A question of litter quality

ciated with inflammatory diseases, it doesnot prevent the hallmark of progressivelycrippling rheumatoid arthritis — thedestruction of joints. This could be due to thelimited effect that aspirin can have on NF- kBactivation, constrained as it is by the narrowtherapeutic window. The most effectivedrugs for reducing joint destruction areimmunosuppressants such as prednisoloneand cyclosporin A. These drugs workbecause they are extremely effective atinhibiting the transcription of genes thatencode pro-inflammatory cytokines. Unfor-tunately, both have dose-limiting toxicitiesassociated with the mechanisms by whichthey function. Cyclosporin A inhibits cal-cineurin, an enzyme that regulates the ac-tivity of transcription factors (therapeuticeffect) in some cells, but also regulates thefunction of ion channels (toxic effect) inother cells. Prednisolone binds to the gluco-corticoid receptor, which then repressestranscription (therapeutic effect) in somecellular contexts, but activates transcription(toxic effect) in others. There is limitedhope of separating the undesirable from thedesirable effects of these drugs. On the other hand, thanks to the work ofYin and colleagues, we can consider two newapproaches to separating the therapeuticfrom the toxic effects of high-dose aspirin.First, IKK- bmight be an excellent moleculartarget for anti-inflammatory drugs, givingpharmacologists a simple, quantitative assayfor the therapeutic activity of new chemicalentities. Second, we now know that selective,but weak, inhibitors of IKK-b exist, givingmedicinal chemists a starting point fromwhich to build more potent inhibitors withgreater target selectivity. Using these tools,we may be able to generate small moleculesthat can prevent rheumatoid joint destruc-tion, rather than just relieving the symptomsassociated with that destruction. Until then, take two aspirin and call me in themorning.