Carbidopa B6 and the PD death rate - a theory
 

This is an important paper. I suspect many researchers will disagree with its conclusions. But that said, its claims are profound and affect almost all PwPs, so it needs to be answered quickly.

Hinz et al. write:

"The only indication for carbidopa and benserazide is the management of ... [levodopa]-induced nausea. Both drugs irreversibly bind to and permanently deactivate pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, and PLP-dependent enzymes. PLP is required for the function of over 300 enzymes and proteins. Virtually every major system in the body is impacted directly or indirectly by PLP. The administration of carbidopa and benserazide potentially induces a nutritional catastrophe. During the first 15 years of prescribing L-dopa, a decreasing Parkinson’s disease death rate was observed. Then, in 1976, 1 year after US Food and Drug Administration approved the original L-dopa/carbidopa combination drug, the Parkinson’s disease death rate started increasing. This trend has continued to the present, for 38 years and counting. The previous literature documents this increasing death rate, but no hypothesis has been offered concerning this trend. Carbidopa is postulated to contribute to the increasing Parkinson’s disease death rate and to the classification of Parkinson’s as a progressive neurodegenerative disease. It may contribute to L-dopa tachyphylaxis.

The alpha-synulcein sanity check: I don't see this as conclusive in any way, but a paper by Doppler [2] gives some support that a B6 shortage is linked to the general ill-health of PwP:

"The finding of alpha-synuclein deposits in skin nerve fibers raises the possibility of a disease-related peripheral neurodegeneration in PD. However, others found an association of the peripheral neuropathy with cumulative levodopa intake and reduced levels of vitamin B12 and B6, suggesting a pharmacotoxic cause: either due to interactions of levodopa metabolism with the methylation pathways of vitamin B12 or the interference of intestinal levodopa and vitamin uptake ".

Reference:

[1] "The Parkinson's disease death rate: carbidopa and vitamin B6"
Hinz M., Stein A., Cole T.
Clinical Parmacology: Advances and Applications, 21 October, 2014
Location from the OP reference, click on Download Article

[2] "Cutaneous neuropathy in Parkinson’s disease: a window into brain pathology"
Kathrin Doppler, Sönke Ebert, [...], and Claudia Sommer
Acta Neuropathologica, 2014,128(1)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059960/

John

and of course the alternative is to use the HINZ protolcol sold by one or more of the authors?

i haven't read the whole article yet but my impression was that prior to carbidopa, l-dopa had to be taken in such large amounts, up to 12 grams, that it was not taken by many people.

of course this gets into the whole system of determining cause of death, more people could be dying from pd just because diagnosis has gotten better, a change in determining cause of death .

i think the better measure is do pd'ers live longer on avg after the addition of carbidopa to l-dopa?

patch would solve this problem
 

Seems like an L-dopa patch would solve this problem: no need for carbidopa since it's not being taken orally.

We have struggled for years with how to take a B vit. supplement without messing up the meds. Even drinking a Vitamin Water (which has B in it) has the effect, for us, of making our drugs even less effective than they already are. If anyone has any suggestions on how to take a B vitamin supplement while you are also having to take sinement/generic version, please share with us all.

B is critical: they have found in nursing homes a staggering majority of patients were deficient in B vitamins. A great many improved when given B (I'm not saying the patients threw away their canes and jumped out of their wheelchairs, but there was improvement, significantly of the cognitive variety). Of course, this is not a hot topic for pharma:(

l-dopa patch isn't possible, l-dopa doesn't pass thru the skin well plus it would have to deliver a lot of l-dopa compared to an agonist like neupro. you still need carbidopa even if you bypass the stomach and small intestine since the blood still circulates thru every cell in the body. the gel used in the duodopa pump contains carbidopa.
http://www.abbvie.ca/content/dam/abb...DOPA_PM_EN.pdf

neuoderm tried a patch, it failed, now developing a insulin pump like device to subcutaneously deliver l-dopa, not sure if their gel has carbidopa or you take it orally.
https://www.michaeljfox.org/foundati...p?grant_id=225

agonists were developed because of this problem with l-dopa breaking down outside and inside the brain , some medical professionals think we need a better agonist and there are already 3 once a day products, mirapex-xr, requip-xr and neupro.

[QUOTE=soccertese;1105565]l-dopa patch isn't possible, l-dopa doesn't pass thru the skin well plus it would have to deliver a lot of l-dopa compared to an agonist like neupro. you still need carbidopa even if you bypass the stomach and small intestine since the blood still circulates thru every cell in the body. the gel used in the duodopa pump contains carbidopa.
[url]
neuoderm tried a patch, it failed, now developing a insulin pump like device to subcutaneously deliver l-dopa, not sure if their gel has carbidopa or you take it orally.
https://www.michaeljfox.org/foundati...p?grant_id=225

QUOTE]

You beat me to the response, ST. NeuroDerm is using a liquid formulation of LD/CD in their belt pump. They tried eliminating carbidopa but it didn't work. As an aside, they will be releasing their top line Phase 2 trial results for the ND0612 pumps later today.

