From an old thread:

http://neurotalk.psychcentral.com/thread44248.html

This article about the failure of MitoQ and CoQQ10:

http://www.medpagetoday.com/MeetingC...eeting/tb/9205

"Richard Newman, M.D., a practicing neurologist in Rockledge, Fla., and discussant at the session, said it was too soon to give up entirely on anti-oxidants.

"Parkinson's disease isn't one disease," he said, but rather a collection of similar syndromes with different causes.

Dr. Newman recommended additional studies in certain patient subgroups -- such as those whose disease is related to exposure to the insecticide rotenone or to Agent Orange, the Vietnam War-era defoliant -- in whom oxidative damage may play an especially strong role.

But Dr. Snow said such studies were unlikely to be funded. In commercial drug development, "you usually only get one chance" to show efficacy, he said. "

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Another example of how choosing patients matters...

From this thread:

http://neurotalk.psychcentral.com/thread29755.html

TOPIC: Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early PD

I wrote:

Thanks to all. But were you tested for LRRK2 mutations prior to the study? Specifically the G2019S? It doesn't make a lot of sense to choose patients with different pathology and genes, especially for a targeted drug like this one.

"The G2019S substitution is situated in the mitogen-activated kinase kinase kinase domain of Lrrk2, within the hinge region of the highly conserved activation segment: Asp-Phe-Gly (DFG).[3] Based on in silico modeling using a series of homologous mixed-lineage kinases as templates, we hypothesize that the mutant form may modulate kinase activity or alter substrate specificity (Fig 2). Notably, Lrrk2 I2012T, G2019S, and I2020T substitutions, which cluster in this domain, also create potential novel targets for phosphorylation. Although the signaling or secondary messenger phosphorylation cascade has yet to be elucidated, we propose Lrrk2 kinase activity may promote -synuclein pathology either directly or indirectly via a protective response. Work in Drosophila melanogaster suggests -synuclein phosphorylation at amino acid S129 may be a critical event in neurotoxicity.[20][21] It remains to be shown whether -synuclein phosphorylation is a direct or downstream target of Lrrk2 mitogen-activated kinase kinase kinase activity; nonetheless, we postulate that Lrrk2 substrates play a crucial role in PD pathogenesis, and the amount of these substrates within the cell may have a major impact on G2019S disease parameters such as age of onset.

Interestingly, phase II/III neuroprotectant therapy for PD[22] with a mixed-lineage mitogen-activated kinase kinase kinase inhibitor (CEP-1347)[23] was initiated by the Parkinson Study Group, but recently was terminated due to ineffectiveness in the interim evaluation. In future clinical studies of mixed-lineage kinase inhibitors, it may be useful to stratify PD patients based on the presence of the G2019S carrier state. "

You think??

From:

Lrrk2 and Lewy body disease

http://www3.interscience.wiley.com/c...RETRY=1&:cool:

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Autopsies of people with LRKK2 mutations show very different pathologies, even within the same family. PD is NOT one disease. So how to choose a cohort that makes sense? They need to figure this out before wasting more money on failed trials. It's as if they don't want to bother doing it right. Heads in sand.

~Zucchini