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The news yesterday that FDA is putting tighter restrictions on Avandia (rosiglitazone), the diabetes drugs, was important but not surprising.

In July, an advisory panel to the agency took a rather dim view of the drug.  Ten of the 32 votes were for increased warnings and tighter restrictions, and 12 were for pulling the drug off the market completely (which is what European regulators decided to do).

Avandia and a related diabetes medicine, Actos (pioglitazone), already had a 鈥渂lack box warning鈥漚bout an increased risk of heart failure. Avandia also carries an additional , about heart attacks. The Health Letter鈥榮 annual list of the top 10 health stories of the year included an item about Avandia in 2007.

And the side effects aren鈥檛 just  limited to the heart.  This is what our Special Health Report on diabetes has to say on the subject:

However, these medications [thiazolidinediones, or TZDs, which include rosiglitazone and pioglitazone] have been linked to to several health problems, prompting some physicians to limit prescribing them. People taking these drugs should be aware that all the TZDs can cause fluid retention and weight gain and may increase the risk of heart failure鈥攁 side effect that in 2007 prompted the FDA to ask the manufacturers of rosiglitazone (Avandia) and pioglitazone (Actos) to add a 鈥渂lack box鈥� warning to these medications. These two medications have also been shown to raise the risk of bone loss and fractures, particularly among women. Rosiglitazone may also increase the risk of heart attack and is generally not recommended.

One begins to wonder who would want to take鈥攐r prescribe, if you鈥檙e a clinician鈥攖hese drugs!

But here鈥檚 the catch: Avandia and other thiazolidinediones are very good at reducing insulin resistance, a central feature of diabetes and a reason blood sugar levels get out hand (insulin ushers blood sugar into cells, so when insulin is resisted, blood sugar levels climb).

Furthermore, the TZDs zero in on fat cells, and the metabolic mischief stirred up by fat cells鈥攖he chemicals and hormones they unleash鈥攊s a driving force behind diabetes.

More specifically, the TZDs work by activating a receptor in the nuclei of fat calls, called . (If you must know, PPAR stands for peroxisome proliferator-activated receptor. Occasionally acronyms can be a real blessing.)

PPAR-gamma has been called master regulator of fat cell biology. By activating PPAR-gama, the TZDs dial down the production of insulin-resistance-inducing agents (TNF-伪, interleukin-1, resistin) while cranking up the production of a insulin-sensitizing hormone, adiponectin.

All good鈥攅xcept, not really, because of the side effects. Switching on PPAR-gama with TZDs seems to produce them, too.

But , a professor of cell biology at Harvard Medical School and the Dana-Farber Cancer Institute, a Harvard affiliate, seems to have come up with an an alternate  strategy for affecting PPAR-gama鈥攐ne that might avoid the side effects.

, Spiegelman and his collaborators reported findings that showed that, in addition to its primary binding activity, rosiglitazone blocks  phosphorylation of PPAR-gama. Phosphorylation is the addition of a phosphate group to an organic compound. In biochemistry, phosphorlyation often triggers an important change in how a compound behaves.

Spiegelman鈥檚 experiments鈥攐ne of which included taking biopsies of fat tissue of people taking rosiglitazone鈥攁lso showed that the inhibition of phosphorylation  of PPAR-gama was associated with anti-diabetic effects.

Put another way, the phosphyloration of PPAR-gama in fat cells may, in fact, be a critical step in the many that wind up producing diabetes.  Stop or retard phosphyloration and you might rein in the metabolic havoc caused by fat cells and their diabetes-producing ways.

compared the research results to 鈥� refreshing wind over the PPAR-gama field鈥� that could revitalize the once-bustling area of research. So rather than give up on PPAR-gama as target, as has been suggested because of Avandia鈥檚 rise and fall,  researchers and drug companies might focus finding ways to affect it more selectively through phosphorlyation.

Elsewhere, the commentators (who clearly have a fondness of metaphor) said the researcher community had been 鈥渇ishing with the wrong bait鈥� and that the Spiegelman results call into question all the effort that has been put into finding  potent PPAR-gama activators,  such as rosiglitazone.

When we spoke to Spiegelman yesterday by phone, he said he was 鈥渘eutral鈥� on the FDA move to restrict access to Avandia.  But he said finding more selective compounds is a realistic goal: 鈥淚t鈥檚 absolutely not pie in the sky.鈥�

Several candidates are mentioned in the Nature article.  They don鈥檛 have names and are labeled with mash-ups of letters and numbers because they鈥檙e still in the early stages of testing and development. Spiegelman told us in an email that none have been tested in humans, yet results from animal studies were promising, though they were abandoned for diabetes for one reason or another. Maybe that will change.

Rosiglitazone could be modified to be more selective, said Spiegelman, but he doubted that drug developers would try for both patent and marketing reasons.