X-Message-Number: 16940
From: 
Date: Tue, 10 Jul 2001 01:44:44 EDT
Subject: Viatmin C

Rafi Haftka and Fair4us asked for clarification on the vitamin C question. 
Fair4us sent the following questions to me via private email and I answered 
them. I hope this answers both peoples' questions to their satisfaction. Bill 
Faloon also sent me an extensive list of references on the benefits of 
vitamin C which I had not seen before. These are available from LEF.


>  1) Apparently the AHA study released to the public by Dr. James Dwyer on 
>  3-2-2000, was not validated by peer review and published in a scientific 
>  journal.

This criticism is valid. I was unaware of this until I read the LEF material. 
I do not subscribe to LE magazine and do not check their website regularly.
  
>  2) Dr. Paul Ward's study commissioned by LEF in response to the AHA/Dwyer 
>  study, in which 23 of 30 subjects showed no evidence of arterial 
thickening.

I'm not very impressed with post hoc studies of this nature or size. It may 
be meaningful, but it is not very persuasive alone; that is not really a 
criticism. More data is needed.

  
>  3) Dozens of other studies in the past 10 years which show benefits of 
>  large Vitamin C doses but no indication of arterial thickening.

To the best of my knowledge they did not look for this change, nor did they 
look for free radical adducts in the urine or serum of people taking vitamin 
C in these studies versus controls. Most of the studies are of low quality 
for the simple reason that it takes a lot of money to do rigorous clinical 
studies and the profit motive is not there for vitamin C. Again, this is not 
a criticism, just a sad commentary on how the world works.

  
>  4) Reasons why you think it is likely to occur, especially in people who 
do 
>  not supplement with iron but who do supplement with other antioxidant 
>  substances.

As I actually said in my original post I think that C may be perfectly fine 
in large doses _if_ other antioxidants are being consumed in supranormal 
amounts as well. I have observed the supplementation habits of hundreds of 
people over the years and noncompliance, great variability in nutrients and 
amounts taken, and other wild cards makes me concerned that many people who 
take large doses of C, in part because of its high visibility, are not taking 
adequate amounts of other antioxidant vitamins.

The benefits of ascorbate are modest in that it does not extend mean life 
span much if at all, and it has only modest positive effects in other areas 
of health. I'm not knocking modest benefits; you take what you can get, 
especially if it is inexpensive and safe.   

Shortly before I left CCR I was working on a rodent head injury model as a 
screening tool for ischemia-reperfusion inhibitory drugs. The model is a 
standard one and was used by Upjohn to evaluate the Lazaroids (a class of 
drugs originally thought to have great promise in CNS trauma). Despite 
considerable effort I could not get the degree of injury I wanted (or the 
Upjohn researcher claimed was possible) without killing the animals acutely. 
This is another way of saying I could not duplicate this researcher's work. 
Even after visiting researchers in Israel and in Pittsburgh I was not able to 
get the injury titrated to the right level (and I might add they weren't 
doing too well with it either!). 

I begin to try to potentiate the injury by using pre and post insult 
pharmacological intervention. Injury was assessed by removing the brains from 
the animals (after humane sacrifice) at 24 hours post insult and sectioning 
them and staining them with a dye called tetrazolium blue (TZB). TZB stains 
only injured areas of brain. I was looking for compounds to increase injury 
which would cause a more "natural" cascade of injury as opposed to drugs like 
MMDA which cause free radical mediated injury but do so in a way atypical of 
that seen in ischemia. One of the most effective agents I found was ascorbic 
acid given by gavage for a week prior to the insult. The animals were on a 
good Purina diet with reasonable levels of E, C, beta carotene and other 
antioxidant nutrients.

I was not able to complete this study before leaving CCR and it was a model 
development study; the endpoint was not to evaluate ascorbate, but rather to 
get larger areas of injury that caused detectable and lasting neurobehavioral 
deficits. I was so impressed with the ability of ascorbate to potentiate head 
injury that I stopped taking the 1 gram a day I have taken for many years. 
The brain selectively concentrates and stores ascorbate and has about 1/3rd 
of the total body ascorbate reserve. 

When injury occurs from stroke, head trauma, ischemia or other reasons, the 
ascorbate is released from the glia and possibly the neurons along with 
glutamate, and it drives the Fenton reaction with incredible power. Free iron 
is also made available on a massive scale especially in stroke and head 
injury, but also in ischemia from hemoglobin and cytochromes.

Atherosclerosis is multifactorial and we are certainly seeing people dying 
with normal or even low LDLs and good HDL/LDL ratios. Many factors have been 
put forth to explain this: chronic chlamydia, EBV or CMV infection of the 
arterial intima, elevated homocysteine levels, and injury from turbulent flow 
(most atheromas begin to form in high turbulence areas where the intima is 
injured). 

High levels of a pro-oxidant in the setting of injury does not strike me as 
good. In fact, in radical stressed animals in my lab in the passed I've seen 
arterial intimal thickening and collagen deposition. Thus, I find it very 
credible that high level supplementation with ascorbate, particularly as a 
monoagent, and especially in a setting of acute or chronic injury could be 
deleterious. It may be that the Dwyer study is invalid and that the many in 
vitro studies showing the radical generating and tissue injuring effects of 
ascorbate are invalid as well, in an in vivo setting. I'm certainly not 
dogmatic about this and it is not my area of expertise; I take criticism well 
and I was impressed with the references Bill Faloon sent me.

I guess I would say that I am very concerned about ascorbate in the setting 
of injury, particularly CNS injury. After my own preliminary work I certainly 
wouldn't want to have a head injury or stroke and be on 1g/day of C!  It's 
too bad I didn't get to follow this lead further and see if adding other 
antioxidants to ascorbate might have decreased injury even over control by 
acting in synergy with ascorbate. In the case of the brain, I tend to doubt 
it because it concentrates ascorbate in some dose dependent fashion (what the 
saturation point is I don't know; and I wasn't measuring brain ascorbate 
levels). It would probably take a lot of other conventional antioxidants to 
damp this injury in the CNS. However, some of the synthetic molecules I was 
evaluating were very effective at blocking it. Interestingly, the iron 
chelator desferoxamine did not block it when given immediately before injury.

More than that I cannot say. 

Mike Darwin

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