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Healthy Skepticism Library item: 11342

Warning: This library includes all items relevant to health product marketing that we are aware of regardless of quality. Often we do not agree with all or part of the contents.

 

Publication type: news

Nagle M.
GSK drug could prove unlikely saviour for Vioxx
DrugResearcher.com 2007 Aug 29
http://www.in-pharmatechnologist.com/news/ng.asp?n=79312-merck-co-glaxosmithkline-university-of-connecticut-ppar-delta-vioxx


Full text:

Vioxx (rofecoxib) might have been offered a lifeline with the news that the drug could be used safely, so long as drugs such as GlaxoSmithKline’s investigational dyslipidaemia compound are administered at the same time.

That is one conclusion of an online article published this week in the Journal of Experimental Medicine, which seeks to explain how the cardiovascular side-effects of the drug occur and crucially, how they can also be controlled.

Timothy Hla, a professor of cell biology, and his team at the University of Connecticut, US, discovered that Vioxx prevents the cyclooxygenase (COX)-2 enzyme performing an anti-blood clot function.

Prof. Hla believes this important function can be restored using a certain unapproved class of drugs, of which a GlaxoSmithKline compound is the most clinically advanced.

He found that a cascade of enzymes working together to metabolise endocannabinoid molecules prevent the formation of blood clots: COX-2 in endothelial cells, together with prostacyclin synthase (PGIS) enzyme, activate a third protein called peroxisomal proliferator-activated receptor (PPAR)-delta.

PPAR-delta, in turn, reduces the amount of tissue factor (TF, also called thromboplastin, or Factor III or CD142), which is an enzyme necessary for thrombin formation and hence the coagulation of blood.

By giving a patient a COX-2 inhibitor, this chain of events is blocked, PPAR-delta levels are reduced, the amount of circulating TF increases and blood clots become more likely. This in turn increases the risk of side-effects such as heart attacks and stroke. Prof. Hla believes this is at least partly why Vioxx can cause adverse cardiovascular events.

Vitally, he also thinks that if Vioxx, or a similar drug, were to be given in combination with a PPAR-delta activator, it is theoretically possible that these side-effects could be avoided and COX-2 inhibitors may be able to be used safely.

GlaxoSmithKline (GSK) has such a PPAR-delta activator in Phase II clinical trials: GW 50156. It is currently the most advanced drug that selectively activates this target and was originally in-licensed from Ligand Pharmaceuticals.

The two companies have been collaborating for over a decade, in particular to develop small molecules capable of controlling the formation and development of blood cells. One of the fruits of this alliance, Revolade (eltrombopag), is currently in Phase III clinical trials and a backup molecule called SB-559448 is in Phase I trials.

Two selective COX-2 inhibitors, Merck & Co.‘s Vioxx and Pfizer’s Bextra (valdecoxib), were withdrawn from the market in 2004 and 2005 following concerns over increased heart problems. However the mechanistic basis of these effects is not well understood.

Whether GSK could prove to be an unlikely saviour for a Merck & Co drug would require a large, long-term clinical trial and even then, Vioxx might not sell, such is the public perception of the drug. However, the news may come as a boost to other drug developers with COX-2 drugs still on the market – such as Pfizer with Celebrex (celecoxib), or to those who still believe COX-2 inhibitors have a place in pain therapy.

 

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Far too large a section of the treatment of disease is to-day controlled by the big manufacturing pharmacists, who have enslaved us in a plausible pseudo-science...
The blind faith which some men have in medicines illustrates too often the greatest of all human capacities - the capacity for self deception...
Some one will say, Is this all your science has to tell us? Is this the outcome of decades of good clinical work, of patient study of the disease, of anxious trial in such good faith of so many drugs? Give us back the childlike trust of the fathers in antimony and in the lancet rather than this cold nihilism. Not at all! Let us accept the truth, however unpleasant it may be, and with the death rate staring us in the face, let us not be deceived with vain fancies...
we need a stern, iconoclastic spirit which leads, not to nihilism, but to an active skepticism - not the passive skepticism, born of despair, but the active skepticism born of a knowledge that recognizes its limitations and knows full well that only in this attitude of mind can true progress be made.
- William Osler 1909