There is a small company, SynAgile, that is also testing an insulin-like pump for PD. They are not combining their drug with carbidopa. SynAgile is developing DopaFuse, a therapy to continuously infuse a dopamine prodrug. DopaFuse contains a novel, highly soluble L-DOPA prodrug that enables a daily dose of L-DOPA to be delivered in a small volume. Upon infusion the prodrug is broken down into L-DOPA, which is absorbed into the patient's plasma. Studies demonstrate promptly increased plasma L-DOPA after infusion of the prodrug into PD patients. Large clinical trials have already demonstrated the safety and efficacy of the prodrug in oral form. SynAgile is reformulating the prodrug so that it can be continuously infused.

I saw a presentation from SynAgile last year but haven't heard much about them recently.

[QUOTE=Tupelo3;1105590]i assume carbidopa is taken orally?

Before everyone gets overly excited about carbidopa and risk of death, let's think this through rationally. Whether carbidopa contributes to an increase in PD death rate is beyond the scope of my knowledge. The science discussed in the review may all make sense. However, let's keep in mind who the lead author is and remember, we can always do plenty of fancy things with statistics to make unrelated outcomes appear to be something factual. Although a case is made for a relationship between the start of carbidopa use and the beginning of an increase in PD death rate, it may also be unrelated to a causal effect and related to some other common variable.

For example, we know two facts that have occurred over the same time period:
1} Average life expectance has increased significantly from 1970 to 2010, and we know that PD, more than anything, is a disease of aging. The rate of occurrence per thousand increases dramatically every year we age, as does the rate of death.

2) There is a much better understanding today of PD, and subsequently many more people getting diagnosed that may have been either undiagnosed back then or misdiagnosed.

3) The interaction of the two items above. Older people have more problems, get more illnesses, and die more often. Many times the death is related to several variables. In the '70s, I never remember someone dying from PD (what actually is that anyway). In fact, I probably never even heard of PD. The cause of a death would probably be listed as the problem that PD instigated. For instance, an 85 year old with PD falls, breaks a hip, gets pneumonia from being bed ridden, and eventually dies from congestive heart failure. What does the doctor put down on the death certificate as the cause?

Finally, percentage increases (as Hinz reports) are usually dramatically huge when starting from a low point, yet not always practically significant. Case in point some numbers from a CDC article that I have (sorry no link so you'll have to trust me). This is a table of deaths per 100,000 for PD over the 10 year time period 2002 - 2011.


Parkinson's disease death rates by age groups:

2011 * * * * * * 0.1 1.3 12.8 76.0 168.1 7.0
2010 * * * * * * 0.2 1.3 11.8 74.8 165.9 6.8
2009 * * * * * * 0.2 1.3 11.2 70.8 157.0 6.5
2008 * * * * * * 0.2 1.2 12.3 71.2 157.4 6.6
2007 * * * * * * 0.1 1.2 11.7 71.5 157.0 6.5
2006 * * * * * * 0.2 1.2 12.0 69.5 157.6 6.5
2005 * * * * * * 0.2 1.4 12.8 71.1 156.0 6.6
2004 * * * * * * 0.2 1.2 11.9 67.4 145.1 6.2
2003 * * * * * * 0.2 1.3 12.6 67.6 145.8 6.3
2002 * * * * * * 0.1 1.2 12.1 63.8 142.2 6.0

Sorry, but it's hard to post a table here. The first column after year is Ages 45-54, then 55-64, 65-74, and 85-94. The last column is the age adjusted average. As can be clearly seen in the first three age groups there is hardly any change in average death rate attributed to PD. The increase does become more apparent in the 75-84 and 85-94 year old groups. And, clearly the trend on age adjusted average is increasing. However, although the increase overall from 6/100,000 to 7/100,000 may be statistically significant, given the size of the population, is it really practical? Is it just possible that people who die with PD have multiple complications at the end and it's just easier for the assigning doctor to list PD as the cause?

Ideally, we would have two groups to compare: levodopa only v levodopa plus carbidopa. In the absence of this Tupelo3's CDC data is very interesting. There are many ways to interpret this. In addition to those that he mentions, I would add that the results could reflect the fact that progress on treatments for PD has, since the introduction of levodopa in the 1970's, been slower than for many other diseases. To see how this could affect the statistics, consider a person aged 60 who survives a heart attack, one which 20 years ago would have been fatal. He may go on to be diagnosed with PD, and ultimately to die with it.

As I see it, the argument in favour of the carbidopa effect would be stronger if the true PD mortality rates had a step change immediately after its introduction but, thereafter, remained constant.

Some more evidence against the carbidopa theory is offered by Morgan et al.[1]:

"Our data indicate that survival was no better or worse in patients starting levodopa within two years of symptom onset versus greater than two years after symptom onset."

I think it is likely that the mention of levodopa in this context actually means levodopa/carbidopa. So, those people who delayed taking levodopa also delayed taking carbidopa. If the carbidopa hypothesis were right this should have given the late administration group an advantage, which was not found.

Reference

[1] "Mortality in Levodopa-Treated Parkinson's Disease"
John C. Morgan,1 Lillian J. Currie,2 Madaline B. Harrison,2 James P. Bennett Jr.,3 Joel M. Trugman,4 and G. Frederick Wooten
Parkinson's Disease (2014)
http://www.hindawi.com/journals/pd/2014/426976/

Quotes
 

This quote seems to fit here:

"To steal the ideas from one person is plagiarism. To steal the ideas of many people is research."

Or
"The proof is in the pudding."

Peggy