COX 1 and 2: The Cyclo-Oxygenase Systems
While many NSAID’s – Non-steroidal anti-inflammatory drugs, are considered to have equivalent efficacy, there is now no doubt that NSAID’s have different side-effect profiles The explosion of knowledge about the different cyclooxygenase enzymes has given us a more fundamental understanding of the actions and side effects of these drugs.
Fries et al showed with The Arthritis, Rheumatism and Aging Medical Information System (ARAMIS) database, of over 17 000 patients in 37 centres in the US and Canada, that there is considerable morbidity and mortality from arthritis. They confirm, as have other researchers, that NSAID’s are not all the same but rather, have different toxicity profiles. They illustrated appropriately, that the disease modifying drugs (DMARDs), used in the therapy of inflammatory arthritis, have an acceptable side effect profile. They showed that the toxicity profile of these drugs used appropriately was of similar scale to the NSAID’s . Therefore correct diagnosis and treatment of the underlying condition with DMARDs where appropriate, is essential. However symptomatic therapies utilizing NSAID’s, have remained essential therapeutic components in the drug regimens of patients with arthritis. NSAID’s remain perhaps the most widely prescribed drugs, worldwide. However they are associated with significant side effects, that complicate their use, especially in the elderly, a population group that is set to rise with the advent of the maturing baby boom generation.
In the 1980’s Needleman showed that COX enzyme was increased in inflamed tissue and that COX was stimulated by interleukin-1 (IL-1) on cultured human dermal fibroblasts. They showed a dose-dependent response curve. This suggested IL-1 dependent transcriptional regulation.
In 1990 he demonstrated the induction of COX by endotoxin. An increase in COX was prevented by glucocorticoids. However it was noted that dexamethasone did not affect baseline prostaglandin formation.
They therefore postulated a second COX enzyme. In 1991 the second COX isoform was cloned. This represented what is now known as COX-2. COX-1 is now known to be present in most tissues as the housekeeper enzyme. COX-2 is inducible by inflammation. It is not present at baseline, but increases in response to inflammation including arthritis. It has 60% homology with COX-1. Both have the same affinity to convert arachidonic acid to prostaglandin. COX-1 maintains normal gastric mucosa and influences kidney function. The inhibition of COX-1 is therefore undesirable. The inhibition of COX-2 on the other-hand is a desirable effect.
The concept of the COX-2 to COX-1 ratio provides us with a mechanism to assess the balance of inhibition of the inducible COX-2. Analysis of these ratios and side effects of the older conventional non-steroidal anti-inflammatories show that the lower the ratio, the lower the COX-1 inhibition, and the lower the overall side effect profile. In the guinea pig macrophage model of Engelhardt, meloxicam had a ratio in the order of 0.33, diclofenac, 2.2 and piroxicam 33.