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Article: Light on ME/CFS I: Bad Reception: A Key to ME Uncovered? The Light Gene Expression Studies

http://blogs.wsj.com/health/2008/07/08/fda-still-mulling-warning-for-pfizers-lyrica/

What can I say.....just one more of this studies by Big Pharma which will help them sell their product......

Cort, do you have any conflict of interest to declare ? Maybe like a little ghost writing fees ??? ;)

And just one more thing, Lucinda Bateman is sitting on the advisory board of Pfizer ....:D

FDA Still Mulling Warning for Pfizers Lyrica

When the FDA started making noises earlier this year about stronger warnings for epilepsy drugs, Pfizer said its drug Lyrica shouldnt be lumped in with other drugs in the class because it didnt carry the same risks for suicidal thinking.

But FDA documents updated online yesterday show that the drug is still on the list of drugs for which the agency is considering beefed-up warnings. One table in the voluminous document says in a group of placebo-controlled trials, seven of 7,201 patients taking Lyrica showed signs of suicidal behavior or ideas, compared with two of 3,125 patients who received placebos. The document refers to Lyrica by its generic name, pregabalin.

The agency wants to add black-box warnings about the risk of suicidal thoughts and behavior associated with 11 epilepsy drugs, Dow Jones Newswires reports. The drugs are also used to treat bipolar disorder. Lyrica is also prescribed for pain and fibromyalgia.

Earlier this year, a Pfizer exec pointed out that, in a different FDA analysis that pooled all of the drugs in the class, Lyrica accounted for 35% of the patients but only about 6.3% of all events related to suicidal thoughts and behavior. And the company says its own data dont show signs of risk. Lyrica, which is also approved to treat several types of pain, had sales of $1.8 billion last year.
 
Latest paper from Lights doesn't really clarify things

I think that, along with XMRV and Rituximab, the 2011 report of increased gene expression in response to exercise (that Cort's written about here) is amongst the most interesting findings to emerge about CFS. However, as with XMRV and Rituximab, replication is crucial.

The biggest concern over the study covered in Cort's article relates to the higher exertion levels of CFS patients than controls, as has been discussed elsewhere in the comments. The authors had indicated that submitted research would demonstrate that in response to exercise MS patients showed no change in the expression of the genes that increased post-exercise in CFS patients. This would go some way to demonstrate the changes were unique to CFS and not related to deconditioning, particularly if the MS patients were well-matched with the CFS ones in terms of activity levels.

We have shown in a recently submitted manuscript that these gene markers are not similarly increased in patients with MS who exhibit unexplained increases in fatigue (White, A.T., Light A.R., Hughen R.W., VanHaitsma T.A., and Light K.C. Differences in metabolite-detecting, adrenergic, and immune gene expression following moderate exercise in multiple sclerosis, chronic fatigue syndrome, and healthy controls, submitted).

This submitted paper on MS patients has now been published and while it shows that metabolite receptor gene expression is not increased in response to gene expression, it also shows that the adrenergic recepotor genes are similarly increased in MS and CFS patients. Which makes it far less conclusive. It's not clear how well matched the MS patients were to the CFS patients.

This further study (from a comment from Alan posted by Cort) looks interesting re deconditioning, but like the MS study, we won't know for sure until it's published.
We also have a study in progress that looks at normal subjects at three different levels of exercise. A VO2 max test,a full cycling time trial, and a full cycling time trial with their core temperature increased by 2 degrees C. So far, with these max tests, most ofthe sensory genes actually go down in these normal subjects. AD2A does go up,but not as much as in patients, and Beta 2 actually goes down in all but the VO2 max test.

What I found of most concern was that the moderate-to-strong link found between gene expression and fatgiue and pain scores across all the genes implicated in this (2011) paper was not replicated in the new MS/CFS paper. The only correlation found was for a single adrenergic gene, P2X4, and then only for pain and not for fatigue. It was this correlation between gene expression and fatigue and pain that made the findings of this 2011 paper so compelling.

Replication studies have not been kind to the XMRV findings to date, though the largest and most rigorous (Lipkin) study has yet to report. Replication of the Rituximab findings are planned by its authors and at least one other group. The authors of these gene expression findings have made it clear they believe their work to date is sufficient:
We believe the published studies we have provided are sufficient to demonstrate that at least some genes that are involved in fatigue detection [and immune cell modulation] are dysregulated in CFS, and that this may contribute to some of their symptoms.
As the CAA, who funded this study say "As with any research, these findings will need to be replicated by another research group in another group of CFS (and FM) patients", to establish that these gene expression are a real and important link to fatigue and pain in CFS. Hopefully other groups will do exactly this.