomethacin, and some other anti-inflammatories.
Another avenue under scrutiny are nanotech drugs, very, very small particle sizes that provide the same bang for the buck in terms of efficacy but the patient doesn’t need to ingest as much drug. This may result in a lesser GI toxicity profile. That’s what’s happening for the future.