Oxidized Anion May Have Role In Vioxx Toxicity

[slutticus]

Oxidation to a maleic anhydride derivative may be a factor in the long-term toxicity of rofecoxib (Vioxx), a new report suggests. This previously unknown reactivity is not shared by other cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib (Celebrex), valdecoxib (Bextra), and lumiracoxib (Prexige). The hypothesis, if proven true, runs counter to the assumption that other COX-2 inhibitors pose the same risk to humans as Vioxx.

Vioxx was withdrawn from the market last September by its manufacturer, Merck, after a clinical trial indicated that it poses an increased risk of cardiovascular events.

Vioxx is a weak acid, and the anion formed when it releases its acidic proton is highly reactive toward atmospheric oxygen, according to laboratory studies by Harvard University chemists Leleti Rajender Reddy and E. J. Corey. The products are principally a maleic anhydride and lesser amounts of a -hydroxybutenolide http://dx.doi.org/10.1016/j.tetlet.2004.12.055>.

According to the authors, the maleic anhydride has not been reported as a Vioxx metabolite. They suggest that some of it may survive long enough in vivo to react with the nucleophilic groups of biomolecules and tissues. “The consequences of this may be a low-level chronic toxicity that is cumulative and possibly dangerous over periods of many months. It is perhaps not irrelevant that the cardiotoxicity of Vioxx was not apparent from short-term (one year or less) studies,” they write.






more...
http://pubs.acs.org/cen/news/83/i02/8302vioxx.html

[Fridays Child]

1. After Vioxx was withdrawn, I started taking a marine lipid supplement...

...called Lyprinol for my arthritis. It reduces pain at least as much as, and probably more than, the COX-2s do. I won't go back, even if all of the COX-2s are found to be perfectly safe. Lyprinol is completely safe, and it supplies Omega-3 and Omega-6 fatty acids, as well. Besides, after completing the six-week loading dose period, Lyprinol costs me less than half of what I had to pay out of pocket per month for the COX-2s.

[Warpy]

2. That doesn't work on rheumatoid arthritis.

Right now I'm living on Prednisone and Tylenol #3. It's all I can afford. I still have half a prescription of Celebrex left, but thought that it might have something to do with the mild right sided failure and shortness of breath I'd been having, so I stopped it when Vioxx was withdrawn. I'd been on it for 3 years.

It's doubtful that the above described mechanism is the correct one. Preliminary research suggests that COX-1 has a pro clotting effect, and that inhibiting COX-2 allows that effect to continue unchecked. There's also research that shows COX-1 has a role in causing arterial plaque to rupture.

The real problem here is the stupid war on drugs. Opiates are the safest and most effective treatments for chronic pain out there, but there is great pressure on pharmaceutical companies to come up with non narcotic analgesics because of the stupid drug war. They've only succeeded in coming up with dangerous drugs that kill people. Remember Zomax?

I'd advise against taking COX-2 inhibitors if there is any other alternative available until the final word is in on the mechanism that has been killing people.

[Fridays Child]

3. I know. I wish it did. RA sufferers have it the worst. And I agree...

...with you about opiates. It has been shown that where opiates are used strictly to control pain, the effect of grogginess--and the danger of driving while medicated, for example--diminish significantly. And if you become resistant and need to increase your dose, it should be up to you to make that decision, based on quality of life factors.

When pain is so bad that death seems a reasonable alternative, the "evil of narcotics" is a moot issue to the sufferer. Yet it has even been suggested to people in that much pain that surgery to sever nervous pathways--rendering them partially paralyzed--is a better solution than the possibility of becoming dependent on opiates.

In my humble opinion, these attitudes ultimately stem from the Judeo-Christian concept of mortification of the flesh: If it feels good, it must be bad, and suffering in this life will reap rewards in the next. It's a preposterous canard, engineered specifically to control the behavior of the masses in a very Machiavellian way. Insight and compassion work so much better.

