RESEARCH - ibs show different molecular effects on lipids may explain different CV risks

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ibs show different molecular effects on lipids may explain different

CV risks

Rheumawire

Nov 23, 2004

Zosia Chustecka

Beverly, MA - New research shows that different COX-2 inhibitors vary in

vitro in the molecular effect they have on lipoprotein oxidation, and

this nonenzymatic effect may explain the differences in cardiovascular

risk that have been seen with these drugs clinically, say the

researchers [1]. However, a clinician questions the relevance of these

findings and says that establishing a link between in vitro findings and

cardiovascular risk will require much further work.

The new findings, reported in the December 2004 issue of

Atherosclerosis, come from a 2-year investigation carried out by Dr

Preston Mason and colleagues at Elucida Research LLC (Beverly, MA), a

private laboratory " dedicated to independent and innovative biomedical

research, " it says in a press release highlighting the findings. No

funding or impetus from the pharmaceutical industry was provided to

initiate or conduct this study, it adds.

The study involved an analysis of the effects of COX-2 inhibitors on

human low-density lipoprotein (LDL) oxidation, an important contributor

to atherosclerotic cardiovascular disease, the researchers explain. " The

essential finding of this study was that the sulfone COX-2 inhibitors,

etoricoxib (Arcoxia, Merck & Co) and rofecoxib (Vioxx, Merck & Co),

exhibited prooxidant activity in human plasma samples and isolated LDL.

The prooxidant effects of these agents were unrelated to COX-2

inhibition, as they were reproduced in pure lipid vesicles enriched with

arachidonic acid. Additionally, we did not observe changes in lipid

peroxidation rates with sulfonamide COX-2 selective inhibitors

(celecoxib [Celebrex, Pfizer] and valdecoxib [bextra, Pfizer]), other

nonsteroidal anti-inflammatory drugs (NSAIDs; naproxen, ibuprofen,

diclofenac) or even sulfone-containing compounds (methyl phenyl

sulfone). "

" The lack of activity for celecoxib was observed even at

suprapharmacologic doses, " the researchers comment. " By contrast, the

prooxidant effects of rofecoxib were dose-dependent. This is of

particular interest as recent clinical investigations indicate an

increase in cardiovascular risk associated with rofecoxib that also

appears to be dose-related. "

The prooxidant activity observed with rofecoxib and etoricoxib appear to

be related to distinct physicochemical changes in lipid structure,

independent of COX-2 inhibition, the researchers comment. This

conclusion is based on small-angle X-ray diffraction analyses of

drug-containing phospholipid bilayers that show a reduction in molecular

packing constraints of acyl chains following treatment with sulfone

agents (etoricoxib and rofecoxib), resulting in potentially increased

permeability to free-radical ions and/or free-radical diffusion.

" Vioxx interacts at a molecular level in a way that Celebrex and other

NSAIDs do not, " Mason comments in the press release. " Abnormal changes

in the structure or shape of lipids caused by Vioxx, especially in LDL,

may explain why they are more susceptible to oxidative damage and

therefore contribute to cardiovascular damage. Similar effects on

susceptibility of lipids to oxidative damage have been observed with

cigarette smoking, diabetes, and in patients who have had a recent heart

attack. Interestingly, these adverse effects were independent of Vioxx's

function as an inhibitor of the COX-2 enzymethus explaining why it could

be different from other drugs in its class. "

" This news should be reassuring to patients and doctors, " says Mason.

" The cardiovascular issues associated with Vioxx should not be

extrapolated to other COX-2 inhibitors. Having for the past 15 years

studied these types of drug-lipid interactions, it was clear to us that

the effects we observed with Vioxx were very unusual and needed to be

reported to the medical community. "

However, Dr Pisetsky (Duke University, Durham, NC), an editorial

consultant to www.jointandbone.org, questions the relevance of these

findings. He tells rheumawire: " While drugs of a class (eg, NSAIDs or

coxibs) may share an action in common, these agents are chemically

distinct and may have other effects, not related to their primary

action, that may have an impact on either efficacy or side effects.

There were, in fact, many studies on NSAIDs that demonstrated

differences in the in vitro properties that potentially could affect

their efficacy as anti-inflammatories. In the same way, coxibs may have

differences in the in vitro properties that could affect their side

effects. The question is whether any of these in vitro activities have

relevance. "

Also asked to comment on this research, cardiologist Dr Topol

(Cleveland Clinic, OH), editor-in-chief of our sibling website,

www.theheart.org, says the findings are " provocative, but only one

possible explanation. "

In their paper, Mason et al note that previous studies have shown that

the COX-2 inhibitors also have distinct effects on endothelial function,

a key indicator of vascular risk. Specifically, celecoxib, but not

rofecoxib, effected an improvement in endothelial-dependent vasodilation

[2,3,4].

However, there are also many similarities across the coxib class, and

they all have the same mechanism of action, selective inhibition of the

COX-2 cyclo-oxygenase enzyme. One theory explaining the cardiovascular

side effects seen with rofecoxib, and now of concern with the other

drugs in the coxib class, is that inhibition of this enzyme alters the

balance between thromboxane and prostacyclin (prostaglandin PGI2),

leading to prothrombotic effects.

A research paper published in the November 18, 2004 issue of Science

highlights the role of COX-2-derived prostacyclin in atherogenesis [5].

The study was carried out in mice and shows that deletion of the

prostacyclin receptor removed the atheroprotective effect of estrogen in

ovariectomized female mice. " This suggests that chronic treatment of

patients with selective inhibitors of COX-2 could undermine protection

from cardiovascular disease in premenopausal females, " say the

researchers. " It raises concern about the use of COX-2 inhibitors in

juvenile arthritis, a disease that predominantly affects females. "

The research team is headed by Dr Garret FitzGerald (University of

Pennsylvania, Philadelphia), who recently reported the meta-analysis

that he says shows an increased cardiovascular risk with valdecoxib but

that has been criticized. The researchers comment: " Although

extrapolation of results in mice to humans is performed with caution,

the experience with rofecoxib has focused attention on the role of

atherogenesis in transformation of cardiovascular risk during chronic

treatment with selective inhibitors of COX-2. "

In an article about this mouse study in the Wall Street Journal, Pfizer

medical director Dr Gail Cawkwell says the study " makes for interesting

science, but the author makes a quantum leap in assuming this has any

relevance to humans or to patients. " And Dr Borer (Cornell

University Weill Medical College, New York, NY) comments that " mechanism

studies are very interesting, but they do not provide firm evidence of a

clinical benefit or a clinical risk. "

Sources

Walter MF, RF, Day CA et al. Sulfone COX-2

inhibitors increase susceptibility of human LDL and plasma to oxidative

modification: comparison to sulfonamide COX-2 inhibitors and NSAIDs

Atherosclerosis 2004:177: 235-243.

Chenevard R, Hurlimann D, Bechir M et al. Selective

COX-2 inhibition improves endothelial function in coronary artery

disease. Circulation 2003; 107:405-409.

Hermann M, Camici G, Fratton A et al. Differential

effects of selective cyclo-oxygenase-2 inhibitors on endothelial

function in salt-induced hypertension Circulation 2003; 108: 2308-2311.

Monakier D, Mates M, Klutstein MW et al. Rofecoxib, a

COX-2 inhibitor, lowers c-reactive protein and interleukin-6 levels in

patients with acute coronary syndrome Chest 2004; 125:1610-1615.

Egan KM, Lawson JA, Fries S et al COX-2 derived

prostacyclin confers atheroprotection on female mice. Science; published

online before print November 18, 2004.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org