OSTEOARTHRITIS: SLIDES & ANIMATIONS

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     In a galaxy far, far away!

Animation 16: The NSAID Wars : This cartoon reflects my thoughts about the drug companies and their battles for their share of the NSAID market.
Animation 17a: Cox-1 in Action : Cox-1 is seen catalyzing its substrate, arachidonic acid.
Animation 17b: A NSAID Blocks Cox-1 : A non selective NSAID reversibly blocks the catalytic site of cox-1.
Animation 17c: A NSAID Blocks both Cox Isoforms : A non selective NSAID reversibly blocks the catalytic site of both cox-1 and cox-2.
Animation 17d: A Selective Cox-2 NSAID in Action : A selective cox-2 NSAID is shown discriminating between the two cox isoforms, blocking only cox-2.
Animation 17e: The Cellular Location of Cox-1 : A cell is entered and the location of cox-1 near the ER is visualized.
Animation 17f: The Cellular Location of Cox-2: A cell is entered and the location of cox-1 near the ER is visualized.

      Author's note: This last paragraph was written in 1998. It is now 2/2005, and the safety issue bombshells concerning the selective cox-2 drugs has fallen. Vioxx (rofecoxib), has been pulled from the market. Not only that, but a possible thrombosis problem with naproxene has been raised. Now, what's a poor little rheumatologist suppose to do? There certainly hasn't been much direction from our big brothers at the ACR, has there?
      I for one remember that mobic (meloxicam) was initially touted as a selective cox-2 drug. And it is, at low doses, i.e.7.5-10 mg a day. As far as I can tell, there is no comparable (to the vioxx, celebrex long term trials) thrombosis safety data for mobic at those doses. And why should there be?. So I guess for now its back to relafen (nabumatone, but at $2 a day??!!), lodine (etodolac, a little better price), arthrotec, and yes, maybe even the old time nsaids (naproxene, ibuprofen, piroxicam ($3 a month!!!! but it's an ulcer maker), diclofenac, etc., given to the healthy young (but I'm not sure I have very many healthy young patients in my practice. That's right, I don't see fibro in follow- ups.). Or perhaps the old time nsaids should be given to patients along with proton pump inhibitors. Anyway, the Chinese do have an old saying. I know, I live with a bunch of them. "May you live in interesting times." It's a curse!

Animation 16: The NSAID Wars : This cartoon reflects my thoughts about the drug companies and their battles for their share of the NSAID market.
Animation17a: Cox-1 in Action : The characteristic structural changes with OA.
Animation 17b: A NSAID Blocks Cox-1. : A non selective NSAID reversibly blocks the catalytic site of cox-1.
Animation 17c: A NSAID Blocks both Cox Isoforms : A non selective NSAID reversibly blocks the catalytic site of both cox-1 and cox-2.
Animation 17d: A Selective Cox2 NSAID in Action :A selective cox-2 NSAID is shown discriminating between the two cox isoforms, blocking only cox-2.
Animation 17e: The Cellular Location of Cox-1 :A cell is entered and the location of cox-1 near the ER is visualized.
Animation 17f: The Cellular Location of Cox-2 :A cell is entered and the location of cox-1 near the ER is visualized.

      Numerous studies suggest that the incidence of clinically significant GI events is from 1-4% per year for NSAID’s. There is a debate whether certain currently marketed compounds are safer and this topic will be discussed. There are now several compounds under study that have been designed to be highly selective inhibitors of cox-2 while sparing cox-1. It is hoped that these agents will have far less toxicity than previous agents while still maintaining efficacy. This topic will be discussed.

     In the animation 17a, arachidonic acid, which is the substrate for the enzyme, cyclooxygenase-1 (cox-1), is seen entering the cox-1 catalytic pocket.
The enzyme facilitates the conversion of the substrate into the product, PGG2.
     A non selective NSAID, such as naproxene, is seen in animation 17b reversibly blocking the cox-1 catalytic site. In the next animation, a non selective NSAID, such as naproxene, blocks the catalytic site of both cox-1 and cox-2.
     Research over the past several years has shown that these two structurally very similar cox isoforms serve quite different purposes in the body. Generally speaking, cox-1 deals with housekeeping functions, such as maintenance of a healthy gastric mucosal lining, whereas cox-2 is inducible, and is central to many inflammatory processes. It made a lot of sense, at the time, to try to selectively block cox-2.
     In animation 17d, a cox-2 selective NSAID, such as the three which have been marketed in the US, celebrex, vioxx, and bextra, are shown reversibly blocking the catalytic site of cox-2, being unable to enter the catalytic site of cox-1.
     As it stands here in 2005, and after a great deal of effort, Merck proved that vioxx was safer on the stomach than non selective nsaids. However, with just as much incredible effort, Searle did not achieve similar proof for celebrex, probably because they allowed baby aspirin in their gastric safety trial.
     Alas, the asymmetry of impact on the cox-1 / cox-2 system apparently has other untoward effects, i.e. the alterations in concentration of all the end products of these two enzymes leads to hypercoagulability.
     In animation 17e we enter a chondrocyte and visualize two cox-1 molecules in action. Note their location near endoplasmic reticulum, and that they are functioning with the need for outside signal influence.
     In general, the role of cox-2 is quite different from cox-1. In animation 17f we witness a proinflammatory cytokine, such as TNF or IL-1, interacting with its membrane receptor, resulting in an intracellular signal which then impacts the nucleus, resulting in transcription, and translation, and ultimately leading to the production of cox-2. Cox-2's location on the nuclear envelope is noted.
The NSAID is non covalently bond, and is free to exit the site.
In the case of aspirin, the catalytic site is entered, and then acetylated, permanently deactivating the enzyme.
     In summary, there are now numerous new concepts about arthritis disease development as well as as variety of new treatment approaches. I expect to see several major advances in the understanding and treatment of arthritis in the next few years. It is a very exciting time for Rheumatology.

Slides, artwork and photos and animation by Craig Wiesenhutter, M.D. unless indicated.

References:

Klippel, John H., and Paul A. Dieppe, Rheumatology, Second Edition. Mosby. This is the best textbook for this subject.

Hubbard, R.C., Koepp, R.J., Yu, S., Talwalker, S., Geis, G.S., Wiesenhutter, C.W., Makarowski, W.S., and H.A. Paulus. SC-58635 (CELECOXIB) A Novel Cox-2 Selective Inhibitor, Is Effective as a Treatment for Osteoarthritis (OA) In a Short-Term Pilot Study. Arthritis Rheumatism, 1996 Sept (Suppl), 39(#9): p. S123 Abstract #574

Hawkey et all "Omeprazole compared with Misoprostol for ulcers associated with NSAIDs" NEJM vol 338, number 11, March 12, 1998 pg 727.