Soapbox put away, now. :)

[nashville_brook]

6. since yer not using that soapbox, don't mind if i do...

i have chronic pain resulting from an ER bungle on my spine (L3-4 no disc now as the result of an infection caused by a dirty needle). i take extended release morphine everyday and have a lower dose of immediate release morphine for breakthru pain. i *never* get high/groggy on my meds. they control the pain and that's all. if i didn't know what they are, i would figure they have me on NSAIDs that really work. there's no euphoria.

opiates allow me to get up in the morning and have a normal life. if it weren't for these drugs i'd be bedridden.

the "evil of drugs" is what landed me with this chronic condition in the first place. i was in florida re-habbing the house i inherited when my parents died and i tweeked my back. i went to the ER in terrible pain (turns out i herniated two discs). i was sent home. the pain got so bad it was blinding so went back a few hours later and the ER doc said "the only thing he could was give me an epidural "and i wouldn't want that would I?" i was like hell-yeah -- i don't care if you hobble a foot -- just do something to take the pain in my back away. so he puts me in this funny chair and preps for the procedure and then gets in front of me and starts waving this huge needle in front of me -- "you sure you want THIS?" he had the gloves and the mask and a needle that was *really* big and i suppose he figured i ws there to get high and i would back down when i saw the needle, but i was desperate in pain -- plus, i have no problem with needles. i guess all the waving and funny business with the needle contaminated it b/c i wound up with osteomylietis (an infection in my spine -- closed system). complications included multiple blood clots in my legs (for which i had to have shots for 8 months); then medicinal hepatitis from the antibiotic therapy; and pancreatitis from the diagnostic procedure on the hep. they did an ERCP -- if you ever have the chance of declining this procedure DO IT -- unless you will die otherwise. you don't want pancreatitis. that made the back pain seem like happy days).

i had been on vioxx and all kinds of other meds (before i went to the pain clinic) and NOTHING even touched my pain. it was a nightmare to get anyone to even whisper in my ear that such a thing as a PAIN CLINIC existed. my neuro-surg and osteo-surg refused to see me b/c i didn't have anything they could operate on (the disc was dying just fine on it's own). finally, one of my nurses clued me in.

now i go to the pain clinic once a month. i'm such a bonehead when it comes to being dependent on ANYTHING, that once a month i usually try to step down my meds and wind up in an unbearable cycle of pain.

without narcs -- writhing pain. with narcs -- function normally.

and just to drive the point home -- the vioxx was $100 a month. the narcs? $15.

[Fridays Child]

8. What a terrible series of events. I hope you recover fully.

Thankfully, you found someone willing to buck the (broken) system by prescribing narcotics for you. And, yes, the cost, alone, makes the non-narcotic pain relievers unaffordable for most people. Prices like that make me wonder if some doctors take kickbacks for steering patients toward expensive prescription drugs.

[nashville_brook]

9. it's worse than that

Federal law enforcement offcials nationwide target docs for prescribing pain meds. there is state intrustion on the patient-doctor relationship and the criminalization of medicine.

i didn't know this. i couldn't understand why my docs wouldn't treat my pain. what else are they there for, i wondered.

with every opiod scrip, doctors risk their careers, freedom and reputations. because of the War On Drugs, doctors risk prison by prescribing narcotics such as oxycontin (which a decade ago was heralded as a miracle drug -- much safer than Darvon or other drugs which can depress respiratory function). under the bush administration, states now receive $138 million to TRACK and MONITOR prescription of opiods.

there is a chilling effect to say the least.

the day i decided i couldn't take the pain anymore was nearly a year after i got out of the hospital (I spent nearly 5 months the hospital, 4 of which i had a morphine pump). i was at work, sitting at my desk in tears. i had gone that whole year barely making it to work and back home to sleep. chronic pain makes your mind play tricks on you. pain gets expressed as fatigue, irritability and depression. the day i started calling my docs the pain had spun out of control. i called my GP and INSISTED they see me immediately, over their objections (my back surg and neuro surg flat out refused to see me). when the nurse took my blood pressure and got my notes, she whispered to me that my doctor would not treat my pain. she said that she had a chronic pain problem and that she had to go to a pain clinic to have it treated. she offered to give me the name and number of her her doc -- but i didn't take it b/c i didn't want to get her in trouble. just knowing the "deal" was enough.

i had never imagined myself as a "chronic pain" sufferer. i got online and read everything i could on chronic pain. so many familiar stories! so many stories of people who finally got treatment. i got jealous. why can't i get treatment?

it took a while, but i'm finally under the care of a great pain clinic. my docs there are awesome! they take the time to talk and educate and they care about how i *feel.*

________________________

i am so glad the info on vioxx and bextra is finally coming out! these drugs did nothing aspirin can't do except make me horribly ill. my intuition is that these drugs were over-prescribed b/c docs wanted an alternative to prescribing real pain relievers.
_________________________

one other thing -- if you ran into me at the at the grocery store you wouldn't be able to tell that i'm anything but a 30-something wearing funky shoes. i have a husband, two dogs and lots of friends. i'm active in the community and very much into being fit and healthy. the stigma is that chronic pain sufferers are shut-ins, chain smokers and "on the dole." that's just not the case.

[Fridays Child]

10. Hurray for pain clinic docs! Hopefully, they are afforded a more...

...reasonable standard by those who decide how many narcotics prescriptions are too many. I wonder, too, how many alcoholics are simply self-medicating because they can't alleviate their pain any other way. You know what they say: A bartender is just a pharmacist with a very limited inventory.

[nashville_brook]

12. they must be. i am actually stunned to have docs talk out loud about

pain. it makes me vaguely nervous.

on the alcoholic thing -- when i was in grad school i worked on a study of homeless veterans in the mountains in east Tennessee. most were chronic pain sufferers and all self-medicated with alcohol or Sterno. the ones who weren't self-medicated for pain do it for psych issues.

thinking further about this... i bet lots of people who can't navigate the system the way i was able to self-medicate with illicitly-bought drugs. there was a while when i was looking on the web for a source. i would have never gone thru with that tho. it felt sleezy just looking.

[lazarus]

11. rheumatoids have it tough, but

Try psoriatic arthritis for a few days.

[NNadir]

4. E. J. Corey, Nobel Laureate, has ties to Pfizer.

Corey is a synthetic guy mostly. Corey is well known as a genius of the highest order, but still, this is pretty new, him publishing about metabolism. I suspect that there may be something of a conflict of interest here.

From the article: "In a footnote, the authors say that they have disclosed their findings to the Food & Drug Administration. Corey is a scientific adviser to Pfizer, the maker of Celebrex and Bextra."

I've been taking a mixed COX-1/COX-2 inhibitor for some thirty years. It's called "Aspirin." It's a damned good drug. It's cheap, readily available and pretty damned effective. It works great on my bad knees and it doesn't - for me at least - have the side effect that Vioxx, Bextra, and Celebrex were invented to prevent - stomache upset.

[slutticus]

5. Yeah...I noticed that about Corey

I just thought it was interesting (and scary) that these non-metabolic pathways are not considered when evaluating compounds like these for potential toxicity.

[Lexingtonian]

7. yeah, I'd worry

I'd worry too. Looks to me like Pfizer's consultant corps is fishing for a way for the company to 'save' Bextra and some of the rest of the drug class.

Prostaglandins (what cox-1/2s generate) don't just function in pain signalling- they do have some role in upkeep of the heart valves. Aspirin exposure right around birth is known to be one of the causes of blue baby syndrome- it seems to hold up the heart valve bypass closure by tissue constriction/fusion. (Don't quote me on this, but aspirin seems to be totally without effect at -all- other times of development.) Since in animals the way wear damage gets fixed is usually via reuse of the old generation and modelling process, it's not a complete surprise that a subset of cox inhibitors would have an effect on regeneration or longterm function of parts of the heart. Not completely predictable, but not beyond prediction either.

I don't think Corey and Pfizer are going to win this one. The chemistry is nice and is a good excuse for proposing Vioxx to be an aberration in its class. But it will take biological testing to decide whether this curiosity of chemistry is of any importance at all.